The Effects of Positive and Negative Reinforcement on Manding by Young Children with Autism

The focus of behavior analytic research on teaching manding to young children with autism is positive reinforcement. Mands maintained by negative reinforcement are understudied. The present study centers on both types in terms of their respective rates to acquisition, effects on inappropriate behaviors and impact on socially desirable behaviors. Following a baseline period, three young children with autism were taught to mand for preferred items (positive reinforcement) and for the removal of non-preferred items (negative reinforcement). Stimulus generalization probes were conducted at various points throughout the teaching phase. Once mastery was achieved, a one week follow-up was conducted to assess for maintenance of the mastered mands. The data show that teaching young children with autism to mand under conditions of both positive and negative reinforcement is beneficial to the development of socially appropriate behavior

Sensory Communication

Contains table of contents on Section 2, an introduction, reports on eleven research projects and a list of publications.National Institutes of Health Grant 5 R01 DC00117National Institutes of Health Grant 5 R01 DC00270National Institutes of Health Contract 2 P01 DC00361National Institutes of Health Grant 5 R01 DC00100National Institutes of Health Contract 7 R29 DC00428National Institutes of Health Grant 2 R01 DC00126U.S. Air Force - Office of Scientific Research Grant AFOSR 90-0200U.S. Navy - Office of Naval Research Grant N00014-90-J-1935National Institutes of Health Grant 5 R29 DC00625U.S. Navy - Office of Naval Research Grant N00014-91-J-1454U.S. Navy - Office of Naval Research Grant N00014-92-J-181

Sensory Communication

Contains table of contents for Section 2, an introduction and reports on twelve research projects.National Institutes of Health Grant 5 R01 DC00117National Institutes of Health Contract 2 P01 DC00361National Institutes of Health Grant 5 R01 DC00126National Institutes of Health Grant R01-DC00270U.S. Air Force - Office of Scientific Research Contract AFOSR-90-0200National Institutes of Health Grant R29-DC00625U.S. Navy - Office of Naval Research Grant N00014-88-K-0604U.S. Navy - Office of Naval Research Grant N00014-91-J-1454U.S. Navy - Office of Naval Research Grant N00014-92-J-1814U.S. Navy - Naval Training Systems Center Contract N61339-93-M-1213U.S. Navy - Naval Training Systems Center Contract N61339-93-C-0055U.S. Navy - Naval Training Systems Center Contract N61339-93-C-0083U.S. Navy - Office of Naval Research Grant N00014-92-J-4005U.S. Navy - Office of Naval Research Grant N00014-93-1-119

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

A role for leukotrienes in cyclosporine nephrotoxicity

A role for leukotrienes in cyclosporine nephrotoxicity. Nephrotoxicity associated with cyclosporine A (CsA) administration is characterized by marked renal vasoconstriction, interstitial fibrosis, and arteriolar hypertrophy. While the molecular mechanisms of CsA toxicity are not well characterized, previous studies have demonstrated that altered arachidonic acid (AA) metabolism plays a role its pathogenesis. Using a rat renal transplant model, the purpose of this study was to examine the effects of CsA on the 5-lipoxygenase (5-LO) pathway of AA metabolism. The PVG (RT1c) strain of rats underwent kidney transplantation, and recipients of nonrejecting kidney transplants were treated with either 50 mg/kg/day CsA or vehicle (N = 24). To determine the physiologic significance of increased leukotriene (LT) production, the peptidoleukotriene receptor antagonist SKF 106203 was administered to CsA-treated animals for six days. CsA caused a substantial reduction in glomerular filtration rate (GFR) in the transplanted rats compared with the vehicle-treated controls (1.5 ± 0.6 vs. 4.1 ± 0.8 mL/min/kg, P < 0.05). The reduction in renal function was associated with enhanced urinary excretion of the peptidoleukotriene metabolites LTE4 (1431 ± 207 vs. 953 ± 125 pg/24 h, P < 0.05) and N-acetyl-LTE4 (4411 ± 848 vs. 463 ± 70 pg/24 h, P < 0.001). LT receptor blockade had a significant protective effect on renal transplant function in CsA-treated animals (GFR, 4.8 ± 1.1 vs. 1.7 ± 0.9 mL/min/kg, P < 0.05), such that CsA-treated animals that received SKF106203 maintained GFR at levels similar to controls that never received CsA (4.1 ± 0.8 mL/min/kg). Peptidoleukotriene receptor blockade also prevented the histomorphological abnormalities caused by CsA, including tubular vacuolization. These studies identify a critical role for LTs in the pathophysiology of CsA nephrotoxicity and suggest that LT antagonists may be useful in preventing CsA-associated kidney toxicity

The effect of North Carolina free clinics on hospitalizations for ambulatory care sensitive conditions among the uninsured

Abstract Background Free clinics are volunteer based organizations that provide health care services to low-income individuals for free or minimal cost. Communities served by a free clinic can provide ambulatory care services for uninsured individuals, reducing reliance on costly hospital admissions for ambulatory care sensitive conditions. This study examines whether free clinics in North Carolina reduce hospitalizations for ambulatory care sensitive conditions for uninsured adults. Methods The study used North Carolina hospital discharge data from 2003 to 2007, restricted to uninsured adults residing in North Carolina (N = 270,325). Prevention Quality Indicators identified hospitalizations for ambulatory care sensitive conditions. The entry of new free clinics in some counties during this time period in conjunction with county-level and year fixed effects allows the logistic regression analysis to simulate a pre/post study design. Results Discharges for ambulatory care sensitive conditions constituted 12.6% of the sample. Despite the limited coverage provided by free clinics, which serve 5.5% of the uninsured in North Carolina, uninsured adults in counties served by a free clinic had an 8.0% reduced odds of a hospitalization being for an ambulatory care sensitive condition. When the model is limited to ambulatory care sensitive conditions related to chronic conditions, the odds of a hospitalization of an uninsured adult for an ambulatory care sensitive condition in counties served by a free clinic is reduced by 9.0%. Conclusion Free clinics are effective providers of primary care services for uninsured individuals, particularly for those with chronic conditions. To enhance this impact by increasing free clinics’ reach, state and local policy makers should support and encourage development of free clinics in high need areas

Model Selection in Binary Trait Locus Mapping

Quantitative trait locus (QTL) mapping methodology for continuous normally distributed traits is the subject of much attention in the literature. Binary trait locus (BTL) mapping in experimental populations has received much less attention. A binary trait by definition has only two possible values, and the penetrance parameter is restricted to values between zero and one. Due to this restriction, the infinitesimal model appears to come into play even when only a few loci are involved, making selection of an appropriate genetic model in BTL mapping challenging. We present a probability model for an arbitrary number of BTL and demonstrate that, given adequate sample sizes, the power for detecting loci is high under a wide range of genetic models, including most epistatic models. A novel model selection strategy based upon the underlying genetic map is employed for choosing the genetic model. We propose selecting the “best” marker from each linkage group, regardless of significance. This reduces the model space so that an efficient search for epistatic loci can be conducted without invoking stepwise model selection. This procedure can identify unlinked epistatic BTL, demonstrated by our simulations and the reanalysis of Oncorhynchus mykiss experimental data

Additional file 1: of The effect of North Carolina free clinics on hospitalizations for ambulatory care sensitive conditions among the uninsured

Confirmation of free clinics. Processes used to identify free clinics. (DOCX 12 kb