The polyether ionophore salinomycin targets multiple cellular pathways to block proliferative vitreoretinopathy pathology.

Proliferative vitreoretinopathy (PVR) is characterized by membranes that form in the vitreous cavity and on both surfaces of the retina, which results in the formation of tractional membranes that can cause retinal detachment and intrinsic fibrosis of the retina, leading to retina foreshortening. Currently, there are no pharmacologic therapies that are effective in inhibiting or preventing PVR formation. One of the key aspects of PVR pathogenesis is retinal pigment epithelial (RPE) cell epithelial mesenchymal transition (EMT). Here we show that the polyether ionophore compound salinomycin (SNC) effectively inhibits TGFß-induced EMT of RPE cells. SNC blocks the activation of TGFß-induced downstream targets alpha smooth muscle actin (αSMA) and collagen 1 (Col1A1). Additionally, SNC inhibits TGFß-induced RPE cell migration and contraction. We show that SNC functions to inhibit RPE EMT by targeting both the pTAK1/p38 and Smad2 signaling pathways upon TGFß stimulation. Additionally, SNC is able to inhibit αSMA and Col1A1 expression in RPE cells that have already undergone TGFß-induced EMT. Together, these results suggest that SNC could be an effective therapeutic compound in both the prevention and treatment of PVR.

Antibody-mediated inhibition of EGFR reduces phosphate excretion and induces hyperphosphatemia and mild hypomagnesemia in mice.

Monoclonal antibody therapies targeting the EGF receptor (EGFR) frequently result in hypomagnesemia in human patients. In contrast, EGFR tyrosine kinase inhibitors do not affect Mg2+ balance in patients and only have a mild effect on Mg2+ homeostasis in rodents at elevated doses. EGF has also been shown to affect phosphate (Pi) transport in rat and rabbit proximal convoluted tubules (PCT), but evidence from studies targeting EGFR and looking at Pi excretion in whole animals is still missing. Thus, the role of EGF in regulating reabsorption of Mg2+ and/or Pi in the kidney remains controversial. Here, we inject mice with the anti-EGFR monoclonal antibody ME-1 for 2 weeks and observe a significant increase in serum Pi and mild hypomagnesemia, but no changes in Pi or Mg2+ excretion. In contrast, a single injection of ME-1 resulted in hyperphosphatemia and a significant reduction in Pi excretion 2 days after treatment, while no changes in serum Mg2+ or Mg2+ excretion were observed. Dietary Mg2+ deprivation is known to trigger a rapid Mg2+ conservation response in addition to hyperphosphatemia and hyperphosphaturia. Interestingly, one dose of ME-1 did not significantly modify the response of mice to 2 days of Mg2+ deprivation. These data show that EGFR plays a significant role in regulating Pi reabsorption in the kidney PCT, but suggest only a minor role in long-term regulation of Mg2+ transport in the distal convoluted tubule.

Hyperbaric programs in the United States: Locations and capabilities of treating decompression sickness, arterial gas embolisms, and acute carbon monoxide poisoning: survey results.

Hyperbaric oxygen therapy is the primary treatment for arterial gas embolism, decompression sickness and acute carbon monoxide poisoning. Though there has been a proliferation of hyperbaric centers throughout the United States, a scarcity of centers equipped to treat emergency indications makes transport of patients necessary. To locate and characterize hyperbaric chambers capable of treating emergency cases, a survey of centers throughout the entire United States was conducted. Using Google, Yahoo, HyperbaricLink and the UHMS directory, a database for United States chambers was created. Four researchers called clinicians from the database to administer the survey. All centers were contacted for response until four calls went unreturned or a center declined to be included. The survey assessed chamber readiness to respond to high-acuity patients, including staff availability, use of medical equipment such as ventilators and intravenous infusion devices, and responding yes to treating hyperbaric emergencies within a 12-month period. Only 43 (11.9%, N = 361) centers had equipment, intravenous infusion pumps and ventilators, and staff necessary to treat high-acuity patients. Considering that a primary purpose of hyperbaric oxygen therapy is the treatment of arterial gas embolism and decompression sickness, more hyperbaric centers nationwide should be able to accommodate these emergency cases quickly and safely.