Little Brown Bird

A personal essay reflecting on patient care and loss in medical school. Berlin Prize 2020 First Place Winning Submissio

The Photodegradation of Endocrine Disrupting Compounds in Aqueous Solutions

Endocrine Disrupting Compounds (EDCs) are hormonal pollutants that negatively impact the reproductive system in humans and animals. Many of these compounds are commercially available in hormone therapies and contraceptives, and are therefore entering the water supply at worrying rates1. 17α-ethinylestradiol (EE2) is a synthetic estrogen that has been found in natural waters in potent, bioactive concentrations2. Wastewater treatment mechanisms are only 85% effective3 at removing this compound, and during the treatment process EE2 can react with hypobromous acid to form brominated derivatives.4 The effect of EE2 on the environment is well understood to have extremely negative consequences for ecosystems and human health5; of the effect of its brominated derivatives, little is known at all. In this paper, I examined the photochemistry of EE2 and two of its brominated derivatives. I aimed to determine how EE2 reacted in direct sunlight, and then to extrapolate to how it would degrade in the natural environment. Natural sunlight was mimicked using a photoreactor to simulate terrestrial solar irradiation, and the degradation was monitored using HPLC with a diode-array detector. The rate of degradation was calculated, and used to calculate the quantum yield or reaction efficiency. EE2 and its mono-brominated derivative had small quantum yields, but they were still within the range where direct photolysis would be a relevant environmental reaction. LC-MS/MS was used to attempt to characterize photoproducts and then hypothesize a mechanism of degradation.The reaction rates and quantum yields were successfully calculated, but little headway was made characterizing products. It was determined that EE2 was reacting during the ionization process, and so it was difficult to discern gas-phase chemistry from photochemistry. While knowledge of products could have led to a proposed mechanism, giving us molecular targets for removal and potential removal pathways that could hopefully be optimized for better wastewater treatment alternatives, the quantum yield of EE2 shows that future studies of its direct photochemistry will be environmentally relevant

Risk of COVID-19 in Dermatologic Patients on Long-term Immunomodulatory Therapy

As the COVID-19 pandemic has rapidly spread around the globe, concern has been raised regarding susceptibility of patients on immunomodulatory therapies to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. While general guidance has been put forth, data regarding infection rate and outcomes in immunosuppressed patients is still rare.1 Recent articles, including the work by Gisondi, et al, suggest that outcomes of patients on systemic immunomodulatory therapies infected with SARS-CoV-2 are similar to the general population.2 These findings may relate to the aberrant cytokine and inflammatory responses in severe COVID-19, which may be treated or partially blunted by cytokine-targeted therapy.3 Given the substantial outbreak of COVID-19 in our community, we tested whether, in addition to similar outcomes, patients on systemic immunomodulatory therapy had similar infection rates compared to the general population

FGF21 Administration Suppresses Retinal and Choroidal Neovascularization in Mice

Pathological neovascularization, a leading cause of blindness, is seen in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Using a mouse model of hypoxia-driven retinal neovascularization, we find that fibroblast growth factor 21 (FGF21) administration suppresses, and FGF21 deficiency worsens, retinal neovessel growth. The protective effect of FGF21 against neovessel growth was abolished in adiponectin (APN)-deficient mice. FGF21 administration also decreased neovascular lesions in two models of neovascular age-related macular degeneration: very-low-density lipoprotein-receptor-deficient mice with retinal angiomatous proliferation and laser-induced choroidal neovascularization. FGF21 inhibited tumor necrosis α (TNF-α) expression but did not alter Vegfa expression in neovascular eyes. These data suggest that FGF21 may be a therapeutic target for pathologic vessel growth in patients with neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration

Cytochrome P450 Oxidase 2C Inhibition Adds to &ohgr;-3 Long-Chain Polyunsaturated Fatty Acids Protection Against Retinal and Choroidal Neovascularization

ObjectivePathological ocular neovascularization is a major cause of blindness. Increased dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but ω-3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of ω-3 LCPUFA on neovascular eye diseases.Approach and resultsThe mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of ω-3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and ω-3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of ω-3 LCPUFA on retinal neovascularization and CNV by 30% and 20%, respectively. In CYP2C8-overexpressing mice fed a ω-3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C ω-3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected ω-3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast.ConclusionsInhibition of CYP2C activity adds to the protective effects of ω-3 LCPUFA on pathological retinal neovascularization and CNV

Cytochrome P450 Oxidase 2C Inhibition Adds to ω-3 Long-Chain Polyunsaturated Fatty Acids Protection Against Retinal and Choroidal Neovascularization

OBJECTIVE: Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal and choroidal neovascularization, but ω-3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of ω-3 LCPUFA on neovascular eye diseases. APPROACH AND RESULTS: The mouse models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) were used to investigate pathological angiogenesis in the retina and choroid respectively. The plasma levels of ω-3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and ω-3 LCPUFA derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of ω-3 LCPUFA on retinal and choroidal neovascularization by 30% and 20% respectively. In CYP2C8 over-expressing mice fed a ω-3 LCPUFA diet, montelukast suppressed retinal and choroidal neovascularization by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C ω-3 LCPUFA-derived active metabolites, increased OIR and CNV in vivo. Exposure to selected ω-3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast. CONCLUSION: Inhibition of CYP2C activity adds to the protective effects of ω-3 LCPUFA on pathological retinal and choroidal neovascularization