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Recent documents in eScholarship@UMMS
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A mouse model of vitiligo with focused epidermal depigmentation requires IFN-gamma for autoreactive CD8(+) T-cell accumulation in the skin

Thu, 11/13/2014 - 2:35pm

Vitiligo is an autoimmune disease of the skin causing disfiguring patchy depigmentation of the epidermis and, less commonly, hair. Therapeutic options for vitiligo are limited, reflecting in part limited knowledge of disease pathogenesis. Existing mouse models of vitiligo consist of hair depigmentation but lack prominent epidermal involvement, which is the hallmark of human disease. They are thus unable to provide a platform to fully investigate disease mechanisms and treatment. CD8(+) T cells have been implicated in the pathogenesis of vitiligo, and expression of IFN-gamma is increased in the lesional skin of patients, however, it is currently unknown what role IFN-gamma has in disease. Here, we have developed an adoptive transfer mouse model of vitiligo using melanocyte-specific CD8(+) T cells, which recapitulates the human condition by inducing epidermal depigmentation while sparing the hair. Like active lesions in human vitiligo, histology of depigmenting skin reveals a patchy mononuclear infiltrate and single-cell infiltration of the epidermis. Depigmentation is accompanied by accumulation of autoreactive CD8(+) T cells in the skin, quantifiable loss of tyrosinase transcript, and local IFN-gamma production. Neutralization of IFN-gamma with antibody prevents CD8(+) T-cell accumulation and depigmentation, suggesting a therapeutic potential for this approach.

Eruption of bullae within psoriatic plaques: a rare adverse effect of narrow-band ultraviolet B (NB-UVB) phototherapy

Thu, 11/13/2014 - 2:35pm

The sudden eruption of bullae within psoriatic plaques is an uncommon adverse effect of narrow-band UVB phototherapy (TL-01 radiation). We report the case of a 49-year-old man who developed a bullous eruption after several NB-UVB treatments and will review important aspects of this unusual phototherapy complication.

Imiquimod reactivation of lichen planus

Thu, 11/13/2014 - 2:35pm

A 44-year-old man who was previously diagnosed with actinic cheilitis was prescribed imiquimod cream 5%, which resulted in thick hemorrhagic crusting of the lower lip after 4 applications. He subsequently noted the development of lichen planus lesions on his arms and legs for the first time in 15 years following imiquimod use. On follow-up he also was noted to have characteristic Wickham striae on his lower lip. Lichen planus is an autoimmune inflammatory condition in which autoreactive T lymphocytes attack keratinocytes. The mechanism of action for imiquimod is upregulation of IFN-alpha and IFN-beta. Treatment with clobetasol cream 0.05% led to resolution of his lichen planus lesions.

Modulation of cellular stress response via the erythropoietin/CD131 heteroreceptor complex in mouse mesenchymal-derived cells

Thu, 11/13/2014 - 10:32am

Tissue-protective properties of erythropoietin (EPO) have let to the discovery of an alternative EPO signaling via an EPO-R/CD131 receptor complex which can now be specifically targeted through pharmaceutically designed short sequence peptides such as ARA290. However, little is still known about specific functions of alternative EPO signaling in defined cell populations. In this study, we investigated effects of signaling through EPO-R/CD131 complex on cellular stress responses and pro-inflammatory activation in different mesenchymal-derived phenotypes. We show that anti-apoptotic, anti-inflammatory effects of ARA290 and EPO coincide with the externalization of CD131 receptor component as an immediate response to cellular stress. In addition, alternative EPO signaling strongly modulated transcriptional, translational, or metabolic responses after stressor removal. Specifically, we saw that ARA290 was able to overcome a TNFα-mediated inhibition of transcription factor activation related to cell stress responses, most notably of serum response factor (SRF), heat shock transcription factor protein 1 (HSF1), and activator protein 1 (AP1). We conclude that alternative EPO signaling acts as a modulator of pro-inflammatory signaling pathways and likely plays a role in restoring tissue homeostasis.

KEY MESSAGE: • Erythropoietin (EPO) triggers an alternative pathway via heteroreceptor EPO/CD131. • ARA290 peptide specifically binds EPO/CD131 but not the canonical EPO/EPO receptor. • Oxidative stress and inflammation promote cell surface expression of CD131. • ARA290 prevents tumor necrosis factor-mediated inhibition of stress-related genes. • Alternative EPO signaling modulates inflammation and promotes tissue homeostasis.

Missed Opportunities in HPV Vaccination

Wed, 11/12/2014 - 11:16am

Objective: To use the 3 dose Human Papillomavirus (HPV) vaccine administration (given at 0, 1-2 and 6 months) to quantify opportunities to improve efficacy in the delivery of preventive health services.

Methods: This was a retrospective, claims-based analysis using data provided by a single managed care plan. Female patients aged 9-26 who were continuously enrolled between 2009 through 2011 and received ≥ dose of the HPV vaccine during 2010 were analyzed. The proportion of initiators who did and did not completed the vaccine series, the timing and location of doses, and the number of outpatient visits during which the vaccine could have been given to non-completers were determined.

Results: 1,830 patients were analyzed in the 2010 sample. 843 (46%) were continuously enrolled during the three-year observation period. 500 (59%) completed 3 doses. Among completers, the interval range between doses 1 and 2 was 27-619 days (median 96 days). The interval range between doses 2 and 3 was 32-621 days (median 127 days). 261 (52%) completers received dose 2, and 139 (28%) received does 3 over 1 month late. Among the 343 non-completers, 137 (40%), and 206 (60%) completed 1 and 2 doses, respectively. 63% of single-dose recipients and 17% of 2-dose recipients had at least 1 visit within the eligible time period for administration.

Conclusion: Nearly half of HPV vaccine initiators do not complete the vaccine series. Of those who do, a large percentage complete it late. This example quantifies the potential for reminders, registries and outreach to improve on-time dosage and completion.