Faculty Bibliography

Retinoids (RA) have been used as therapeutic agents for numerous skin diseases, from psoriasis to acne and wrinkles. While RA is known to inhibit keratinocyte differentiation, the molecular effects of RA in epidermis have not been comprehensively defined. To identify the transcriptional targets of RA in primary human epidermal keratinocytes, we compared the transcriptional profiles of cells grown in the presence or absence of all-trans retinoic acid for 1, 4, 24, 48, and 72 h, using large DNA microarrays. As expected, RA suppresses the protein markers of cornification; however the genes responsible for biosynthesis of epidermal lipids, long-chain fatty acids, cholesterol, and sphingolipids, are also suppressed. Importantly, the pathways of RA synthesis, esterification and metabolism are activated by RA; therefore, RA regulates its own bioavailability. Unexpectedly, RA regulates many genes associated with the cell cycle and programmed cell death. This led us to reveal novel effects of RA on keratinocyte proliferation and apoptosis. The response to RA is very fast: 315 genes were regulated already after 1 h. More than one-third of RA-regulated genes function in signal transduction and regulation of transcription. Using in silico analysis, we identified a set of over-represented transcription factor binding sites in the RA-regulated genes. Many psoriasis-related genes are regulated by RA, some induced, others suppressed. These results comprehensively document the transcriptional changes caused by RA in keratinocytes, add new insights into the molecular mechanism influenced by RA in the epidermis and demonstrate the hypothesis-generating power of DNA microarray analysis

BACKGROUND: Chronic wounds, including diabetic foot ulcers (DFU), pressure ulcers (PU), and venous ulcers (VU) result from multiple physiologic impairments. Operative debridement is a mainstay of treatment to remove nonviable tissue and to stimulate wound healing. Unlike tumor resection, however, operative wound specimens are not routinely sent for pathology. The objective of this study was to describe the pathology present in chronic wounds. STUDY DESIGN: Pathology reports of the skin edge and wound base from 397 initial debridements in 336 consecutive patients with chronic wounds were retrospectively reviewed. All data were entered and stored in a Wound Electronic Medical Record. Pathology data were extracted from the Wound Electronic Medical Record, coded, and quantified. RESULTS: Up to 15 distinct histopathologic findings across 7 tissue types were observed after review of pathology reports from chronic wounds. Specifically, the pathology of epidermis revealed hyperkeratosis: 66% in DFUs, 31% in PUs, and 29% in VUs. Dermal pathology revealed fibrosis in 49% of DFUs, 30% of PUs, and 15% of VUs. Wound bed pathology revealed necrosis in the subcutaneous tissue in 67% of DFUs, 55% of PUs, and 19% of VUs. Fibrosis was reported in between 19% and 52% of all wound types. Acute osteomyelitis was present in 39% of DFUs, 33% of PUs, and 29% of VUs. CONCLUSIONS: This observational study of the histopathology of initial surgical debridement of chronic wounds revealed a wide range of findings across multiple tissue levels. Although certain findings such as osteomyelitis and gangrene have been shown to directly relate to impaired wound healing and amputation, other findings require additional investigation. To rigorously define a margin of debridement, a prospective study relating histopathology and clinical outcomes such as healing rates and amputation is needed

BACKGROUND: Infection in severe pressure ulcers can lead to sepsis with a 6-month mortality as high as 68%. METHODS: Operative records of 142 consecutive operative debridements on 60 patients in a dedicated wound healing inpatient unit were reviewed, from the Wound Electronic Medical Record, for identification of key steps in debridement technique, mortality, unexpected returns, and time to discharge following debridement. RESULTS: The mean age of the patients was 73.1 years, and 45% were men. Most wounds (53%) were located on the hip (ischial or trochanteric); others were on the sacrum (32%) and the heels (14%). The mean initial wound area prior to debridement was 14.0 cm(2), and 83% of debridements were performed on stage IV pressure ulcers. The postoperative hospital stay averaged 4.1 days. Key steps in the technique included (1) exposure of areas of undermining by excising overlying tissue; (2) removal of callus from wound edges; (3) removal of all grossly infected tissue; and (4) obtaining a biopsy of the deep tissue after debridement of all nonviable or infected tissue for culture and pathology to determine the presence of infection, fibrosis, and granulation tissue. There was one death 9 days post-debridement of a sacral ulcer and one unplanned return to the operating room for bleeding 8 days post-debridement. CONCLUSIONS: Operative debridement of pressure ulcers is safe, despite the medical co-morbidities in patients with severe pressure ulcers. Proper debridement technique may prevent sepsis and death in patients with multiple co-morbid conditions

BACKGROUND: A chronic wound is tissue with an impaired ability to heal. This is often a consequence of one of the following etiologies: diabetes, venous reflux, arterial insufficiency sickle cell disease, steroids, and/or pressure. Healing requires granulation tissue depending on epithelialization and angiogenesis. Currently no growth factor is available to treat patients with impaired healing that stimulates both epithelialization and angiogenesis. The objective is to review is the multiple mechanisms of vascular endothelial growth factor (VEGF) in wound healing. MATERIALS AND METHODS: The authors reviewed the literature on the structure and function of VEGF, including its use for therapeutic angiogenesis. Particular attention is given to the specific role of VEGF in the angiogenesis cascade, its relationship to other growth factors and cells in a healing wound. RESULTS: VEGF is released by a variety of cells and stimulates multiple components of the angiogenic cascade. It is up-regulated during the early days of healing, when capillary growth is maximal. Studies have shown the efficacy of VEGF in peripheral and cardiac ischemic vascular disease with minimal adverse effects. Experimental data supports the hypothesis that VEGF stimulates epithelialization and collagen deposition in a wound. CONCLUSION: VEGF stimulates wound healing through angiogenesis, but likely promotes collagen deposition and epithelialization as well. Further study of the molecule by utilizing the protein itself, or novel forms of delivery such as gene therapy, will increase its therapeutic possibilities to accelerate closure of a chronic wound

Osteomyelitis affects up to 32% of full-thickness pressure ulcers and increases treatment costs and the risk of systemic complications. Current diagnosis and treatment practices are variable. A literature and retrospective chart review, using a wound electronic medical record (WEMR), were conducted to develop an evidence-based protocol of care for treatment of osteomyelitis in pressure ulcers and to evaluate outcomes of care. The seven steps in the protocol of care include: 1) acknowledgment of osteomyelitis risk in patients with Stage IV pressure ulcers, 2) clinical evaluation for local or systemic signs of infection upon initial presentation, 3) radiographic evaluation (magnetic resonance imaging or bone scan), 4) surgical debridement to remove all nonviable tissue and/or scarred and infected bone, 5) obtaining pathology reports from sterile bone biopsy and deep microbial cultures, 6) targeted systemic antimicrobial therapy, and 7) tissue reconstruction following resolution of infection. WEMR data review (177 patients) identified 50 patients with osteomyelitis (prevalence 28%). Of those, 41 underwent 87 bone debridements for osteomyelitis. Eight (20%) patients experienced complications elated to treatment. Average time to discharge following debridement was 4.3 +/- 5.7 days and 76% of wounds with more than two consecutive WEMR entries showed a decrease in area at their final visit. The outcomes observed are encouraging and the WEMR facilitates implementation and evaluation of the treatment protocol. Ongoing data acquisition will help assess outcomes and refine the current management protocol and should improve diagnosis and care