Caldag-Gefi Down-Regulation in the Striatum as a Neuroprotective Change in Huntington's Disease.

Huntingtin protein (Htt) is ubiquitously expressed, yet Huntington’s disease (HD), a fatal neurologic disorder produced by expansion of an Htt polyglutamine tract, is characterized by neurodegeneration that occurs primarily in the striatum and cerebral cortex. Such discrepancies between sites of expression and pathology occur in multiple neurodegenerative disorders associated with expanded polyglutamine tracts. One possible reason is that disease-modifying factors are tissue-specific. Here we show that the striatum-enriched protein, CalDAG-GEFI, is severely down-regulated in the striatum of mouse HD models and is down-regulated in HD individuals. In the R6/2 transgenic mouse model of HD, striatal neurons with the largest aggregates of mutant Htt have the lowest levels of CalDAG-GEFI. In a brain-slice explant model of HD, knock-down of CalDAG-GEFI expression rescues striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt exon 1. These findings suggest that the striking down-regulation of CalDAG-GEFI in HD could be a protective mechanism that mitigates Htt-induced degeneration.Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (R01-HD28341)National Institute of Mental Health (U.S.) (F32-MH065815)Wellcome Trust (London, England)Cure Huntington’s Disease Initiative, Inc.MGH/MIT Morris Udall Center of Excellence in Parkinson Disease Research (P50-NS038372

Symptom Dimensions in OCD: Item-Level Factor Analysis and Heritability Estimates

To reduce the phenotypic heterogeneity of obsessive-compulsive disorder (OCD) for genetic, clinical and translational studies, numerous factor analyses of the Yale-Brown Obsessive Compulsive Scale checklist (YBOCS-CL) have been conducted. Results of these analyses have been inconsistent, likely as a consequence of small sample sizes and variable methodologies. Furthermore, data concerning the heritability of the factors are limited. Item and category-level factor analyses of YBOCS-CL items from 1224 OCD subjects were followed by heritability analyses in 52 OCD-affected multigenerational families. Item-level analyses indicated that a five factor model: (1) taboo, (2) contamination/cleaning, (3) doubts, (4) superstitions/rituals, and (5) symmetry/hoarding provided the best fit, followed by a one-factor solution. All 5 factors as well as the one-factor solution were found to be heritable. Bivariate analyses indicated that the taboo and doubts factor, and the contamination and symmetry/hoarding factor share genetic influences. Contamination and symmetry/hoarding show shared genetic variance with symptom severity. Nearly all factors showed shared environmental variance with each other and with symptom severity. These results support the utility of both OCD diagnosis and symptom dimensions in genetic research and clinical contexts. Both shared and unique genetic influences underlie susceptibility to OCD and its symptom dimensions.Obsessive Compulsive FoundationTourette Syndrome AssociationAnxiety Disorders Association of AmericaAmerican Academy of Child and Adolescent Psychiatr

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Children’s psychological and behavioral responses following pediatric intensive care unit hospitalization: the caring intensively study

Abstract Background Pediatric intensive care unit (PICU) hospitalization places children at increased risk of persistent psychological and behavioral difficulties following discharge. Despite tremendous advances in medical technology and treatment regimes, approximately 25% of children demonstrate negative psychological and behavioral outcomes within the first year post-discharge. It is imperative that a broader array of risk factors and outcome indicators be explored in examining long-term psychological morbidity to identify areas for future health promotion and clinical intervention. This study aims to examine psychological and behavioral responses in children aged 3 to 12 years over a three year period following PICU hospitalization, and compare them to children who have undergone ear, nose and/or throat (ENT) day surgery. Methods/Design This mixed-methods prospective cohort study will enrol 220 children aged 3 to 12 years during PICU hospitalization (study group, n = 110) and ENT day surgery hospitalization (comparison group, n = 110). Participants will be recruited from 3 Canadian pediatric hospitals, and followed for 3 years with data collection points at 6 weeks, 6 months, 1 year, 2 years and 3 years post-discharge. Psychological and behavioral characteristics of the child, and parent anxiety and parenting stress, will be assessed prior to hospital discharge, and again at each of the 5 subsequent time points, using standardized measures. Psychological and behavioral response scores for both groups will be compared at each follow-up time point. Multivariate regression analysis will be used to adjust for demographic and clinical variables at baseline. To explore baseline factors predictive of poor psychological and behavioral scores at 3 years among PICU patients, correlation analysis and multivariate linear regression will be used. A subgroup of 40 parents of study group children will be interviewed at years 1 and 3 post-discharge to explore their perceptions of the impact of PICU hospitalization on their children and enhance our understanding of findings generated from standardized measures in the larger cohort study. An interpretive descriptive approach will guide qualitative data collection and analysis. Discussion This study aims to generate new information regarding the magnitude and duration of psychological and behavioral disturbances among children admitted to PICUs, potentially leading to remedial or preventive interventions

NEGOTIATING INDEPENDENT MOTHERHOOD

The authors examine the experiences and ideals of African American working-class mothers through 20 intensive interviews. They focus on the women's negotiations with racialized norms of motherhood, represented in the assumptions that legal marriage and an exclusively bonded dyadic relationship with one's children are requisite to good mothering. The authors find, as did earlier phenomenological studies, that the mothers draw from distinct ideals of community-based independence to resist each of these assumptions and carve out alternative scripts based on nonmarital relationships with male partners and shared care of children.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66930/2/10.1177_089124396010002007.pd

Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion

Adenosine deaminase (ADA)–deficient severe combined immune deficiency (SCID) may be treated by allogeneic hematopoietic stem cell transplantation without prior cytoreductive conditioning, although the mechanism of immune reconstitution is unclear. We studied this process in a murine gene knockout model of ADA-deficient SCID. Newborn ADA-deficient pups received transplants of intravenous infusion of normal congenic bone marrow, without prior cytoreductive conditioning, which resulted in long-term survival, multisystem correction, and nearly normal lymphocyte numbers and mitogenic proliferative responses. Only 1% to 3% of lymphocytes and myeloid cells were of donor origin without a selective expansion of donor-derived lymphocytes; immune reconstitution was by endogenous, host-derived ADA-deficient lymphocytes. Preconditioning of neonates with 100 to 400 cGy of total body irradiation before normal donor marrow transplant increased the levels of engrafted donor cells in a radiation dose–dependent manner, but the chimerism levels were similar for lymphoid and myeloid cells. The absence of selective reconstitution by donor T lymphocytes in the ADA-deficient mice indicates that restoration of immune function occurred by rescue of endogenous ADA-deficient lymphocytes through cross-correction from the engrafted ADA-replete donor cells. Thus, ADA-deficient SCID is unique in its responses to nonmyeloablative bone marrow transplantation, which has implications for clinical bone marrow transplantation or gene therapy

Latent class analysis of the Yale-Brown Obsessive-Compulsive Scale symptoms in obsessive-compulsive disorder

Objective: Obsessive-compulsive disorder (OCD) is phenomenologically heterogeneous, and findings of underlying structure classification based on symptom grouping have been ambiguous to date. Variable-centered approaches, primarily factor analysis, have been used to identify homogeneous groups of symptoms; but person-centered latent methods have seen little use. This study was designed to uncover sets of homogeneous groupings within 1611 individuals with OCD based on symptoms. Method: Latent class analysis models using 61 obsessive-compulsive symptoms collected from the Yale-Brown Obsessive-Compulsive Scale were fit. Relationships between latent class membership and treatment response, sex, symptom severity, and comorbid tic disorders were tested for relationship to class membership. Results: Latent class analysis models of best fit yielded 3 classes. Classes differed only in frequency of symptom endorsement. Classes with higher symptom endorsement were associated with earlier age of onset, being male, higher Yale-Brown Obsessive-Compulsive Scale symptom severity scores, and comorbid tic disorders. There were no differences in treatment response between classes. Conclusions: These results provide support for the validity of a single underlying latent OCD construct, in addition to the distinct symptom factors identified previously via factor analyses. (C) 2011 Elsevier Inc. All rights reserve