Hilary Wallace

Complete resolution of recurrent calciphylaxis with long‐term intravenous sodium thiosulfate

A 35‐year‐old morbidly obese woman on home haemodialysis presented with painful indurated subcutaneous nodules histologically characteristic of calciphylaxis. After failing to respond to conventional treatment, she was commenced on an intravenous infusion of 25 g of sodium thiosulfate three times per week. Two weeks after commencing sodium thiosulfate, the pain resolved completely. By 12 weeks, the lesions had healed and the infusions were ceased. Two months later, skin lesions recurred, but resolved again within 3 months of recommencement of sodium thiosulfate treatment, which was continued for 8 months. The treatment was well tolerated. There has been no recurrence of lesions in the 18 months since the cessation of sodium thiosulfate. Clinical trials to determine the optimum dose and duration of therapy for sodium thiosulfate treatment of calciphylaxis should be given priority because of its high rate of success in treating what is otherwise a severe and mostly lethal condition.

Induction of MMP-1, MMP-3 and TIMP-1 in normal dermal fibroblasts by chronic venous leg ulcer wound fluid

In the wound bed of chronic venous leg ulcers, an imbalance of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) may cause excessive proteolysis and impair wound granulation. Soluble mediators in the wound environment may be responsible for this imbalance. The in vitro effect of wound fluid from venous leg ulcers on dermal fibroblast production of MMP‐1, MMP‐3 and TIMP‐1 was compared with the effect of acute wound fluid from two different sources: fluid from post‐mastectomy axillary drains and fluid from skin graft donor sites. Significantly higher MMP‐1 and MMP‐3 levels were induced by chronic venous leg ulcer wound fluid compared with both types of acute wound fluid (P < 0·005). Chronic venous ulcer wound fluid reduced TIMP‐1 protein levels significantly more than acute graft fluid (P < 0·05). Venous ulcer wound fluid significantly increased MMP‐1 and MMP‐3 production in dermal fibroblasts and reduced TIMP‐1 production, confirming that mediators in the leg ulcer microenvironment can potentially induce excessive proteolysis in the ulcer dermis by altering the balance between MMPs and TIMPs. Inflammatory mediators including interleukin‐1β and tumour necrosis factor‐α can induce these MMPs. Further work is required to confirm the factors responsible for the induction of a high MMP and low TIMP profile in fibroblasts by venous ulcer wound fluid.

Human pilot studies reveal the potential of a vitronectin: growth factor complex as a treatment for chronic wounds.

Several different advanced treatments have been used to improve healing in chronic wounds, but none have shown sustained success. The application of topical growth factors (GFs) has displayed some potential, but the varying results, high doses and high costs have limited their widespread adoption. Many treatments have ignored the evidence that wound healing is driven by interactions between extracellular matrix proteins and GFs, not just GFs alone. We report herein that a clinical Good Manufacturing Practice‐grade vitronectin:growth factor (cVN:GF) complex is able to stimulate functions relevant to wound repair in vitro, such as enhanced cellular proliferation and migration. Furthermore, we assessed this complex as a topical wound healing agent in a single‐arm pilot study using venous leg ulcers, as well as several ‘difficult to heal’ case studies. The cVN:GF complex was safe and re‐epithelialisation was observed in all but 1 of the 30 patients in the pilot study. In addition, the case studies show that this complex may be applied to several ulcer aetiologies, such as venous leg ulcers, diabetic foot ulcers and pressure ulcers. These findings suggest that further evaluation is warranted to determine whether the cVN:GF complex may be an effective topical treatment for chronic wounds.

Changes in cutaneous innervation in patients with chronic pain after burns

BACKGROUND Chronic pain is a common occurrence for burn patients and has significant impact on quality of life. However, the etiology is not well understood. Understanding the mechanisms underlying the restoration of sensory function and the development of chronic pain after burn is critical to improving long-term outcomes. OBJECTIVE To determine whether cutaneous innervation in burn patients with chronic pain is altered when compared to patients without chronic pain. METHODS Twelve patients with unilateral injury and who reported chronic pain were recruited. Each patient underwent sensory function testing and both scar and matched site uninjured skin biopsy. Biopsies were analyzed for total nerve density and nociceptive C-fiber density using immunohistochemistry. Results were compared to a control group of 33 patients with unilateral injury and no reported long-term pain. RESULTS Sensory function was significantly diminished in scar compared to uninjured tissue in both study groups, but chronic pain patients did not have significantly diminished function when compared to control. Total nerve density was not significantly different between scar and uninjured sites in either group, or between groups. However, the density of nociceptive nerve fibers was significantly elevated in both uninjured (p=0.0193) and scar sites (p=0.0316) of the patients with chronic pain when compared to the control group. CONCLUSIONS This data suggests that differences in cutaneous innervation may contribute to chronic pain after burn. There also appears to be a systemic difference in cutaneous innervation extending to distal uninjured sites. Therefore efforts to affect cutaneous reinnervation after burn may lead to less patients experiencing chronic pain.

A Preliminary investigation of the reinnervation and return of sensory function in burn patients treated with INTEGRA

BACKGROUND Loss of sensory function in scar after burn is common, although the basis for this loss is not clear. Additionally, little is known about the effects of different treatment modalities on sensory function and neuroanatomical outcomes in burn patients. Here, we investigated the effects of the use of the INTEGRA(®) dermal scaffold on neuroanatomy and sensory function in acute burn patients. HYPOTHESIS AND OBJECTIVES We hypothesized that the use of artificial dermal templates would inhibit or reduce reinnervation after excision, since regrowth of nerves requires complex molecular interactions. Therefore the primary objective of this study was to identify whether there is regrowth of nerve fibres in the INTEGRA(®) dermal scaffold. The secondary objective was to identify whether the INTEGRA(®) dermal scaffold reduced nerve regrowth or limited sensory function outcomes in acute burn patients. METHODS Five patients treated with INTEGRA(®), cultured epithelial autograft spray (prepared using ReCell(®) (CEA)) and split skin graft (SSG) were assessed for sensory function in scar and uninjured contralateral control skin. Neuroanatomy of scar and control sites was assessed using immunohistochemistry for PGP9.5, CGRP and substance P neuronal markers. Nerve density and sensory function was also assessed in a comparative group (n=8) treated with CEA and SSG only. RESULTS Neuroanatomy was not significantly different in the INTEGRA(®) patients when compared to the CEA/SSG group only. The patients treated with INTEGRA(®) had worse sensory function than those with CEA/SSG only. CONCLUSIONS Peripheral nerves do reinnervate the INTEGRA(®) dermal scaffold. There is no statistically significant reduction in reinnervation observed when compared to a control group. It is possible that the use of artificial dermal constructs, while permissive for nerve regrowth, limit functionality when compared to nerves that regrow through dermal tissue. Further research to understand the causes of this, and into enhancing reinnervation in dermal scaffolds may improve sensory outcome in the most severely burned patients.

Determinants of burn first aid knowledge: Cross-sectional study

INTRODUCTION This study investigated demographic factors, experience of burn/care and first aid course attendance as factors influencing burn first aid knowledge. METHODS A cross-sectional study was undertaken using convenience sampling of members of sporting and recreation clubs. The main outcome measure was the proportion of correct responses to multiple-choice questions relating to four burn scenarios: (1) scald, (2) contact burn, (3) ignited clothing, and (4) chemical burn. RESULTS A total of 2602 responses were obtained. Large gaps (30-50% incorrect answers) were identified in burn first aid knowledge across all scenarios. 15% more individuals gave correct answers if they had attended a first aid course compared to those who had not (p<0.0001); this proportion increased if the course was undertaken within the previous five years (p<0.0001) or contained a burns-specific component (p<0.0001). Males and younger (≤25 years) and older (≥65 years) age-groups had relatively lower levels of burn first aid knowledge. Gender and age were significant predictors of first aid course attendance, with males and younger (≤25 years) and older (≥65 years) age-groups less likely to have attended a first aid course. CONCLUSION In this sample, first aid training undertaken within the last 5 years with a specific burns component was associated with enhanced burn first aid knowledge.

Intentional burns in Nepal: A comparative study

AIMS Intentional burns injuries are associated with high mortality rates, and for survivors, high levels of physical and psychological morbidity. This study provides a comprehensive assessment of intentional burn admissions to the adult Burns Unit at Bir Hospital, Kathmandu, Nepal, during the period 2002-2013. METHODS A secondary data analysis of de-identified data of patients hospitalized at Bir Hospital, Kathmandu, with a burn during the period of 1 January 2002 to 31 August 2013. Socio-demographic, injury and psychosocial factors of patients with intentional and unintentional burns are described and compared. Chi-square tests, Fishers exact test and Wilcoxon rank sum tests were used to determine statistical significance. RESULTS There were a total of 1148 burn admissions of which 329 (29%) were for intentional burn, 293 (26%) were self-inflicted and 36 (3%) were due to assault. Mortality rates for intentional burns were approximately three times those for unintentional burns (60 vs. 22%). When compared to unintentional burns, patients with intentional burns were more likely to be female (79 vs. 48%), married (84 vs. 67%), younger (25 vs. 30 years), have more extensive burns (total body surface area, %: 55 vs. 25) and higher mortality (60 vs. 22%). Intentional burns were more likely to occur at home (95 vs. 67%), be caused by fire (96 vs. 77%), and kerosene was the most common accelerant (91 vs. 31%). A primary psychosocial risk factor was identified in the majority of intentional burn cases, with 60% experiencing adjustment problems/interpersonal conflict and 32% with evidence of a pre-existing psychological condition. A record of alcohol/substance abuse related to the patient or other was associated with a greater proportion of intentional burns when compared with unintentional burns (17 vs. 4%). CONCLUSIONS The majority of intentional burn patients were female. Almost all intentional burns occurred in the home and were caused by fire, with kerosene the most common accelerant used. Underlying psychosocial risk factors were identified in most cases. Intentional burns resulted in severe burns with high mortality. Intentional burns are not only a serious medical issue; they represent significant public health and gender issues in Nepal.

Characterization of tumor necrosis factor–α block haplotypes associated with susceptibility to chronic venous leg ulcers in Caucasian patients

Polymorphisms in the central major histocompatibility complex (MHC) are associated with several immunopathologic and inflammatory diseases, including chronic venous leg ulcers (CVLU). Because of strong linkage disequilibrium, identification of loci affecting disease susceptibility must be based on comparisons between haplotypes. Here we examine the association of conserved tumor necrosis factor (TNF) block haplotypes with CVLU susceptibility. A total of 171 Caucasian patients with CVLU were compared with 173 age-/gender-matched controls, excluding individuals with type 1 diabetes or rheumatoid arthritis. A total of 194 healthy subjects formed a separate population-based control group. Samples were typed for 38 tumor necrosis factor (TNF) block single nucleotide polymorphisms (SNP), human leukocyte antigen (HLA)-B and HLA-DRB1 alleles. TNF haplotypes were derived using the PHASE algorithm and assigned numbers (FVx) defined previously. The patients and matched controls shared 16 TNF block haplotypes. The patients had increased carriage of FV16 and alleles of the 8.1 and 60.3 MHC ancestral haplotypes (AH). CVLU risk is modulated by alleles within FV16 (e.g., TNF-308A and BAT1intron10 C insertion) or near FV16 in the 8.1AH. CVLU risk may also be mediated by unidentified alleles (not in FV22) marked by HLA-B40 and HLA-DR13. FV16 appears to be the best MHC and TNF block marker of susceptibility. After disease onset, an individuals TNF block haplotype does not modulate CVLU severity.

High-frequency ultrasound measurement for assessing post-thrombotic syndrome and monitoring compression therapy in chronic venous disease

BACKGROUND The purpose of this study was to validate high-frequency ultrasound (HFU) measurement of dermal thickness for quantification of edema in patients with different severities of chronic venous disease. METHODS HFU measurements of dermal thickness were made with a 17-MHz probe (Philips iU22 Ultrasound scanner, Bothell, Wash) or a 20-MHz medium-focus probe (DermaScan-C, Cortex Technology, Denmark), 7.5 cm above the medial malleolus. For validation, 20 patients with venous leg ulcers who were not receiving compression therapy, 20 patients with previous deep vein thrombosis (DVT) and symptoms of post-thrombotic syndrome (PTS) without ulceration, and 31 age-matched healthy controls were measured on a single occasion. To investigate the effect of compression on dermal thickness, the leg ulcer patients from the validation study were treated with compression therapy for 7 weeks and measured after 1, 3, 5, and 7 weeks. The association between dermal thickness and the clinical (C) component of the CEAP classification was examined in a cross-sectional analysis of 157 patients with a confirmed history of DVT >or=3 years ago. RESULTS Dermal thickness in patients with venous leg ulcers before compression therapy (median, 2.56 mm; interquartile range [IQR], 2.31-2.82 mm) was significantly greater (P = .002) than that in patients with symptoms of PTS without ulceration (median, 2.16 mm; IQR, 1.90-2.36 mm). Dermal thickness in both groups was significantly greater (P < .0001) than the control group (median, 1.34 mm; IQR, 1.29-1.44 mm). Compression therapy caused a steady and significant decrease in dermal thickness during the first 5 weeks until normal control levels were achieved. Dermal thickness increased with increasing CEAP category. In 121 patients with a positive diagnosis of DVT >or=3 years ago from Radiology Department records, a hypothetical test cutoff of 1.985 mm for the prediction of severe PTS noted as C(4b), C(5), and C(6) (lipodermatosclerosis or leg ulceration) had a positive predictive value of 46.9% and a negative predictive value of 90.3%. CONCLUSION HFU measurement of dermal thickness enables the monitoring of edema reduction by compression therapy. A prospective study is required to determine the temporal dynamics of dermal thickness changes after DVT and the relationship to the development of PTS. This test has the potential to be beneficial in the follow-up of patients after a DVT and provide clinical evidence for using graduated elastic compression stockings to control edema and prevent the development of more advanced skin changes.

Interpretation of the DermaLab Combo® pigmentation and vascularity measurements in burn scar assessment: An exploratory analysis

BACKGROUND The DermaLab Combo® measures pigmentation and vascularity of a burn scar more reliably than the modified Vancouver Scar Scale (mVSS). This study aims to examine how the DermaLab Combo® continuous measurements of pigmentation and vascularity of burns scars relate to the mVSS, a standard clinical scar assessment method; and secondly, to obtain evidence to support the concurrent validity of DermaLab Combo® measurements for pigmentation and vascularity. METHOD Scar assessments were performed on an index burn scar of 100 subjects using two methods: the mVSS (two raters) and the DermaLab Combo® device (one rater). Using the DermaLab Combo®, measurements of pigmentation and vascularity for the index scar and an adjacent normal skin site were obtained. Indices were generated to represent the scar pigmentation (melanin index, MI%) and scar vascularity (erythema index, EI%) relative to the patients matched normal skin. Exploratory univariate and bivariate analyses were conducted and the concordance of classification by mVSS score using DermaLab® cut-off values was assessed. RESULTS For pigmentation, the results suggest a 80% classification concordance for the DermaLab Combo® MI% values into mVSS pigmentation categories (hypopigmentation, normal pigmentation and hyperpigmentation) using two predictors (MI% and EI%) and visually fitted discriminant axis cut-offs. Due to the high degree of overlap of EI% values between the vascularity categories, meaningful classification of EI% values using the mVSS was not possible. CONCLUSION Quantifying percentage changes in melanin and erythema relative to matched normal skin improved understanding of the DermaLab Combo® pigmentation and vascularity measurements. The DermaLab Combo® pigmentation MI% values were able to be classified into pigmentation categories of the mVSS, and pigmentation classification concordance was further improved with consideration of the scars DermaLab Combo® vascularity EI% values. The DermaLab Combo® is an objective tool; however, while the measurement provides continuous numerical data that may be useful for identifying change over time in clinical scar monitoring of pigmentation and vascularity, further work will be useful to understand the DermaLab Combo® measurements to optimise the interpretation of these data.