Angiotensin-(1-7) improves cognitive function and reduces inflammation in mice following mild traumatic brain injury.

Introduction: Traumatic brain injury (TBI) is a leading cause of disability in the US. Angiotensin 1-7 (Ang-1-7), an endogenous peptide, acts at the G protein coupled MAS1 receptors (MASR) to inhibit inflammatory mediators and decrease reactive oxygen species within the CNS. Few studies have identified whether Ang-(1-7) decreases cognitive impairment following closed TBI. This study examined the therapeutic effect of Ang-(1-7) on secondary injury observed in a murine model of mild TBI (mTBI) in a closed skull, single injury model. Materials and methods: Male mice (n = 108) underwent a closed skull, controlled cortical impact injury. Two hours after injury, mice were administered either Ang-(1-7) (n = 12) or vehicle (n = 12), continuing through day 5 post-TBI, and tested for cognitive impairment on days 1-5 and 18. pTau, Tau, GFAP, and serum cytokines were measured at multiple time points. Animals were observed daily for cognition and motor coordination via novel object recognition. Brain sections were stained and evaluated for neuronal injury. Results: Administration of Ang-(1-7) daily for 5 days post-mTBI significantly increased cognitive function as compared to saline control-treated animals. Cortical and hippocampal structures showed less damage in the presence of Ang-(1-7), while Ang-(1-7) administration significantly changed the expression of pTau and GFAP in cortical and hippocampal regions as compared to control. Discussion: These are among the first studies to demonstrate that sustained administration of Ang-(1-7) following a closed-skull, single impact mTBI significantly improves neurologic outcomes, potentially offering a novel therapeutic modality for the prevention of long-term CNS impairment following such injuries.

Extracellular circular RNA profiles in plasma and urine of healthy, male college athletes.

Circular RNA (circRNA) are a recently discovered class of RNA characterized by a covalently-bonded back-splice junction. As circRNAs are inherently more stable than other RNA species, they may be detected extracellularly in peripheral biofluids and provide novel biomarkers. While circRNA have been identified previously in peripheral biofluids, there are few datasets for circRNA junctions from healthy controls. We collected 134 plasma and 114 urine samples from 54 healthy, male college athlete volunteers, and used RNASeq to determine circRNA content. The intersection of six bioinformatic tools identified 965 high-confidence, characteristic circRNA junctions in plasma and 72 in urine. Highly-expressed circRNA junctions were validated by qRT-PCR. Longitudinal samples were collected from a subset, demonstrating circRNA expression was stable over time. Lastly, the ratio of circular to linear transcripts was higher in plasma than urine. This study provides a valuable resource for characterization of circRNA in plasma and urine from healthy volunteers, one that can be developed and reassessed as researchers probe the circRNA contents of biofluids across physiological changes and disease states.

Survival as a Function of Nonsteroidal Anti-inflammatory Drug Use in Patients with Glioblastoma.

Background Findings of both case control and in vitro investigations suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may play a beneficial role in the occurrence, growth, and subsistence of glioblastoma multiforme (GBM) brain tumor in humans. Objective In the present retrospective cohort study, we assessed the impact of NSAID use on survival in patients diagnosed with and treated for GBM brain tumors. Methods The impact of NSAID use and six other potential prognostic indicators of survival were assessed in 71 patients treated for GBM brain tumors from February 2011 to June 2016. Survival analysis and cross-tabulation analyses were performed to examine the potential relationship between NSAID use and occurrence of intracranial hemorrhage over the course of treatment for GBM. Results Kaplan-Meier analysis revealed no significant difference in survival between patients with and without NSAID use (p = 0.75; 95% CI: 10.12, 18.13). Multiple Cox regression analysis identified only treatment with chemotherapy as imposing any statistically significant effect on survival (Hazard Ratio (HR) = 3.31; p < 0.001; 95% CI: 1.80, 6.07). Cross-tabulation revealed no significant effect of NSAID use on occurrence of hemorrhage during treatment, X2 (2, N = 71) = 0.65, p2-Sided = 0.42, (Fisher's Exact Test: p2-sided = 0.56, p1-sided = 0.31). Conclusion These results suggest that history of NSAID use is not a determinant of survival in GBM patients. More rigorous, prospective investigations of the effect of NSAID use on tumor progression are necessary before the utility of this family of drugs in the treatment of GBM can be adequately appraised.

Destabilization of the Upright Posture Through Elevation of the Center of Mass.

The inverted pendulum model predicts that the major challenge for neural control of the upright posture is the inherent instability of the body due to the center of mass (COM) being above the base of support (BOS). If so, even slight elevation of the COM may substantially destabilize posture. The destabilizing effect of heavy load positioned above the COM has been demonstrated. We examined sensitivity of posture to light (1-5% of body weight) load by placing weights on the shoulders and assessing functional reach distance in the forward, right, and left directions and postural sway during quiet stance. At each load level, the quiet stance task was tested with and without vision. The 1% of body weight load significantly shortened reach distance in the forward direction. It also increased postural sway. Interestingly, additional weight did not result in further deficits. The results support high sensitivity of postural stability to COM elevation that increases the challenge for neural control of posture and that can potentially be used for early detection of declines in postural stability.

Corrigendum to "The Role of Descending Modulation in Manual Therapy and Its Analgesic Implications: A Narrative Review".

[This corrects the article DOI: 10.1155/2015/292805.].

Rare Variants in Cardiomyopathy Genes Associated With Stress-Induced Cardiomyopathy.

BACKGROUND: Stress-induced cardiomyopathy (SIC) is a poorly understood condition associated with periods of emotional and physical stress. The clinical approaches for management of SIC are supportive and reactive to patient symptoms. OBJECTIVE: To utilize next-generation exome sequencing to define genetic variation associated with, and potentially responsible for, this disease. METHODS: We performed exome sequencing of 7 white female patients with SIC. Filtering of the identified variants was performed to limit our investigation to those sequences that passed quality control criteria, were rare or novel, were determined algorithmically to have high impact on the associated protein, and were within regions of high species conservation. All variants were verified by using Sanger sequencing. RESULTS: Exome-sequencing analysis revealed that each patient carried predicted deleterious variants affecting known cardiomyopathy genes. In each case, the identified variant was either not previously found in public human genome data or was previously annotated in a database of clinical variants associated with cardiac dysfunction. CONCLUSION: Patients with SIC harbor deleterious mutations in established cardiomyopathy genes at a level higher than healthy controls. We hypothesize that patients at highest risk for SIC likely live in a compensated state of cardiac dysfunction that manifests clinically only after the myocardium is stressed. In short, we propose that SIC is another example of an occult cardiomyopathy with a distinct physiological trigger and suggest that alternative clinical approaches to these patients may be warranted. ABBREVIATIONS: CADD, Combined Annotation Dependent DepletionFPKM, fragments per kilobase pair of exon per million fragments mappedNHLBI GO ESP, National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing ProjectPCR, polymerase chain reactionSIC, stress-induced cardiomyopathy.

The Role of Descending Modulation in Manual Therapy and Its Analgesic Implications: A Narrative Review.

Manual therapy has long been a component of physical rehabilitation programs, especially to treat those in pain. The mechanisms of manual therapy, however, are not fully understood, and it has been suggested that its pain modulatory effects are of neurophysiological origin and may be mediated by the descending modulatory circuit. Therefore, the purpose of this review is to examine the neurophysiological response to different types of manual therapy, in order to better understand the neurophysiological mechanisms behind each therapy's analgesic effects. It is concluded that different forms of manual therapy elicit analgesic effects via different mechanisms, and nearly all therapies appear to be at least partially mediated by descending modulation. Additionally, future avenues of mechanistic research pertaining to manual therapy are discussed.