Staphylococcus Agr virulence is critical for epidermal colonization and associates with atopic dermatitis development.

Atopic dermatitis (AD) is commonly associated with colonization by Staphylococcus aureus in the affected skin. To understand the role of S. aureus in the development of AD, we performed whole-genome sequencing of S. aureus strains isolated from the cheek skin of 268 Japanese infants 1 and 6 months after birth. About 45% of infants were colonized with S. aureus at 1 month regardless of AD outcome. In contrast, skin colonization by S. aureus at 6 months of age increased the risk of developing AD. Acquisition of dysfunctional mutations in the S. aureus Agr quorum-sensing (QS) system was primarily observed in strains from 6-month-old infants who did not develop AD. Expression of a functional Agr system in S. aureus was required for epidermal colonization and the induction of AD-like inflammation in mice. Thus, retention of functional S. aureus agr virulence during infancy is associated with pathogen skin colonization and the development of AD.

Topical steroid application can induce branched/reticular vessels in Bowen disease on the upper trunk.

We aimed to elucidate the dermoscopic vasculature of patients with Bowen Disease (BD) that was misdiagnosed as chronic eczema and had branched and/or reticular vessels after topical steroid application. The medical records of 19 patients with BD on the upper trunk were retrospectively reviewed for steroid use history, vascular structure observed in dermoscopy, and corresponding histological findings. Four patients treated with strong topical steroids showed remarkable branched and/or reticular vessels on dermoscopy. Histopathology showed partial epidermal atrophy with irregular thin elongation of the rete ridges, atypical keratinocyte proliferation in the epidermis, and vasodilation in the superficial dermis. We considered that vasodilation and partial epidermal atrophy may be induced by topical steroid application in BD-affected areas. In cases of suspected BD with reddish-brown plaque showing branched and/or reticulated vessels in dermoscopy, confirming a history of topical steroid use is helpful.

Glucagonoma With Necrolytic Migratory Erythema: Metabolic Profile and Detection of Biallelic Inactivation of DAXX Gene.

Context: Necrolytic migratory erythema (NME) occurs in approximately 70% of patients with glucagonoma syndrome. Excessive stimulation of metabolic pathways by hyperglucagonemia, which leads to hypoaminoacidemia, contributes to NME pathogenesis. However, the molecular pathogenesis of glucagonoma and relationships between metabolic abnormalities and clinical symptoms remain unclear. Patient: A 53-year-old woman was referred to our hospital with a generalized rash and weight loss. NME was diagnosed by histopathological examination of skin biopsy tissue. Laboratory tests revealed diabetes, hyperglucagonemia, marked insulin resistance, severe hypoaminoacidemia, ketosis, and anemia. Enhanced computed tomography scans detected a 29-mm pancreatic hypervascular tumor, which was eventually diagnosed as glucagonoma. Preoperative treatment with octreotide long-acting release reduced the glucagon level, improved the amino acid profile, and produced NME remission. Surgical tumor excision normalized the metabolic status and led to remission of symptoms, including NME. Interventions: Whole-exome sequencing (WES) and subsequent targeted capture sequencing, followed by Sanger sequencing and pyrosequencing, identified biallelic alteration of death-domain associated protein (DAXX) with a combination of loss of heterozygosity and frameshift mutations (c.553_554del:p.R185fs and c.1884dupC:p.C629fs) in the glucagonoma. Consistently, immunohistochemistry confirmed near-absence of DAXX staining in the tumor cells. Tumor expression of glucagon and somatostatin receptor subtype 2 and 3 messenger RNA was markedly upregulated. Conclusions: This is a report of glucagonoma with biallelic inactivation of DAXX determined by WES. The tumor manifested as glucagonoma syndrome with generalized NME. This case showed the relationship between hypoaminoacidemia and NME status. Further investigations are required to elucidate the underlying mechanisms of NME onset and glucagonoma tumorigenesis.

Staphylococcus aureus Virulent PSMα Peptides Induce Keratinocyte Alarmin Release to Orchestrate IL-17-Dependent Skin Inflammation.

Staphylococcus aureus commonly colonizes the epidermis, but the mechanisms by which the host senses virulent, but not commensal, S. aureus to trigger inflammation remain unclear. Using a murine epicutaneous infection model, we found that S. aureus-expressed phenol-soluble modulin (PSM)α, a group of secreted virulence peptides, is required to trigger cutaneous inflammation. PSMα induces the release of keratinocyte IL-1α and IL-36α, and signaling via IL-1R and IL-36R was required for induction of the pro-inflammatory cytokine IL-17. The levels of released IL-1α and IL-36α, as well as IL-17 production by γδ T cells and ILC3 and neutrophil infiltration to the site of infection, were greatly reduced in mice with total or keratinocyte-specific deletion of the IL-1R and IL-36R signaling adaptor Myd88. Further, Il17a-/-f-/- mice showed blunted S. aureus-induced inflammation. Thus, keratinocyte Myd88 signaling in response to S. aureus PSMα drives an IL-17-mediated skin inflammatory response to epicutaneous S. aureus infection.

Hypoxia-ischemia induces hypo-phosphorylation of collapsin response mediator protein 2 in a neonatal rat model of periventricular leukomalacia.

Collapsin response mediator protein2 (CRMP2) is a brain-specific protein involved in neuronal polarity and axonal guidance, and phosphorylation of CRMP2 regulates the function and the activity. CRMP2 has shown to be implicated in several neurodegenerative diseases (Alzheimer's disease, epilepsy and ischemia) and this study was designed to assess the role of CRMP2 in periventricular leukomalacia (PVL). We developed a PVL model using 3-day-old rats to investigate the expression and phosphorylation of CRMP2 in the newborn brain. Hypoxia-ischemia was applied by unilateral carotid ligation followed by exposure to 5% oxygen for 30min. Pathological changes were evaluated from 0h to 21d post-HI, and white matter damage including severe necrosis, white matter rarefaction and lateral ventricle dilatation were found. In the PVL model astrogliosis and axonal damage were detected in the injured white matter by immunohistochemistry at 48-168h post-HI, and delayed myelination was verified by Western blotting after 21-day post-HI. We confirmed that this model showed neuropathological features of PVL. Next, significant changes of CRMP2 were observed in the brain of the PVL model. Western blotting and immunohistochemistry showed that cleavage and hypo-phosphorylation of CRMP2 occurred after 48h post-HI in the PVL brain. Our results suggest that cleaved CRMP2 could represent hypo-phosphorylated-CRMP2 and HI could induce activation of CRMP2 in the PVL brain. The activated CRMP2 may play an important role in neuronal plasticity in PVL. Our findings suggest that future treatment strategies of PVL should target the phosphorylation mechanism of CRMP2.

Ascorbic acid protects the newborn rat brain from hypoxic-ischemia.

Ascorbic acid (AA) is a potent antioxidant, and its neuroprotective effect has not been established yet. Using the Rice-Vannucci model, we examined the effect of AA on hypoxic-ischemic (HI) injury in the immature rat brain. Under isoflurane anesthesia, 7-day-old rat pups received 750 mg/kg of AA by intraperitoneal injection just before hypoxic exposure; 8% oxygen for 90 min. Vehicle controls received an equal volume of saline. AA decreased a macroscopic brain injury score at 48 and 168 h post-HI compared with vehicle controls (48 h post-HI, AA 1.38+/-0.45 vs. controls 2.94+/-0.24, p<0.05; 168 h post-HI, 1.13+/-0.44 vs. 2.50+/-0.25, p<0.05). AA injection significantly decreased the number of both necrotic and apoptotic cells in cortex, caudate putamen, thalamus and hippocampus, and also seemed to reduce the number of TUNEL-positive cells. Western blot analysis showed that AA significantly suppressed 150/145 kDa subunits of alpha-fodrin breakdown products (FBDP) in cortex, striatum, thalamus and hippocampus at 24 and 48 h post-HI, and also 120 kDa subunit of FBDP in all examined regions except for thalamus, which indicated that AA injection inhibited both calpain and caspase-3 activation. Western blot analysis of nitrotyrosine failed to show inhibition of free radical production by AA, however, our results show that AA inhibits both necrotic and apoptotic cell death and that AA is neuroprotective after HI in immature rat brain.