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Restoration of Visual Function by Enhancing Conduction in Regenerated Axons. - Cell
Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian CNS, it remains unclearÂ whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC) but not significant recovery of visual function. Further analyses suggestÂ that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after retinal axon injury.Copyright Â© 2016 Elsevier Inc. All rights reserved.
Can Holo NMR Chemical Shifts be Directly Used to Resolve RNA-Ligand Poses? - Journal of chemical information and modeling
Using a set of machine learning based predictors that are capable of predicting ligand-induced shielding effects on 1H and 13C non-exchangeable nuclei, it was discovered that holo NMR chemical shifts can be used to resolve RNA-ligand poses. This was accomplished by quantitatively comparing measured and predicted holo chemical shifts in conformationally diverse "decoy" pools for three test cases, and then for each, comparing the native pose to the pose in the decoy pool that exhibited the lowest error. For three test cases, the poses in the decoy pools that exhibited the best agreement between measured and predicted holo chemical shifts were within 0.28, 1.12, and 2.38 Ã… of the native poses. Interestingly, the predictors used in this study were trained on a database containing, only, apo RNA data. The agreement between the chemical shift-selected poses and the native NMR poses suggests that the predictors used in this study were able to "learn" general chemical shift-structure relationships from apo RNA data that could be used to account for ligand-induced shielding effects on RNA nuclei for the test cases studied.
The validity and reliability of attending evaluations of medicine residents. - SAGE open medicine
To assess the reliability and validity of faculty evaluations of medicine residents.We conducted a retrospective study (2004-2012) involving 228 internal medicine residency graduates at the Medical College of Wisconsin who were evaluated by 334 attendings. Measures included evaluations of residents by attendings, based on six competencies and interns and residents' performance on the American Board of Internal Medicine certification exam and annual in-service training examination. All residents had at least one in-service training examination result and 80% allowed the American Board of Internal Medicine to release their scores.Attending evaluations had good consistency (Cronbach's Î±â€‰=â€‰0.96). There was poor construct validity with modest inter-rater reliability and evidence that attendings were rating residents on a single factor rather than the six competencies intended to be measured. There was poor predictive validity as attending ratings correlated weakly with performance on the in-service training examination or American Board of Internal Medicine certification exam.We conclude that attending evaluations are poor measures for assessing progress toward competency. It may be time to move beyond evaluations that rely on global, end-of-rotation appraisals.
Uncertain for a century: quantum mechanics and the dilemma of interpretation. - Annals of the New York Academy of Sciences
Quantum mechanics, the physical theory describing the microworld, is one of science's greatest triumphs. Remarkably, however, after more than 100 years it is still unclear what quantum mechanics means in terms of basic philosophical questions about the nature of reality. While there are many interpretations of the mathematical machinery of quantum physics, there remain no experimental means to distinguish between most of them. In this contribution, I wish to consider the ways in which the enduring lack of an agreed-upon interpretation of quantum physics influences a number of critical philosophical debates about physics and reality. I briefly review two problems affected by quantum interpretations: the meaning of the term universe and the nature of consciousness.Â© 2015 New York Academy of Sciences.
Ligament and meniscus loading in the ovine stifle joint during normal gait. - The Knee
The ovine stifle joint is an ideal preclinical model to study knee joint biomechanics. Knowledge of the ovine ligamentous and meniscal loading during normal gait is currently limited.The in vivo kinematics of the ovine stifle joint (N=4) were measured during "normal" gait using a highly accurate instrumented spatial linkage (ISL, 0.3Â±0.2mm). These motions were reproduced in vitro using a unique robotic testing platform and the loads carried by the anterior/posterior cruciate ligaments (ACL/PCL), medial/lateral collateral ligaments (MCL/LCL), and medial/lateral menisci (MM/LM) during gait were determined.Considerable inter-subject variability in tissue loads was observed. The load in the ACL was near zero at hoof-strike (0% gait) and reached a peak (100 to 300N) during early-stance (~10% gait). The PCL reached a peak load (200 to 500N) just after hoof-strike (~5% gait) and was mostly unloaded throughout the remainder of stance. Load in the MCL was substantially lower than the cruciate ligaments, reaching a maximum of 50 to 100N near the beginning of stance. The LCL carried a negligible amount of load through the entire gait cycle. There was also a major contribution of the MM and LM to load transfer from the femur to the tibia during normal gait. The total meniscal load reached a maximum average between 350 and 550N during gait.Knowledge of joint function during normal motion is essential for understanding normal and pathologic joint states. The considerable variability in the magnitudes and patterns of tissue loads among animals simulates clinical variability in humans.III.Copyright Â© 2015 Elsevier B.V. All rights reserved.
Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques. - PLoS pathogens
Increased chronic immune activation and inflammation are hallmarks of HIV/SIV infection and are highly correlated with progression to AIDS and development of non-AIDS comorbidities, such as hypercoagulability and cardiovascular disease. Intestinal dysfunction resulting in microbial translocation has been proposed as a lead cause of systemic immune activation and hypercoagulability in HIV/SIV infection. Our goal was to assess the biological and clinical impact of a therapeutic strategy designed to reduce microbial translocation through reduction of the microbial content of the intestine (Rifaximin-RFX) and of gut inflammation (Sulfasalazine-SFZ). RFX is an intraluminal antibiotic that was successfully used in patients with hepatic encephalopathy. SFZ is an antiinflammatory drug successfully used in patients with mild to moderate inflammatory bowel disease. Both these clinical conditions are associated with increased microbial translocation, similar to HIV-infected patients. Treatment was administered for 90 days to five acutely SIV-infected pigtailed macaques (PTMs) starting at the time of infection; seven untreated SIVsab-infected PTMs were used as controls. RFX+SFZ were also administered for 90 days to three chronically SIVsab-infected PTMs. RFX+SFZ administration during acute SIVsab infection of PTMs resulted in: significantly lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4+ T cells and significantly lower levels of hypercoagulation biomarkers. This effect was clear during the first 40 days of treatment and was lost during the last stages of treatment. Administration of RFX+SFZ to chronically SIVsab-infected PTMs had no discernible effect on infection. Our data thus indicate that early RFX+SFZ administration transiently improves the natural history of acute and postacute SIV infection, but has no effect during chronic infection.
Enhancement of HIV-1 infection and intestinal CD4+ T cell depletion ex vivo by gut microbes altered during chronic HIV-1 infection. - Retrovirology
Early HIV-1 infection is characterized by high levels of HIV-1 replication and substantial CD4 T cell depletion in the intestinal mucosa, intestinal epithelial barrier breakdown, and microbial translocation. HIV-1-induced disruption of intestinal homeostasis has also been associated with changes in the intestinal microbiome that are linked to mucosal and systemic immune activation. In this study, we investigated the impact of representative bacterial species that were altered in the colonic mucosa of viremic HIV-1 infected individuals (HIV-altered mucosal bacteria; HAMB) on intestinal CD4 T cell function, infection by HIV-1, and survival in vitro. Lamina propria (LP) mononuclear cells were infected with CCR5-tropic HIV-1BaL or mock infected, exposed to high (3 gram-negative) or low (2 gram-positive) abundance HAMB or control gram-negative Escherichia coli and levels of productive HIV-1 infection and CD4 T cell depletion assessed. HAMB-associated changes in LP CD4 T cell activation, proliferation and HIV-1 co-receptor expression were also evaluated.The majority of HAMB increased HIV-1 infection and depletion of LP CD4 T cells, but gram-negative HAMB enhanced CD4 T cell infection to a greater degree than gram-positive HAMB. Most gram-negative HAMB enhanced T cell infection to levels similar to that induced by gram-negative E. coli despite lower induction of T cell activation and proliferation by HAMB. Both gram-negative HAMB and E. coli significantly increased expression of HIV-1 co-receptor CCR5 on LP CD4 T cells. Lipopolysaccharide, a gram-negative bacteria cell wall component, up-regulated CCR5 expression on LP CD4 T cells whereas gram-positive cell wall lipoteichoic acid did not. Upregulation of CCR5 by gram-negative HAMB was largely abrogated in CD4 T cell-enriched cultures suggesting an indirect mode of stimulation.Gram-negative commensal bacteria that are altered in abundance in the colonic mucosa of HIV-1 infected individuals have the capacity to enhance CCR5-tropic HIV-1 productive infection and depletion of LP CD4 T cells in vitro. Enhanced infection appears to be primarily mediated indirectly through increased expression of CCR5 on LP CD4 T cells without concomitant large scale T cell activation. This represents a novel mechanism potentially linking intestinal dysbiosis to HIV-1 mucosal pathogenesis.
Arthroscopic-Assisted Acromioclavicular Joint Reconstruction Using the TightRope Device With Allograft Augmentation: Surgical Technique. - Arthroscopy techniques
Surgical management of acromioclavicular (AC) joint separations remains challenging, especially in the revision setting. Most commonly, Rockwood type I and II injuries are managed nonoperatively whereas type IV, V, and VI injuries are managed with surgery. Type III separations are more controversial, with evidence supporting both nonoperative and operative treatment options. Multiple different arthroscopic techniques have been described; however, there is no current gold standard. AC joint reconstruction with the TightRope device (Arthrex, Naples, FL) with the patient in the lateral decubitus position is a method of restoring joint stability that allows for a minimally invasive, low-profile fixation construct using a single drill hole through the clavicle. Allograft augmentation of this fixation construct helps to eliminate the stress risers potentially created by this device while increasing overall repair construct stability. The purpose of this article is to describe the surgical technique for arthroscopic AC joint reconstruction using a TightRope device with allograft augmentation.
Successful ageing in lesbian, gay and bisexual older people: a concept analysis. - International journal of older people nursing
The aim of this study was to report on an analysis of the concept of successful ageing in lesbian, gay and bisexual older people.Research indicates that lesbian, gay and bisexual older people experience significant health disparities. Yet there is a lack of understanding on what factors contribute to successful ageing in this population. Nursing has lagged behind other disciplines in investigating the health of lesbian, gay and bisexual older people.A concept analysis using Rodgers' evolutionary method.Twenty studies were retrieved by searching PubMed, CINAHL, PsycInfo, EMBASE, Cochrane Library and Scopus for English-language peer-reviewed studies published from January 2004 to March 2014.The antecedents, attributes and consequences of the concept were identified through the Rodgers' method of concept analysis.Attributes included support from families of origin and/or families of choice, access to lesbian, gay, and bisexual-friendly services and crisis competence. Self-realisation of lesbian, gay and bisexual identity (coming out to oneself) and age >50 were identified as antecedents. Three consequences of successful ageing in lesbian, gay and bisexual older people were social engagement, optimism and resilience.Successful ageing in lesbian, gay and bisexual older people is defined as a subjective and multifactorial concept that is characterised by support from families of origin/families of choice, access to lesbian, gay, and bisexual-friendly services and the development of crisis competence skills which impact the ageing experience of LGB individuals.Successful ageing models can provide a roadmap for developing culturally competent interventions to address key healthcare issues present in this population. The nursing profession's multidisciplinary knowledge and competence in providing health promotion makes nurses well positioned to take a leading role in reducing disparities of lesbian, gay and bisexual older people.Â© 2016 John Wiley & Sons Ltd.
Fixation of Soft Tissue to Bone: Techniques and Fundamentals. - The Journal of the American Academy of Orthopaedic Surgeons
A myriad of orthopaedic injuries require surgical fixation of torn connective tissue to an osseous insertion site with either direct repair or reconstruction with a soft-tissue graft. Numerous factors influence the strength of a soft-tissue-to-bone fixation construct, including tissue quality, implant strength, contact area and pressure, and tensioning. Each fixation technique differs with respect to biologic integration, biomechanical stability, and failure mechanism. Fixation methods may or may not require an implant, such as interference screws, staples, internal buttons, transfixion pins, or suture anchors. Understanding the optimal method of soft-tissue fixation for a given scenario is crucial for successful repair or reconstruction.
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