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Cutaneous wound healing: an update.

Our understanding of wound-healing mechanisms has progressed over the past decade. Wound healing is traditionally divided into three phases--the inflammatory phase, the proliferation phase, and the remodeling phase--and involves a well-orchestrated interaction among blood vessels (platelets, macrophages, neutrophils, endothelial cells, and smooth muscle cells), epidermis (keratinocytes, melanocytes, and Langerhans cells), adnexal structures (outer root sheath cells and hair dermal papilla cells), dermis (fibroblasts and myofibroblasts), nervous system (neurons), and subcutaneous fatty layers (adipocytes). We review recent discoveries of basic and clinical aspects of wound healing including several revolutions that occurred in wound management: occlusive dressing therapy, use of living skin equivalents, and topical administration of growth factors. As we previously proposed, the use of tissue substitutes and autologous epidermal sheets led to a new concept of skin grafting through the keratinocyte activation phase in the graft healing mechanism. In this review, we also discuss a representative patient who presented with plantar wounds caused by calcaneal osteomyelitis and healed by the coverage of epidermal grafting.

Humans↗

A case of docetaxel-induced erythrodysesthesia.

Chemotherapy-induced acral erythema (CIAE) is a rare cutaneous reaction to high-dose chemotherapy, clinically featuring painful erythema on the palms and soles. Docetaxel (Taxotere), an anticancer agent, is known to cause various reactions, including CIAE. We experienced a case of docetaxel-induced acral erythema with facial edematous erythema that coincidentally emerged and regressed with appearance and disappearance of the acral lesions. Docetaxel-induced acral erythema exhibits a widespread distribution and intense sensations of intolerable pain and numbness. Therefore, some authors use the term erythrodysesthesia instead of acral erythema. We speculated that the facial erythema might be part of the spectrum of erythrodysesthesia. Our case was finally diagnosed as decetaxel-induced erythrodysesthesia. Although CIAE is self-limiting, the patients frequently require treatment because of intolerable pain. Reported treatments for CIAE include topical or systemic steroids, elevation of the legs, and application of cold compression to the lesion. In our case, application of a steroid ointment with the occlusive dressing technique (ODT) alleviated the clinical manifestations and was also prophylactic for the erythrodysesthesia.

Aged↗

A case of crusted scabies with a bullous pemphigoid-like eruption and nail involvement.

We report a case of a 71-year-old man infected at a nursing home who developed a bullous pemphigoid-like eruption with nail involvement. He was diagnosed by his family doctor as suffering from eczema and was treated with topical corticosteroids, then blisters started appearing. He was next diagnosed as suffering from bullous pemphigoid and treated with oral prednisolone, which worsened his condition. He was finally diagnosed as having crusted scabies with bullous pemphigoid-like eruptions and nail involvement at our clinic. He was then prescribed oral ivermectin (two doses of 12 mg ivermectin with a 1-week interval) and topical lindane (1%gamma-BHC in petrolatum) for scabies with 5% salicylic acid in plastibase as an additional treatment for the crusted lesions on his soles. He showed remarkable improvement in 2 weeks, and his nails showed complete recovery after 7 weeks of occlusive dressing treatment with 1%gamma-BHC. One and a half years later, the patient showed no sign of a recurrence of scabies. The histology of a blister taken from this patient was similar to that of bullous pemphigoid. Direct immunofluorescence showed immunoglobulin (Ig)G and C3 deposition at the dermoepidermal junction similar to that of bullous pemphigoid, but indirect immunofluorescence was negative. The bullous symptoms of this patient were considered to be due to the scabies, because the patient recovered completely after receiving treatment for scabies. Indirect immunofluorescent study is important to distinguish between scabies with blister formation and true bullous pemphigoid.

Aged↗

Experimentally induced steroid atrophy in the domestic pig and man.

A histological method of ranking topical steroid preparations according to the degree of epidermal thinning they cause in pig skin has been shown to be applicable to human skin. A 0-05% ointment of the new compound, clobetasone butyrate (Molivate), has been shown to cause less thinning than either fluocinolone acetonide 0-025% (Synalar) or flurandrenolone 0-0125% (Haelan) when applied without the use of occlusive dressings for 3 weeks to the human forearm.

Adult↗

Contact sensitivity to Candida albicans--comparative studies in man and animal (guinea-pig).

We studied the elicitation of contact sensitivity to Candida albicans antigen in guinea-pigs with experimental cutaneous candidiasis and in humans, using commercially available potent 1:100 C. albicans antigen (Torii) by patch testing on abraded skin. In guinea-pigs, non-immune animals became patch test-reactive 4-5 days after topical application of viable C. albicans, either under occlusion or without occlusive dressings, concurrently with the demonstrability of delayed responses to intradermally injected 1:10 000 Candida antigen. In humans, all healthy adults who showed delayed hypersensitivity reactions to intradermally injected 1:10 000 C. albicans antigen demonstrated positive patch-test reactions to 1:100 C. albicans antigen. There was a significant correlation between the magnitude of responses to these tests. In contrast, no positive patch test reactions were elicited to the 1:100 C. albicans antigen on neonatal skin, emphasizing the lack of irritability of this test agent. These results also indicate that in humans contact sensitivity to Candida antigen occurs during later life because C. albicans is a ubiquitous organism. The practical value of this Candida patch test for evaluation of patients' immune function was assessed by a prospective study in patients with various skin disorders. The results obtained suggested some potential value of the test for evaluation of cell-mediated immune function of patients with regard to ubiquitous recall antigens.

Adult↗

Time-course of corticosteroid-induced blood flow reduction in normal cutaneous tissue--quantitative measurements during 72 h of treatment.

In eight healthy individuals, the skin fold between the thumb and the forefinger was treated with 0.05% clobetasol propionate ointment under a hydrocolloid occlusive dressing. Using the atraumatic epicutaneous 133Xe wash-out technique on the outer 2 mm of the skin fold, covering the rest of the hand with a lead shield, we were able to monitor cutaneous blood flow. Blood flow was measured after 0, 10, 24, 48 and 72 h of treatment. During the first 10 h of treatment no significant change in blood flow was observed. However, compared to untreated tissue, cutaneous blood flow decreased significantly after a 24-h period (P less than 0.05). Furthermore a significant blood flow reduction from 0-48 (P less than 0.02) and from 0-72 h (P less than 0.01) was observed. Placebo did not decrease cutaneous blood flow, but a minor increase was demonstrated. The results of the present work demonstrate a long-lasting blood flow reducing effect of topical corticosteroid in normal human cutaneous tissue.

Adrenal Cortex Hormones↗

Percutaneous absorption of amorolfine following a single topical application of an amorolfine cream formulation.

In an open-label, parallel-group, randomized study percutaneous absorption of 14C-labelled amorolfine incorporated into a cream formulation was assessed in healthy male volunteers (n = 12). A single dose of 0.5 g of the 0.25% cream formulation was applied to 100 cm2 of intact (n = 6) and stripped (n = 6) skin for 24 h using occlusive dressing. The remaining drug was removed and the treated skin area of both groups was stripped with adhesive tape. Total urine and faeces were collected in portions up to 3 weeks after the experiment and blood samples were taken at intervals for 3 weeks. Radioactivity was measured in the skin strippings and in the urine, faeces and plasma samples. The intact drug was assessed in the plasma samples. Using mass balance techniques it could be shown that a mean of 92% (range: 84-101%) of the applied radioactivity could be recovered. Small differences in the absorption and elimination of the radioactivity were observed between the two groups but they were not statistically significant (alpha = 0.05). Therefore data from the two groups were pooled. Elimination of drug and drug-related material from the body was very slow. During the 3-week collection period, a mean of 7% (range: 3.8-10.2%) of the dose was excreted in urine and faeces. Another 0.9-3.3% of the dose was retained in the upper layers of the skin as shown by the skin strippings after treatment. Levels of radioactivity and of intact drug in plasma were below the detection limit of 0.5 ng-equiv./ml, respectively. Present data suggest that mean percutaneous absorption of amorolfine following topical application of the 0.25% cream formulation should not exceed 8-10% of the dose applied.

Administration, Cutaneous↗

Simplified experimental human dermatophytosis model.

The authors have improved and simplified previous methods for producing localized mycotic skin infections in an attempt to compare topical antifungal agents for their bioequivalency. Healthy human volunteers who had negative results for commercial, purified Trichophyton antigen (Trichophytin) were inoculated with Trichophyton mentagrophytes on two sites on each forearm in a randomized study designed to compare the antifungal activities of two ciclopirox olamine formulations. The lesions, easily induced by the authors' method, were localized and did not spread under the occlusive dressings. Infections established at the four sites on 26 subjects were treated twice daily for 14 days with the two active drug formulations and their vehicles. There were no significant differences in culture-documented cure rates or alleviation of clinical signs and symptoms between ciclopirox olamine lotion and cream. Each drug was significantly better than its vehicle. The authors' method seems to be effective and suitable for therapeutic studies.

Adult↗

Clinical study with allogeneic cultured dermal substitutes for chronic leg ulcers.

BACKGROUND: Clinical studies of the use of allogeneic cultured dermal substitutes (CDSs) have been conducted in 30 medical centers across Japan with the support of the Millennium Project of the Ministry of Health, Labor and Welfare. The CDS is prepared by plating cultured fibroblasts on a spongy matrix made from hyaluronic acid and atelo-collagen. The aim of the present clinical study was to evaluate an allogeneic CDS as cell therapy in which cytokines are released to promote wound healing. MATERIALS AND METHODS: The CDS was applied repeatedly at an interval of 5-7 days to 13 patients being treated with intractable chronic leg ulcers, using the CDS as a dermatological treatment. Intractable leg ulcers, whether venous or arterial, are difficult to heal because they occur as a secondary change of disease. RESULTS: None of these patients had responded to conventional therapies such as topical or surgical methods, but 77% of the patients had an efficacy score of > 80 points for wound healing with allogeneic CDS. A high safety level was obtained: A, 84.6%; B and C, 7.7%; D, 0%. In 92% of the patients, the final assessment of wound healing was good or very good. CONCLUSIONS: For promotion of wound healing, the present CDS is superior to existing topical agents and occlusive dressings.

Aged↗

Multiple periungual pyogenic granulomas following systemic 5-fluorouracil.

A 65-year-old man presented with a 7-month history of eight bleeding periungual lesions on both feet. The clinical diagnosis of multiple pyogenic granulomas was confirmed by histological examination. Historically, the pyogenic granulomas appeared 3 months after commencing 5-fluorouracil chemotherapy for rectal carcinoma, suggesting a possible causative relationship. Chemotherapy was ceased by the supervising oncologist. Resolution occurred after two lesions had been treated with curettage and diathermy, and the remaining lesions with occlusive dressings over Kenacomb ointment (triamcinolone acetonide 0.1%, neomycin sulphate 0.25%, gramicidin 0.025%, nystatin 100,000 U/g) topically twice daily for a period of 3 months.

Adenocarcinoma↗

Efficacy and safety of a new clobetasol propionate 0.05% foam in alopecia areata: a randomized, double-blind placebo-controlled trial.

BACKGROUND: Clinical efficacy of topical corticosteroids in alopecia areata (AA) is still controversial. Positive clinical results have been obtained using ointments with occlusive dressing but this approach has a low patient compliance. Recently, a new topical formulation (thermophobic foam: Versafoam) of clobetasol propionate 0.05% has been introduced on the market (Olux, Mipharm, Milan, Italy) (CF). This formulation is easy to apply. After application to the skin the foam quickly evaporates without residues and it has a good patient compliance. In vitro studies have also shown that this formulation enhances the delivery of the active compound through the skin. AIM: To evaluate the efficacy, safety and tolerability of CF in the treatment of moderate to severe AA. SUBJECTS AND METHODS: Thirty-four patients with moderate to severe AA (eight men, mean age 40+/-13 years) were enrolled in a randomized, double-blind, right-to-left, placebo-controlled, 24-week trial. Alopecia grading score (AGS) was calculated at baseline and after 12 and 24 weeks of treatment using a 0-5 score (0=no alopecia; 5=alopecia totalis). Clobetasol foam and the corresponding placebo foam (PF) were applied twice a day for 5 days/week for 12 weeks (phase 1) using an intrapatient design (right vs. left). From weeks 13 to 24 each enrolled patient continued only with the treatment (both on the right and left site) that was judged to have a greater efficacy than that on the contralateral side (phase 2). The primary outcome of the trial, evaluated on an intention-to-treat basis, was the hair regrowth rate, which was evaluated using a semiquantitative score (RGS) (from 0: no regrowth, to 4: regrowth of 75%). RESULTS: At baseline the AGS was 4.1 (range: 2-5). Nine (26%) patients prematurely concluded the trial. At the end of phase 1, a greater hair regrowth was observed in 89% of the head sites treated with CF vs. 11% in the sites treated with PF. The RGS was 1.2+/-1.6 in the CF-treated sites and 0.4+/-0.8 in the PF-treated sites (P=0.001). A RGS of 2 (hair regrowth of more than 25%) was observed in 42% CF-treated sites and in 13% of PF-treated sites (P=0.027). In seven subjects (20%) a RGS of 3 to 4 (hair regrowth of 50%) was observed in CF-treated sites. In three subjects (9%) a RGS of 4 (hair regrowth of 75%) was observed in CF-treated sites. In one patient only, in a PF-treated region, a RGS of 3 was observed. The AS was reduced to 3.8 by CF treatment at the end of phase 1 and to 3.3 at the end of phase 2 (P=0.01). From weeks 12 to 24 the treatment with CF induced a further increase in the RGS (from 1.2 to 1.5+/-1.4). Forty-seven per cent of CF-treated patients had a RGS of 2 at the end of the trial. A total of eight patients (25%) at the end of the treatment with CF showed a RGS of 3. Folliculitis occurred in two patients. No significant modifications in cortisol and ACTH blood levels were observed during the trial. CONCLUSION: This new formulation of clobetasol propionate foam is an effective, safe and well-tolerated topical treatment for AA. This formulation has a good cosmetic acceptance and patient compliance profile.

Administration, Topical↗

EMLA. A new and effective topical anesthetic.

A eutectic mixture of local anesthetics (EMLA) contains 2.5% lidocaine and 2.5% prilocaine in an oil and water emulsion and has been found to give effective, safe analgesia on normal and diseased skin, making it useful for numerous medical and surgical procedures, such as anesthesia for superficial surgery, split-thickness skin grafts, venipuncture, argon laser treatment, epilation, and debridement of infected ulcers. Other indications have included use in postherpetic neuralgia, hyperhidrosis, painful ulcers, and inhibition of itching and burning. To be effective, EMLA should ideally be applied to the desired area for at least 1 hour under an occlusive dressing. The medication has been approved since May 1991 in Canada for use on intact skin and has been available in Europe for many years. This study discusses the background, efficacy, and current and potential uses of EMLA.

Administration, Cutaneous↗

Infections complicating pulsed carbon dioxide laser resurfacing for photoaged facial skin.

BACKGROUND: With proper technique and instrumentation, laser resurfacing for facial wrinkles has been found to be highly effective and relatively safe. Most, if not all, of the noninfectious complications such as pigmentary changes, scarring, and persistent erythema can either be avoided or managed with appropriate therapy. Postoperative infections, on the other hand, may develop despite proper technique and instrumentation. Without proper management, they may cause significant physical morbidity and psychological distress defying the expected benefit of the procedure. OBJECTIVE: To quantify the incidence and to study the characteristics of infections arising after laser resurfacing for facial wrinkles with pulsed carbon dioxide laser treatment. METHOD: A retrospective study was carried out by reviewing the records of all patients undergoing laser resurfacing for facial wrinkles from January 1, 1995 to April 30, 1996. An infection is defined as a positive culture in the presence of signs or symptoms of an infection. RESULTS: Over 16 months, 395 procedures were performed and 17 cases of culture-proven infection recorded, an incidence of 4.3%. All patients had symptoms starting between days 2 and 10 after the operation. Over half of the patients had multiple infections with two to three microorganisms. Pseudomonas aeruginosa was the most common causative agent, found in 41% of all infected cases, followed by Staphylococcus aureus (35%), S. epidermidis (35%), and Candida species (24%). Multiple drug-resistant, gram-negative bacteria were found in four cases, implicating the possibility of hospital-acquired infections. Almost all isolates of gram-positive bacteria were resistant to both erythromycin and penicillin, but not oxacillin. With proper treatment, most patients healed normally. Only one patient had persistent, multiple atrophic scars due to locally disseminated herpes simplex infection despite proper prophylaxis and treatment. CONCLUSIONS: Postoperative infection is uncommon and manageable with early recognition and proper treatment. The types of infectious agents being found are very similar to those reported in burn patients. This complication has been found to be much more common in patients undergoing full face resurfacing and those using a bio-occlusive dressing postoperatively. With comprehensive preventive and management measures, it is likely that this type of uncommon, yet distressful, complication can be avoided and more successfully treated. Recommendations are made for prevention and management of suspected postoperative infections.

Candidiasis↗

EMLA and ear surgery: is it possible to achieve full-thickness anesthesia with EMLA?

BACKGROUND: Topical local anesthetic applications offer painless, effective analgesia with slow onset but prolonged duration and minimal side effects. EMLA (Eczacibasi Pharmaceuticals, Istanbul, Turkey) is the most universally used topical local anesthetic. OBJECTIVE: The aim of this prospective, randomized, double-blind study is to evaluate the efficacy of EMLA on total anesthesia of the external ear. METHODS: Twenty-two patients with helical lesions were divided into two groups. Group A received EMLA on both the anterior and posterior surfaces of the ear, and group B received EMLA on only one side of the ear. After 120 minutes of occlusive dressing, the surgery was performed. The short form of the McGill Pain Questionnaire and a numerical visual analog scale were used to measure overall pain quality and intensity during and at the end of surgery. RESULTS: Visual analog scale scores (four for group A and six for group B6) between two groups using Student's t-test (p=0210) and concerning McGill Pain Questionnaire scores with Wilcoxon signed ranks test (p=0.058) between two groups showed no statistical significant difference. CONCLUSION: It seems that EMLA cream is not a good and first option for achieving full anesthesia on the ear because of its poor anesthetic effect. We do not consider EMLA cream to be clinically useful for major surgical attempt on the ear.

Adolescent↗

Discrete pigmentation after chemotherapy.

Discrete areas of cutaneous hyperpigmentation were seen in two children with metastatic sarcoma who received chemotherapeutic bone marrow ablation with cyclophosphamide, etoposide, and carboplatin prior to autologous bone marrow transplantation. The hyperpigmented patches occurred only in areas of skin occluded by tape, electrocardiogram pads, or elastic bandages. Identical skin findings were reported in five adult women who received intravenous thiotepa and cyclophosphamide. Measurable levels of thiotepa were detected in these patients' serum, skin, sweat, and occluded gauze, suggesting that the chemical was excreted onto the skin surface in sweat and accumulated under occlusive dressing, thus producing some toxic effect on the epidermis or melanocytes resulting in abnormal pigmentation. We suspect that a similar mechanism was operative in our patients to produce the unusual patterned hyperpigmentation, and suggest that this complication may be prevented by minimizing sweat accumulation in areas occluded by adhesive materials.

Adolescent↗

Development of a histomorphologic scale to quantify cutaneous scars after burns.

OBJECTIVE: Cutaneous wound healing in adults invariably results in scarring; however, there are few scales to quantify the degree of such scarring. The authors developed a histomorphologic scale for quantifying scarring after cutaneous burn injury. METHODS: As part of a randomized trial comparing a variety of burn therapies, 40 partial-thickness burns were created on the backs and flanks of anesthetized pigs and treated with a tissue adhesive, antibiotic ointment, occlusive dressing, or dry gauze. Gross scar appearance was independently assessed by two investigators at 90 days on a 100-mm visual analog scale (VAS) marked "best appearance" at the high end. One of the investigators repeated the observation 30 days later. Full-thickness biopsies were taken 90 days after injury and evaluated histologically by a dermatopathologist for the presence of hyperkeratosis, epidermal hyperplasia, presence and depth of scar (defined as abnormally oriented collagen under polarized light), fibroplasia, vascular proliferation, and absence of adnexa, including hair follicles, apocrine glands, and smooth muscles. One point was assigned for each category in the presence of a normal finding, whereas an abnormal finding was assigned a score of zero. The normal dermis (absence of abnormal collagen) was given a score of 3, while decreasing scores of 2 to 0 were given for progressively deeper scars (i.e., 2 for papillary dermis, 1 for upper half of reticular dermis, and 0 for deep dermal lower half). The total histomorphologic score was derived by adding the scores on the individual items. The score ranges from 0 to 10 from worst scarring to absence of scarring, respectively. A subset of observations was evaluated a second time by one of the observers one month later. Intraobserver reliability of the histomorphologic scale was assessed with Spearman's correlation. Inter- and intraobserver Pearson's correlations for the gross scar VAS were calculated, and the correlation between gross and histomorphologic scores was assessed. RESULTS: Intraobserver correlation for individual histomorphologic categories ranged from 0.19 to 1.00. Intraobserver correlation for the total histologic score was 0.95. Inter- and intraobserver correlations for the gross scar VAS were 0.8 each. Correlation between the histomorphologic scale and the gross scar VAS was 0.38. CONCLUSIONS: A new reliable histomorphologic method for quantifying and scoring cutaneous scars is described together with a reliable scar VAS. However, these two scales are not highly correlated.

Adult↗

Photodynamic therapy of interdigital mycoses of the feet with topical application of 5-aminolevulinic acid.

BACKGROUND: Findings of in vitro studies have demonstrated that dermatophytes and yeasts can be effectively photosensitized after topical delivery of 5-aminolevulinic acid (ALA). This procedure, called photodynamic therapy (PDT), seems to lack mutagenic activity and hazard of selection of drug-resistant strains. METHODS: Twenty percent ALA preparation in Eucerin cream was applied under an occlusive dressing to skin lesions of nine patients with clinical and microbiological evidence of interdigital mycosis of the feet. After 4 h, lesions were irradiated with 75 J/cm(2) of broad-band red light. Interdigital lesions of the other foot served as control (treated with only light or only ALA). After 7 days from the first treatment, no further treatment was delivered if lesions were not clinically evident and direct microscopic examination was negative. Otherwise, three additional weekly treatments were delivered. Four weeks after the last treatment, patients had a final follow-up clinical and laboratory examination. RESULTS: Clinical and microbiological recovery was seen in six out of nine patients after one (four cases) or four (two cases) treatments. However, after 4 weeks, recurrences were seen in four patients. Overall tolerability was always good. CONCLUSION: Under the conditions employed in the present study, ALA-PDT had good therapeutic effects on interdigital mycosis of the feet. However, recurrences were quick. In vivo environmental conditions, i.e. temperature, humidity and pH of the interdigital skin, could induce a poor cell uptake of ALA and a deficient biosynthesis of photosensitizing protoporphyrin IX. In addition, the irregular tridimensional shape of this peculiar anatomical area could lead to a non-uniform delivery of light and/or ALA cream. However, the present results can stimulate further studies on the PDT of superficial skin mycoses.

Administration, Cutaneous↗

Photodynamic therapy with methylaminolevulinate as a valuable treatment option for unilesional cutaneous T-cell lymphoma.

BACKGROUND: Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma (CTCL). Unilesional MF is characterized by a limited involvement of the skin and a chronical, though indolent course. If lesions are refractory to topical steroids, therapies such as localized chemotherapy, photochemotherapy and radiotherapy are available. However, they have several acute and chronic side-effects and toxicity may accumulate if repeated and protracted treatment cycles are delivered to refractory or relapsing lesions. The present study aims to assess the efficacy of photodynamic therapy (PDT) with topical methylaminolevulinate (MAL) in the treatment of unilesional MF. METHODS: Five patients were enrolled who had unilesional MF that did not respond to treatment with topical steroids, localized psoralen and UVA therapy or UVA1 phototherapies. A 20% MAL (Metvix cream) cream was applied under occlusive dressing for 3 h. Soon afterwards, skin was irradiated with 37.5 J/cm(2) of red light (635+/-18 nm) delivered by an Aktilite CL128 lamp (PhotoCure ASA) with an irradiance of 86 W/cm(2) at skin level. PDT was repeated once weekly until complete clearing of the lesions was obtained, or, in the case of partial clearing, the therapy was interupted when three successive treatments provided no further improvement. All patients underwent a skin biopsy before and after PDT. RESULTS: A complete remission was observed in four patients and a partial improvement in one. The median number of treatments was six (range 1-9). In no cases was recurrence seen at follow-up (ranging from 12 to 34 months). Treatments were well tolerated and local anesthesia was never requested. CONCLUSION: In conclusion, here, PDT was seen to be an effective and well-tolerated treatment option for unilesional MF.

Administration, Cutaneous↗