Adenosine A2A receptor plays an important role in radiation-induced dermal injury.

Ionizing radiation is a common therapeutic modality and following irradiation dermal changes, including fibrosis and atrophy, may lead to permanent changes. We have previously demonstrated that occupancy of A2A receptor (A2AR) stimulates collagen production, so we determined whether blockade or deletion of A2AR could prevent radiation-induced fibrosis. After targeted irradiation (40 Gy) of the skin of wild-type (WT) or A2AR knockout (A2ARKO) mice, the A2AR antagonist ZM241385 was applied daily for 28 d. In irradiated WT mice treated with the A2AR antagonist, there was a marked reduction in collagen content and skin thickness, and ZM241385 treatment reduced the number of myofibroblasts and angiogenesis. After irradiation, there is an increase in loosely packed collagen fibrils, which is significantly diminished by ZM241385. Irradiation also induced an increase in epidermal thickness, prevented by ZM241385, by increasing the number of proliferating keratinocytes. Similarly, in A2ARKO mice, the changes in collagen alignment, skin thickness, myofibroblast content, angiogenesis, and epidermal hyperplasia were markedly reduced following irradiation. Radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2ARKO mice. Radiation therapy is administered to a significant number of patients with cancer, and radiation reactions may limit this therapeutic modality. Our findings suggest that topical application of an A2AR antagonist prevents radiation dermatitis and may be useful in the prevention or amelioration of radiation changes in the skin.

Isolated Scaphoid Dislocation From Low-Energy Wrist Trauma.

Isolated scaphoid dislocation is an extremely rare injury typically caused by high-energy trauma. We present the first observed case of isolated scaphoid dislocation resulting from a non-traumatic injury of the wrist in power-grip tension in a patient with a questionable history of Marfan Syndrome. A 20-year-old right-hand dominant man presented to the emergency department with right wrist pain and deformation after carrying a table. The patient reported a possible history of Marfan Syndrome, but it had never been definitively diagnosed. Imaging revealed radial dislocation of the scaphoid. Bedside closed reduction was performed followed by outpatient ligament reconstruction with return to normal activities at 6 months. Early diagnosis and management lead to an improved prognosis for isolated scaphoid dislocation. Regardless of patient history or mechanism of injury, treatment options include closed reduction, percutaneous fixation, and/or open reduction with internal fixation and ligamentous reconstruction.

Pyoderma Gangrenosum after Fat Grafting in Alloplastic Breast Reconstruction: An Unusual Outcome.

Pyoderma gangrenosum (PG) is a rare and painful inflammatory skin disorder that has been recently associated with breast surgery. It is commonly mistaken for postoperative ischemia or wound infection and does not show response to antibiotics or debridement. We describe the first case of post-surgical PG (PSPG) after alloplastic breast reconstruction involving fat grafting. A 47-year-old woman underwent bilateral mastectomy and 2-stage alloplastic breast reconstruction, with fat grafting from the abdomen. Two days post-surgery, she developed bilateral erythema with tender grouped pustules that progressed rapidly into necrotic ulcerations. She did not respond to antibiotics and serial debridement. Subsequent biopsy confirmed a diagnosis of PG. She was started on steroid therapy and responded well. She was discharged on a steroid regimen, local wound care, and eventually a T-cell inhibitor. Over the next 12 months, her wounds healed without surgical intervention. PSPG has been observed in a variety of reconstructive breast surgeries, but never reported in the setting of fat grafting. As PG involves subcutaneous fat, fat grafting may accelerate and exacerbate the course of disease. Treatment for PSPG includes systemic steroid therapy or other immunomodulatory agents (or both). Surgical management remains controversial, as serial debridement and reconstruction have shown to exacerbate and stimulate disease progression. A long-term follow-up is recommended to monitor for wound healing. Delayed diagnosis of PG in breast reconstruction patients can lead to severe morbidity and disfigurement. This is first case of PSPG following fat grafting in the literature.

Ex Vivo Major Histocompatibility Complex I Knockdown Prolongs Rejection-free Allograft Survival.

BACKGROUND: Widespread application of vascularized composite allotransplantation (VCA) is currently limited by the required lifelong systemic immunosuppression and its associated morbidity and mortality. This study evaluated the efficacy of ex vivo (after procurement but before transplantation) engineering of allografts using small interfering RNA to knockdown major histocompatibility complex I (MHC-I) and prolong rejection-free survival. METHODS: Endothelial cells (ECs) were transfected with small interfering RNA targeted against MHC-I (siMHC-I) for all in vitro experiments. MHC-I surface expression and knockdown duration were evaluated using quantitative polymerase chain reaction (qPCR) and flow cytometry. After stimulating Lewis recipient cytotoxic lymphocytes (CTL) with allogeneic controls or siMHC-I-silenced ECs, lymphocyte proliferation, CTL-mediated and natural killer-mediated EC lysis were measured. Using an established VCA rat model, allografts were perfused ex vivo with siMHC-I before transplantation. Allografts were analyzed for MHC-I expression and clinical/histologic evidence of rejection. RESULTS: Treatment with siMHC-I resulted in 80% knockdown of mRNA and 87% reduction in cell surface expression for up to 7 days in vitro (P < 0.05). Treatment of ECs with siMHC-I reduced lymphocyte proliferation and CTL-mediated cytotoxicity (77% and 50%, respectively, P < 0.01), without increasing natural killer-mediated cytotoxicity (P = 0.66). In a rat VCA model, ex vivo perfusion with siMHC-I reduced expression in all tissue compartments by at least 50% (P < 0.05). Knockdown prolonged rejection-free survival by 60% compared with nonsense-treated controls (P < 0.05). CONCLUSIONS: Ex vivo siMHC-I engineering can effectively modify allografts and significantly prolong rejection-free allograft survival. This novel approach may help reduce future systemic immunosuppression requirements in VCA recipients.

Restoration of Nrf2 Signaling Normalizes the Regenerative Niche.

Chronic hyperglycemia impairs intracellular redox homeostasis and contributes to impaired diabetic tissue regeneration. The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system, and its dysfunction has been implicated in numerous pathologies. Here we characterize the effect of chronic hyperglycemia on Nrf2 signaling within a diabetic cutaneous regeneration model. We characterized the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous wound regeneration. We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor Keap1 and the subsequent changes in Nrf2 signaling. We also developed a topical small interfering RNA (siRNA)-based therapy to restore redox homeostasis within diabetic wounds. Western blotting demonstrated that chronic hyperglycemia-associated oxidative stress inhibits nuclear translocation of Nrf2 and impairs activation of antioxidant genes, thus contributing to ROS accumulation. Keap1 inhibition increased Nrf2 nuclear translocation, increased antioxidant gene expression, and reduced ROS production to normoglycemic levels, both in vitro and in vivo. Topical siKeap1 therapy resulted in improved regenerative capacity of diabetic wounds and accelerated closure. We report that chronic hyperglycemia weakens the endogenous antioxidant response, and the consequences of this defect are manifested by intracellular redox dysregulation, which can be restored by Keap1 inhibition. Targeted siRNA-based therapy represents a novel, efficacious strategy to reestablish redox homeostasis and accelerate diabetic cutaneous tissue regeneration.