Pharmacologic inhibition of RGD-binding integrins ameliorates fibrosis and improves function following kidney injury

Fibrosis is a final common pathway for many causes of progressive chronic kidney disease (CKD). Arginine-glycine-aspartic acid (RGD)-binding integrins are important mediators of the pro-fibrotic response by activating latent TGF-β at sites of injury and by providing myofibroblasts information about the composition and stiffness of the extracellular matrix. Therefore, blockade of RGD-binding integrins may have therapeutic potential for CKD. To test this idea, we used small-molecule peptidomimetics that potently inhibit a subset of RGD-binding integrins in a murine model of kidney fibrosis. Acute kidney injury leading to fibrosis was induced by administration of aristolochic acid. Continuous subcutaneous administration of CWHM-12, an RGD integrin antagonist, for 28 days improved kidney function as measured by serum creatinine. CWHM-12 significantly reduced Collagen 1 (Col1a1) mRNA expression and scar collagen deposition in the kidney. Protein and gene expression markers of activated myofibroblasts, a major source of extracellular matrix deposition in kidney fibrosis, were diminished by treatment. RNA sequencing revealed that inhibition of RGD integrins influenced multiple pathways that determine the outcome of the response to injury and of repair processes. A second RGD integrin antagonist, CWHM-680, administered once daily by oral gavage was also effective in ameliorating fibrosis. We conclude that targeting RGD integrins with such small-molecule antagonists is a promising therapeutic approach in fibrotic kidney disease

Intact Bilateral Resting-State Networks in the Absence of the Corpus Callosum

Temporal correlations between different brain regions in the resting-state BOLD signal are thought to reflect intrinsic functional brain connectivity (Biswal et al., 1995; Greicius et al., 2003; Fox et al., 2007). The functional networks identified are typically bilaterally distributed across the cerebral hemispheres, show similarity to known white matter connections (Greicius et al., 2009), and are seen even in anesthetized monkeys (Vincent et al., 2007). Yet it remains unclear how they arise. Here we tested two distinct possibilities: (1) functional networks arise largely from structural connectivity constraints, and generally require direct interactions between functionally coupled regions mediated by white-matter tracts; and (2) functional networks emerge flexibly with the development of normal cognition and behavior and can be realized in multiple structural architectures. We conducted resting-state fMRI in eight adult humans with complete agenesis of the corpus callosum (AgCC) and normal intelligence, and compared their data to those from eight healthy matched controls. We performed three main analyses: anatomical region-of-interest-based correlations to test homotopic functional connectivity, independent component analysis (ICA) to reveal functional networks with a data-driven approach, and ICA-based interhemispheric correlation analysis. Both groups showed equivalently strong homotopic BOLD correlation. Surprisingly, almost all of the group-level independent components identified in controls were observed in AgCC and were predominantly bilaterally symmetric. The results argue that a normal complement of resting-state networks and intact functional coupling between the hemispheres can emerge in the absence of the corpus callosum, favoring the second over the first possibility listed above

Morphogenesis by symbiogenesis

Here we review cases where initiation of morphogenesis, including the differentiation of specialized cells and tissues, has clearly evolved due to cyclical symbiont integration. For reasons of space, our examples are drawn chiefly from the plant, fungal and bacterial kingdoms. Partners live in symbioses and show unique morphological specializations that result when they directly and cyclically interact. We include here brief citations to relevant literature where plant, bacterial or fungal partners alternate independent with entirely integrated living. The independent, or at least physically unassociated stages, are correlated with the appearance of distinctive morphologies that can be traced to the simultaneous presence and strong interaction of the plant with individuals that represent different taxa

An end-to-end framework for real-time automatic sleep stage classification.

Sleep staging is a fundamental but time consuming process in any sleep laboratory. To greatly speed up sleep staging without compromising accuracy, we developed a novel framework for performing real-time automatic sleep stage classification. The client-server architecture adopted here provides an end-to-end solution for anonymizing and efficiently transporting polysomnography data from the client to the server and for receiving sleep stages in an interoperable fashion. The framework intelligently partitions the sleep staging task between the client and server in a way that multiple low-end clients can work with one server, and can be deployed both locally as well as over the cloud. The framework was tested on four datasets comprising ≈1700 polysomnography records (≈12000 hr of recordings) collected from adolescents, young, and old adults, involving healthy persons as well as those with medical conditions. We used two independent validation datasets: one comprising patients from a sleep disorders clinic and the other incorporating patients with Parkinson's disease. Using this system, an entire night's sleep was staged with an accuracy on par with expert human scorers but much faster (≈5 s compared with 30-60 min). To illustrate the utility of such real-time sleep staging, we used it to facilitate the automatic delivery of acoustic stimuli at targeted phase of slow-sleep oscillations to enhance slow-wave sleep

The Values Grounded Learning Environment: Developing a Positive School Culture and Student Success

The Values Grounded Learning Environment training provides educators with a comprehensive positive behavior management model, including basic strategies for effective limit setting and positive reinforcement. It is a user friendly model that can be implemented in a variety of educational settings and provides a framework for thoughtfully responding to student behaviors and emphasizing student and staff accountability

Distance Perception with a Camera-Based Rear Vision System in Actual Driving

Participants drove an instrumented car equipped with conventionalrearview mirrors and with a camera rear vision system. They observed theapproach of an overtaking car in the alternative rear vision systems and indicatedthe last moment at which it would be safe to initiate a lane-change maneuver infront of it. Their judgments were strongly affected by the type of display used toobserve the overtaking car. The longest distances were obtained with the camerabaseddisplay at unit magnification. Distances were substantially shorter with theconventional mirror and with the camera-based display at 0.5 minification. Theseresults are consistent with results from an earlier study conducted under staticconditions

Connecting Religion and Work: Patterns and Influences of Work-Faith Integration

Religiosity can significantly impact human behavior yet little is known about how religious belief and practice integrate with work. Using the Faith at Work Scale, we surveyed Christian workers in the United States (n = 374) and found that work-faith integration was positively associated with faith maturity, church attendance, age and denominational strictness, and negatively associated with organizational size. Denominational groups varied in their degree of integration but displayed similar patterns across dimensions of integration.Work-faith integration was manifest most strongly in integration related to the self, and somewhat less so in areas related to others and in transcendent aspects of work. Respondents attributed spiritual disciplines and workplace mentors as salient influences of work-faith integration. Implications for workplace spirituality scholarship and management are explored

Managing for change: March 6, 1989

Bi-weekly newsletter of University Hospital's Change Project, provided to managers at the hospital

Gait, function and quadriceps strength after intraarticular hyaluronan injections in patients with symptomatic knee osteoarthritis

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenIntroduction: Knee OA is a common cause of decline in function and is generally associated with joint malalignment and laxity, joint space narrowing, quadriceps weakness, as well as sclerosis and attrition of subchondral bone. Intraarticular (IA) injections of Hyaluronic Acid (HA) are indicated to palliate symptoms and improve function in patients with knee OA. Primary outcome measures in studies on the efficacy of this treatment are largely self reports of pain and function. The purpose of the study was to investigate the effects of HA injections on knee function and sagittal plane kinematics in patients with knee OA. Materials and Methods: Thirteen subjects with symptomatic knee OA and scheduled for 5, weekly, IA injections of HA were recruited. Each subject was tested for baseline data. Posttreatment testing sessions were conducted within 3 weeks of finishing the series of HA and again five months after treatment. Kinematic data were collected at 120 Hz using an eight camera motion analysis system (VICON, Oxford Metrics). Subjects walked along a 10 m walkway at self-selected pace. Ten walking trials were collected and averaged. Knee function was assessed with a knee specific questionnaire (Knee Outcome Survey (KOS)), goniometric range of motion (ROM) measures, a six minute walk (6MW) and a timed stair climbing task. Quadriceps strength was evaluated isometrically at 90° with a KinCom dynamometer (Chattanooga Group, Inc., Chattanooga, TN) and expressed as a ratio of the force output of the involved vs. uninvolved side (Quadriceps Index (QI)). Repeated measures analysis of variance (ANOVA) with pairwise comparisons, multivariate analysis, linear regression analysis and paired t-tests were used to analyze the data. Alpha was set at 0.05. Results: Multivariate analysis of knee flexion angles was used at two stages of weight acceptance; initial contact (IC) and peak knee flexion (PKF) between involved (INV) and uninvolved (UNINV) knees across the three testing times. The analysis showed an interaction between stage of weight acceptance and side (F=18.716; p=0.001). There were significant interlimb differences in knee excursion during weight acceptance (flexion angle from IC to PKF) for the first (5.3°; p=0.005), second (5.2°; p=0.001) and third (5.2°; p=0.001) testing times; the affected knee demonstrating less movement. Excursions of the INV and the UNINV knees did not change across testing times. Multivariate analysis of goniometric total knee ROM between the INV and UNINV knee across testing times showed an interaction by side (F=29.996; p<0.001) but not for testing time. The INV knee’s ROM was on average 8° less than that of the UNINV at the first testing session (p=0.003), 5.2° less at the second (p<0.001) and 7.2° less at the third testing session (p=0.001). Knee ROM of either knee did not change across testing times. Larger knee flexion ROM at baseline predicted greater improvement on KOS scores on the first post-treatment testing session (r2=.540; p=0.004). Larger knee flexion ROM at the first post-treatment predicted greater improvements on KOS scores at the later testing session (r2=.398; p=0.021). Significant within-subjects effects of testing times on KOS scores were found(F=4.65; p=0.02),on 6MW distance (F=12.010; p<0.001) and QI (F=5.903; p=0.013). Discussion: Subjects demonstrated significantly improved function after a series of intra-articular hyaluronan injections as evaluated with the KOS and functional testing. Kinematic interlimb differences were unchanged across testing times despite these improvements. Goniometric measures of total knee range of motion confirmed interlimb differences in available joint ROM. Although subjects demonstrated ample functional ROM, this was not utilized during weight acceptance. The truncated knee flexion may impede the shock absorbing mechanism of the knee and impact the progression of knee OA. While improvements in self reported scores were not maintained at the 5 month evaluation, walking distance continued to improve over time. This indicates that functional improvements persisted despite concurrently increasing symptoms