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Pyoderma gangrenosum (PG) is a neutrophilic dermatosis with chronic painful skin ulcers of unknown etiology. The diagnosis of PG continues to be one of exclusion. There are no specific laboratory tests or absolute diagnostic histopathologic features for PG. Multiple cases of postoperative PG with devastating ulcers and disfiguring scars after elective surgical interventions including esthetic surgeries were reported. PG is a heterogeneous and relatively rare skin disease. However, several amino acid changing (missense) mutations in the PSTPIP1 gene were identified in patients with syndromic PG, characterized by pyogenic sterile arthritis with PG and acne (PAPA syndrome). In this study, we performed whole-exome sequencing of the genomic DNA from 47 year old Hispanic female with postoperative PG. No missense mutation in the coding sequence of the PSTPIP1 gene was detected, which indicates the role of different genes in pathogenesis of PG. We identified over a hundred novel mutations/ polymorphisms which change amino acid sequence of different proteins involved in immune/ inflammation processes and/or are within candidate genes identified in prior SNP array genotyping studies. We found several rare missense mutations in the genes from IL1-signaling pathway (IL1RAP, IL1RL1 and IL18R1) and the granulocyte-macrophage colony-stimulating factor receptor (CSF2RB). This is the first study in PG using whole-exome sequencing. This pilot study is limited to a single exome analysis, but it will form a base for comparison and identification of candidate genes, which might play role in pathogenesis of PG. The early assessment of the genetic predisposition and the risk of developing PPG before not life threatening surgeries carries a great benefit to the patients.

Fibroblast culture model of dysregulated collagen homeostasis in aged human skin: Identification of natural compounds with restorative activity T He, JJ Voorhees and GJ Fisher Department of Dermatology, University of Michigan, Ann Arbor, MI Cumulative oxidative damage is thought to play a crucial role in the pathophysiology of many chronic diseases that are associated with aging. A prominent feature of aged human skin is reduced dermal strength and function, due to fragmentation and decreased production of type I collagen fibrils, which comprise the bulk of the dermis. We have established a fibroblast culture model that mimics the imbalance in collagen homeostasis that is observed in aged human skin and employed this model to identify natural compounds that are able to restore the balance. Primary adult human skin fibroblast cultures were exposed to hydrogen peroxide (H 2 O 2 , 200mM), for one hour on two consecutive days. This treatment resulted in timedependent alterations in collagen homeostasis, as observed in aged human skin. Five days post treatment, type I procollagen mRNA and protein levels were reduced 84% and 88%, respectively (p<0.01, n¼8). Matrix metalloproteinase-1 (MMP-1), which initiates collagen fibril degradation, mRNA and protein levels were elevated 5.2-fold and 6.4-fold (p<0.01, n¼8), respectively. We tested 15 natural compounds, which are present in a variety of botanicals, that have reported medicinal properties. Of these compounds, we found that the alkaloid berberine, found in a variety of herbs, was effective at restoring type I collagen expression. Berberine acted in a dose-dependent manner, increasing type 1 procollagen 4fold (p<0.01, n¼6) at a concentration of 50 mM. The flavonoid kaempferol, which is found in a variety of common fruits and vegetables, was effective at reducing MMP-1 expression.Kaempferol (10 mM) reduced MMP-1 levels to near baseline (p<0.01, n¼6). Interestingly, the combination of berberine and kaempferol effectively restored type I procollagen and reduced MMP-1 levels. Taken together, the above data demonstrate establishment of a fibroblast cell culture model of age-related collagen dysregulation and the use of this model to identify natural compounds, that improve collagen homeostasis. With the onset of puberty, presence of excessive sebum creates a conducive milieu for unhindered proliferation of Propionibacterium acnes (P. acnes), which further leads to a sustained inflammatory cycle involving complex interplay of multiple host factors and cytokines. Moreover, extensive use of oral and topical antibiotics for acne treatment has resulted in the generation of resistant strains of P. acnes, which has affected the current acne therapeutic regimen. The need of the moment is development of new antibiotics that are bactericidal in nature, as well as capable of abating host-mediated inflammation by reducing expression of different P. acnes induced cytokines. Here, we report a rationally-designed novel fluoroquinolone, VCD-008, that exhibits high potency against across a w...