Equity under the knife: justice and evidence in surgery.

Surgery is an increasingly common and expensive mode of medical intervention. The ethical dimensions of the surgeon-patient relationship including respect for personal autonomy and informed consent are much discussed, but broader equity issues have not received the same attention. This paper extends the understanding of surgical ethics by considering the nature of evidence in surgery and its relationship to a just provision of healthcare for individuals and their populations. Keywords: Surgery; Equity; Justice; Evidence; Health technology assessments; Public health ethic

Understanding Corporate Responsibility: Culture and Complicity

Kipnis's fictional account of the televised treatment of Elaine Robbins clearly shows the surgeon's negligence (Kipnis 2011). The problems with Anodyne's support for the telesurgery breakfast are harder to discern, but show up clearly when we take into consideration how surgical evidence is generated, evaluated, and used by surgeons. Current evidentiary practices in surgery have two major weaknesses, related to the epistemic culture of surgery and to practices of knowledge transmission. We argue that this is a systemic problem, which companies such as Anodyne both contribute to and benefit from. Thus, while we agree with Kipnis's claim that Anodyne is complicit in creating “conditions of danger,” we believe that Anodyne's contributory roles extend beyond creating moral hazards for susceptible surgeons and harms for individual patients. The Epistemic Culture of Surgery By the epistemic culture of surgery, we mean the traditions and practices surrounding the generation, transmission, and uptake of new knowledge in surgery. The traditional research-totreatment pathway starts with a series of clinical trials to test the safety and efficacy of a new drug or device. Such research results are communicated to practitioners via publications in reputable peer-reviewed journals, and used by regulatory bodies such as the U.S. Food and Drug Administration in decisions about whether to approve use of the novel treatment. For several reasons this ideal pathway does not function well in surgery

Equity under the knife: justice and evidence in surgery.

Surgery is an increasingly common and expensive mode of medical intervention. The ethical dimensions of the surgeon-patient relationship including respect for personal autonomy and informed consent are much discussed, but broader equity issues have not received the same attention. This paper extends the understanding of surgical ethics by considering the nature of evidence in surgery and its relationship to a just provision of healthcare for individuals and their populations. Keywords: Surgery; Equity; Justice; Evidence; Health technology assessments; Public health ethic

Understanding Corporate Responsibility: Culture and Complicity

Kipnis's fictional account of the televised treatment of Elaine Robbins clearly shows the surgeon's negligence (Kipnis 2011). The problems with Anodyne's support for the telesurgery breakfast are harder to discern, but show up clearly when we take into consideration how surgical evidence is generated, evaluated, and used by surgeons. Current evidentiary practices in surgery have two major weaknesses, related to the epistemic culture of surgery and to practices of knowledge transmission. We argue that this is a systemic problem, which companies such as Anodyne both contribute to and benefit from. Thus, while we agree with Kipnis's claim that Anodyne is complicit in creating “conditions of danger,” we believe that Anodyne's contributory roles extend beyond creating moral hazards for susceptible surgeons and harms for individual patients. The Epistemic Culture of Surgery By the epistemic culture of surgery, we mean the traditions and practices surrounding the generation, transmission, and uptake of new knowledge in surgery. The traditional research-totreatment pathway starts with a series of clinical trials to test the safety and efficacy of a new drug or device. Such research results are communicated to practitioners via publications in reputable peer-reviewed journals, and used by regulatory bodies such as the U.S. Food and Drug Administration in decisions about whether to approve use of the novel treatment. For several reasons this ideal pathway does not function well in surgery

An investigation into the role of matrix metalloproteinases in matrix remodelling and contraction by Dupuytren's fibroblasts.

Dupuytren's disease is a common fibroproliferative condition of the hand that results in disability through progressive digital contracture. Despite advances in operative technique, recurrence remains an unsolved problem. The matrix metalloproteases (MMPs) are a large family of proteolytic enzymes that have been shown to play a critical role in cell-mediated collagen contraction and tissue scarring. The aim of this project was to investigate the effect of ilomastat, a broad-spectrum MMP inhibitor, on matrix contraction and remodelling by Dupuytren's fibroblasts in vitro. Paired nodule and cord-derived fibroblasts were isolated by explant culture from five Dupuytren's patients, carpal ligament fibroblasts acted as the control. We employed two different in vitro models to assess the effect of ilomastat on contraction and remodelling by each cell population. A stress-release fibroblast populated collagen lattice (FPCL) model was employed to assess collagen contraction. Generation of mechanical tension was determined using a culture force monitor (CFM). Following dynamic force generation, treatment with cytochalasin-D was used to assess residual matrix tension (RMT) in the collagen lattice, allowing quantification of matrix remodelling. The expression of a range of MMPs (MMP-1, MMP-2, MT1-MMP) and Tissue Inhibitors of Metalloproteinases (TIMP-1, TIMP-2), was established by RT-PCR. Protein levels and enzyme activity were assessed by western blotting, zymography and ELISA. In the FPCL model, ilomastat significantly (p<0.01) inhibited contraction by all tissue-derived fibroblasts at 100uM. In the CFM model, ilomastat significantly reduced force development by cord and nodule-derived fibroblasts (p<0.01), but did not significantly affect RMT. In both models, treatment with ilomastat suppressed activity of MMP-1 and MMP-2, however gene expression and levels of secreted protein were unaffected. Conversely, the expression and activity of MT1-MMP was upregulated in response to ilomastat, whereas, TIMP-1 and TIMP-2 were unaffected. Our findings demonstrate an important role for MMP activity in matrix processing and organisation by Dupuytren's fibroblasts in vitro and suggest that inhibition of MMP activity may well provide a means of controlling or reducing contracture in vivo, by reducing fibroblast-mediated matrix contraction and remodelling

Successful Strategies for Discharging Medicaid Nursing Home Residents with Mental Health Diagnoses to the Community

The state and federal push to transition Medicaid residents from nursing homes to the community calls for effective discharge strategies targeted to residents’ diverse needs. This exploratory, mixed-methods study utilized the Minimum Data Set to describe demographics, health characteristics, and transition patterns of Kansas Medicaid residents with mental health diagnoses who were discharged from nursing homes from 2005 to 2008. Discharged residents (n = 720) had multiple comorbidities, and more than half remained in the community following their first nursing home event. In-depth interviews with nursing home staff (n = 11) explored successful discharge strategies. Successful strategies support an ecological approach to meeting individual, family, organizational, and community needs. This includes creating/sustaining a culture of discharge, encompassing informal and formal community supports in the discharge process, proactively addressing physical environment needs, and assisting individuals and their family members in managing physical and mental health conditions. Findings suggest that policies in the areas of preadmission screening, caregiver support, and revised Medicaid reimbursement are needed to better support continuity of care and promote discharge for nursing home residents with complex care needs. Future research could examine individual and family perspectives on the discharge process and track outcomes when transitioning between settings

The Role of Oxygen Sensors, Hydroxylases, and HIF in Cardiac Function and Disease

Ischemic heart disease is the leading cause of death worldwide. Oxygen-sensing proteins are critical components of the physiological response to hypoxia and reperfusion injury, but the role of oxygen and oxygen-mediated effects is complex in that they can be cardioprotective or deleterious to the cardiac tissue. Over 200 oxygen-sensing proteins mediate the effects of oxygen tension and use oxygen as a substrate for posttranslational modification of other proteins. Hydroxylases are an essential component of these oxygen-sensing proteins. While a major role of hydroxylases is regulating the transcription factor HIF, we investigate the increasing scope of hydroxylase substrates. This review discusses the importance of oxygen-mediated effects in the heart as well as how the field of oxygen-sensing proteins is expanding, providing a more complete picture into how these enzymes play a multifaceted role in cardiac function and disease. We also review how oxygen-sensing proteins and hydroxylase function could prove to be invaluable in drug design and therapeutic targets for heart disease

MicroRNAs 1, 133, and 206: Critical factors of skeletal and cardiac muscle development, function, and disease

microRNAs (miRNAs) are a class of highly conserved small non-coding RNAs that negatively regulate gene expression post-transcriptionally. miRNAs are known to mediate myriad cell processes, including proliferation, differentiation, and apoptosis. With more than 600 miRNAs identified in humans, it is generally believed that many miRNAs function through simultaneously inhibiting multiple regulatory mRNA targets, suggesting that miRNAs participate in regulating the expression of many, if not all, genes. While many miRNAs are expressed ubiquitously, some are expressed in a tissue specific manner. The muscle specific miR-1, miR-133 and miR-206 are perhaps the most studied and best characterized miRNAs to date. Many studies demonstrate that these miRNAs are necessary for proper skeletal and cardiac muscle development and function, and have a profound influence on multiple myopathies, such as hypertrophy, dystrophy, and conduction defects

Sent to Destroy: The Ubiquitin Proteasome System Regulates Cell Signaling and Protein Quality Control in Cardiovascular Development and Disease

The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible due to their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative “specific” mechanisms. The cytosolic receptors p62, NBR, and HDAC6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of “selective autophagy”. Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the cross-talk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease

The Ubiquitin Ligase ASB4 Promotes Trophoblast Differentiation through the Degradation of ID2

Vascularization of the placenta is a critical developmental process that ensures fetal viability. Although the vascular health of the placenta affects both maternal and fetal well being, relatively little is known about the early stages of placental vascular development. The ubiquitin ligase Ankyrin repeat, SOCS box-containing 4 (ASB4) promotes embryonic stem cell differentiation to vascular lineages and is highly expressed early in placental development. The transcriptional regulator Inhibitor of DNA binding 2 (ID2) negatively regulates vascular differentiation during development and is a target of many ubiquitin ligases. Due to their overlapping spatiotemporal expression pattern in the placenta and contrasting effects on vascular differentiation, we investigated whether ASB4 regulates ID2 through its ligase activity in the placenta and whether this activity mediates vascular differentiation. In mouse placentas, ASB4 expression is restricted to a subset of cells that express both stem cell and endothelial markers. Placentas that lack Asb4 display immature vascular patterning and retain expression of placental progenitor markers, including ID2 expression. Using JAR placental cells, we determined that ASB4 ubiquitinates and represses ID2 expression in a proteasome-dependent fashion. Expression of ASB4 in JAR cells and primary isolated trophoblast stem cells promotes the expression of differentiation markers. In functional endothelial co-culture assays, JAR cells ectopically expressing ASB4 increased endothelial cell turnover and stabilized endothelial tube formation, both of which are hallmarks of vascular differentiation within the placenta. Co-transfection of a degradation-resistant Id2 mutant with Asb4 inhibits both differentiation and functional responses. Lastly, deletion of Asb4 in mice induces a pathology that phenocopies human pre-eclampsia, including hypertension and proteinuria in late-stage pregnant females. These results indicate that ASB4 mediates vascular differentiation in the placenta via its degradation of ID2