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Five-year Safety Data from 5 Clinical Trials of Subcutaneous Golimumab in Patients with Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis

Fri, 04/14/2017 - 11:33am

OBJECTIVE: Assess 5-year golimumab (GOL) safety in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS).

METHODS: Subcutaneous (SC) GOL (50 mg or 100 mg every 4 weeks) was evaluated in phase 3 trials of patients with active RA, PsA, and AS. Safety data through Year 5 were pooled across 3 RA trials [1 each evaluating methotrexate (MTX)-naive, MTX-experienced, and antitumor necrosis factor (TNF)-experienced patients], 1 PsA trial, and 1 AS trial. Data summarized was derived from both placebo-controlled (through weeks 24-52) and uncontrolled study periods. For adverse events (AE) of special interest [serious infections (SI), opportunistic infections (OI), deaths, malignancies, demyelination, tuberculosis (TB)], incidence per 100 patient-years (pt-yrs) was determined.

RESULTS: Across all trials, 639 patients received placebo and 2228 received SC GOL 50 mg only (n = 671), 50 mg and 100 mg (n = 765), or 100 mg only (n = 792). Safety followup extended for averages of 28.5 and 203.2 weeks for placebo and GOL, respectively. Respective placebo and GOL AE incidence/100 pt-yrs (95% CI) through Year 5 were 4.86 (2.83-7.78) and 3.29 (2.92-3.69) for SI, 0.00 (0.00-0.86) and 0.23 (0.14-0.35) for TB, 0.00 (0.00-0.86) and 0.22 (0.13-0.34) for OI, 0.00 (0.00-0.86) and 0.10 (0.05-0.20) for lymphoma, 0.00 (0.00-0.86) and 0.08 (0.03-0.17) for demyelination, and 0.29 (0.01-1.59) and 0.41 (0.29-0.57) for death. TB, OI, lymphoma, and demyelination incidence appeared to be higher among patients receiving GOL 100 mg only.

CONCLUSION: SC GOL safety through Year 5 remained consistent with previously reported Year 3 findings and with other TNF antagonists. Numerically higher incidences of TB, OI, lymphoma, and demyelination were observed with 100 mg versus 50 mg. Clinicaltrials.gov identifiers: NCT00264537 (GO-BEFORE), NCT00264550 (GO-FORWARD), NCT00299546 (GO-AFTER), NCT00265096 (GO-REVEAL), and NCT00265083 (GO-RAISE).

The p150N domain of chromatin assembly factor-1 regulates Ki-67 accumulation on the mitotic perichromosomal layer

Fri, 04/14/2017 - 11:33am

Chromatin assembly factor 1 (CAF-1) deposits histones during DNA synthesis. The p150 subunit of human CAF-1 contains an N-terminal domain (p150N) that is dispensable for histone deposition but promotes the localization of specific loci (nucleolar-associated domains [NADs]) and proteins to the nucleolus during interphase. One of the p150N-regulated proteins is proliferation antigen Ki-67, whose depletion also decreases the nucleolar association of NADs. Ki-67 is also a fundamental component of the perichromosomal layer (PCL), a sheath of proteins surrounding condensed chromosomes during mitosis. We show here that a subset of p150 localizes to the PCL during mitosis and that p150N is required for normal levels of Ki-67 accumulation on the PCL. This activity requires the sumoylation-interacting motif within p150N, which is also required for the nucleolar localization of NADs and Ki-67 during interphase. In this manner, p150N coordinates both interphase and mitotic nuclear structures via Ki67.

Visualization of self-delivering hydrophobically modified siRNA cellular internalization

Fri, 04/14/2017 - 11:33am

siRNAs are a new class of therapeutic modalities with promising clinical efficacy that requires modification or formulation for delivery to the tissue and cell of interest. Conjugation of siRNAs to lipophilic groups supports efficient cellular uptake by a mechanism that is not well characterized. Here we study the mechanism of internalization of asymmetric, chemically stabilized, cholesterol-modified siRNAs (sd-rxRNAs(R)) that efficiently enter cells and tissues without the need for formulation. We demonstrate that uptake is rapid with significant membrane association within minutes of exposure followed by the formation of vesicular structures and internalization. Furthermore, sd-rxRNAs are internalized by a specific class of early endosomes and show preferential association with epidermal growth factor (EGF) but not transferrin (Tf) trafficking pathways as shown by live cell TIRF and structured illumination microscopy (SIM). In fixed cells, we observe approximately 25% of sd-rxRNA co-localizing with EGF and < 5% with Tf, which is indicative of selective endosomal sorting. Likewise, preferential sd-rxRNA co-localization was demonstrated with EEA1 but not RBSN-containing endosomes, consistent with preferential EGF-like trafficking through EEA1-containing endosomes. sd-rxRNA cellular uptake is a two-step process, with rapid membrane association followed by internalization through a selective, saturable subset of the endocytic process. However, the mechanistic role of EEA1 is not yet known. This method of visualization can be used to better understand the kinetics and mechanisms of hydrophobic siRNA cellular uptake and will assist in further optimization of these types of compounds for therapeutic intervention.

Long-term cardiovascular mortality after radiotherapy for breast cancer: A systematic review and meta-analysis

Fri, 04/14/2017 - 11:33am

BACKGROUND: Radiotherapy (RT) is frequently associated with late cardiovascular (CV) complications. The mean cardiac dose from irradiation of a left-sided breast cancer is much higher than that for a right-sided breast cancer. However, data is limited on the long-term risks of RT on CV mortality.

HYPOTHESIS: RT for breast cancer is associated with long term CV mortality and left sided RT carries a greater mortality than right sided RT.

METHODS: We searched PubMed, Cochrane Central, Embase, EBSCO, Web of Science, and CINAHL databases from inception through December 2015. Studies reporting CV mortality with RT for left- vs right-sided breast cancers were included. The principal outcome of interest was CV mortality. We calculated summary risk ratio (RR) and 95% confidence intervals (CI) with the random-effects model.

RESULTS: The analysis included 289 109 patients from 13 observational studies. Women who had received RT for left-sided breast cancer had a higher risk of CV death than those who received RT for a right-sided breast cancer (RR: 1.12, 95% CI: 1.07-1.18, P < 0.001; number needed to harm: 353). Difference in CV mortality between left- vs right-sided breast RT was more apparent after 15 years of follow-up (RR: 1.23, 95% CI: 1.08-1.41, P < 0.001; number needed to harm: 95).

CONCLUSIONS: CV mortality from left-sided RT was significantly higher compared with right-sided RT for breast cancer and was more apparent after > /=15 years of follow-up.

HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans

Fri, 04/14/2017 - 11:32am

Autophagy is an evolutionarily conserved intracellular system that maintains cellular homeostasis by degrading and recycling damaged cellular components. The transcription factor HLH-30/TFEB-mediated autophagy has been reported to regulate tolerance to bacterial infection, but less is known about the bona fide bacterial effector that activates HLH-30 and autophagy. Here, we reveal that bacterial membrane pore-forming toxin (PFT) induces autophagy in an HLH-30-dependent manner in Caenorhabditis elegans. Moreover, autophagy controls the susceptibility of animals to PFT toxicity through xenophagic degradation of PFT and repair of membrane-pore cell-autonomously in the PFT-targeted intestinal cells in C. elegans. These results demonstrate that autophagic pathways and autophagy are induced partly at the transcriptional level through HLH-30 activation and are required to protect metazoan upon PFT intoxication. Together, our data show a new and powerful connection between HLH-30-mediated autophagy and epithelium intrinsic cellular defense against the single most common mode of bacterial attack in vivo.

A compendium of human genes regulating feeding behavior and body weight, its functional characterization and identification of GWAS genes involved in brain-specific PPI network

Mon, 04/10/2017 - 11:27am

BACKGROUND: Obesity is heritable. It predisposes to many diseases. The objectives of this study were to create a compendium of genes relevant to feeding behavior (FB) and/or body weight (BW) regulation; to construct and to analyze networks formed by associations between genes/proteins; and to identify the most significant genes, biological processes/pathways, and tissues/organs involved in BW regulation.

RESULTS: The compendium of genes controlling FB or BW includes 578 human genes. Candidate genes were identified from various sources, including previously published original research and review articles, GWAS meta-analyses, and OMIM (Online Mendelian Inheritance in Man). All genes were ranked according to knowledge about their biological role in body weight regulation and classified according to expression patterns or functional characteristics. Substantial and overrepresented numbers of genes from the compendium encoded cell surface receptors, signaling molecules (hormones, neuropeptides, cytokines), transcription factors, signal transduction proteins, cilium and BBSome components, and lipid binding proteins or were present in the brain-specific list of tissue-enriched genes identified with TSEA tool. We identified 27 pathways from KEGG, REACTOME and BIOCARTA whose genes were overrepresented in the compendium. Networks formed by physical interactions or homological relationships between proteins or interactions between proteins involved in biochemical/signaling pathways were reconstructed and analyzed. Subnetworks and clusters identified by the MCODE tool included genes/proteins associated with cilium morphogenesis, signal transduction proteins (particularly, G protein-coupled receptors, kinases or proteins involved in response to insulin stimulus) and transcription regulation (particularly nuclear receptors). We ranked GWAS genes according to the number of neighbors in three networks and revealed 22 GWAS genes involved in the brain-specific PPI network. On the base of the most reliable PPIs functioning in the brain tissue, new regulatory schemes interpreting relevance to BW regulation are proposed for three GWAS genes (ETV5, LRP1B, and NDUFS3).

CONCLUSIONS: A compendium comprising 578 human genes controlling FB or BW was designed, and the most significant functional groups of genes, biological processes/pathways, and tissues/organs involved in BW regulation were revealed. We ranked genes from the GWAS meta-analysis set according to the number and quality of associations in the networks and then according to their involvement in the brain-specific PPI network and proposed new regulatory schemes involving three GWAS genes (ETV5, LRP1B, and NDUFS3) in BW regulation. The compendium is expected to be useful for pathology risk estimation and for design of new pharmacological approaches in the treatment of human obesity.

Circulating Inflammatory-Associated Proteins in the First Month of Life and Cognitive Impairment at Age 10 Years in Children Born Extremely Preterm

Mon, 04/10/2017 - 11:27am

OBJECTIVES: To evaluate whether in children born extremely preterm, indicators of sustained systemic inflammation in the first month of life are associated with cognitive impairment at school age.

STUDY DESIGN: A total of 873 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborn Study from 2002 to 2004 were evaluated at age 10 years. We analyzed the relationship between elevated blood concentrations of inflammation-associated proteins in the first 2 weeks ("early elevations"; n = 812) and the third and fourth week ("late elevations"; n = 532) of life with neurocognition.

RESULTS: Early elevations of C-reactive protein, tumor necrosis factor-alpha, interleukin (IL)-8, intercellular adhesion molecule (ICAM)-1, and erythropoietin were associated with IQ values > 2 SD below the expected mean (ORs: 2.0-2.3) and with moderate to severe cognitive impairment on a composite measure of IQ and executive function (ORs: 2.1-3.6). Additionally, severe cognitive impairment was associated with late protein elevations of C-reactive protein (OR: 4.0; 95% CI 1.5, 10), IL-8 (OR: 5.0; 1.9, 13), ICAM-1 (OR: 6.5; 2.6, 16), vascular endothelial growth factor-receptor 2 (OR: 3.2; 1.2, 8.3), and thyroid-stimulating hormone (OR: 3.1; 1.3, 7.3). Moderate cognitive impairment was most strongly associated with elevations of IL-8, ICAM-1, and vascular endothelial growth factor-receptor 2. When 4 or more inflammatory proteins were elevated early, the risk of having an IQ < 70 and having overall impaired cognitive ability was more than doubled (ORs: 2.1-2.4); the presence of 4 or more inflammatory protein elevated late was strongly linked to adverse cognitive outcomes (ORs: 2.9-4.8).

CONCLUSIONS: Extremely preterm children who had sustained elevations of inflammation-related proteins in the first postnatal month are more likely than extremely preterm peers without such elevations to have cognitive impairment at 10 years.

The Prevalence of Bipolar Disorders and Association With Quality of Life in a Cohort of Patients With Multiple Sclerosis

Mon, 04/10/2017 - 11:27am

Clinical observations of mood instability in multiple sclerosis (MS) have led to the hypothesis that bipolar disorder (BD) may be more prevalent in persons with MS than in the general population. This cross-sectional study assesses the prevalence of BD among patients with MS using standardized psychiatric diagnostic interviews and evaluates quality of life. This study demonstrates a higher prevalence of BD in patients with MS compared with the general population. It also reveals the negative impact of BD on quality of life, raises the concern that BD can occur before the onset of neurological symptoms in MS, and suggests that, in some cases, BD may delay diagnosis of MS.

Altered neural connectivity in adult female rats exposed to early life social stress

Mon, 04/10/2017 - 11:27am

The use of a variety of neuroanatomical techniques has led to a greater understanding of the adverse effects of stress on psychiatric health. One recent advance that has been particularly valuable is the development of resting state functional connectivity (RSFC) in clinical studies. The current study investigates changes in RSFC in F1 adult female rats exposed to the early life chronic social stress (ECSS) of the daily introduction of a novel male intruder to the cage of their F0 mothers while the F1 pups are in the cage. This ECSS for the F1 animals consists of depressed maternal care from their F0 mothers and exposure to conflict between their F0 mothers and intruder males. Analyses of the functional connectivity data in ECSS exposed adult females versus control females reveal broad changes in the limbic and reward systems, the salience and introspective socioaffective networks, and several additional stress and social behavior associated nuclei. Substantial changes in connectivity were found in the prefrontal cortex, nucleus accumbens, hippocampus, and somatosensory cortex. The current rodent RSFC data support the hypothesis that the exposure to early life social stress has long term effects on neural connectivity in numerous social behavior, stress, and depression relevant brain nuclei. Future conscious rodent RSFC studies can build on the wealth of data generated from previous neuroanatomical studies of early life stress and enhance translational connectivity between animal and human fMRI studies in the development of novel preventative measures and treatments.

Developing a research agenda for understanding the stigma of addictions Part I: Lessons from the Mental Health Stigma Literature

Mon, 04/10/2017 - 11:27am

BACKGROUND AND OBJECTIVES: Although advocates and providers identify stigma as a major factor in confounding the recovery of people with SUDs, research on addiction stigma is lacking, especially when compared to the substantive literature examining the stigma of mental illness.

METHODS: A review of key studies from the stigma literature that yielded empirically supported concepts and methods from the mental health arena was contrasted with the much smaller and mostly descriptive findings from the addiction field.

RESULTS: Integration of this information led to Part I of this two part paper, development of a research paradigm seeking to understand phenomena of addiction stigma (eg, stereotypes, prejudice, and discrimination) and its different types (public, self, and label avoidance).

CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: In Part II paper (American Journal of Addictions, Vol 26, pages 67-74, this issue), we address how this literature informs a research program meant to develop and evaluate and stigma strategies (eg, education, contact, and protest). Both papers end with recommendations for next steps to jumpstart the addiction stigma portfolio. Here in Part I, we offer one possible list of key research issues for studies attempting to describe or explain addiction stigma. (Am J Addict 2017;26:59-66).

Developing a research agenda for reducing the stigma of addictions, part II: Lessons from the mental health stigma literature

Mon, 04/10/2017 - 11:26am

BACKGROUND AND OBJECTIVES: Although advocates and providers identify stigma as a major factor in confounding the recovery of people with SUDs, research on addiction stigma is lacking, especially when compared to the substantive literature examining the stigma of mental illness.

METHODS: A comprehensive review of the stigma literature that yielded empirically supported concepts and methods from the mental health arena was contrasted with the much smaller and mostly descriptive findings from the addiction field. In Part I of this two part paper (American Journal of Addictions, Vol 26, pages 59-66, this issue), constructs and methods from the mental health stigma literature were used to summarize research that seeks to understand the phenomena of addiction stigma.

RESULTS: In Paper II, we use this summary, as well as the extensive literature on mental illness stigma change, to outline a research program to develop and evaluate strategies meant to diminish impact on public and self-stigma (eg, education and contact).

CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The paper ends with recommendations for next steps in addiction stigma research. (Am J Addict 2017;26:67-74).

Perisylvian GABA levels in schizophrenia and bipolar disorder

Mon, 04/10/2017 - 11:26am

The aim of this study is to measure GABA levels of perisylvian cortices in schizophrenia and bipolar disorder patients, using proton magnetic resonance spectroscopy (1H-MRS). Patients with schizophrenia (n=25), bipolar I disorder (BD-I; n=28) and bipolar II disorder (BD-II; n=20) were compared with healthy controls (n=30). 1H-MRS data was acquired using a Siemens 3T whole body scanner to quantify right and left perisylvian structures' (including superior temporal lobes) GABA levels. Right perisylvian GABA values differed significantly between groups [chi2=9.62, df: 3, p=0.022]. GABA levels were significantly higher in the schizophrenia group compared with the healthy control group (p=0.002). Furthermore, Chlorpromazine equivalent doses of antipsychotics correlated with right hemisphere GABA levels (r2=0.68, p=0.006, n=33). GABA levels are elevated in the right hemisphere in patients with schizophrenia in comparison to bipolar disorder and healthy controls. The balance between excitatory and inhibitory controls over the cortical circuits may have direct relationship with GABAergic functions in auditory cortices. In addition, GABA levels may be altered by brain regions of interest, psychotropic medications, and clinical stage in schizophrenia and bipolar disorder.

Decreased Functional Connectivity of Insular Cortex in Drug Naive First Episode Schizophrenia: In Relation to Symptom Severity

Mon, 04/10/2017 - 11:26am

BACKGROUND: This study was to examine the insular cortical functional connectivity in drug naive patients with first episode schizophrenia and to explore the relationship between the connectivity and the severity of clinical symptoms.

METHODS: Thirty-seven drug naive patients with schizophrenia and 25 healthy controls were enrolled in this study. A seed-based approach was used to analyze the resting-state functional imaging data. Insular cortical connectivity maps were bilaterally extracted for group comparison and validated by voxel-based morphometry (VBM) analysis. Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS).

RESULTS: There were significant reductions in the right insular cortical connectivity with the Heschl's gyrus, anterior cingulate cortex (ACC), and caudate (p's < 0.001) in the patient group compared with the healthy control (HC) group. Reduced right insular cortical connectivity with the Heschl's gyrus was further confirmed in the VBM analysis (FDR corrected p < 0.05). Within the patient group, there was a significant positive relationship between the right insula-Heschl's connectivity and PANSS general psychopathology scores (r = 0.384, p = 0.019).

CONCLUSION: Reduced insula-Heschl's functional connectivity is present in drug naive patients with first episode schizophrenia, which might be related to the manifestation of clinical symptoms.

Dopamine Transporter Amino and Carboxyl Termini Synergistically Contribute to Substrate and Inhibitor Affinities

Mon, 04/10/2017 - 11:26am

Extracellular dopamine and serotonin concentrations are determined by the presynaptic dopamine (DAT) and serotonin (SERT) transporters, respectively. Numerous studies have investigated the DAT and SERT structural elements contributing to inhibitor and substrate binding. To date, crystallographic studies have focused on conserved transmembrane domains, where multiple substrate binding and translocation features are conserved. However, it is unknown what, if any, role the highly divergent intracellular N and C termini contribute to these processes. Here, we used chimeric proteins to test whether DAT and SERT N and C termini contribute to transporter substrate and inhibitor affinities. Replacing the DAT N terminus with that of SERT had no effect on DA transport Vmax but significantly decreased DAT substrate affinities for DA and amphetamine. Similar losses in uptake inhibition were observed for small DAT inhibitors, whereas substituting the DAT C terminus with that of SERT affected neither substrate nor inhibitor affinities. In contrast, the N-terminal substitution was completely tolerated by the larger DAT inhibitors, which exhibited no loss in apparent affinity. Remarkably, all affinity losses were rescued in DAT chimeras encoding both SERT N and C termini. The sensitivity to amino-terminal substitution was specific for DAT, because replacing the SERT N and/or C termini affected neither substrate nor inhibitor affinities. Taken together, these findings provide compelling experimental evidence that DAT N and C termini synergistically contribute to substrate and inhibitor affinities.

Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis

Mon, 04/10/2017 - 11:26am

While innovative modern neuroscience approaches have aided in discerning brain circuitry underlying negative emotional behaviors including fear and anxiety responses, how these circuits are recruited in normal and pathological conditions remains poorly understood. Recently, genetic tools that selectively manipulate single neuronal populations have uncovered an understudied circuit, the medial habenula (mHb)-interpeduncular (IPN) axis, that modulates basal negative emotional responses. Interestingly, the mHb-IPN pathway also represents an essential circuit that signals heightened anxiety induced by nicotine withdrawal. Insights into how this circuit interconnects with regions more classically associated with anxiety, and how chronic nicotine exposure induces neuroadaptations resulting in an anxiogenic state, may thereby provide novel strategies and molecular targets for therapies that facilitate smoking cessation, as well as for anxiety relief.

An exploratory study of Mindfulness Based Stress Reduction for emotional eating

Mon, 04/10/2017 - 11:26am

Emotional eating is an important predictor of weight loss and weight regain after weight loss. This two part study's primary aim was to explore changes in emotional eating in a general population of individuals taking the Mindfulness Based Stress Reduction (MBSR) program, with a secondary aim to explore whether changes in mindfulness predicted changes in emotional eating. Self-reported survey data exploring these questions were collected before and after the intervention for two sequential studies (Study 1 and Study 2). While there were no control groups for either study, in both studies emotional eating scores following the MBSR were significantly lower than scores prior to taking the MBSR (p < 0.001; p < 0.001) In Study 2, changes in mindfulness were correlated with changes in emotional eating (r = 0.317, p = 0.004). These results suggest that MBSR may be an effective intervention for emotional eating, and that further research is warranted to examine effects on weight loss and maintenance.

Diagnostic performance and optimal cut-off scores of the Massachusetts youth screening instrument-second version in a sample of Swiss youths in welfare and juvenile justice institutions

Mon, 04/10/2017 - 11:26am

BACKGROUND: There is a growing consensus about the importance of mental health screening of youths in welfare and juvenile justice institutions. The Massachusetts Youth Screening Instrument-second version (MAYSI-2) was specifically designed, normed and validated to assist juvenile justice facilities in the United States of America (USA), in identifying youths with potential emotional or behavioral problems. However, it is not known if the USA norm-based cut-off scores can be used in Switzerland. Therefore, the primary purpose of the current study was to estimate the diagnostic performance and optimal cut-off scores of the MAYSI-2 in a sample of Swiss youths in welfare and juvenile justice institutions. As the sample was drawn from the French-, German- and Italian-speaking parts of Switzerland, the three languages were represented in the total sample of the current study and consequently we could estimate the diagnostic performance and the optimal cut-off scores of the MAYSI-2 for the language regions separately. The other main purpose of the current study was to identify potential gender differences in the diagnostic performance and optimal cut-off scores.

METHODS: Participants were 297 boys and 149 girls (mean age = 16.2, SD = 2.5) recruited from 64 youth welfare and juvenile justice institutions (drawn from the French-, German- and Italian-speaking parts of Switzerland). The MAYSI-2 was used to screen for mental health or behavioral problems that could require further evaluation. Psychiatric classification was based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime version (K-SADS-PL). The MAYSI-2 scores were submitted into Receiver-Operating Characteristic (ROC) analyses to estimate the diagnostic performance and optimal 'caution' cut-off scores of the MAYSI-2.

RESULTS: The ROC analyses revealed that nearly all homotypic mappings of MAYSI-2 scales onto (cluster of) psychiatric disorders revealed above chance level accuracy. The optimal 'caution' cut-off scores derived from the ROC curve for predicting (cluster of) psychiatric disorders were, for several MAYSI-2 scales, comparable to the USA norm-based 'caution' cut-off scores. For some MAYSI-2 scales, however, higher optimal 'caution' cut-off scores were found.

CONCLUSIONS: With adjusted optimal 'caution' cut-off scores, the MAYSI-2 screens potential emotional or behavioral problems well in a sample of Swiss youths in welfare and juvenile justice institutions. However, as for choosing the optimal 'caution' cut off score for the MAYSI-2, both language as well as gender seems to be of importance. The results of this study point to a compelling need to test the diagnostic performance and optimal 'caution' cut-off scores of the MAYSI-2 more elaborately in larger differentiated language samples in Europe.

Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease

Mon, 04/10/2017 - 11:26am

Canavan disease (CD) is a debilitating and lethal leukodystrophy caused by mutations in the aspartoacylase (ASPA) gene and the resulting defect in N-acetylaspartate (NAA) metabolism in the CNS and peripheral tissues. Recombinant adeno-associated virus (rAAV) has the ability to cross the blood-brain barrier and widely transduce the CNS. We developed a rAAV-based and optimized gene replacement therapy, which achieves early, complete, and sustained rescue of the lethal disease phenotype in CD mice. Our treatment results in a super-mouse phenotype, increasing motor performance of treated CD mice beyond that of WT control mice. We demonstrate that this rescue is oligodendrocyte independent, and that gene correction in astrocytes is sufficient, suggesting that the establishment of an astrocyte-based alternative metabolic sink for NAA is a key mechanism for efficacious disease rescue and the super-mouse phenotype. Importantly, the use of clinically translatable high-field imaging tools enables the noninvasive monitoring and prediction of therapeutic outcomes for CD and might enable further investigation of NAA-related cognitive function.

Improvement in Depression is Associated with Improvement in Cognition in Late-Life Psychotic Depression

Mon, 04/10/2017 - 11:26am

OBJECTIVE: To characterize cognitive function at baseline and investigate the relationship between change in cognition, depression, and psychosis after treatment among older adults with major depressive disorder with psychotic features.

METHODS: This was a secondary analysis of a double-blind, randomized, controlled treatment trial at inpatient and outpatient settings at four academic health centers on "Young Old" (aged 60-71 years, N = 71) and "Older" (aged 72-86 years, N = 71) participants diagnosed with psychotic depression. Olanzapine plus sertraline or olanzapine plus placebo were given until week 12 or termination.

RESULTS: At baseline, Young Old and Older participants did not differ on measures of depression severity or global cognition, information processing speed, and executive function. Improvement in depressive and psychotic symptoms from baseline to treatment end was similar in both the Young Old and Older groups. However, improvement in depressive symptoms was significantly associated with improvement in global cognitive function in Young Old participants but not in Older participants.

CONCLUSION: Cognitive dysfunction was not a detriment to improvement in symptoms of psychotic major depression in our geriatric patients. Young Old and Older patients improved to a similar degree on measures of depression and delusions from baseline to treatment end. However, improvement in cognition over the course of treatment was more prominent in the Young Old group than in the Older group.

Differential burden of musculoskeletal pain in African Americans and whites patients at the time of total joint replacement surgery

Fri, 04/07/2017 - 2:38pm

Objective: African Americans patients have greater operative joint pain and functional limitation at the time of total joint replacement (TJR) compared to white patients. We examined the factors associated with this apparent disparity.

Methods: A consecutive sample of 5745 patients with advanced knee and hip osteoarthritis [who elected to undergo TJR in 2011-201] reported, preoperatively, medical comorbidities, operative and non-operative hip/ knee pain using Hip and Knee Disability and Osteoarthritis Outcome Scores (HOOS/KOOS), function using Short Form 36 Physical Component Score (PCS). Total burden of musculoskeletal pain was quantified as moderate/severe pain in non-operative hip and knee joints and lumbar back pain using Oswestry Disability Index (ODI). Associations among race, medical co-morbidites (modified Charlson), total musculoskeletal pain burden, operative joint pain, and functional limitations were examined using multivariable regression models.

Results:Compared to Whites, African Americans (143 hips and 201 knees) reported worse surgical joint pain (mean pain: 39.3 vs. 49.2 [hip]; 43.4 vs. 53.2 [knee]), poorer surgical joint function (mean function: 38.9 vs. 45.7 [hip]; 45.9 vs. 53.4 [knee]), poorer global function (mean PCS: 30.0 vs. 31.6 [hip]; 31.3 vs. 33.1 [knee]), and more non-operative joints pain (p

Conclusions: Greater burden of musculoskeletal pain explains differences in pre-operative pain and function between African American and white patients and likely impacts rehabilitation and subsequent TJR outcomes.