Faculty Bibliography

BACKGROUND:Statins, an example of the most commonly prescribed medications to the elderly, are not without side effects. Dermatologic events are often overlooked as arising from medications, particularly those which are taken chronically. Moreover, elderly patients are prone to pharmacologic interactions due to multiple medications. In this report, we describe a case of a statin-induced eczematous dermatitis with a psoriasis-like clinical presentation and review the skin manifestations that may arise from statin therapy. CASE PRESENTATION/METHODS:An 82-year-old man with gout and hypercholesterolemia presented to dermatology clinic with new onset of pruritic, scaly erythematous plaques bilaterally on the extensor surfaces of his arms. He had never had similar lesions before. Despite various topical and systemic treatments over several months, the rash continued to evolve. The patient was then advised to discontinue his long-term statin, which led to gradual resolution of his symptoms. He was subsequently diagnosed with statin-induced eczematous dermatitis. CONCLUSIONS:This case report describes an adverse cutaneous reaction to statins that is rarely reported in the literature. Medications, including longstanding therapies, should be suspected in cases of refractory dermatologic lesions.

PURPOSE OF REVIEW/OBJECTIVE:The applications for extracorporeal membrane oxygenation for lung support are constantly evolving. This review highlights fundamental concepts in extracorporeal lung support and describes directions for future research. RECENT FINDINGS/RESULTS:Since the 1950s, extracorporeal lung support has experienced continuous advancements in circuit design and safety in acute respiratory distress syndrome, chronic obstructive pulmonary disease exacerbations, as a bridge to transplantation, intraoperative cardiopulmonary support, and for transportation to referral centers. Patients on extracorporeal membrane oxygenation are now capable of being awake, extubated, and ambulatory for accelerated recovery or optimization for transplantation. SUMMARY/CONCLUSIONS:Extracorporeal lung support is a safe and an easily implemented intervention for refractory respiratory failure. Recent advances have extended its use beyond acute illnesses and the developments for chronic support will facilitate the development of durable devices and possible artificial lung development.

OBJECTIVE:To determine whether a surgical interest group run entirely by preclinical students can influence medical students to enter general surgery residency programs. DESIGN/METHODS:Matriculation rates into general surgery and affiliated subspecialties from Columbia University College of Physicians and Surgeons residency match lists were compared to National Residency Match Program data for all U.S. senior students from 2006 to 2014. SETTING/METHODS:The Columbia University College of Physicians and Surgeons. RESULTS:After establishing the interest group, entrance rates into general surgery programs tripled from the early 2000s to more than 12% of 2006 Columbia University College of Physicians and Surgeons graduates. After 8 years, our data illustrate sustained results, with more than 8% of students entering surgical residencies, significantly higher than the National Residency Match Program's average (p < 0.025). CONCLUSIONS:Surgical interest groups spark early and lasting interest in surgery that may influence residency decisions. Moreover, these programs can be successfully run entirely by preclinical students and implemented in other institutions.

The occurrence of acute kidney injury (AKI) following aortic valve replacement (AVR) has very serious clinical implications and has therefore been the focus of several studies. The authors report the results of previous studies evaluating both transcatheter AVR (TAVR) and indirectly surgical AVR (SAVR) through looking at cardiopulmonary bypass (CPB) cardiac surgeries, and identify the incidence, predictors and outcomes of AKI following AVR. In most studies, AKI was defined using the Risk, Injury, Failure, Loss and End Stage, Valve Academic Research Consortium (modified Risk, Injury, Failure, Loss and End Stage) or Valve Academic Research Consortium-2 (Acute Kidney Injury Network) AKI classification criteria. Twelve studies including more than 90,000 patients undergoing cardiac surgery on CPB were considered as well as 26 studies with more than 6000 patients undergoing TAVR. Depending on the definition used, AKI occurred in 3.4-43% of SAVR cases with up to 2.5% requiring dialysis, and in 3.4-57% of TAVR cases. Factors identified as independent predictors of AKI were: baseline kidney failure, EUROSCORE, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, anemia, peripheral vascular disease, heart failure, surgical priority, CPB time, reoperation, use of intra-aortic balloon pump, need for re-exploration, contrast agent volume, transapical access, blood transfusion, postoperative thrombocytopenia, postoperative leukocytosis as well as demographic variables such as age and female gender. The 30-day mortality rate for patients with AKI following SAVR ranged from 5.5 to 46% and was 3- to 16-times higher than in those without AKI. Similarly, patients who developed AKI after TAVR had a mortality rate of 7.8-29%, which was two- to eight-times higher than those who did not suffer from AKI. AKI confers up to a fourfold increase in 1-year mortality. Finally, hospital length of stay was significantly increased in patients with AKI in both SAVR and TAVR groups, with increases up to 3- and 2.5-times, respectively.

A recent revival of global interest for reconstruction of long-segment tracheal defects, which represents one of the most interesting and complex problems in head and neck and thoracic reconstructive surgery, has been witnessed. The trachea functions as a conduit for air, and its subunits including the epithelial layer, hyaline cartilage, and segmental blood supply make it particularly challenging to reconstruct. A myriad of attempts at replacing the trachea have been described. These along with the anatomy, indications, and approaches including microsurgical tracheal reconstruction will be reviewed. Novel techniques such as tissue-engineering approaches will also be discussed. Multiple attempts at replacing the trachea with synthetic scaffolds have been met with failure. The main lesson learned from such failures is that the trachea must not be treated as a "simple tube." Understanding the anatomy, developmental biology, physiology, and diseases affecting the trachea are required for solving this problem.

Tracheal transplantation with a long-segment recellularized tracheal allograft has previously been performed without the need for immunosuppressive therapy. Recipients' mesenchymal stromal cells (MSC) and tracheal epithelial cells (TEC) were harvested, cultured, expanded, and seeded on a donor trachea within a bioreactor. Prior techniques used for cellular seeding have involved only static-seeding methods. Here, we describe a novel bioreactor for recellularization of long-segment tracheae. Tracheae were recellularized with epithelial cells on the luminal surface and bone marrow-derived MSC on the external surface. We used dynamic perfusion seeding for both cell types and demonstrate an increase in both cellular counts and homogeneity scores compared with traditional methods. Despite these improvements, orthotopic transplantation of these scaffolds revealed no labeled cells at postoperative day 3 and lack of re-epithelialization within the first 2 weeks. The animals in this study had postoperative respiratory distress and tracheal collapse that was incompatible with life.

PURPOSE/OBJECTIVE:Organ cold storage and subsequent transplantation are associated with significant ischemia-reperfusion injury, leading to cell death, graft inflammation and decreased graft function. MATERIALS AND METHODS/METHODS:CORM-3s reduce oxidative stress and prevent inflammation in kidneys stored at 4C and subsequently transplanted. Graft survival and function are markedly improved compared to kidneys preserved and stored in University of Wisconsin solution alone. We determined whether CORM-3 has direct antiapoptotic effects on in vitro preparations of human HUVECs exposed to anoxic conditions. We also determined whether direct administration of CORM-3 to renal grafts before and/or after cold storage would prevent renal damage during the transplantation process. RESULTS:CORM-3 supplementation led to a significantly increased frequency of live cells (mean ± SD 72.3% ± 1.9%, p <0.01), reduced apoptosis (14.9% ± 6.1%, p <0.01) and decreased mitochondrial transmembrane potential (40.2% ± 7.2%, p <0.05) in HUVECs exposed to 20 hours of cold storage compared to controls (11.6% ± 3.5%, 82.2% ± 2.3% and 78.2% ± 3.2%, respectively). In keeping with this antiapoptotic effect CORM-3 supplementation led to a mean 7.4 ± 2.1-fold up-regulation in Bcl-2 gene expression. CORM-3 supplementation in standard preservation solution was most beneficial at initial ischemic injury and before cold storage exposure. However, additional reflushing before vascular reperfusion showed an additive benefit to graft survival and function after transplantation. This was confirmed by decreased glomerular and tubular necrosis, and apoptosis in double flushed grafts. CONCLUSIONS:CORM-3 supplementation in standard University of Wisconsin solution has a significant impact on decreasing cellular and graft injury, and improving survival through its antiapoptotic effects, which are likely mediated through mitochondrial membrane stabilization.

Tracheal transplantation without immunosuppressive therapy has been accomplished with a tissue-engineering approach using decellularized biological scaffolds in combination with recipient progenitor cells. The mechanisms of immune response directed towards these tracheal allografts have not been fully determined. In this study, we evaluated the immunogenicity of these grafts at the protein level, and functionally, in vitro and in vivo in a large animal model. Long-segment circumferential tracheal allografts were decellularized using two different protocols and recellularized using recipient mesenchymal stromal cells (MSC) and tracheal epithelial progenitor cells (TEC). Residual MHCI and MHCII immunostaining was found surrounding the submucosal glands despite cyclical decellularization. In an in vitro lymphocyte proliferation assay, CD4+ T cells continued to proliferate on decellularized pieces and this proliferation was inhibited by co-culture with autologous MSC. Allografts were heterotopically transplanted under a muscle flap in the neck of the recipients and decellularization was found to delay leukocyte infiltration but resulted in eventual cartilage degradation. Recellularization prevented this infiltration up to 3 weeks post-transplantation and allowed for preservation of the cartilage. The immune cells found within these grafts included a significant number of CD4+CD25+Foxp3+ regulatory T cells. Furthermore, gene expression of anti-inflammatory cytokines, such as IL-10 and TGF-β1, involved in proliferation, differentiation and function of regulatory T cells was found in these grafts. These results indicate that the immunological modification induced by recellularized tracheal scaffolds is an active process involving the recruitment of immunosuppressive cells, rather than simply the removal of donor-derived antigenic components.

Tracheal reconstruction is indicated in cases of malignancy, traumatic injury, and subglottic or tracheal stenosis. Recent progress in airway transplantation has provided renewed optimism for potential solutions for defects involving more than half of the tracheal length in adults or one-third of the tracheal length in children. Biologic scaffolds derived from decellularized tissues and organs have shown great promise in tracheal allotransplantation, and cyclical decellularization techniques have been hypothesized as abrogating the need for immunosuppressive therapy. In this study, we performed a direct comparison of three decellularization protocols (Protocols A, B, and C) previously described in the literature, two of which were described in tracheal tissue (Protocols A and B). We concentrated on the immunogenicity within the epithelium and mucosa, quantified and qualified the extracellular matrix (ECM) components, and performed compliance measurements on large circumferential decellularized tracheal scaffolds following cyclical decellularization techniques using all three protocols. Quantitative measurements of glycosaminoglycans (GAGs) showed a significant decrease in the mucosal component following 17 cycles of all 3 protocols as well as a significant decrease of GAGs in the cartilaginous component following cycles 1, 9, and 17 of Protocol A and cycle 17 of Protocol C. Compliance measurements were also shown to be different between the protocols, with grafts becoming more compliant at physiologic pressures after cyclical decellularization with Protocols A and B and slightly less compliant but remaining similar to native trachea using Protocol C. Positive staining for anti-major histocompatibility complex Class I (anti-MHCI) and anti-MHCII remained within the submucosal glandular components despite multiple cycles of decellularization using all three protocols. This study illustrated that there are significant differences in ECM composition and resultant structural integrity of decellularized tracheal scaffolds depending on the decellularization protocol. Protocol B was shown to maintain the GAGs components despite an increase in tracheal compliance, while Protocol C decreases GAGs components following multiple cycles, despite showing a tracheal compliance resembling that of the native trachea at physiologic airway pressures.