Person-Specific Methods for Characterizing the Course and Temporal Dynamics of Concussion Symptomatology: A Pilot Study.

Better characterization of acute concussion symptomatology is needed in order to advance clinical and scientific understanding of persistent concussion symptoms. This paper aims to illustrate a novel framework for conceptualizing, collecting, and analyzing concussion symptom data. To that end, we describe the temporal and structural dynamics of acute concussion symptoms at the individual-patient level. Ten recently concussion adolescents and young adults completed 20 days of ecological momentary assessment (EMA) of post-concussion symptoms. Follow-up assessments were completed at 3 months post-injury. Network modeling revealed marked heterogeneity across participants. In the overall sample, temporal patterns explained the most variance in light sensitivity (48%) and the least variance in vomiting (5%). About half of the participants had symptom networks that were sparse after controlling for temporal variation. The other individualized symptom networks were densely interconnected clusters of symptoms. Networks were highly idiosyncratic in nature, yet emotional symptoms (nervousness, emotional, sadness), cognitive symptoms (mental fogginess, slowness), and symptoms of hyperacusis (sensitivity to light, sensitivity to noise) tended to cluster together across participants. Person-specific analytic techniques revealed a number of idiosyncratic features of post-concussion symptomatology. We propose applying this framework to future research to better understand individual differences in concussion recovery

Harnessing bioluminescence for drug discovery and epigenetic research

The naturally occurring phenomenon of bioluminescence has intrigued on-lookers for decades and is now being developed as a powerful tool for medical research and preclinical imaging. Luciferase enzymes emit light upon substrate encounter, enabling their activity to be visualised and dynamically tracked. By inserting luciferase genes into specific sites in the genome, it is possible to engineer reporters to monitor gene expression in its native context, and to detect epigenetic change in vivo. Endogenous bioluminescent reporters provide a highly sensitive, quantitative read-out of gene expression that is both well suited to longitudinal studies and can be adapted for high-throughput drug screens. In this article we outline some of the applications and benefits of bioluminescent reporters for epigenetic research, with a particular focus on revealing new therapeutic options for treating genetic and epigenetic disorders

Xeroderma Pigmentosum Group C Deficiency Alters Cigarette Smoke DNA Damage Cell Fate and Accelerates Emphysema Development

Cigarette smoke (CS) exposure is a major risk factor for the development of emphysema, a common disease characterized by loss of cells comprising the lung parenchyma. The mechanisms of cell injury leading to emphysema are not completely understood but are thought to involve persistent cytotoxic or mutagenic DNA damage induced by CS. Using complementary cell culture and mouse models of CS exposure, we investigated the role of the DNA repair protein, xeroderma pigmentosum group C (XPC), on CS-induced DNA damage repair and emphysema. Expression of XPC was decreased in mouse lungs after chronic CS exposure and XPC knockdown in cultured human lung epithelial cells decreased their survival after CS exposure due to activation of the intrinsic apoptosis pathway. Similarly, cell autophagy and apoptosis were increased in XPC-deficient mouse lungs and were further increased by CS exposure. XPC deficiency was associated with structural and functional changes characteristic of emphysema, which were worsened by age, similar to levels observed with chronic CS exposure. Taken together, these findings suggest that repair of DNA damage by XPC plays an important and previously unrecognized role in the maintenance of alveolar structures. These findings support that loss of XPC, possibly due to chronic CS exposure, promotes emphysema development and further supports a link between DNA damage, impaired DNA repair, and development of emphysema

EFFECT OF TREADMILL RUNNING ON CARDIAC AND SKELETAL MUSCLE METABOLISM AND RIGHT VENTRICLE INFLAMMATION IN RATS WITH PULMONARY ARTERIAL HYPERTENSION

poster abstractIt has been suggested that a shift from oxidative to non-oxidative (glycolytic) metabolism promotes a right ventricle (RV) and skeletal muscle dysfunction in patients with pulmonary arterial hypertension (PAH), contributing to their reduced exercise tolerance. Exercise training may ameliorate this glycolytic switch in PAH as it does for other cardiopulmonary diseases. However, whether exercise-induced cardiac stress also promotes detrimental RV inflammation in PAH has not yet been thoroughly examined. We hypothesized that exercise training will promote a shift back towards the more efficient oxidative metabolism in cardiac and skeletal muscle of PAH rats and that 45 minutes of exercise at a prescribed moderate intensity will not promote greater RV inflammation in PAH rats. Tissues were obtained from monocrotaline-induced PAH and healthy control rats immediately following a 45 min treadmill run (75% VO2max) that concluded a 4 week treadmill familiarization/running program (15-45 min, 4x/wk). A group of unexercised PAH and healthy rats served as sedentary controls. Immunofluorescent staining (IF) for inflammatory markers CD45 (lymphocytes) and CD68 (macrophages) in cryofixed RV sections were used to assess the acute inflammatory response to exercise. In fixed soleus and RV sections, IF for the glucose transporter Glut1, and for capillary marker CD31, were used as indicators of glycolytic metabolism and tissue capillarization, respectively. Data thus far indicates no greater acute exercise-induced RV inflammation in PAH rats compared to healthy rats. We observed higher expression of Glut1 and lower capillarization in the RV and soleus of PAH rats, indicative of a shift toward greater dependency on non-oxidative metabolism. However, since Glut1 levels for exercised rats were measured in tissue harvested immediately following a run bout, evaluation of a chronic training effect on Glut1 expression is potentially confounded by the acute exercise effect and therefore remains to be investigated in a follow-up study

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

While our previous studies suggest that limiting bleomycin-induced complement activation suppresses TGF-β signaling, the specific hierarchical interactions between TGF-β and complement in lung fibrosis are unclear. Herein, we investigated the mechanisms underlying TGF-β-induced complement activation in the pathogenesis of lung fibrosis. C57-BL6 mice were given intratracheal instillations of adenoviral vectors overexpressing TGF-β (Ad-TGFβ) or the firefly gene-luciferase (Ad-Luc; control). Two weeks later, mice with fibrotic lungs were instilled RNAi specific to receptors for C3a or C5a-C3ar or C5ar, and sacrificed at day 28. Histopathological analyses revealed that genetic silencing of C3ar or C5ar arrested the progression of TGF-β-induced lung fibrosis, collagen deposition and content (hydroxyproline, col1a1/2); and significantly suppressed local complement activation. With genetic silencing of either C3ar or C5ar, in Ad-TGFβ-injured lungs: we detected the recovery of Smad7 (TGF-β inhibitor) and diminished local release of DAF (membrane-bound complement inhibitor); in vitro: TGF-β-mediated loss of DAF was prevented. Conversely, blockade of the TGF-β receptor prevented C3a-mediated loss of DAF in both normal primary human alveolar and small airway epithelial cells. Of the 52 miRNAs analyzed as part of the Affymetrix array, normal primary human SAECs exposed to C3a, C5a or TGF-β caused discrete and overlapping miRNA regulation related to epithelial proliferation or apoptosis (miR-891A, miR-4442, miR-548, miR-4633), cellular contractility (miR-1197) and lung fibrosis (miR-21, miR-200C, miR-31HG, miR-503). Our studies present potential mechanisms by which TGF-β activates complement and promotes lung fibrosis

Commode Cardiaâ Death by Valsalva Maneuver: A Case Series

The Valsalva maneuver is used in clinical medicine for the diagnosis and/or treatment of various cardiovascular conditions. It can also be used in activities of daily living, such as defecation. Due to the cardiovascular effects produced during the Valsalva maneuver, it may be contraindicated in certain medical conditions and could be a trigger of sudden cardiac death. The incidence and prevalence of death following Valsalva maneuver in the presence of underlying cardiovascular disease, or â commode cardia,â has not been examined. In 2012, the Wayne County Medical Examiner’s Office (Detroit, MI) investigated 21 deaths that occurred on the toilet, fourteen of which were due to cardiovascular disease. In another 31 deaths in the bathroom due to cardiovascular disease, the possibility that the decedent defecated immediately prior to death could not be excluded. Hence, the incidence of commode cardia in this population ranges from 2.3 to 7.4% of all cardiovascularâ related deaths.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134829/1/jfo13196_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134829/2/jfo13196.pd

The VIRUS-P Exploration of Nearby Galaxies (VENGA): Survey Design and First Results

VENGA is a large-scale extragalactic IFU survey, which maps the bulges, bars and large parts of the outer disks of 32 nearby normal spiral galaxies. The targets are chosen to span a wide range in Hubble types, star formation activities, morphologies, and inclinations, at the same time of having vast available multi-wavelength coverage from the far-UV to the mid-IR, and available CO and 21cm mapping. The VENGA dataset will provide 2D maps of the SFR, stellar and gas kinematics, chemical abundances, ISM density and ionization states, dust extinction and stellar populations for these 32 galaxies. The uniqueness of the VIRUS-P large field of view permits these large-scale mappings to be performed. VENGA will allow us to correlate all these important quantities throughout the different environments present in galactic disks, allowing the conduction of a large number of studies in star formation, structure assembly, galactic feedback and ISM in galaxies.Comment: 7 pages, 3 figures, proceedings of the "Third Biennial Frank N. Bash Symposium, New Horizons in Astronomy" held in Austin, TX, Oct. 2009. To be published in the Astronomical Society of the Pacific Conference Series, eds. L. Stanford, L. Hao, Y. Mao, J. Gree

Acute Exercise Activates Pulmonary eNOS and Lowers Pulmonary Pressure in Rats with Pulmonary Arterial Hypertension

poster abstractNO-dependent arterial relaxation is impaired in pulmonary arterial hypertension (PAH). Exercise may be beneficial in PAH, just as it is for systemic vascular disease, via upregulation of endothelial nitric oxide synthase (eNOS) expression and activity. However, exercise-induced cardiac stress in PAH could also promote detrimental RV inflammation. We investigated pulmonary pressure and eNOS, as well inflammatory indicators in the RV, following a single 45 min run bout at moderate intensity in a rat model of PAH. Male Sprague-Dawley rats received either monocrotaline to induce PAH, or saline, for healthy controls. A subset of PAH and healthy controls performed 4 wks of progressive TM familiarization (15-30min, 8-20 m/min) in preparation for their final 45 min run @ 75% of VO2max. Immediately following the run, RV systolic pressure was measured and RV and lung tissues were harvested and cryofixed. eNOS and phosphorylated (at Ser1177) eNOS (p-eNOS) was measured via immunoblotting in lung homogenates and expressed normalized to vinculin. Immunofluorescence for inflammatory markers CD45/68 in cryofixed RV sections evaluated the acute inflammatory response to exercise. MCT reduced VO2max and caused RV hypertrophy (expressed as RV/LV+septum) as consistent with this model. RVSP (normalized by systemic BP) was lower in PAH-Ex vs. unexercised PAH with no difference between exercised and unexercised controls. Greater p-eNOS was measured in PAH-Ex lung compared to unexercised PAH, with no difference between exercised and unexercised controls. PAH-Ex also tended to have greater pulmonary eNOS than their unexercised counterparts. No greater exercise-induced CD45/68 infiltration was observed in RV of PAH compared to that of controls. In rats with moderate MCT-induced PAH, a single exercise bout does not increase acute RV inflammation but lowers pulmonary pressure, possibly mediated in part via pulmonary eNOS activation

Hormonal correlates of pathogen disgust: Testing the Compensatory Prophylaxis Hypothesis

Raised progesterone during the menstrual cycle is associated with suppressed physiological immune responses, reducing the probability that the immune system will compromise the blastocyst's development. The Compensatory Prophylaxis Hypothesis proposes that this progesterone-linked immunosuppression triggers increased disgust responses to pathogen cues, compensating for the reduction in physiological immune responses by minimizing contact with pathogens. Although a popular and influential hypothesis, there is no direct, within-woman evidence for correlated changes in progesterone and pathogen disgust. To address this issue, we used a longitudinal design to test for correlated changes in salivary progesterone and pathogen disgust (measured using the pathogen disgust subscale of the Three Domain Disgust Scale) in a large sample of women (N = 375). Our analyses showed no evidence that pathogen disgust tracked changes in progesterone, estradiol, testosterone, or cortisol. Thus, our results provide no support for the Compensatory Prophylaxis Hypothesis of variation in pathogen disgust

Histological and transcriptomic effects of 17α-methyltestosterone on zebrafish gonad development.

BACKGROUND: Sex hormones play important roles in teleost ovarian and testicular development. In zebrafish, ovarian differentiation appears to be dictated by an oocyte-derived signal via Cyp19a1a aromatase-mediated estrogen production. Androgens and aromatase inhibitors can induce female-to-male sex reversal, however, the mechanisms underlying gonadal masculinisation are poorly understood. We used histological analyses together with RNA sequencing to characterise zebrafish gonadal transcriptomes and investigate the effects of 17α-methyltestosterone on gonadal differentiation. RESULTS: At a morphological level, 17α-methyltestosterone (MT) masculinised gonads and accelerated spermatogenesis, and these changes were paralleled in masculinisation and de-feminisation of gonadal transcriptomes. MT treatment upregulated expression of genes involved in male sex determination and differentiation (amh, dmrt1, gsdf and wt1a) and those involved in 11-oxygenated androgen production (cyp11c1 and hsd11b2). It also repressed expression of ovarian development and folliculogenesis genes (bmp15, gdf9, figla, zp2.1 and zp3b). Furthermore, MT treatment altered epigenetic modification of histones in zebrafish gonads. Contrary to expectations, higher levels of cyp19a1a or foxl2 expression in control ovaries compared to MT-treated testes and control testes were not statistically significant during early gonad development (40 dpf). CONCLUSION: Our study suggests that both androgen production and aromatase inhibition are important for androgen-induced gonadal masculinisation and natural testicular differentiation in zebrafish