Unusual isolated cytomegalovirus cutaneous infections: A subtle histopathologic diagnosis with review of the literature.

Cytomegalovirus (CMV) infection is common and often self-limited. Reactivation results in a variety of disease presentations, especially in the setting of immunocompromise. While cutaneous manifestations of systemic CMV infection are rare, dermatologic manifestations of CMV are increasingly reported with a wide morphologic spectrum clinically. Three male patients, with untreated human immunodeficiency virus (HIV), penile lichenoid dermatitis treated with long-term topical and intralesional corticosteroids, and metastatic Merkel cell carcinoma on immune checkpoint inhibitor therapy, each presented with isolated cutaneous ulcers. The ulcers were located on the perianal skin, glans of the penis, and distal thumb. In each case, nonspecific histopathologic features were seen. However, very rare dermal cytomegalic cells with nuclear and cytoplasmic inclusions were present and highlighted with an immunohistochemical stain for CMV. Isolated ulcers due to CMV infection may occur in the setting of systemic or localized immunosuppression. A high index of suspicion is needed upon histopathologic evaluation, as few cytomegalic cells may be present and accurate diagnosis is crucial for prompt and appropriate clinical management.

[Experimental Study of Using Aloe Vera Gel to Treat Diabetic Chronic Cutaneous Ulcers in Bama Miniature Pigs].

Objective: To investigate the efficacy, safety, and mechanism of topical application of aloe vera gel (AVG) to treat diabetic chronic cutaneous ulcers in Bama miniature pigs. Methods: The Bama miniature pig model of diabetic chronic skin wounds was constructed and the model pigs were randomly assigned to AVG daily administration group (AVG QD), aloe vera gel every-other-day administration group (AVG QOD), and diabetic control group (DC). A non-diabetic chronic skin wounds model pig was set as the non-diabetic control group (NDC). Treatment efficacy was evaluated based on the amount of time needed for complete healing of the wounds, healing rates, granulation growth rates, and skin histopathological changes. Safety was evaluated according to whether adverse reactions were observed. In addition, the dynamic changes of the relative expression levels of miR21, miR29a, miR126, miR146a, miR155, and miR210 in wound granulation tissues were examined. Results: 1) Efficacy and safety: The amount of time needed for complete healing of the wounds was shorter in the NDC group than those of the three other groups, DC group, AVG QD group, and AVG QOD group (all P<0.05). The amount of time needed for complete healing of the wounds was shorter in the AVG QD group and AVG QOD group than that of DC group (all P<0.05). The amount of time needed for complete healing of the wounds was shorter in the AVG QOD group than that of AVG QD group (all P<0.05). No adverse reactions were detected in the whole process of AVG topical treatment. The granulation growth rate of NDC group was higher than those of DC group, AVG QD group, and AVG QOD group (all P<0.05). The wound healing rate of NDC group was higher than those of DC group, AVG QD group, and AVG QOD group (all P<0.05); the wound healing rate of AVG QOD group was higher than those of DC group and AVG QD group (all P<0.05). 2) Histopathology: The results of HE staining light microscopy showed that collagen fiber production increased, and that microvascular formation with slight inflammatory cell infiltration was observed in the dermal interstitium at the initial stage of wound healing after AVG treatment. One year of after complete healing, pathological examination results of wound healing skin showed that the epidermal keratinization was complete, that collagen was arranged neatly and orderly, and that many microvessels were found in the interstitium. The results of picric acid celestite scarlet staining showed that, after AVG treatment, type Ⅰ collagen mainly increased in the initial stage of wound healing, type Ⅲ collagen gradually increased when the wound healed completely, and the collagen was arranged neatly during the whole process. 3) The relative expression of microRNAs: The relative expression of miR21, miR126, and miR210 in NDC group, AVG QD group, and AVG QOD group were higher than that in DC group (all P<0.05). The relative expression of miR29a and miR155 in NDC group, AVG QD group, and AVG QOD group was lower than that in DC group (all P<0.05). The relative expression of miR146a in NDC group was higher than that in DC group ( P<0.05). Conclusion: AVG topical application can shorten the time needed for complete healing of diabetic chronic wounds in Bama minipigs. The wound healing speed of the alternate-day treatment group was faster than that of the daily treatment group. No adverse reactions were observed over the course of the treatment. The mechanism may be related to the up-regulation of the expressions of miR21, miR126, and miR210 and the down-regulation of miR29a and miR155 in wound granulation tissue.

Cytomegalovirus-induced cutaneous ulcer mimicking vasculitis in a patient with systemic lupus erythematous: A case report and review of the literature.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which can be complicated with cytomegalovirus (CMV) infection during its course. CMV reactivation can mimic an SLE flare and lead to delay in diagnosis. Here, we reported a previously diagnosed SLE patient who presented with fever, leukopenia, and cutaneous ulcers. Initially, this was diagnosed as an SLE flare and the patient was treated with higher doses of corticosteroids but no improvement was observed. Both nuclear and cytoplasmic inclusions inside the endothelial cells in the skin biopsy as well as positive immunohistochemistry (IHC) staining for CMV antigen were clues to the correct diagnosis of CMV reactivation. Treatment with ganciclovir resulted in clinical resolution. In this report, a very rare clinical form of CMV infection manifesting as cutaneous necrotizing vasculitis on the lower extremity is described and the literature regarding this case is reviewed.

Clostridioides difficile-related toxic megacolon after Cryptococcus neoformans cellulitis: A complex of two rare infections in an immunocompromised host.

A 76-year-old Japanese woman was admitted due to uncontrolled cellulitis of the right lower leg. She had deep vein thrombosis on the right limb. Moreover, she had a long history of rheumatoid arthritis treated with corticosteroids. Skin biopsy and lumbar puncture were performed to diagnose disseminated cryptococcosis. She was administered antifungal agents (liposomal amphotericin B and 5-fluorocytosine). On treatment day 14, debridement was performed, and cryptococcosis was controlled. However, she developed toxic megacolon due to Clostridioides difficile infection (CDI). On day 32, she was transferred to the intensive care unit due to severe acidosis and acute kidney injury secondary to CDI-related toxic megacolon. Vancomycin, metronidazole, and tigecycline were administered for treatment of CDI. After several weeks of intensive care, toxic megacolon was improved, but renal replacement therapy was discontinued according to the patient's will. On day 73, she died of renal failure. We experienced a complex of rare diseases, Cryptococcus neoformans cellulitis and Clostridioides difficile-related toxic megacolon. Both diseases were presumed to be the result of corticosteroid and methotrexate use. Hence, careful monitoring is required when treating immunocompromised hosts to reduce the risk of developing complications.

Estimation of Biological Parameters of Cutaneous Ulcers Caused by Leishmaniasis in an Animal Model Using Diffuse Reflectance Spectroscopy.

Cutaneous leishmaniasis (CL) is a neglected tropical disease that requires novel tools for its understanding, diagnosis, and treatment follow-up. In the cases of other cutaneous pathologies, such as cancer or cutaneous ulcers due to diabetes, optical diffuse reflectance-based tools and methods are widely used for the investigation of those illnesses. These types of tools and methods offer the possibility to develop portable diagnosis and treatment follow-up systems. In this article, we propose the use of a three-layer diffuse reflectance model for the study of the formation of cutaneous ulcers caused by CL. The proposed model together with an inverse-modeling procedure were used in the evaluation of diffuse-reflectance spectral signatures acquired from cutaneous ulcers formed in the dorsal area of 21 golden hamsters inoculated with Leishmanisis braziliensis. As result, the quantification of the model's variables related to the main biological parameters of skin were obtained, such as: diameter and volumetric fraction of keratinocytes, collagen; volumetric fraction of hemoglobin, and oxygen saturation. Those parameters show statistically significant differences among the different stages of the CL ulcer formation. We found that these differences are coherent with histopathological manifestations reported in the literature for the main phases of CL formation.

Two-Dimensional and Three-Dimensional Ultrasound of Artificial Skin.

Wound healing may be a difficult problem, and variable types of artificial skin prototypes have been developed for supporting this process. Using ultrasound, we studied 4 cellulose-derived artificial skin prototypes and assessed their two-dimensional and three-dimensional morphology. These prototypes were identified on ultrasound both on in vitro and in vivo studies. They allowed the sonographic observation of deeper layers on different types of surfaces of the body with good definition on the in vivo examinations performed on healthy skin and cutaneous ulcers. The ultrasound detection of these artificial biomaterials may potentially support the noninvasive monitoring of wound healing.

Using 16s rRNA sequencing to characterize the microbiome of tropical cutaneous ulcer disease: insights into the microbial landscape and implications for diagnosis and treatment.

Cutaneous ulcers are common in yaws-endemic areas. Although often attributed to 'Treponema pallidum subsp. pertenue' and Haemophilus ducreyi, quantitative PCR has highlighted a significant proportion of these ulcers are negative for both pathogens and are considered idiopathic. This is a retrospective analysis utilising existing 16S rRNA sequencing data from two independent yaws studies that took place in Ghana and the Solomon Islands. We characterized bacterial diversity in 38 samples to identify potential causative agents for idiopathic cutaneous ulcers. We identified a diverse bacterial profile, including Arcanobacterium haemolyticum, Campylobacter concisus, Corynebacterium diphtheriae, Staphylococcus spp. and Streptococcus pyogenes, consistent with findings from previous cutaneous ulcer microbiome studies. No single bacterial species was universally present across all samples. The most prevalent bacterium, Campylobacter ureolyticus, appeared in 42% of samples, suggesting a multifactorial aetiology for cutaneous ulcers in yaws-endemic areas. This study emphasizes the need for a nuanced understanding of potential causative agents. The findings prompt further exploration into the intricate microbial interactions contributing to idiopathic yaw-like ulcers, guiding future research toward comprehensive diagnostic and therapeutic strategies.

[Analysis of notifications of drug-induced skin ulcers in Spain]. / Análisis de las notificaciones de úlceras cutáneas inducidas por medicamentos en España.

Skin ulcers are a serious health problem with significant socioeconomic and labour repercussions and a high tendency to chronicity and recurrence; approximately, up to 50% remain active between six months to one year. AIM: To study the role of drugs in the aetiology of skin ulcers. MATERIAL AND METHOD: A comprehensive study of all spontaneous reports related to skin ulcers that appear in the Spanish Pharmacovigilance System of Medicines for Human Use database. RESULTS: A total of 292 reports were identified containing suspected adverse drug reactions (ADRs) of ulcer lesion type. Three hundred sixty-nine medications with 427 active ingredients were identified. The ulcers appeared mainly in women with a mean age of 56.6 years. The most frequently reported suspected drugs were SGLT-2, vaccines against COVID-19, methotrexate, hydroxycarbamide, trimethoprim-sulfamethoxazole, foscarnet trisodium hexahydrate, ribavirin, docetaxel, acenocumarol and imiquimod, and the combination of lidocaine Hcl-pentosan polysulfate sodium-triamcinolone acetonide. DISCUSSION: Numerous medications may cause ulcers as an adverse reaction. This possibility should not be ruled out when a new skin lesion appears after the administration of new drugs since 25% of the ADRs were unknown at the time of their notification, as were the cases of ulcers associated with i-SGLT2 and vaccines against COVID at the beginning of their commercialization. However, informative health alerts can be generated by continuously notifying suspected ADRs, so we strongly advise reporting any suspected ADRs to the regional pharmacovigilance system.

Spider Bite Presenting as Fever, Macrophage Activation Syndrome and a Skin Ulcer.

Introduction: Fever of unknown origin (FUO) refers to a condition of prolonged increased body temperature, without identified causes. The most common cause of FUO worldwide are infections; arthropod bites (loxoscelism) should be considered in view of the spread of the fiddleback spider. Loxoscelism can present in a cutaneous form (a necrotic cutaneous ulcer) or in a systemic form with fever, haemolytic anaemia, rhabdomyolysis and, rarely, macrophage activation syndrome (MAS). For this suspicion, it is important to have actually seen the spider. Case description: A 71-year-old man was admitted to our department because of intermittent fever, arthralgia and a necrotic skin lesion on his right forearm that appeared after gardening. Laboratory tests were negative for infectious diseases, and several courses of antibiotics were administered empirically without clinical benefit. Whole-body computed tomography showed multiple colliquative lymphadenomegalies, the largest one in the right axilla, presumably of reactive significance. A shave biopsy of the necrotic lesion was performed: culture tests were negative and histological examination showed non-specific necrotic material, so a second skin and lymph node biopsy was performed. The patient developed MAS for which he received corticosteroid therapy with clinical/laboratory benefit. Cutaneous and systemic loxoscelism complicated by MAS was diagnosed. Subsequently, the second biopsy revealed morphological and immunophenotypic findings consistent with primary cutaneous anaplastic large cell lymphoma (PC-ALCL). Conclusions: Skin lesions and lymphadenomegalies of unknown origin should always be biopsied. It is very common to get indeterminate results, but this does not justify not repeating the procedure to avoid misdiagnosis. LEARNING POINTS: In case of necrotic skin lesions with fever, malignancy (and in particular cutaneous lymphoma) should always be considered.Misdiagnosis of loxoscelism is common. Definitive diagnosis requires the identification of the responsible spider.It is frequent to obtain inconclusive results from biopsies, but this does not justify not repeating the procedure to avoid misdiagnosis.

Study on the regulatory effect of Panax notoginseng saponins combined with bone mesenchymal stem cell transplantation on IRAK1/TRAF6-NF-κB pathway in patients with diabetic cutaneous ulcers.

Panax notoginseng saponins (PNSs) have been found as the major active ingredient of Panax notoginseng (Burkill) F.H.Chen (PN) leaves, which has the effect of reducing inflammatory response, facilitating fibroblast proliferation, as well as promoting angiogenesis. This study aimed to investigate the molecular basis of PNS combined with bone mesenchymal stem cells (BMSCs) for treating diabetic cutaneous ulcers (DCU) and its mechanism of action. METHODS: A total of 75 SD rats were selected to make diabetic cutaneous ulcers model. According random number table method, the rats were randomly divided into a control group, a DCU group, a BMSCs group, a PNS group and BMSCs + PNS group. Five groups of rats were given without treatment. After being treated for 7 days, the rats were anesthetized with pentobarbital, and granulation tissue was collected from the central point of the wound. They were used for pathological analysis, Western blot (WB) and polymerase chain reaction (PCR) assays. RESULTS: The wound healing area was the largest in the BMSCs + PNS group. HE staining results showed that the PNS + BMSCs group could promote the formation of new epidermis and reduce the infiltration of inflammatory cells. Immunohistochemistry (IHC) results showed that the PNS + BMSCs group could up-regulate the expression of Ki67 protein and cell proliferation. In addition, PNS combined with BMSCs up-regulated the expression of miR-146-5p and down-regulated the expression of IL-1ß, IL-6 and TNF-α, IRAK1, TRAF6 and p65 in the NF-κB signaling pathway (p < 0.05). CONCLUSIONS: PNS combined with bone mesenchymal stem cell transplantation up-regulated miR-146a-5p targeting and binding to IRAK1/TRAF6, inhibiting the activation of NF-κB pathway, which reduced the inflammatory response of DCU and facilitated the skin healing of DCU. Thus, this study provides a theoretical basis and a novel therapeutic option for the treatment of DFU with PNS combined with BMSCs.

Calciphylaxis in a Biopsy of Pyoderma Gangrenosum in a Patient Without End-Stage Kidney Disease.

Calciphylaxis is a rare condition characterized by calcification of the blood vessels in the subcutaneous tissue with tissue ischemia. Calcium deposition is observed within scarred and occluded blood vessels of the subcutaneous tissue when a biopsy of the lesion is performed. Calciphylaxis is usually associated with end-stage kidney disease. We describe the case of a patient with mild renal insufficiency and without end-stage kidney disease, who underwent a wound biopsy with pathology suggestive of pyoderma gangrenosum with calciphylaxis. The wound was successfully treated with surgical debridement, topical antibiotic, and systemic steroid therapy with significant improvement over the course of management. The patient underwent a workup in order to determine the potential causes of calciphylaxis.

Comprehensive Analysis of Cell Therapy on Chronic Skin Wound Healing: A Meta-Analysis.

Wound healing has been greatly challenging in different acute and chronic skin injuries. Among them, nonrevascularizable critical limb ischemic ulcers, venous leg ulcers, and diabetic lower limb or extremity ulcers are well-known refractory skin injuries that are difficult to treat. Partly differentiated, progenitor cell-based graft transplantation or direct injection of autologous stem cells might promote the wound healing process. Studies aiming to comprehensively analyze the effects of cell therapy on skin wound healing could provide clinical evidence for skin injury treatment. Different databases were searched for full-text publications on the comparison between cell therapy and regular therapy. Heterogeneity was detected by the I2 method, and a fixed effect model was applied for data pooling if heterogeneity was absent. Publication bias was analyzed using a funnel plot, and 10 studies were finally included in this study. After a long-term follow-up, fewer patients underwent major amputation in the cell therapy group, compared with the standard therapy group, and those in the cell therapy group were characterized by a smaller ulcer area. Moreover, there was a significant difference in the wound healing rate between the intervention and control groups. However, pain caused by skin wounds was hardly mitigated by cell therapy in patients with critical limb ischemia. In this study, cell therapy proved effective in decreasing the size of ulcers and improving the wound closure rate. Additionally, the major amputation rate was decreased in the cell therapy group. However, the symptoms of pain were hardly alleviated by cell therapy in patients with cutaneous ulcers caused by peripheral artery disease-related critical limb ischemia.

Cutaneous necrotic lesion: A wonderful delay adverse effect of interferon beta-1b injection for multiple sclerosis treatment.

Multiple sclerosis (MS) is a chronic and inflammatory autoimmune disease. These patients may manifest severe inflammatory cutaneous reactions after using interferon beta-1b. This article describes a 55-year-old man with severe injection site reactions after 10 years administration of interferon beta-1b. The biopsy specimens revealed skin and subcutaneous tissue necrosis. Histologic evaluation revealed nonspecific inflammatory reactions with no evidence of vasculitis or granulomatous reactions. Based on clinical and pathological findings, the diagnosis of skin and soft tissue necrosis due to interferon injection was given. The injection of interferon beta-1b in the affected areas was stopped, and the patient's clinical condition improved by wound care. This report is aimed to increase awareness about severe adverse skin reactions, which may infrequently occur with subcutaneous interferon beta-1b injection after several years. Early diagnosis of this reaction can help to prevent associated complications.

Consensus on the diagnosis and management of chronic leg ulcers - Brazilian Society of Dermatology.

BACKGROUND: Chronic leg ulcers affect a large portion of the adult population and cause a significant social and economic impact, related to outpatient and hospital care, absence from work, social security expenses, and reduced quality of life. The correct diagnosis and therapeutic approach are essential for a favorable evolution. OBJECTIVE: To gather the experience of Brazilian dermatologists, reviewing the specialized literature to prepare recommendations for the diagnosis and treatment of the main types of chronic leg ulcers. METHODS: Seven specialists from six university centers with experience in chronic leg ulcers were appointed by the Brazilian Society of Dermatology to reach a consensus on the diagnosis and therapeutic management of these ulcers. Based on the adapted DELPHI methodology, relevant elements were considered in the diagnosis and treatment of chronic leg ulcers of the most common causes; then, the recent literature was analyzed using the best scientific evidence. RESULTS: The following themes were defined as relevant for this consensus - the most prevalent differential etiological diagnoses of chronic leg ulcers (venous, arterial, neuropathic, and hypertensive ulcers), as well as the management of each one. It also included the topic of general principles for local management, common to chronic ulcers, regardless of the etiology. CONCLUSION: This consensus addressed the main etiologies of chronic leg ulcers and their management based on scientific evidence to assist dermatologists and other health professionals and benefit the greatest number of patients with this condition.

Development of de novo epithelialization method for treatment of cutaneous ulcers.

Cutaneous ulcers are a common cause of morbidity. We have developed a de novo epithelialization method for treating cutaneous ulcers by means of reprogramming wound-resident mesenchymal cells in vivo into cells able to form a stratified epithelium: induced stratified epithelial progenitors (iSEPs). Administration of 4 transcription factors (DNP63A, GRHL2, TFAP2A, and cMYC) expressed via adeno-associated viral vectors enabled generation of epithelial cells and tissues, thereby acheiving de novo epithelialization from the surfaces of cutaneous ulcers in a mouse model. Generated epithelia, having barrier functions equivalent to the original epidermis, were maintained for more than 6 months. Our findings constitute a proof of concept for future development towards innovative therapies for cutaneous ulcers via de novo epithelialization.

Methotrexate-induced nonhealing cutaneous ulcers in a nonpsoriatic patient without pancytopenia.

Methotrexate forms one of the main drugs in the pharmacological management of rheumatoid arthritis, psoriasis, and some neoplastic diseases. Methotrexate rarely causes cutaneous ulceration and most cases are reported in patients with psoriasis and have been accompanied by pancytopenia. The author here reports occurrence of multiple (two) cutaneous ulcers due to methotrexate in a nonpsoriatic patient. The patient was on methotrexate for seronegative rheumatoid arthritis for 10 years. To the best of the Author's knowledge, this is a rare case of cutaneous ulceration due to methotrexate in a nonpsoriatic patient reported in the literature so far, and probably one of its kind without pancytopenia or other hematological abnormalities. Stopping this medication led to complete healing of the ulcerated lesion in about four to six weeks.

"Malignant Cutaneous Ulcer".

Renal cell carcinoma (RCC) is an aggressive malignancy and the rich vascular supply enables it to metastasize early via haematogenous route. Skin lesions are a late manifestation of the disease. Clinicians should be aware of cutaneous presentation of RCC while evaluating a case of unknown primary with skin lesions.

Diagnóstico e tratamento de úlcera hipertensiva de Martorell: artigo de revisão / Diagnóstico y tratamiento de la úlcera hipertensiva de Martorell: artículo de revisión / Diagnosis and treatment of Martorell's hypertensive ulcer: review article

Introdução: A úlcera hipertensiva de Martorell é uma ferida crônica, associada a hipertensão arterial sistêmica, dedifícil manejo clínico e subdiagnosticada. Objetivo: Investigar os métodos de diagnóstico e os tratamentos existentes para a UHM. Método: Estudo descritivo e qualitativo de revisão integrativa com a análise sistemática de referências bibliográficas nas bases de dados PubMed, SciELO, MEDLINE e LILACS no período de 2016 e 2021, e periódicos da CAPES. Resultados: Clinicamente o paciente apresenta uma ferida pequena, de forma arredondada, superficial, com margens necróticas e cianóticas e eritema perilesional eventual. Os pulsos distais usualmente estão presentes e há ausência de edema e varizes locais. De todos os sinais e sintomas relatados, destaca-se a dor, descrita como intensa e desproporcional à sua dimensão. Conclusão: O cerne ao diagnóstico é avaliação clínica e o tratamento é a normalização da pressão arterial sistêmica e curativos regulares e, uso de analgésicos, antibióticos e vasodilatadores periféricos.(AU)

lntroduction: Martorell's hypertensive ulcer is a chronic wound, associated with systemic hypertension withdifficult clinicai management and it is often underdiagnosed. Goal: To investigate the diagnostic method and current treatments for Martorell's hypertensive ulcer disease. Method: A descriptive and qualitative study of integrative literature review with a systematic analysis of bibliographic references from PubMed, SciELO, MEDLINE and LILACS databases, ranging from 2016 to 2021, as well as selected articles from CAPES journals. Results: patients usually present with a small, rounded and superficial wound with cyanotic and necrotic edges and occasional perilesional erythema. Distal pulses are usually present and there is an absence of edema and local varicose veins. From all the signs and symptoms reported by patients with this type of injury, it is possible to point out that the pain is intense and disproportionate to its dimension. Conclusion: The core of diagnosis is the clinicai evaluation and the treatment is controlled systemic blood pressure, regular bandages and, if needed, analgesics, antibiotics and peripheral vasodilators. (AU)

lntrodución: La úlcera hipertensiva de Martorell es una herida crónica, asociada a la hipertensión arterial sistémica,de difícil manejo clínico y muchas veces subdiagnosticada. Objetivo: Investigar los métodos de diagnóstico y tratamientos existentes para este tipo de lesión. Método: Se realizá un análisis sistemático de referencias bibliográficas en las bases de datas PubMed, SciELO, MEDLINE y LILACS en el período de publicación entre 2016 y 2021, además de artículos seleccionados de revistas CAPES. Resultados: Clínicamente el paciente suele presentarse con una pequena herida, redondeada, superficial, con márgenes necróticos y cianóticos con eritema perilesional ocasional. Los pulsos distales suelen estar presentes y hay ausencia de edema y venas varicosas locales. De todos los signos y síntomas reportados por los pacientes con este tipo de lesiones, se destaca el dolor, que se describe como intenso y desproporcionado con la zona de la herida y su tamafio. Conclusión: La base dei tratamiento es la normalización de la presión arterial sistémica y los apósitos regulares y, si necesario, analgésicos, antibióticos y vaso dilatadores periféricos(AU)