Therapeutic plasma exchange for persistent encephalopathy associated with Covid-19.

Patients infected with COVID-19 virus, show a highly variable symptomatology which can include central nervous system (CNS) dysfunction. One of the most disabling CNS manifestations is persistent severe encephalopathy seen for weeks after the resolution of the acute viral pneumonia and associated acute systemic illnesses. The precise pathophysiology of this persistent Post COVID Encephalopathy is unknown but may involve direct viral invasion of microvascular endothelium, microvascular thrombosis, toxic neuronal effects of inflammatory products, vasoactive pathology at arteriolar level or leptomeningeal inflammation. Currently, there are no established specific treatments for Post COVID -19 encephalopathy. We present a case series of three patients that underwent Therapeutic Plasma Exchange (TPE) with salinized albumin that suggests a positive therapeutic effect. We believe that the results warrant further evaluation for the role of TPE with a prospective randomized trial in persistent Post COVID -19 encephalopathy syndrome.

Interleukin 6 regulates psoriasiform inflammation-associated thrombosis.

Psoriasis patients are at increased risk of heart attack and stroke and have elevated MRP8/14 levels that predict heart attack. The KC-Tie2 psoriasiform mouse model exhibits elevated MRP8/14 and is prothrombotic. Mrp14-/- mice, in contrast, are protected from thrombosis, but, surprisingly, KC-Tie2xMrp14-/- mice remain prothrombotic. Treating KC-Tie2xMrp14-/- mice with anti-IL-23p19 antibodies reversed the skin inflammation, improved thrombosis, and decreased IL-6. In comparison, IL-6 deletion from KC-Tie2 animals improved thrombosis despite sustained skin inflammation, suggesting that thrombosis improvements following IL-23 inhibition occur secondary to IL-6 decreases. Psoriasis patient skin has elevated IL-6 and IL-6 receptor is present in human coronary atheroma, supporting a link between skin and distant vessel disease in patient tissue. Together, these results identify a critical role for skin-derived IL-6 linking skin inflammation with thrombosis, and shows that in the absence of IL-6 the connection between skin inflammation and thrombosis comorbidities is severed.

Racial disparities in melanoma survival.

BACKGROUND: Melanoma is a cutaneous malignancy common in the white population but can also occur in other racial groups. OBJECTIVE: We sought to evaluate survival across racial groups in patients given a diagnosis of malignant melanoma. METHODS: The Surveillance, Epidemiology, and End Results database was used to populate a cohort of 96,953 patients given a diagnosis of cutaneous melanoma as their primary cancer, from 1992 to 2009. RESULTS: White patients had the longest survival time (P < .05), followed by Hispanic (P < .05), Asian American/Native American/Pacific Islander (P < .05), and black (P < .05) patients, respectively. Survival stratified by race and stage showed that for stages I and III, blacks had a significantly lower survival (P < .05), and increased hazard ratios (stage I hazard ratio, 3.037 [95% confidence interval, 2.335-3.951]; stage III hazard ratio, 1.864 [95% confidence interval, 1.211-2.87]). The proportion of later stage cutaneous melanoma (stages II-IV) was greater in blacks compared with whites. CONCLUSION: Despite higher incidence of cutaneous melanoma in whites, overall survival for cutaneous melanoma in non-whites was significantly lower. Our results suggest that more emphasis is needed for melanoma screening and awareness in non-white populations to improve survival outcomes.

Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation.

IL-17C is a functionally distinct member of the IL-17 family that binds IL-17 receptor E/A to promote innate defense in epithelial cells and regulate Th17 cell differentiation. We demonstrate that IL-17C (not IL-17A) is the most abundant IL-17 isoform in lesional psoriasis skin (1058 versus 8 pg/ml; p < 0.006) and localizes to keratinocytes (KCs), endothelial cells (ECs), and leukocytes. ECs stimulated with IL-17C produce increased TNF-α and KCs stimulated with IL-17C/TNF-α produce similar inflammatory gene response patterns as those elicited by IL-17A/TNF-α, including increases in IL-17C, TNF-α, IL-8, IL-1α/ß, IL-1F5, IL-1F9, IL-6, IL-19, CCL20, S100A7/A8/A9, DEFB4, lipocalin 2, and peptidase inhibitor 3 (p < 0.05), indicating a positive proinflammatory feedback loop between the epidermis and ECs. Psoriasis patients treated with etanercept rapidly decrease cutaneous IL-17C levels, suggesting IL-17C/TNF-α-mediated inflammatory signaling is critical for psoriasis pathogenesis. Mice genetically engineered to overexpress IL-17C in KCs develop well-demarcated areas of erythematous, flakey involved skin adjacent to areas of normal-appearing uninvolved skin despite increased IL-17C expression in both areas (p < 0.05). Uninvolved skin displays increased angiogenesis and elevated S100A8/A9 expression (p < 0.05) but no epidermal hyperplasia, whereas involved skin exhibits robust epidermal hyperplasia, increased angiogenesis and leukocyte infiltration, and upregulated TNF-α, IL-1α/ß, IL-17A/F, IL-23p19, vascular endothelial growth factor, IL-6, and CCL20 (p < 0.05), suggesting that IL-17C, when coupled with other proinflammatory signals, initiates the development of psoriasiform dermatitis. This skin phenotype was significantly improved following 8 wk of TNF-α inhibition. These findings identify a role for IL-17C in skin inflammation and suggest a pathogenic function for the elevated IL-17C observed in lesional psoriasis skin.

Low ascorbic acid and increased oxidative stress in gulo(-/-) mice during development.

Vitamin C (ascorbic acid, AA) depletion during prenatal and postnatal development can lead to oxidative stress in the developing brain and other organs. Such damage may lead to irreversible effects on later brain function. We studied the relationship between AA deficiency and oxidative stress during development in gulonolactone oxidase (gulo) knockout mice that are unable to synthesize their own ascorbic acid. Heterozygous gulo(+/-) mice can synthesize AA and typically have similar tissue levels to wild-type mice. Gulo(+/-) dams were mated with gulo(+/-) males to provide offspring of each possible genotype. Overall, embryonic day 20 (E20) and postnatal day 1 (P1) pups were protected against oxidative stress by sufficient AA transfer during pregnancy. On postnatal day 10 (P10) AA levels were dramatically lower in liver and cerebellum in gulo(-/-) mice and malondialdehyde (MDA) levels were significantly increased. In postnatal day 18 pups (P18) AA levels decreased further in gulo(-/-) mice and oxidative stress was observed in the accompanying elevations in MDA in liver, and F(2)-isoprostanes in cortex. Further, total glutathione levels were higher in gulo(-/-) mice in cortex, cerebellum and liver, indicating that a compensatory antioxidant system was activated. These data show a direct relationship between AA level and oxidative stress in the gulo(-/-) mice. They reinforce the critical role of ascorbic acid in preventing oxidative stress in the developing brain in animals that, like humans, cannot synthesize their own AA.

Vitamin C distribution and retention in the mouse brain.

Vitamin C (VC) is a crucial antioxidant in the brain. To assess whether different brain regions vary in their sensitivity to oxidative stress induced by VC depletion, we used the gulonolactone oxidase (gulo) knockout mouse. This mouse, like humans, cannot synthesize VC and thus its tissue VC levels can be varied by dietary VC intake. Gulo knockout mice were fed drinking water containing standard (0.33g/L), low (0.033g/L) or zero (0g/L) VC supplementation levels. After 4weeks, mice were sacrificed and different brain regions removed for assay of VC and malondialdehyde, a marker of lipid peroxidation. Compared to age-matched wild-type controls, the cerebellum, olfactory bulbs and frontal cortex had the highest VC content, whereas the pons and spinal chord had the lowest. However, in mice that did not receive VC, area differences were no longer significant as all values trended towards zero. Malondialdehyde increased in the cortex as VC supplementation was decreased. The same changes were not observed in the cerebellum or pons, suggesting that cortex is more susceptible to oxidative damage from low VC. These results suggest enhanced susceptibility of the cortex to oxidative stress induced by low VC compared to other brain regions.