Report of the 13th Annual International Pachyonychia Congenita Consortium Symposium.

The International Pachyonychia Congenita Consortium (IPCC) is a group of physicians and scientists from around the world dedicated to developing therapies for pachyonychia congenita, a rare autosomal dominant skin disorder. The research presented at the 13th Annual Research Symposium of the IPCC, held on 10-11 May 2016, in Scottsdale, AZ, U.S.A., is reported here.

Pachyonychia congenita cornered: report on the 11th Annual International Pachyonychia Congenita Consortium Meeting.

This is a report of the research presented at the 11th Annual Meeting of the International Pachyonychia Congenita Consortium, held on 6 May 2014 in Albuquerque, NM, U.S.A. This year's meeting was divided into five corners concerning pachyonychia congenita (PC) research: (i) 'PC Pathogenesis Cornered', an overview of recent keratin research, for PC and other skin disorders; (ii) 'From All Corners of …', an outline of other genetic disorders that we can learn from; (iii) 'Fighting For Our Corner', an outline of National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases programmes and U.S. funding opportunities applicable to rare skin disorders; (iv) 'The PC Corner', focusing on recent clinical studies related to PC; and (v) 'Clinical Corners: Turning the Corner?', an update on ongoing PC clinical trials.

Molecular mechanisms of nonablative fractionated laser resurfacing.

BACKGROUND: Nonablative fractionated laser resurfacing improves the texture of treated skin, but little is known about the molecular mechanisms that underlie clinical improvements. OBJECTIVES: We sought to examine and quantify the time course and magnitude of dermal matrix changes that occur in response to nonablative fractionated laser resurfacing, with the dual goals of better understanding the molecular mechanisms that underlie clinical improvements and of gaining knowledge that will enable evidence-based treatment parameter optimization. METHODS: Twenty patients (mean age 58 years) with photodamaged skin were focally treated on dorsal forearms with a nonablative fractionated laser. Serial skin samples were obtained at baseline and at various times after treatment. Biopsies were examined with real-time polymerase chain reaction technology and immunohistochemical techniques. RESULTS: Laser treatment resulted in an initial inflammatory response as indicated by statistically significant induction of proinflammatory cytokines (interleukin-1ß and tumour necrosis factor-α). This was followed by substantial increases in levels of several matrix metalloproteinases and later by significant induction of type I collagen. Dermal remodelling was noted with both low and high microbeam energy treatment parameters. CONCLUSIONS: Nonablative fractionated laser resurfacing induces a well-organized wound-healing response that leads to substantial dermal remodelling and collagen induction. Surprisingly, only minimal differences were observed between lower and higher microbeam energy settings. These data suggest that lower microbeam energy/higher microbeam density treatment parameters, which are generally better tolerated by patients, may yield dermal changes similar to those that result from higher microbeam energy/lower microbeam density treatment parameters.

In vitro glycoxidation alters the interactions between collagens and human polymorphonuclear leucocytes.

Glycation and glycoxidation processes, which are increased in diabetes mellitus, are generally considered causative mechanisms of long-term complications. With reference to our previous studies, type-I and -IV collagens could induce differentially the adhesion and stimulation of polymorphonuclear leucocytes (PMNs). As PMNs play a role in sustained diabetic oxidative stress, the present study was designed to determine whether in vitro glycoxidation of these macromolecules could alter PMN adhesion, activation and migration. The adhesion of PMNs to in vitro-glycoxidized collagens was significantly increased when compared with control collagens: +37% (P<0.05) and +99% (P<0.01) for collagens I and IV, respectively. Glycoxidized type-I collagen increased the chemotactic properties of PMNs without significant stimulatory effect on respiratory burst, whereas pre-incubation of PMNs with glycoxidized type-I collagen induced a priming on subsequent stimulation by N-formyl-methionyl-leucyl-phenylalanine. Glycoxidation of type-IV collagen suppressed its inhibitory effect on further PMN stimulation or migration. Collectively, these results indicate that glycoxidation of two major extracellular-matrix collagens considerably alters their ability to modulate PMN migration and production of reactive oxygen species. This imbalance in PMN metabolism may be a major event in the increased oxidative status that characterizes diabetes mellitus.

Human blood monocytes interact with type I collagen through alpha x beta 2 integrin (CD11c-CD18, gp150-95).

Human blood monocytes are attracted into connective tissues during early steps of inflammation and wound healing, and locally interact with resident cells and extracellular matrix proteins. We studied the effects of type I collagen on monocyte adhesion and superoxide anion production, using human monocytes elutriated from peripheral blood and type I collagen obtained from rat tail tendon. Both acid-soluble and pepsin-digested type I collagens promoted the adhesion of monocytes, whereas only acid-soluble collagen with intact telopeptides induced the production of superoxide. Adhesion and activation of monocytes on acid-soluble type I collagen depended on the presence of divalent cations. mAbs directed against integrin subunits CD11c and CD18 specifically inhibited adhesion and activation of monocytes on type I collagen. Protein membrane extracts obtained from monocytes were submitted to affinity chromatography on collagen I-Sepharose 4B, and analyzed by Western blotting using specific anti-integrin subunit Abs. In the case of both acid-soluble and pepsin-digested collagens, two bands were revealed with mAbs against CD11c and CD18 integrin subunits. Our results demonstrate that monocytes interact with type I collagen through CD11c-CD18 (alpha x beta 2) integrins, which promote their adhesion and activation. For monocyte activation, specific domains of the type I collagen telopeptides are necessary. Interactions between monocytes and collagen are most likely involved in the cascade of events that characterize the initial phases of inflammation.

Decreased contraction of glycated collagen lattices coincides with impaired matrix metalloproteinase production.

Nonenzymatic glycation of extracellular matrix (ECM) proteins is increased in diabetes mellitus and aging and triggers cellular events leading to an imbalance in ECM homeostasis. We studied the influence of collagen glycation on matrix metalloproteinase production by dermal fibroblasts using the model of lattice cultures. Contraction of glycated collagen lattices was strongly reduced when compared to controls. Meanwhile, fibroblasts synthesized lower amounts of interstitial collagenase (MMP-1). Gelatinase A (MMP-2) production was not modified, but its activation was strongly inhibited. These effects were independent from the intensity of lattice contraction and from any simultaneous modification of tissue inhibitors of metalloproteinase (TIMP-1 and 2) production. These results demonstrate that the impaired ability of fibroblasts to remodel and contract a glycated extracellular matrix coincides with a decrease in MMP production.