Despite improvements in awareness and treatment of type II diabetes mellitus (TIIDM), this disease remains a major source of morbidity and mortality worldwide, and prevalence continues to rise. Oxidative damage caused by free radicals has long been known to contribute to the pathogenesis and progression of TIIDM and its complications. Only recently, however, has the role of the Nrf2/Keap1/ARE master antioxidant pathway in diabetic dysfunction begun to be elucidated. There is accumulating evidence that this pathway is implicated in diabetic damage to the pancreas, heart, and skin, among other cell types and tissues. Animal studies and clinical trials have shown promising results suggesting that activation of this pathway can delay or reverse some of these impairments in TIIDM. In this review, we outline the role of oxidative damage and the Nrf2/Keap1/ARE pathway in TIIDM, focusing on current and future efforts to utilize this relationship as a therapeutic target for prevention, prognosis, and treatment of TIID.

: The first facial transplantation in 2005 ushered in a new era in reconstructive surgery, offering new possibilities for the repair of severe disfigurements previously limited by conventional techniques. Advances in allograft design, computerized preoperative planning, surgical technique, and postoperative revisions have helped push the boundaries in this new frontier of vascularized composite allotransplantation. Over the past 12 years, 40 of these procedures have been performed across the world, offering the field the opportunity to reflect on current outcomes. Successes achieved in the brief history of facial transplantation have resulted in a new set of obstacles the field must now overcome. In this review, we aim to highlight the achievements, major challenges, and future directions of this rapidly evolving field.

Background: The incidence of nipple-sparing mastectomy is rising, but no single incision type has been proven to be superior. This study systematically evaluated the rate and efficacy of various nipple-sparing mastectomy incision locations, focusing on nipple-areola complex necrosis and reconstructive method. Methods: A systematic literature review was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines identifying studies on nipple-sparing mastectomy where incision type was described. Pooled descriptive statistics meta-analysis of overall (nipple-areola complex) necrosis rate and nipple-areola complex necrosis by incision type was performed. Results: Fifty-one studies (9975 nipple-sparing mastectomies) were included. Thirty-two incision variations were identified and categorized into one of six groups: inframammary fold, radial, periareolar, mastopexy/prior scar/reduction, endoscopic, and other. The most common incision types were inframammary fold [3634 nipple-sparing mastectomies (37.8 percent)] and radial [3575 nipple-sparing mastectomies (37.2 percent)]. Meta-analysis revealed an overall partial nipple-areola complex necrosis rate of 4.62 percent (95 percent CI, 3.14 to 6.37 percent) and a total nipple-areola complex necrosis rate of 2.49 percent (95 percent CI, 1.87 to 3.21 percent). Information on overall nipple-areola complex necrosis rate by incision type was available for 30 of 51 studies (4645 nipple-sparing mastectomies). Periareolar incision had the highest nipple-areola complex necrosis rate (18.10 percent). Endoscopic and mastopexy/prior scar/reduction incisions had the lowest rates of necrosis at 4.90 percent and 5.79 percent, respectively, followed by the inframammary fold incision (6.82 percent). The rate of single-stage implant reconstruction increased during this period. Conclusions: For nipple-sparing mastectomy, the periareolar incision maintains the highest necrosis rate because of disruption of the nipple-areola complex blood supply. The inframammary fold incision has become the most popular incision, demonstrating an acceptable complication profile.

Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.

Background: Cleft deformities of the lip and palate affect nearly one in 500 to 700 births, and lead to increased morbidity and mortality if untreated. Nevertheless, significant global disparities in access to timely and appropriate care still exist. The relatively basic infrastructure required to surgically correct these deformities and large unmet disease burden have resulted in a significant number of foundation-based cleft care initiatives focused on developing countries. In this study, the authors evaluate the peer-reviewed literature generated by these foundations in an attempt to assess their clinical, scientific, educational, and economic impact. Methods: A comprehensive review of the literature was performed using key search terms, and the level of evidence of identified articles was determined. Data were then analyzed to determine the different models of foundation-based cleft care in developing countries, and their clinical, scientific, educational, and economic impact. Results: A total of 244 articles were identified through the authors’ search and reviewed. Foundation-based cleft care initiatives in developing countries have significantly contributed to a better understanding of disease epidemiology, barriers to care, safety considerations, complications and outcomes, and international and local cleft surgery education. The cleft care center model is more cost-effective than the surgical mission model and provides more sustainable care. Conclusions: Foundation-based cleft care prevents significant morbidity in developing countries and has provided valuable resources for capacity building. The surgical mission model should be considered as a transitory conduit for establishing the more effective and sustainable cleft care center model of care.

Mesenchymal stem cells (MSCs) are known to both have powerful immunosuppressive properties and promote allograft tolerance. Determining the environmental oxygen tension and inflammatory conditions under which MSCs are optimally primed for this immunosuppressive function is essential to their utilization in promoting graft tolerance. Of particular interest is the mechanisms governing the interaction between MSCs and regulatory T cells (Tregs), which is relatively unknown. We performed our experiments utilizing rat bone marrow derived MSCs. We observed that priming MSCs in hypoxia promotes maintenance of stem-like characteristics, with greater expression of typical MSC cell-surface markers, increased proliferation, and maintenance of differentiation potential. Addition of autologous MSCs to CD4+/allogeneic endothelial cell (EC) co-culture increases regulatory T cell (Treg) proliferation, which is further enhanced when MSCs are primed in hypoxia. Furthermore, MSC-mediated Treg expansion does not require direct cell-cell contact. The expression of indolamine 2,3-dioxygenase, a mediator of MSC immunomodulation, increases when MSCs are primed in hypoxia, and inhibition of IDO significantly decreases the expansion of Tregs. Priming with inflammatory cytokines IFNγ and TNFα increases also expression of markers associated with MSC immunomodulatory function, but decreases MSC proliferation. The expression of IDO also increases when MSCs are primed with inflammatory cytokines. However, there is no increase in Treg expansion when MSCs are primed with IFNγ, suggesting an alternate mechanism for inflammatory-stimulated MSC immunomodulation. Overall, these results suggest that MSCs primed in hypoxia or inflammatory conditions are optimally primed for immunosuppressive function. These results provide a clearer picture of how to enhance MSC immunomodulation for clinical use.

The latent transforming growth factor (TGF) β binding proteins (LTBP) are crucial mediators of TGFβ function, as they control growth factor secretion, matrix deposition, presentation and activation. Deficiencies in specific LTBP isoforms yield discrete phenotypes representing defects in bone, lung and cardiovascular development mediated by loss of TGFβ signaling. Additional phenotypes represent loss of unique TGFβ-independent features of LTBP effects on elastogenesis and microfibril assembly. Thus, the LTBPs act as sensors for the regulation of both growth factor activity and matrix function.

Background: Marko Godina, in his landmark paper in 1986, established the principle of early flap coverage for reconstruction of traumatic lower extremity injuries. The aim of this study was to determine how timing influences outcomes in lower extremity traumatic free flap reconstruction based on Godina’s original findings. Methods: A retrospective review identified 358 soft-tissue free flaps from 1979 to 2016 for below knee trauma performed within 1 year of injury. Patients were stratified based on timing of coverage: 3 days or less (early), 4 to 90 days (delayed), and more than 90 days (late). The delayed group was further divided into two groups: 4 to 9 days and 10 to 90 days. Flap outcomes were examined based on timing of reconstruction. Results: Flaps performed within 3 days after injury compared with between 4 to 90 days had decreased risk of major complications (OR, 0.40, p = 0.04). A receiver operating curve demonstrated day 10 to be the optimal day for predicting flap success. Flaps performed less than or equal to 3 days versus 4 to 9 days had no differences in any flap outcomes. In contrast, flaps performed within 4 to 9 days of injury compared to within 10 to 90 days were associated with significantly lower total flap failure rates (relative risk, 0.29, p = 0.025) and major complications (relative risk, 0.37, p = 0.002). Conclusions: Early free flap reconstruction performed within 3 days of injury had superior outcomes compared with the delayed (4 to 90 day) group, consistent with Godina’s original findings. However, as an update to his paradigm, this ideal early period of reconstruction can be safely extended to within 10 days of injury without an adverse effect on outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.