The Protective and Therapeutic Function of Small Heat Shock Proteins in Neurological Diseases

Historically, small heat shock proteins (sHSPs) have been extensively studied in the context of being intracellular molecular chaperones. However, recent studies looking at the role of sHSPs in neurological diseases have demonstrated a near universal upregulation of certain sHSPs in damaged and diseased brains. Initially, it was thought that sHSPs are pathological in these disease states because they are found in the areas of damage. However, transgenic overexpression and exogenous administration of sHSPs in various experimental disease paradigms have shown just the contrary – that sHSPs are protective, not pathological. This review examines sHSPs in neurological diseases and highlights the potential for using these neuroprotective sHSPs as novel therapeutics. It first addresses the endogenous expression of sHSPs in a variety of neurological disorders. Although many studies have examined the expression of sHSPs in neurological diseases, there are no review articles summarizing these data. Furthermore, it focuses on recent studies that have investigated the therapeutic potential of sHSPs for neurological diseases. Finally, it will explain what we think is the function of endogenous sHSPs in neurological diseases

Is Your Neighborhood Designed to Support Physical Activity? A Brief Streetscape Audit Tool.

INTRODUCTION:Macro level built environment factors (eg, street connectivity, walkability) are correlated with physical activity. Less studied but more modifiable microscale elements of the environment (eg, crosswalks) may also affect physical activity, but short audit measures of microscale elements are needed to promote wider use. This study evaluated the relation of a 15-item neighborhood environment audit tool with a full version of the tool to assess neighborhood design on physical activity in 4 age groups. METHODS:From the 120-item Microscale Audit of Pedestrian Streetscapes (MAPS) measure of street design, sidewalks, and street crossings, we developed the 15-item version (MAPS-Mini) on the basis of associations with physical activity and attribute modifiability. As a sample of a likely walking route, MAPS-Mini was conducted on a 0.25-mile route from participant residences toward the nearest nonresidential destination for children (n = 758), adolescents (n = 897), younger adults (n = 1,655), and older adults (n = 367). Active transportation and leisure physical activity were measured with age-appropriate surveys, and accelerometers provided objective physical activity measures. Mixed-model regressions were conducted for each MAPS item and a total environment score, adjusted for demographics, participant clustering, and macrolevel walkability. RESULTS:Total scores of MAPS-Mini and the 120-item MAPS correlated at r = .85. Total microscale environment scores were significantly related to active transportation in all age groups. Items related to active transport in 3 age groups were presence of sidewalks, curb cuts, street lights, benches, and buffer between street and sidewalk. The total score was related to leisure physical activity and accelerometer measures only in children. CONCLUSION:The MAPS-Mini environment measure is short enough to be practical for use by community groups and planning agencies and is a valid substitute for the full version that is 8 times longer

Reconciling Incongruous Qualitative and Quantitative Findings in Mixed Methods Research: Exemplars from Research with Drug Using Populations

Mixed methods research is increasingly being promoted in the health sciences as a way to gain more comprehensive understandings of how social processes and individual behaviours shape human health. Mixed methods research most commonly combines qualitative and quantitative data collection and analysis strategies. Often, integrating findings from multiple methods is assumed to confirm or validate the findings from one method with the findings from another, seeking convergence or agreement between methods. Cases in which findings from different methods are congruous are generally thought of as ideal, whilst conflicting findings may, at first glance, appear problematic. However, the latter situation provides the opportunity for a process through which apparently discordant results are reconciled, potentially leading to new emergent understandings of complex social phenomena. This paper presents three case studies drawn from the authors’ research on HIV risk amongst injection drug users in which mixed methods studies yielded apparently discrepant results. We use these case studies (involving injection drug users [IDUs] using a Needle/Syringe Exchange Program in Los Angeles, CA, USA; IDUs seeking to purchase needle/syringes at pharmacies in Tijuana, Mexico; and young street-based IDUs in San Francisco, CA, USA) to identify challenges associated with integrating findings from mixed methods projects, summarize lessons learned, and make recommendations for how to more successfully anticipate and manage the integration of findings. Despite the challenges inherent in reconciling apparently conflicting findings from qualitative and quantitative approaches, in keeping with others who have argued in favour of integrating mixed methods findings, we contend that such an undertaking has the potential to yield benefits that emerge only through the struggle to reconcile discrepant results and may provide a sum that is greater than the individual qualitative and quantitative parts

Altered Baroreflex-Mediated Cardiovascular Responses to Acute Hypotension in Heart Failure Patients Compared to Healthy Adults

Patients with heart failure (HF) exhibit baroreflex dysfunction, which is associated with increased morbidity and mortality. Orthostatic hypotension, a decrease in blood pressure (BP) upon standing, is a condition that often occurs in HF, and may be linked with altered baroreflex responsiveness in this population. However, data on baroreflex-mediated cardiovascular responses to acute hypotension in HF patients are limited. Therefore, 8 HF patients (7 men; mean±SEM 65±3y; ejection fraction 30.5±3.1%) and 7 healthy control (CON) adults (6 men; 65±2y) underwent 7.5 minutes of unilateral lower-limb ischemia via inflation of a thigh cuff on one leg to non-pharmacologically induce acute hypotension upon cuff deflation. Beat-to-beat systolic BP, diastolic BP, and mean arterial BP (MAP; photoplethysmographic finger cuff) and heart rate (HR; electrocardiogram) were recorded continuously before, during, and after cuff inflation. Statistical analysis involved independent-samples t-tests. Baseline values were not different between groups (systolic BP: 128±8 vs. 128±4mmHg; diastolic BP: 73±3 vs. 82±5mmHg; MAP: 90±3 vs. 97±4mmHg; HR: 62±2 vs. 56±2b.min-1 for HF and CON, respectively; P\u3e0.05). The magnitude of the induced decrease in MAP was similar in both groups (HF -11±1 vs. CON -12±2mmHg; P\u3e0.05). However, the time-to-peak MAP decrease was significantly longer in HF compared to CON (HF 11±2 vs. CON 6±1s; PP\u3e0.05). However, the time-to-peak HR increase was longer in HF compared to CON (HF 9±1 vs. CON 6±1s; PP\u3e0.05). However, the time-to-peak HR increase was longer in HF compared to CON (HF 9±1 vs. CON 6±1s;

Pea3 Transcription Factors and Wnt1-Induced Mouse Mammary Neoplasia

The role of the PEA3 subfamily of Ets transcription factors in breast neoplasia is controversial. Although overexpression of PEA3 (E1AF/ETV4), and of the related factors ERM (ETV5) and ER81 (ETV1), have been observed in human and mouse breast tumors, PEA3 factors have also been ascribed a tumor suppressor function. Here, we utilized the MMTV/Wnt1 mouse strain to further interrogate the role of PEA3 transcription factors in mammary tumorigenesis based on our previous observation that Pea3 is highly expressed in MMTV/Wnt1 mammary tumors. Pea3 expression in mouse mammary tissues was visualized using a Pea3NLSlacZ reporter strain. In normal mammary glands, Pea3 expression is predominantly confined to myoepithelial cells. Wnt1 transgene expression induced marked amplification of this cell compartment in nontumorous mammary glands, accompanied by an apparent increase in Pea3 expression. The pattern of Pea3 expression in MMTV/Wnt1 mammary glands recapitulated the cellular profile of activated β-catenin/TCF signaling, which was visualized using both β-catenin immunohistochemistry and the β-catenin/TCF-responsive reporter Axin2NLSlacZ. To test the requirement for PEA3 factors in Wnt1-induced tumorigenesis, we employed a mammary-targeted dominant negative PEA3 transgene, ΔNPEA3En. Expression of ΔNPEA3En delayed early-onset tumor formation in MMTV/Wnt1 virgin females (P = 0.03), suggesting a requirement for PEA3 factor function for Wnt1-driven tumor formation. Consistent with this observation, expression of the ΔNPEA3En transgene was profoundly reduced in mammary tumors compared to nontumorous mammary glands from bigenic MMTV/Wnt1, MMTV/ΔNPEA3En mice (P = 0.01). Our data provide the first description of Wnt1-mediated expansion of the Pea3-expressing myoepithelial compartment in nontumorous mammary glands. Consistent with this observation, mammary myoepithelium was selectively responsive to Wnt1. Together these data suggest the MMTV/Wnt1 strain as a potential model of basal breast cancer. Furthermore, this study provides evidence for a protumorigenic role of PEA3 factors in breast neoplasia, and supports targeting the PEA3 transcription factor family in breast cancer

Dynamical Masses for Low-Mass Pre-Main Sequence Stars: A Preliminary Physical Orbit for HD 98800 B

We report on Keck Interferometer observations of the double-lined binary (B) component of the quadruple pre-main sequence (PMS) system HD 98800. With these interferometric observations combined with astrometric measurements made by the Hubble Space Telescope Fine Guidance Sensors (FGS), and published radial velocity observations we have estimated preliminary visual and physical orbits of the HD 98800 B subsystem. Our orbit model calls for an inclination of 66.8 $\pm$ 3.2 deg, and allows us to infer the masses and luminosities of the individual components. In particular we find component masses of 0.699 $\pm$ 0.064 and 0.582 $\pm$ 0.051 M_{\sun} for the Ba (primary) and Bb (secondary) components respectively. Modeling of the component SEDs finds temperatures and luminosities in agreement with previous studies, and coupled with the component mass estimates allows for comparison with PMS models in the low-mass regime with few empirical constraints. Solar abundance models seem to under-predict the inferred component temperatures and luminosities, while assuming slightly sub-solar abundances bring the models and observations into better agreement. The present preliminary orbit does not yet place significant constraints on existing pre-main sequence stellar models, but prospects for additional observations improving the orbit model and component parameters are very good.Comment: 20 pages, 6 figures, ApJ in press; tables 2 and 3 to be included in ApJ versio

Reduction in Dynamic Visual Acuity Reveals Gaze Control Changes Following Spaceflight

INTRODUCTION: Exposure to microgravity causes adaptive changes in eye-head coordination that can lead to altered gaze control. This could affect postflight visual acuity during head and body motion. The goal of this study was to characterize changes in dynamic visual acuity after long-duration spaceflight. METHODS: Dynamic Visual Acuity (DVA) data from 14 astro/cosmonauts were collected after long-duration (~6 months) spaceflight. The difference in acuity between seated and walking conditions provided a metric of change in the subjects ability to maintain gaze fixation during self-motion. In each condition, a psychophysical threshold detection algorithm was used to display Landolt ring optotypes at a size that was near each subject s acuity threshold. Verbal responses regarding the orientation of the gap were recorded as the optotypes appeared sequentially on a computer display 4 meters away. During the walking trials, subjects walked at 6.4 km/h on a motorized treadmill. RESULTS: A decrement in mean postflight DVA was found, with mean values returning to baseline within 1 week. The population mean showed a consistent improvement in DVA performance, but it was accompanied by high variability. A closer examination of the individual subject s recovery curves revealed that many did not follow a pattern of continuous improvement with each passing day. When adjusted on the basis of previous long-duration flight experience, the population mean shows a "bounce" in the re-adaptation curve. CONCLUSION: Gaze control during self-motion is altered following long-duration spaceflight and changes in postflight DVA performance indicate that vestibular re-adaptation may be more complex than a gradual return to normal