Behavioral Phenotyping of Juvenile Long-Evans and Sprague-Dawley Rats: Implications for Preclinical Models of Autism Spectrum Disorders.

The laboratory rat is emerging as an attractive preclinical animal model of autism spectrum disorder (ASD), allowing investigators to explore genetic, environmental and pharmacological manipulations in a species exhibiting complex, reciprocal social behavior. The present study was carried out to compare two commonly used strains of laboratory rats, Sprague-Dawley (SD) and Long-Evans (LE), between the ages of postnatal day (PND) 26-56 using high-throughput behavioral phenotyping tools commonly used in mouse models of ASD that we have adapted for use in rats. We detected few differences between young SD and LE strains on standard assays of exploration, sensorimotor gating, anxiety, repetitive behaviors, and learning. Both SD and LE strains also demonstrated sociability in the 3-chamber social approach test as indexed by spending more time in the social chamber with a constrained age/strain/sex matched novel partner than in an identical chamber without a partner. Pronounced differences between the two strains were, however, detected when the rats were allowed to freely interact with a novel partner in the social dyad paradigm. The SD rats in this particular testing paradigm engaged in play more frequently and for longer durations than the LE rats at both juvenile and young adult developmental time points. Results from this study that are particularly relevant for developing preclinical ASD models in rats are threefold: (i) commonly utilized strains exhibit unique patterns of social interactions, including strain-specific play behaviors, (ii) the testing environment may profoundly influence the expression of strain-specific social behavior and (iii) simple, automated measures of sociability may not capture the complexities of rat social interactions

Effects of midodrine and L-NAME on systemic and cerebral hemodynamics during cognitive activation in spinal cord injury and intact controls

This is the published version.We previously showed that increases in mean arterial pressure (MAP) following administration of midodrine hydrochloride (MH) and nitro-L-arginine methyl ester (L-NAME) resulted in increased mean cerebral blood flow velocity (MFV) during head-up tilt in hypotensive individuals with spinal cord injury (SCI) and question if this same association was evident during cognitive activation. Herein, we report MAP and MFV during two serial subtraction tasks (SSt) given before (predrug) and after (postdrug) administration of MH; (10 mg), L-NAME (1 mg/kg) or no drug (ND) in 15 subjects with SCI compared to nine able-bodied (AB) controls. Three-way factorial analysis of variance (ANOVA) models were used to determine significant main and interaction effects for group (SCI, AB), visit (MH, L-NAME, ND), and time (predrug, postdrug) for MAP and MFV during the two SSt. The three-way interaction was significant for MAP (F = 4.262; P = 0.020); both MH (30 ± 26 mmHg; P < 0.05) and L-NAME (27 ± 22 mmHg; P < 0.01) significantly increased MAP in the SCI group, but not in the AB group. There was a significant visit by time interaction for MFV suggesting an increase from predrug to postdrug following L-NAME (6 ± 8 cm/sec; P < 0.05) and MH (4 ± 7 cm/sec; P < 0.05), regardless of study group, with little change following ND (3 ± 3 cm/sec). The relationship between change in MAP and MFV was significant in the SCI group following administration of MH (r2 = 0.38; P < 0.05) and L-NAME (r2 = 0.32; P < 0.05). These antihypotensive agents, at the doses tested, raised MAP, which was associated with an increase MFV during cognitive activation in hypotensive subjects with SCI

Optical Manufacturing and Testing Requirements Identified by the NASA Science Instruments, Observatories and Sensor Systems Technology Assessment

In August 2010, the NASA Office of Chief Technologist (OCT) commissioned an assessment of 15 different technology areas of importance to the future of NASA. Technology assessment #8 (TA8) was Science Instruments, Observatories and Sensor Systems (SIOSS). SIOSS assess the needs for optical technology ranging from detectors to lasers, x-ray mirrors to microwave antenna, in-situ spectrographs for on-surface planetary sample characterization to large space telescopes. The needs assessment looked across the entirety of NASA and not just the Science Mission Directorate. This paper reviews the optical manufacturing and testing technologies identified by SIOSS which require development in order to enable future NASA high priority missions

Prevalence of Abnormal Systemic Hemodynamics in Veterans with and without Spinal Cord Injury

Advances in the clinical management of patients with acute and chronic spinal cord injury (SCI) have contributed to extended life expectancies; however longevity in those with SCI remains below that of the general population.(1) Reduced longevity in the SCI population has been attributed to increased incidence of age-associated chronic illnesses,(2) premature cardiovascular aging,(3) and increased prevalence of heart disease, stroke (4) and diabetes mellitus, (5) compared to the general population. In fact, cardiovascular disease (CVD) is now a leading cause of morbidity and mortality in the SCI population, which may be amplified due to increased risk factors such as inactivity, chronic inflammation, and impairment in autonomic cardiovascular control.(6) The American Spinal Injury Association (ASIA) impairment scale (AIS) is used to document remaining motor and sensory function following SCI; (7, 8) however, the degree of autonomic nervous system impairment is not considered within this classification schema.(9, 10) That said, impaired autonomic control of the cardiovascular system after SCI results in measurable changes in heart rate (HR) and blood pressure (BP) that loosely reflect the level and completeness of SCI documented using the AIS classification, (11, 12) but may also reflect orthostatic positioning.(6, 12, 13) The impact of these changes in HR and BP on cardiovascular health and longevity is not fully appreciated in the SCI population; however, prior to identifying the consequences of these cardiovascular abnormalities, prevalence rates of HR and BP values which fall outside the expected normal range should be documented. The International Standards to Document Autonomic Function (post-SCI) initially established guidelines for the assessment of HR and BP abnormalities in 2009, (10) which was updated in 2012, but the thresholds remained consistent. (14) Specifically, bradycardia is defined as a HR ≤ 60 beats/minute (bpm) and tachycardia as a HR ≥ 100 bpm. (14) Hypotension is defined as a systolic BP (SBP) ≤ 90 mmHg and a diastolic BP (DBP) ≤ 60 mmHg; hypertension is SBP ≥ 140 and/or DBP ≥ 90 mmHg. (14) While these definitions comply with standards established in the non-SCI population, due to decentralized cardiovascular control, they may not be appropriate for use in the SCI population. In addition, relatively recent evidence has emerged which associates adverse outcomes in the general population using other HR (15, 16) and BP (17-21) thresholds. Beyond the clinical consequences of alterations in HR and BP, persons with SCI may experience loss of independence and life quality related to the inability to adequately maintain cardiovascular homeostasis; however, until we gain a better understanding of the prevalence of these abnormalities, the development and testing of effective treatment strategies will not be a priority. Therefore, the goal of this investigation was to assess HR and BP in veterans with (SCI) and without SCI (non SCI). Similar to a recent report, (6) we hypothesized that level of SCI (i.e., the higher the lesion level the greater the prevalence of abnormal HR and BP recordings) and orthostatic positioning (i.e., increased prevalence of abnormal HR and BP recordings in the seated versus the supine position) would influence the prevalence of HR and BP abnormalities. In addition, we hypothesized that the prevalence of comorbid cardiovascular medical conditions, current smoking status, age and use of prescription anti-hypertensive (anti-HTN) medications would influence the prevalence of HR and BP abnormalities in veterans with and without SCI

Summary of the NASA Science Instrument, Observatory and Sensor System (SIOSS) Technology Assessment

Technology advancement is required to enable NASA's high priority missions of the future. To prepare for those missions requires a roadmap of how to get from the current state of the art to where technology needs to be in 5, 10, 15 and 20 years. SIOSS identifies where substantial enhancements in mission capabilities are needed and provides strategic guidance for the agency's budget formulation and prioritization process

Critical perspectives on ‘consumer involvement’ in health research: epistemological dissonance and the know-do gap

Researchers in the area of health and social care (both in Australia and internationally) are encouraged to involve consumers throughout the research process, often on ethical, political and methodological grounds, or simply as ‘good practice’. This paper presents findings from a qualitative study in the UK of researchers’ experiences and views of consumer involvement in health research. Two main themes are presented in the paper. Firstly, we explore the ‘know-do gap’ which relates to the tensions between researchers’ perceptions of the potential benefits of, and their actual practices in relation to, consumer involvement. Secondly, we focus on one of the reasons for this ‘know-do gap’, namely epistemological dissonance. Findings are linked to issues around consumerism in research, lay/professional knowledges, the (re)production of professional and consumer identities and the maintenance of boundaries between consumers and researchers

Damage to tropical forests caused by cyclones is driven by wind speed but mediated by topographical exposure and tree characteristics

Each year, an average of 45 tropical cyclones affect coastal areas and potentially impact forests. The proportion of the most intense cyclones has increased over the past four decades and is predicted to continue to do so. Yet, it remains uncertain how topographical exposure and tree characteristics can mediate the damage caused by increasing wind speed. Here, we compiled empirical data on the damage caused by 11 cyclones occurring over the past 40 years, from 74 forest plots representing tropical regions worldwide, encompassing field data for 22,176 trees and 815 species. We reconstructed the wind structure of those tropical cyclones to estimate the maximum sustained wind speed (MSW) and wind direction at the studied plots. Then, we used a causal inference framework combined with Bayesian generalised linear mixed models to understand and quantify the causal effects of MSW, topographical exposure to wind (EXP), tree size (DBH) and species wood density (ρ) on the proportion of damaged trees at the community level, and on the probability of snapping or uprooting at the tree level. The probability of snapping or uprooting at the tree level and, hence, the proportion of damaged trees at the community level, increased with increasing MSW, and with increasing EXP accentuating the damaging effects of cyclones, in particular at higher wind speeds. Higher ρ decreased the probability of snapping and to a lesser extent of uprooting. Larger trees tended to have lower probabilities of snapping but increased probabilities of uprooting. Importantly, the effect of ρ decreasing the probabilities of snapping was more marked for smaller than larger trees and was further accentuated at higher MSW. Our work emphasises how local topography, tree size and species wood density together mediate cyclone damage to tropical forests, facilitating better predictions of the impacts of such disturbances in an increasingly windier world

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

Lung Injury Prediction Score Is Useful in Predicting Acute Respiratory Distress Syndrome and Mortality in Surgical Critical Care Patients

Background. Lung injury prediction score (LIPS) is valuable for early recognition of ventilated patients at high risk for developing acute respiratory distress syndrome (ARDS). This study analyzes the value of LIPS in predicting ARDS and mortality among ventilated surgical patients. Methods. IRB approved, prospective observational study including all ventilated patients admitted to the surgical intensive care unit at a single tertiary center over 6 months. ARDS was defined using the Berlin criteria. LIPS were calculated for all patients and analyzed. Logistic regression models evaluated the ability of LIPS to predict development of ARDS and mortality. A receiver operator characteristic (ROC) curve demonstrated the optimal LIPS value to statistically predict development of ARDS. Results. 268 ventilated patients were observed; 141 developed ARDS and 127 did not. The average LIPS for patients who developed ARDS was 8.8 ± 2.8 versus 5.4 ± 2.8 for those who did not (p \u3c 0.001). An ROC area under the curve of 0.79 demonstrates LIPS is statistically powerful for predicting ARDS development. Furthermore, for every 1-unit increase in LIPS, the odds of developing ARDS increase by 1.50 (p \u3c 0.001) and odds of ICU mortality increase by 1.22 (p \u3c 0.001). Conclusion. LIPS is reliable for predicting development of ARDS and predicting mortality in critically ill surgical patients