Skeletal Muscle Regeneration and Oxidative Stress Are Altered in Chronic Kidney Disease

Skeletal muscle atrophy and impaired muscle function are associated with lower health-related quality of life, and greater disability and mortality risk in those with chronic kidney disease (CKD). However, the pathogenesis of skeletal dysfunction in CKD is unknown. We used a slow progressing, naturally occurring, CKD rat model (Cy/+ rat) with hormonal abnormalities consistent with clinical presentations of CKD to study skeletal muscle signaling. The CKD rats demonstrated augmented skeletal muscle regeneration with higher activation and differentiation signals in muscle cells (i.e. lower Pax-7; higher MyoD and myogenin RNA expression). However, there was also higher expression of proteolytic markers (Atrogin-1 and MuRF-1) in CKD muscle relative to normal. CKD animals had higher indices of oxidative stress compared to normal, evident by elevated plasma levels of an oxidative stress marker, 8-hydroxy-2' -deoxyguanosine (8-OHdG), increased muscle expression of succinate dehydrogenase (SDH) and Nox4 and altered mitochondria morphology. Furthermore, we show significantly higher serum levels of myostatin and expression of myostatin in skeletal muscle of CKD animals compared to normal. Taken together, these data show aberrant regeneration and proteolytic signaling that is associated with oxidative stress and high levels of myostatin in the setting of CKD. These changes likely play a role in the compromised skeletal muscle function that exists in CKD

Will a Good Citizen Actively Support Organizational Change? Investigation of Psychological Processes Underlying Active Change Support

The present study investigated motivational factors of employees active change support (ACS). It also investigated good citizens response to the change by highlighting convergence and divergence of motivational factors between ACS and traditional extra-role behavior. The findings based on 166 staff responses and 346 supervisor assessments in a hospital that recently implemented a sharedgovernance structure suggest that active change support is a result of an active thinking process that involves perception of potential benefit from change but not necessarily the consequence of conventional predictors of extra-role behaviors (i.e., positive attitudes). The findings also suggest that good citizens are not necessarily the supporters of organizational change and that in actuality they confront motivational dilemma especially when they hold high quality relationship with their employer because they are reluctant to challenge the status quo

Urinary-Cell mRNA Profile and Acute Cellular Rejection in Kidney Allografts

Background—The standard test for the diagnosis of acute rejection in kidney transplants is the renal biopsy. Noninvasive tests would be preferable. Methods—We prospectively collected 4300 urine specimens from 485 kidney-graft recipients from day 3 through month 12 after transplantation. Messenger RNA (mRNA) levels were measured in urinary cells and correlated with allograft-rejection status with the use of logistic regression. Results—A three-gene signature of 18S ribosomal (rRNA)–normalized measures of CD3ε mRNA and interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA discriminated between biopsy specimens showing acute cellular rejection and those not showing rejection (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 by receiver-operatingcharacteristic curve analysis). The cross-validation estimate of the AUC was 0.83 by bootstrap resampling, and the Hosmer–Lemeshow test indicated good fit (P = 0.77). In an externalvalidation data set, the AUC was 0.74 (95% CI, 0.61 to 0.86; P<0.001) and did not differ significantly from the AUC in our primary data set (P = 0.13). The signature distinguished acute cellular rejection from acute antibody-mediated rejection and borderline rejection (AUC, 0.78; 95% CI, 0.68 to 0.89; P<0.001). It also distinguished patients who received anti–interleukin-2 receptor antibodies from those who received T-cell–depleting antibodies (P<0.001) and was diagnostic of acute cellular rejection in both groups. Urinary tract infection did not affect the signature (P = 0.69). The average trajectory of the signature in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection, but in the group with rejection, there was a sharp rise during the weeks before the biopsy showing rejection (P<0.001). Conclusions—A molecular signature of CD3ε mRNA, IP-10 mRNA, and 18S rRNA levels in urinary cells appears to be diagnostic and prognostic of acute cellular rejection in kidney allografts

Empirical Evaluation of Bone Extraction Protocols

The application of high-resolution analytical techniques to characterize ancient bone proteins requires clean, efficient extraction to obtain high quality data. Here, we evaluated many different protocols from the literature on ostrich cortical bone and moa cortical bone to evaluate their yield and relative purity using the identification of antibody-antigen complexes on enzyme-linked immunosorbent assay and gel electrophoresis. Moa bone provided an ancient comparison for the effectiveness of bone extraction protocols tested on ostrich bone. For the immunological part of this study, we focused on collagen I, osteocalcin, and hemoglobin because collagen and osteocalcin are the most abundant proteins in the mineralized extracellular matrix and hemoglobin is common in the vasculature. Most of these procedures demineralize the bone first, and then the remaining organics are chemically extracted. We found that the use of hydrochloric acid, rather than ethylenediaminetetraacetic acid, for demineralization resulted in the cleanest extractions because the acid was easily removed. In contrast, the use of ethylenediaminetetraacetic acid resulted in smearing upon electrophoretic separation, possibly indicating these samples were not as pure. The denaturing agents sodium dodecyl sulfate, urea, and guanidine HCl have been used extensively for the solubilization of proteins in non-biomineralized tissue, but only the latter has been used on bone. We show that all three denaturing agents are effective for extracting bone proteins. One additional method tested uses ammonium bicarbonate as a solubilizing buffer that is more appropriate for post-extraction analyses (e.g., proteomics) by removing the need for desalting. We found that both guanidine HCl and ammonium bicarbonate were effective for extracting many bone proteins, resulting in similar electrophoretic patterns. With the increasing use of proteomics, a new generation of scientists are now interested in the study of proteins from not only extant bone but also from ancient bone

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy

Gene duplication and fragmentation in the zebra finch major histocompatibility complex

BACKGROUND: Due to its high polymorphism and importance for disease resistance, the major histocompatibility complex (MHC) has been an important focus of many vertebrate genome projects. Avian MHC organization is of particular interest because the chicken Gallus gallus, the avian species with the best characterized MHC, possesses a highly streamlined minimal essential MHC, which is linked to resistance against specific pathogens. It remains unclear the extent to which this organization describes the situation in other birds and whether it represents a derived or ancestral condition. The sequencing of the zebra finch Taeniopygia guttata genome, in combination with targeted bacterial artificial chromosome (BAC) sequencing, has allowed us to characterize an MHC from a highly divergent and diverse avian lineage, the passerines. RESULTS: The zebra finch MHC exhibits a complex structure and history involving gene duplication and fragmentation. The zebra finch MHC includes multiple Class I and Class II genes, some of which appear to be pseudogenes, and spans a much more extensive genomic region than the chicken MHC, as evidenced by the presence of MHC genes on each of seven BACs spanning 739 kb. Cytogenetic (FISH) evidence and the genome assembly itself place core MHC genes on as many as four chromosomes with TAP and Class I genes mapping to different chromosomes. MHC Class II regions are further characterized by high endogenous retroviral content. Lastly, we find strong evidence of selection acting on sites within passerine MHC Class I and Class II genes. CONCLUSION: The zebra finch MHC differs markedly from that of the chicken, the only other bird species with a complete genome sequence. The apparent lack of synteny between TAP and the expressed MHC Class I locus is in fact reminiscent of a pattern seen in some mammalian lineages and may represent convergent evolution. Our analyses of the zebra finch MHC suggest a complex history involving chromosomal fission, gene duplication and translocation in the history of the MHC in birds, and highlight striking differences in MHC structure and organization among avian lineages

Toward a Unified Framework of Perceived Negative Leader Behaviors Insights from French and British Educational Sectors

In this paper, we challenge the commonly held assumption that actors in the education sector are largely ethical, and that there is therefore little need to scrutinize leader behaviors in this sector. We also overcome past scholars’ tendencies to either focus selectively on positive leader behaviors, or to stay content with categorizing leader behaviors into effective and ineffective (if at all they do focus on negative leader behaviors). Using data (Critical Incidents) from three case studies previously conducted in eight British and French academic establishments, we show that not only do negative leader behaviors abound in the education sector, but they can also be differentiated into three types: (1) behaviors emanating from leaders’ lack of functional skills i.e., ineffective behaviors, (2) behaviors emanating from leaders’ insouciance toward harming the organization and its members i.e., dysfunctional behaviors, and (3) behaviors emanating from leaders’ lack of honesty, integrity, ethicality, and transparency i.e., unauthentic behaviors. We enrich current understanding on ineffective, dysfunctional, and unauthentic leader behaviors, and offer a unified (yet differentiated) framework of negative leader behaviors in the academic sector. Since each type of negative behavior emanates from different motivational drivers, different measures are required to curb them. These are also discussed. A comparison of our findings with those from leadership studies in other sectors reveals that negative leader behaviors in the education sector are quite similar to those in other sectors

Passing the Torch of Wildlife and Fisheries Management: Comparing the Attitudes and Values of Younger and Older Conservation Professionals

Wildlife-related values in American society are undergoing considerable change. Within the last few decades, non-consumptive recreational use of wildlife has increased dramatically; groups that subscribe to animal protection values (ranging from animal welfare to animal rights to animal liberation) are exercising increasing influence over wildlife policy, and the ranks of people who practice wildlife rehabilitation have grown significantly. In this time of questioning and change, it should not be surprising that the attitudes and values of conservation professionals are in transition as well. Within many agencies and academic institutions, the traditional focus on game management (Geist et al. 2001) is giving way to an emphasis on biodiversity conservation, endangered species protection and ecosystem approaches to management. Changing professional values are reflected, to varying degrees, in changing curricula offered by academic departments in colleges and universities (Organ and Fritzell 2000) and in the changing management strategies of conservation organizations-non-governmental as well as state and federal agencies. Within many organizations and agencies, employees with more traditional-value perspectives often work alongside employees who possess non-traditional values, sometimes in an uneasy state of co-existence

Corporate and Hospital Profiteering in Emergency Medicine: Problems of the Past, Present, and Future.

BackgroundHealth care delivery in the United States has evolved in many ways over the past century, including the development of the specialty of Emergency Medicine (EM). With the creation of this specialty, many positive changes have occurred within hospital emergency departments (EDs) to improve access and quality of care of the nation's de facto "safety net." The specialty of EM has been further defined and held to high standards with regard to board certification, sub-specialization, maintenance of skills, and research. Despite these advances, problems remain.ObjectiveThis review discusses the history and evolution of for-profit corporate influence on EM, emergency physicians, finance, and demise of democratic group practice. The review also explores federal and state health care financing issues pertinent to EM and discusses potential solutions.DiscussionThe monopolistic growth of large corporate contract management groups and hospital ownership of vertically integrated physician groups has resulted in the elimination of many local democratic emergency physician groups. Potential downsides of this trend include unfair or unlawful termination of emergency physicians, restrictive covenants, quotas for productivity, admissions, testing, patient satisfaction, and the rising cost of health care. Other problems impact the financial outlook for EM and include falling federal, state, and private insurance reimbursement for emergency care, balance-billing, up-coding, unnecessary testing, and admissions.ConclusionsEmergency physicians should be aware of the many changes happening to the specialty and practice of EM resulting from corporate control, influence, and changing federal and state health care financing issues

Corporate and Hospital Profiteering in Emergency Medicine: Problems of the Past, Present, and Future.

BackgroundHealth care delivery in the United States has evolved in many ways over the past century, including the development of the specialty of Emergency Medicine (EM). With the creation of this specialty, many positive changes have occurred within hospital emergency departments (EDs) to improve access and quality of care of the nation's de facto "safety net." The specialty of EM has been further defined and held to high standards with regard to board certification, sub-specialization, maintenance of skills, and research. Despite these advances, problems remain.ObjectiveThis review discusses the history and evolution of for-profit corporate influence on EM, emergency physicians, finance, and demise of democratic group practice. The review also explores federal and state health care financing issues pertinent to EM and discusses potential solutions.DiscussionThe monopolistic growth of large corporate contract management groups and hospital ownership of vertically integrated physician groups has resulted in the elimination of many local democratic emergency physician groups. Potential downsides of this trend include unfair or unlawful termination of emergency physicians, restrictive covenants, quotas for productivity, admissions, testing, patient satisfaction, and the rising cost of health care. Other problems impact the financial outlook for EM and include falling federal, state, and private insurance reimbursement for emergency care, balance-billing, up-coding, unnecessary testing, and admissions.ConclusionsEmergency physicians should be aware of the many changes happening to the specialty and practice of EM resulting from corporate control, influence, and changing federal and state health care financing issues