Thrombolytic Salvage of Threatened Frostbitten Extremities and Digits: A Systematic Review.

Frostbite is a cold injury that results in soft tissue loss and can lead to amputation. Vascular thrombosis following injury causes ischemic tissue damage. Despite understanding the pathology, its treatment has remained largely unchanged for over 30 years. Threatened extremities may be salvaged with thrombolytics to restore perfusion. The authors performed a systematic review to determine whether thrombolytic therapy is effective and to identify patients who may benefit from this treatment. The Pubmed, EBSCO, and Google Scholar databases were queried using the key words "thrombolytics," "frostbite," "fibrinolytics," and "tPA." Studies written after 1990 in English met inclusion criteria. Exclusion criteria were failure to delineate anatomic parts injured, failure to report number of limbs salvaged, animal studies, and non-English language publications. Thrombolytic therapy was defined as administration of tPA, alteplase, urokinase, or streptokinase. Forty-two studies were identified and 17 included. Included were 1 randomized trial, 10 retrospective studies, 2 case series, and 4 case reports. One thousand eight hundred and forty-four limbs and digits in 325 patients were studied and 216 patients treated with thrombolytics and 346 amputations performed. The most common means of thrombolysis was intra-arterial tPA. The most common duration of therapy was 48 hours. Limb salvage rates ranged from 0% to 100% with a weighted average of 78.7%. Thrombolytics are a safe and effective treatment of severe frostbite. They represent the first significant advancement in frostbite treatment by preventing otherwise inevitable amputations warranting both greater utilization and further research to clarify the ideal thrombolytic protocol.

Vimentin expression is required for the development of EMT-related renal fibrosis following unilateral ureteral obstruction in mice.

Most renal transplants ultimately fail secondary to chronic allograft nephropathy (CAN). Vimentin (vim) is a member of the intermediate filament family of proteins and has been shown to be important in the development of CAN. One of the pathways leading to chronic renal fibrosis after transplant is thought to be epithelial to mesenchymal transition (EMT). Even though vim expression is one of the main steps of EMT, it is unknown whether vim expression is required for EMT leading to renal fibrosis and allograft loss. To this end, the role of vim in renal fibrosis was determined via unilateral ureteral obstruction (UUO) in vim knockout mice (129 svs6 vim -/-). Following UUO, kidneys were recovered and analyzed via Western blotting, immunofluorescence, and transcriptomics. Cultured human proximal renal tubular (HK-2) cells were subjected to lentiviral-driven inhibition of vim expression and then treated with transforming growth factor (TGF)-ß to undergo EMT. Immunoblotting as well as wound healing assays were used to determine development of EMT. Western blotting analyses of mice undergoing UUO reveal increased levels of vim soon after UUO. As expected, interstitial collagen deposition increased in control mice following UUO but decreased in vim -/- kidneys. Immunofluorescence analyses also revealed altered localization of ß-catenin in vim -/- mice undergoing UUO without significant changes in mRNA levels. However, RNA sequencing revealed a decrease in ß-catenin-dependent genes in vim -/- kidneys. Finally, vim-silenced HK-2 cell lines undergoing EMT were shown to have decreased cellular migration during wound healing. We conclude that vim inhibition decreases fibrosis following UUO by possibly altering ß-catenin localization and downstream signaling.