The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury.

Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by keratinocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis.

Vitamin D in allergic disease: shedding light on a complex problem.

Vitamin D is unique among nutritional factors because the intake of this special vitamin represents the sum of vitamin D obtained from diet, nutritional supplements, and endogenous production after exposure to sunlight. The current recommended nutritional intake requirements reflect needs based on its established role in calcium absorption and bone health. However, recent studies have revealed that vitamin D has important functions in the immune system and might influence the course of immune-mediated disorders, including atopic dermatitis and asthma. This review discusses the scientific rationale for a role for vitamin D in immune function, gives an update on allergic disease associations with lower vitamin D serum levels, and discusses recent observations relating to vitamin D in immune function.

Characteristic Skin Eruptions with a Distinct Histological Pattern Allow Early Diagnosis of Vitamin C Deficiency.

Introduction: Scurvy has become a rare disease in western countries with potentially high morbidity. Early diagnosis is crucial and can be challenging. Case Presentation: We present the case of a 56-year-old male patient who developed hemorrhagic diathesis after trivial impact trauma. Previously, the patient suffered from fatigue and loss of appetite. Characteristic skin eruptions and a distinct skin histology along with a decreased serum vitamin C level led to the diagnosis of scurvy. Following vitamin C supplementation, symptoms improved rapidly. Conclusion: In conclusion, vitamin C deficiency should be considered in cases with unclear hemorrhagic diathesis and a medical history of nutritional irregularities. Especially in cases of scurvy that do not yet show the full clinical spectrum of symptoms or have only moderately decreased serum vitamin C levels, thorough clinical dermatological examination and a skin biopsy are essential for early diagnosis and to prevent complications.

Acute Generalized Exanthematous Pustulosis: Clinical Features, Differential Diagnosis, and Management.

Acute generalized exanthematous pustulosis (AGEP) is a rare, acute, severe cutaneous adverse reaction mainly attributed to drugs, although other triggers, including infections, vaccinations, ingestion of various substances, and spider bites, have also been described. AGEP is characterized by the development of edema and erythema followed by the eruption of multiple punctate, non-follicular, sterile pustules and subsequent desquamation. AGEP typically has a rapid onset and prompt resolution within a few weeks. The differential diagnoses for AGEP are broad and include infectious, inflammatory, and drug-induced etiologies. Diagnosis of AGEP depends on both clinical and histologic criteria, as cases of overlap with other disease processes have been reported. Management includes removal of the offending drug or treatment of the underlying cause, if necessary, and supportive care, as AGEP is a self-limited disease. This review aims to provide an overview and update on the epidemiology, pathogenesis, reported precipitating factors, differentials, diagnosis, and management of AGEP.

Early Rupture of a Giant Basilar Artery Aneurysm after LEO Stenting: Case Report and Review of the Literature.

BACKGROUND: Advances in the endovascular armamentarium, such as flow diversion and stenting devices, provide treatment options for posterior circulation intracranial aneurysms (IAs) with complex angioarchitecture. Delayed IA rupture following flow diversion is a rare but often fatal complication. Giant IAs likely pose a higher risk because of the extensive clot formation and its suspected detrimental effect on the aneurysmal wall. However, mechanisms that lead to delayed rupture are poorly understood, and few cases provide thorough documentation of macroscopic and histologic findings. CLINICAL PRESENTATION: After our 60-year-old patient with a giant basilar aneurysm underwent treatment with a LEO stent, the postoperative clinical course remained uneventful until day 4 when he suffered an unexpected fatal subarachnoid hemorrhage (SAH). Autopsy demonstrated extensive hemorrhage, large intraluminal thrombus, and ruptured IA wall. The aneurysm, which ruptured linearly, was completely filled with a clot that seemed to have outgrown the thin aneurysm wall. Histologic specimens revealed thinning and degenerative changes of the aneurysm's wall, and sparse neutrophilic and histiocytic inflammatory infiltrate adjacent to the rupture site, a finding consistent with recently published cases of IA rupture. CONCLUSIONS: Our case report highlighting the clinical course and autopsy findings of a fatal SAH shortly after stenting this giant basilar artery aneurysm adds to the few previously reported fatal cases of IA rupture after endovascular treatment. Our macroscopic and histologic findings suggested that multimodal changes of inflammation, wall sheer tress (mechanical), and recanalization were involved.

Assessment of immunization status in hospitalized children followed by counseling of parents and primary care physicians improves vaccination coverage: an interventional study.

This prospective, intervention-control study in hospitalized, underimmunized children assessed the effect of vaccination reminders to parents during hospitalization and provides postdischarge rates of catch-up immunizations. One month after hospital discharge, significantly more children in the intervention group (27%) than the controls (8%) had received catch-up immunizations (P < .001).

Distinct innate immune gene expression profiles in non-melanoma skin cancer of immunocompetent and immunosuppressed patients.

Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most frequent skin cancers in humans. An intact immune system is critical for protection against SCC since organ transplant recipients (OTR) have a 60- to 100-fold higher risk for developing these tumors. The role of the innate immune system in tumor immunosurveillance is unclear. Our aim was to determine the expression of selected innate immune genes in BCC and SCC arising in immunocompetent and OTR patients. Lesional and peri-lesional skin from 28 SCC and 19 BCC were evaluated for mRNA expression of toll-like receptors (TLR) 1-9, downstream TLR signaling molecules, and antimicrobial peptides. 11 SCC occurring in OTR patients were included in the analysis. We found that SCC but not BCC showed significantly elevated expression of TLRs 1-3, 5-8, TRIF and TRAF1. TNF was increased in SCC compared to normal skin. BCC showed increased IFNγ. hBD1, hBD2 and psoriasin mRNA and protein expression were significantly higher in SCC than in normal skin and higher than in BCC. SCC from OTR showed only an increase in hBD2 but no increase in hBD1 or psoriasin. We conclude that innate immune gene expression in SCC is distinct from normal skin and BCC. BCC shows lesser induction of innate immune genes. SCC from OTR patients have depressed expression of hBD1 and psoriasin compared to SCC from immunocompetent patients.

PTH/PTHrP and vitamin D control antimicrobial peptide expression and susceptibility to bacterial skin infection.

The production of antimicrobial peptides is essential for protection against a wide variety of microbial pathogens and plays an important role in the pathogenesis of several diseases. The mechanisms responsible for expression of antimicrobial peptides are incompletely understood, but a role for vitamin D as a transcriptional inducer of the antimicrobial peptide cathelicidin has been proposed. We show that 1,25-dihydroxyvitamin D(3) (1,25-D3) acts together with parathyroid hormone (PTH), or the shared amino-terminal domain of PTH-related peptide (PTHrP), to synergistically increase cathelicidin and immune defense. Administration of PTH to mouse skin decreased susceptibility to skin infection by group A Streptococcus. Mice on dietary vitamin D(3) restriction that responded with an elevation in PTH have an increased risk of infection if they lack 1,25-D3. These results identify PTH/PTHrP as a variable that serves to compensate for inadequate vitamin D during activation of antimicrobial peptide production.

Ultraviolet radiation damages self noncoding RNA and is detected by TLR3.

Exposure to ultraviolet B (UVB) radiation from the sun can result in sunburn, premature aging and carcinogenesis, but the mechanism responsible for acute inflammation of the skin is not well understood. Here we show that RNA is released from keratinocytes after UVB exposure and that this stimulates production of the inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) from nonirradiated keratinocytes and peripheral blood mononuclear cells (PBMCs). Whole-transcriptome sequencing revealed that UVB irradiation of keratinocytes induced alterations in the double-stranded domains of some noncoding RNAs. We found that this UVB-damaged RNA was sufficient to induce cytokine production from nonirradiated cells, as UVB irradiation of a purified noncoding RNA (U1 RNA) reproduced the same response as the one we observed to UVB-damaged keratinocytes. The responses to both UVB-damaged self-RNAs and UVB-damaged keratinocytes were dependent on Toll-like receptor 3 (TLR3) and Toll-like receptor adaptor molecule 1 (TRIF). In response to UVB exposure, Tlr3(-/-) mice did not upregulate TNF-α in the skin. Moreover, TLR3 was also necessary for UVB-radiation-induced immune suppression. These findings establish that UVB damage is detected by TLR3 and that self-RNA is a damage-associated molecular pattern that serves as an endogenous signal of solar injury.

Cancer/testis antigen MAGE-A4 expression pattern differs in epithelial skin tumors of organ-transplant recipients and immunocompetent patients.

BACKGROUND: Lifetime risk for squamous cell carcinoma (SCC) of the skin is 1:30. Risk in organ-transplant recipients (OTR) is increased over 60-fold through long-term drug-induced immunosuppression. MAGE family-derived peptides are cancer/testis antigens recognized by specific CD8(+) T cells and employed for immunotherapy. We were interested in the frequency and distribution of MAGE-A4 in epithelial skin tumors of OTR and immunocompetent patients. METHODS: mAb 57B predominantly recognizing MAGE-A4 was used to stain 119 formalin-fixed, paraffin-embedded epithelial skin tumors (actinic keratosis, bowenoid actinic keratosis, Bowen's disease, and SCC; n = 17, 25, 61, 16, respectively) in immunocompetent patients (n = 84) and OTR (n = 35). RESULTS: All four epithelial skin tumors showed comparable immunoreactivity ranging from (25-71%, p = 0.361). Scattered immunoexpression pattern was more frequent in OTR (p = 0.025). SCC showed polarized immunoreactivity basally (p = 0.002). CONCLUSION: MAGE-A4 was expressed in a large part of epithelial skin tumors with predominantly scattered immunoexpression pattern in OTR. The difference in immunoexpression pattern for immune status was limited, suggesting important non-immunosuppressor-mediated mechanisms for increased skin carcinogenesis in OTR. mAb 57B may be a helpful tool for immunohistochemistry and micrographic surgery using formalin-fixed paraffin-embedded tissue.

Prospective surveillance of hospitalisations associated with varicella-zoster virus infections in children and adolescents.

UNLABELLED: Our goal was to determine the epidemiology of severe varicella-zoster virus (VZV) infections in hospitalised paediatric patients. Admissions associated with VZV infection of patients aged 0-16 years were reported by all 38 paediatric units in Switzerland to the Swiss Paediatric Surveillance Unit (SPSU) during 3 consecutive years (4/2000-3/2003). We verified completeness of reporting by capture-recapture analysis with patient records identified by ICD-10 codes. Outcome of illness was assessed 6 months after hospitalisation. A total of 335 cases (235 identified by SPSU reports, 100 by ICD-10 code) were included in this study. Mean age of patients was 4.1 years (median 3.5 years, range 0-16 years); 54% were male. Some 293 (87%) patients presented with chickenpox, 42 (13%) with herpes zoster and 291 (87%) patients were not immunocompromised. A total of 319 complications occurred in 237 (71%) patients: secondary bacterial infections (n =109); central nervous system involvement (n =76); VZV pneumonitis (n =7); others (n =127). Eleven (3%) patients required intensive care and three died. On follow-up, 303 (96%) of 315 patients had completely recovered; sequelae were present in 12 (4%) patients. The calculated hospitalisation rate was 13 per 10(4) cases. CONCLUSION: This study describes a sizeable hospitalisation and complication rate of varicella-zoster virus infections and provides a solid basis for future immunisation recommendations in Switzerland.