To test the hypothesis that hepatic regulation of α-tocopherol metabolism would be sufficient to prevent over-accumulation of α-tocopherol in extrahepatic tissues and that administration of high doses of α-tocopherol would up-regulate extrahepatic xenobiotic pathways, rats received daily subcutaneous injections of either vehicle or 0.5, 1, 2, or 10 mg α-tocopherol/100 g body wt for 9 days. Liver α-tocopherol increased 15-fold in rats given 10 mg α-tocopherol/100 g body weight (mg/ 100 g) compared with controls. Hepatic α-tocopherol metabolites increased with increasing α-tocopherol doses, reaching 40-fold in rats given the highest dose. In rats injected with 10 mg/100 g, lung and duodenum α-tocopherol concentrations increased 3-fold, while α-tocopherol concentrations of other extrahepatic tissues increased 2-fold or less. With the exception of muscle, daily administration of less than 2 mg/100 g) failed to increase α-tocopherol concentrations in extrahepatic tissues. Lung cytochrome P450 3A and 1A levels were unchanged by administration of α-tocopherol at any dose. In contrast, lung P-glycoprotein (MDR-1) levels increased dose dependently and expression of this xenobiotic transport protein was correlated with lung α-tocopherol concentrations (R 2 = 0.88, P < 0.05). Increased lung MDR1 may provide protection from exposure to environmental toxins by increasing alveolar space α-tocopherol.

Importance Bites from the brown recluse spider (BRS) can cause extreme pain. We propose cytokine release as a cause of the discomfort and a central mechanism through glial cell upregulation to explain measured pain levels and time course. Observations Twenty-three BRS bites were scored at a probable or documented level clinically, and an enzyme-linked immunosorbent assay was used to confirm the presence of BRS venom. The mean (SD) pain level in these cases 24 hours after the spider bite was severe: 6.74 (2.75) on a scale of 0 to 10. Narcotics may be needed to provide relief in some cases. The difference in pain level by anatomic region was not significant. Escalation observed in 22 of 23 cases, increasing from low/none to extreme within 24 hours, is consistent with a cytokine pain pattern, in which pain increases concomitantly with a temporal increase of inflammatory cytokines. Conclusions and Relevance These findings in BRS bites support the hypothesis of cytokine release in inflammatory pain. A larger series is needed to confirm the findings reported here. The extreme pain from many BRS bites motivates us to find better prevention and treatment techniques.

Background. In dermoscopic images, multiple shades of pink have been described in melanoma without specifying location of these areas within the lesion. Objective. The purpose of this study was to determine the statistics for the presence of centrally and peripherally located pink melanoma and benign melanocytic lesions. Methods. Three observers, untrained in dermoscopy, each retrospectively analyzed 1290 dermoscopic images (296 melanomas (170 in situ and 126 invasive), 994 benign melanocytic nevi) and assessed the presence of any shade of pink in the center and periphery of the lesion. Results. Pink was located in the peripheral region in 14.5% of melanomas and 6.3% of benign melanocytic lesions, yielding an odds ratio of 2.51 (95% CI: 1.7–3.8, P < 0.0001). Central pink was located in 12.8% of melanomas and 21.8% of benign lesions, yielding an odds ratio of 0.462 (95% CI: 0.67, P = 0.204). Pink in melanoma in situ tended to be present throughout the lesion (68% of pink lesions). Pink in invasive melanoma was present in 17% of cases, often presenting as a pink rim. Conclusions. The presence of pink in the periphery or rim of a dermoscopic melanocytic lesion image provides an indication of malignancy. We offer the “pink rim sign” as a clue to the dermoscopic diagnosis of invasive melanoma.

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