Non-healing Lesions Research Articles

BOB.1/OBF.1 controls the balance of TH1 and TH2 immune responses

BOB.1/OBF.1 is a transcriptional coactivator essential at several stages of B-cell development. In T cells, BOB.1/OBF.1 expression is inducible by co-stimulation. However, a defined role of BOB.1/OBF.1 for T-cell function had not been discovered so far. Here, we show that BOB.1/OBF.1 is critical for T helper cell function. BOB.1/OBF.1(-/-) mice showed imbalanced immune responses, resulting in increased susceptibility to Leishmania major infection. Functional analyses revealed specific defects in TH1 and TH2 cells. Whereas expression levels of TH1 cytokines were reduced, the secretion of TH2 cytokines was increased. BOB.1/OBF.1 directly contributes to the IFNgamma and IL2 promoter activities. In contrast, increased TH2 cytokine production is controlled indirectly, probably via the transcription factor PU.1, the expression of which is regulated by BOB.1/OBF.1. Thus, BOB.1/OBF.1 regulates the balance of TH1 versus TH2 mediated immunity.

Imported Cutaneous Melioidosis in Traveler, Belgium

To the Editor: In some tropical areas, melioidosis, a disease caused by infection with Burkholderia pseudomallei, results in sepsis (1). This disease affects mostly adults with an underlying predisposing condition (2). With the increase in international travel, melioidosis has been identified in patients returning from disease-endemic areas (3). We report a case of a travel-associated cutaneous melioidosis without any systemic involvement. A 90-year-old woman came to the Hopital Erasme in Brussels with a nonhealing erythematous and ulcerated cutaneous lesion on the side of her left elbow. The lesion was a papule that gradually increased in size. The patient had diabetes mellitus but was otherwise healthy when she had traveled to Bangladesh 8 weeks earlier. She stayed 3 weeks in a village in the northwestern area of Rangpur District during the rainy season. She reported multiple insect and mosquito bites that evolved into intensely pruritic papules. This led to uncontrolled scratching and repeated washing of bite lesions with untreated well water. Two weeks after her return, the lesion developed; it increased steadily in size, despite application of topical antimicrobial ointment. Three weeks later, after three visits to a physician, she was admitted to our institution. She did not report any fever, rigors, sweating, malaise, weight loss, or respiratory symptoms. Skin examination showed an irregular (3.0 cm × 4.0 cm), erythematous, fluctuant, tender, painful plaque (Appendix Figure, panel A). She did not have palpable regional lymph nodes. Results of a physical examination and laboratory investigations were normal. Five blood cultures at different times failed to isolate any microorganism. A skin biopsy specimen from the plaque showed an inflammatory granulomatous reaction. Gram staining of biopsy specimens showed scanty lymphocytes, no polymorphonuclear leukocytes, and no microorganisms. Specimens were ground and placed on Columbia agar containing 5% horse blood and Schaedler enrichment broth and incubated aerobically for 3 days and on Schaedler agar containing 5% horse blood and incubated anaerobically for 10 days. After 72 hours, Schaedler broth showed a few colonies of an aerobic gram-negative bacillus that was identified as B. pseudomallei on the basis of typical biochemical characteristics. The strain was mobile at 37°C; grew at 42°C, oxidized but did not ferment glucose; produced cytochrome oxidase, arginine dihydrolase, and gelatinase; and was resistant to 300 IU polymyxin B 300 (DiaTabs; Rosco, Taastrup, Denmark). The isolate had a negative reaction for metabolism of arabinose. Antimicrobial drug testing showed susceptibility to temocillin, amoxicillin-clavulanic acid (MIC 2 mg/L), piperacillin-tazobactam, ceftazidime, cefepime, meropenem (MIC 0.75 mg/L), doxycycline, and cotrimoxazole, and resistance to cefazolin, cefoxitin, ampicillin, gentamicin, ciprofloxacine, and amikacin. Results of tests for systemic involvement, as well as sputum and urine cultures, were negative. The patient was discharged and received oral doxycycline, 100 mg twice a day, and amoxicillin/clavulanic acid, 875 mg twice a day, for 32 weeks. The lesion dramatically improved 8 weeks after treatment was started (Appendix Figure, panel B) and had disappeared by 20 weeks after treatment was started (Appendix Figure, panel C). At 24 months after the diagnosis, no relapse had occurred. Our patient with imported melioidosis had an unusual clinical course. She had never been febrile and had an uncomplicated localized skin infection skin despite her predisposing diabetes. A similar course has been reported in 2 tourists from Finland after the tsunami in Thailand in December 2004 (4), but most imported cases have pulmonary or systemic involvement associated with a severe prognosis (5,6). The mode of acquisition in our patient herein was probably by an insect bite, contaminated water, or direct contact with wet soil during the rainy season. This mode of acquisition reinforces the hypothesis of a predominant role of percutaneous B. pseudomallei infection (7). Although the lesion healed, the patient was advised to have lifelong follow-up because relapses have been observed several years after infection. Imported melioidosis is no longer a rare disease. With the increase in international travel and adventure tourism to disease-endemic regions, melioidosis is more likely to develop among travelers, even in those with short-term exposure. Recent reports suggest that melioidosis is probably widespread but poorly recognized throughout Bangladesh (5). Clinicians who treat patients returning from disease-endemic tropical areas, including the Indian subcontinent, should consider the disease in the differential diagnosis of febrile illnesses and isolated skin ulcers. Diagnosis is based on isolation of B. pseudomallei from blood, sputum, or biopsy specimens from lesions. Microbiologists should also be aware of the characteristics of the agent, and cultures should be handled under laboratory biosafety level 3 containment. Moreover, B. pseudomallei is a potential bioterrorism agent (8). Assessment of geographic and seasonal exposure is needed for identifiying this polymorphic exotic disease. Furthermore, travel advertisements to disease-endemic countries should include prophylactic measures to avoid contact with wet soils and contaminated water.

Cytokines, Signaling Pathways, and Effector Molecules Required for the Control ofLeishmania(Viannia)braziliensisin Mice

Cutaneous leishmaniasis is caused by protozoan parasites of the genus Leishmania. The mechanisms of pathogen control have been established primarily in the mouse model of Leishmania major infection, but they might not hold true for other Leishmania species associated with cutaneous disease. Here, we analyzed the role of cytokines, signaling components, and effector molecules in the control of New World cutaneous leishmaniasis due to L. braziliensis. Unlike L. major, L. braziliensis caused small, nonulcerative, and self-healing skin swelling in C57BL/6 mice, as well as BALB/c mice. In contrast to the results obtained for L. mexicana, mice deficient for interleukin-12 or its key signaling molecule, signal transducer and activator of transcription 4, rapidly succumbed to severe visceral leishmaniasis. Infection of tumor necrosis factor knockout mice with L. braziliensis led to progressive, nonhealing skin lesions with erosions and hemorrhagic ulcerations, but in contrast to the results with L. major, only 20 to 30% of the mice developed fatal visceral disease. As seen with L. major, mice with a deleted inducible nitric oxide synthase gene (iNOS(-/-)) were unable to contain L. braziliensis in the skin, whereas the control of the parasite in the spleen remained unimpaired. Unlike what happens in L. major infections, NADPH oxidase had no impact on the course of disease in L. braziliensis-infected mice. These results not only define essential components of a protective immune response to L. braziliensis but also illustrate that the requirements for the control of cutaneous leishmaniasis vary between different parasite species.

Localized Cutaneous Cryptococcus albidus Infection in a 14‐Year‐Old Boy on Etanercept Therapy

Immune-modulating medications, such as the tumor necrosis factor-alpha inhibitors, are establishing a niche in the dermatologic therapeutic armamentarium as novel, effective, and relatively safe alternatives in the treatment of numerous inflammatory dermatoses. The benefits of anti-tumor necrosis factor-alpha inhibitor therapy are well known. However, these agents are also associated with an increased risk of infectious complications--most commonly granulomatous infections with mycobacteria and fungi. We present a teenaged boy with localized, cutaneous Cryptococcus albidus infection on the scalp which occurred after he began etanercept for refractory psoriasis. The infection resolved after a course of fluconazole. This is the second report of localized, cutaneous C. albidus infection, but the first occurring in association with etanercept therapy. Our patient's findings remind us that extra vigilance is imperative in monitoring patients on immunosuppressive regimens and that any persistent, nonhealing lesion in these patients should prompt evaluation for potential infection, not only from common and typical pathogens but also from more unusual, atypical ones.

CD4+CD25−Foxp3− Th1 cells are the source of IL-10–mediated immune suppression in chronic cutaneous leishmaniasis

Nonhealing forms of leishmaniasis in humans are commonly associated with elevated levels of the deactivating cytokine IL-10, and in the mouse, normally chronic infections can be cleared in the absence of IL-10. Using a Leishmania major strain that produces nonhealing dermal lesions in a T helper type 1 (Th1) cell–polarized setting, we have analyzed the cellular sources of IL-10 and their relative contribution to immune suppression. IL-10 was produced by innate cells, as well as CD4+CD25+Foxp3+ and CD4+CD25−Foxp3− T cells in the chronic lesion. Nonetheless, only IL-10 production by antigen-specific CD4+CD25−Foxp3− T cells, the majority of which also produced IFN-γ, was necessary for suppression of acquired immunity in Rag−/− reconstituted mice. Surprisingly, Rag−/− mice reconstituted with naive CD4+ T cells depleted of natural T regulatory cells developed more severe infections, associated with elevated levels of IL-10 and, especially, Th2 cytokines in the site. The data demonstrate that IL-10–producing Th1 cells, activated early in a strong inflammatory setting as a mechanism of feedback control, are the principal mediators of T cell–derived IL-10–dependent immune suppression in a chronic intracellular infection.

Lymphocutaneous and nasal sporotrichosis in a dog from Southern Italy: Case Report

Sporotrichosis is a chronic, granulomatous and usually lymphocutaneous infection of humans and animals caused by the dimorphic fungus, Sporothrix schenckii. This study reports a case of lymphocutaneous and nasal sporotrichosis in a hunting dog with a three month history of non-healing skin lesions. Cytological examination of nasal discharge and of the material collected from ulcerated skin surfaces showed a few cigar-shaped organisms within macrophages. Fungal cultures of nasal and ulcerated skin swabs yielded colonies of S. schenckii. The dog received oral itraconazole but died of unrelated causes. Necropsic examination was not performed.

Osteonecrosis of the jaws: maxillofacial recommendations for bisphosphonate prescribers

Osteonecrosis of the jaws: maxillofacial recommendations for bisphosphonate prescribers

Periorbital Tuberculosis

An observational case series of seven cases of periorbital tuberculosis, a rare tubercular presentation occurring in patients with and without systemic disease, is presented. Non-healing sinus and osteomyelitis of periorbital flat bones was observed. All cases had a positive Monteaux test and PCR. AFB cultures of the sinus discharge were negative. The response to triple-drug therapy was dramatic. Follow-up at the end of one year showed clinical recovery. The authors stress the need for a high index of suspicion in cases of non-healing lesions and atypical inflammatory presentation in the periorbital region.

Interruption of Bisphosphonates (BP) Therapy in Multiple Myeloma (MM) Patients and Osteonecrosis of the Jaw (ONJ).

ONJ is a serious complication in MM patients; incidence is time-dependent with highest risk seen after long-term use of BP in older MM patients, often after dental surgical procedure (Badros, et al JCO 2006). Therapy has focused on debridement of necrotic bone, infection management, pain control and discontinuation of BP. The association between BP and ONJ remains provisional; theoretically and anecdotally, however there is evidence that BP withdrawal may allow for recovery of normal osteoclast function and reversal of antiangiogenic effects of the drug on the periosteum allowing for bone healing. We have observed an increased risk of skeletal complications in MM patients after long interruptions of BP therapy (6–12+months), even though patients had been on BP therapy for a median of 3 yrs (range: 2–10+yrs). Table below summarizes the complications that occurred off BP therapy in MM patients with ONJ (n=28) and without ONJ who stopped BP ahead of dental procedures (n=20). Skeletal complications included avascular necrosis of the hip (AVN), fractures, new lytic lesions on skeletal surveys and bone pain; all occurred in relapsed patients with active MM. These events highlighted the importance of BP cornerstone for treatment of skeletal complications of MM; of the 28 ONJ patients, 8 died from progressive MM and 3 patients had non-healing oral lesions and did not resume BP. Twelve of 17 ONJ patients were restarted on BP after complete healing of the oral lesions; all of whom had relapsed MM and bone disease. They received pamidronate every 3 months. So far 3 of 12 patients (25%) had recurrent ONJ and none had skeletal complications. Of the 20 patients who stopped BP before dental procedures, 3 (15%) went on to develop ONJ. Fifteen had restarted BP 2–3 months after the procedure site was well-healed; one patient developed ONJ at the healed extraction site 6 months after restarting BP therapy. This patient was in remission on maintenance thalidomide but with extensive myeloma bone disease. In conclusion, interruption of BP in MM patients with ONJ as well as before and after dental procedures had inconsistent results with regards to both healing and prevention of ONJ. On the other hand, the damage of holding BP therapy is evident with increased frequency of skeletal complications. Until further studies define the optimal frequency and duration of BP therapy, we propose continuous administration of BP therapy probably less frequently after 2 years of monthly infusions with careful assessment of the risk status of each individual patient.Skeletal complications off bisphosphonate therapyFracturesΔAVNNew lytic lesionsBone painONJ; n=285524Dental Procedure; n=20313λ1πΔ Fractures affecting long bones or ribs. λ Two had bone disease as first site of relapse. π One patient had a femoral Infarction and severe pain.

An 80-year-old man with a nonhealing glabellar lesion. Primary cutaneous nocardiosis.

An 80-year-old man with a nonhealing glabellar lesion. Primary cutaneous nocardiosis.

Cutaneous cryptococcosis in a donkey

A 7-year-old indigenous male donkey presented with a 3-month history of non-healing ulcerated nodular lesions involving the skin and subcutaneous tissue of the ears. The affected ears were misshapen due to firm, small, often ulcerated nodules along with seropurulent discharge and some local. There was histopathologically granulomatous dermatitis composed of multinucleated giant cells, macrophages, lymphocytes, plasma cells, and eosinophils in the dermis. Numerous ovoid or spherical, yeast-like organisms in small clear halo or spaces were present both freely and in the cytoplasm of macrophages and giant cells. The capsule was stained by periodic acid schiff and Alcian blue stains. Based on lesion histopathology, it was diagnosed as cutaneous cryptococcosis. The following article documents previously unreported gross and histologic findings of cutaneous cryptococcosis in a donkey.

Mycobacterium Ulcerans Ulcers

Mycobacterium ulcerans (MU) is the third common mycobacterial infection after tuberculosis and leprosy. In endemic areas, MU ulcers should be considered in the differential diagnosis of any unusual or nonhealing lesion or ulcer. Diagnosis and treatment should be instigated promptly. Delay may lead to disfiguring or disabling scars. Surgical management, therefore, should aim towards early excision, with clear margins of the ulcer. We present 4 consecutive patients treated by our department within a 6-month period for MU ulcers. The presentation, diagnosis and surgical management are described. Based on our experience and after reviewing the literature, we have developed a surgical algorithm for the management of MU ulcers.

Analysis of Outcomes Following Failed Endovascular Treatment of Chronic Limb Ischemia

Despite recent studies highlighting the advantages of endoluminal intervention in the management of chronic limb ischemia (CLI), outcomes following failed peripheral angioplasty remain less well described. We present a retrospective analysis of failed transluminal infrainguinal percutaneous arterial angioplasty with or without stenting (PTA/S) in patients with CLI. A database of patients undergoing infrainguinal PTA/S between 2002 and 2005 was maintained. Patients underwent duplex scanning follow-up at 2 weeks, 3 months, and every 6 months after the intervention. Angiograms were reviewed in all cases to assess lesion characteristics. Results were standardized to current Transatlantic Inter-Society Consensus (TASC) criteria. Kaplan-Meier survival analyses were performed to assess time-dependent outcomes. In total, our analysis involved 246 patients who underwent treatment for CLI using PTA/S. Eighteen percent of procedures (n = 46) were considered an intervention failure secondary to restenosis by duplex ultrasound, returning clinical symptoms, a nonhealing foot lesion, or the absence of a prior palpable pulse. Indications for the original procedure in patients whose PTA/S failed were tissue loss in 44%, claudication in 44%, and rest pain in 12%, while TASC lesion grades were A (0%), B (18%), C (18%), and D (64%). Of patients failing PTA/S, 4% failed in the first 30 days, 78% failed between 1 and 18 months, while 18% failed following 18 months, with a mean time to failure of 8.7 months. Also, 82% of PTA/S failures were candidates for a second endovascular procedure, 11% were suitable for only traditional open bypass, and 4% demonstrated progression of disease necessitating amputation. Of patients undergoing a second endovascular procedure, limb salvage rates were 86% at 12-month follow-up and there was a single periprocedural mortality and complication rate of 6.6%. Of patients requiring open surgical bypass after failed PTA/S, 20% (n = 1) required a major amputation and there were no mortalities. Failure of endoluminal therapy for treatment of lower extremity arterial occlusive disease is amenable to subsequent endovascular intervention for limb salvage with limited morbidity and mortality.

Lip lesions

When a patient walks into the surgery, his/her lips are always on view. Patients may arrive with a specific complaint for which they are seeking advice or, if the nurse or doctor is observant, he/she may notice some abnormality themselves. Some of these problems may seem so trivial that the patient does not feel the need to discuss them but, from the medical point of view, it may be possible to offer advice that will at least render the patient more comfortable. Sometimes, however, action can be initiated that may save the patient more troublesome or serious consequences. Lacerations of the lip, infections, swollen and dry lips, non-healing lesions and vascular lesions are some examples of lip conditions which will be discussed in this article.

Unresponsiveness to Glucantime Treatment in Iranian Cutaneous Leishmaniasis due to Drug-Resistant Leishmania tropica Parasites

BackgroundRecent circumstantial evidence suggests that an increasing number of Iranian patients with cutaneous leishmaniasis are unresponsive to meglumine antimoniate (Glucantime), the first line of treatment in Iran. This study was designed to determine whether the clinical responses (healing, or non-healing) were correlated with the susceptibility of Leishmania parasites to Glucantime. Methods and FindingsIn vitro susceptibility testing was first performed on 185 isolated parasites in the intracellular mouse peritoneal macrophage model. A strong correlation between the clinical outcome and the in vitro effective concentration 50% (EC 50) values was observed. Parasites derived from patients with non-healing lesions had EC 50 values at least 4-fold higher than parasites derived from lesions of healing patients. A selection of these strains was typed at the molecular level by pulsed-field gels and by sequencing the pteridine reductase 1 (PTR1) gene. These techniques indicated that 28 out of 31 selected strains were Leishmania tropica and that three were Leishmania major. The L. major isolates were part of a distinct pulsed-field group, and the L. tropica isolates could be classified in three related additional pulsed-field groups. For each pulsed-field karyotype, we selected sensitive and resistant parasites in which we transfected the firefly luciferase marker to assess further the in vitro susceptibility of field isolates in the monocyte cell line THP1. These determinations confirmed unequivocally that patients with non-healing lesions were infected with L. tropica parasites resistant to Glucantime. Additional characterization of the resistant isolates showed that resistance is stable and can be reversed by buthionine sulfoximine, an inhibitor of glutathione biosynthesis. ConclusionsTo the authors' knowledge, this is the first report of proven resistant parasites contributing to treatment failure for cutaneous leishmaniasis and shows that primary Glucantime-resistant L. tropica field isolates are now frequent in Iran.

Ultrasonographic demonstration of a type 1 omphalomesenteric duct remnant

The vitelline or omphalomesenteric duct malformations constitute a rare group and are seen in only 2% of people. The malformations can take the form of a patent duct, a cyst, a fistula, or a sinus. They may or may not be symptomatic depending on the type of malformation. We present ultrasonographic features of a patent omphalomesenteric duct remnant in a 3-week-old boy who presented to our hospital with a non-healing umbilical lesion. Ultrasound can prove beneficial in the work-up of such cases.

Osteonecrosis of the Mandible or Maxilla Associated with the use of New Generation Bisphosphonates

The use of bisphosphonates is well established for the treatment of patients with metastatic bone disease, osteoporosis, and Paget's disease. Osteonecrosis of the mandible or maxilla associated with the use of bisphosphonates is a newly described entity never before discussed in the otolaryngology literature. In this paper, we review a series of patients diagnosed with osteonecrosis, all treated with new generation bisphosphonates. Our objective is to inform and educate others, particularly otolaryngologists/head and neck surgeons, about this drug induced entity, a condition that should be recognized early to avoid potential devastating consequences. Retrospective chart review of a series of patients from a tertiary referral center. Pathology reports of specimens submitted from either the mandible or maxilla were reviewed from the previous 12 months. Any patient diagnosed with osteonecrosis without evidence of metastatic disease at that site was included; those with a previous history of radiation therapy were excluded. Each patient's medical history and profile were reviewed. Twenty-three patients were identified with osteonecrosis of the mandible or maxilla. All of these were associated with the use of new generation bisphosphonates: zolendronate (Zometa, Novartis), pamidronate (Aredia, Novartis), and alendronate (Fosamax, Merck). Eighteen patients with known bone metastases had been treated with the intravenous form, whereas five patients with either osteoporosis or Paget's disease were using oral therapy. Patients typically presented with a nonhealing lesion, often times the result of previous dental intervention. Although the majority of these patients were treated with conservative surgical debridement, we present a case requiring a near total maxillectomy. Drug induced osteonecrosis of the mandible or maxilla has been recently recognized as a sequelae of treatment with the new generation of bisphosphonates. Most patients can be treated with conservative surgical debridement and cessation of bisphosphonate therapy, whereas a few may require radical surgical intervention. Other recommendations include regimented prophylactic care with an assessment of dental status before the administration of bisphosphonates, avoidance of dental procedures, and close monitoring of oral hygiene.

Penile pyoderma gangrenosum

We present a case of penile pyoderma gangrenosum (PG) that responded dramatically to an 8-week course of prednisone and has not recurred over a 6-month period. Although quite uncommon, penile PG should be a diagnostic consideration in any patient with non-healing ulcerative lesions of the penis. A correct diagnosis in this situation precludes unnecessary or harmful therapeutic interventions and leads to proper management.

Foot Skin Blood Flow Following Infrainguinal Revascularization for Critical Lower Limb Ischemia

Introduction The aim of this study was to assess the blood flow in the feet before and after lower limb revascularization using laser Doppler imaging (LDI). Methods Ten patients with critical lower limb ischemia were prospectively enrolled from June to October 2004. All patients underwent successful unilateral surgical interventions including above-knee bypass, distal bypass and endarterectomy. Skin blood flow (SBF) over the plantar surface of both forefeet and heels was measured by LDI 24 h before and 10 days after revascularization, expressed in perfusion units (PU), and reported as mean±SD. Results Measurements in the forefoot and heel were similar. Before revascularization mean SBF was significantly lower in the ischemic foot (130±71 PU) compared to the contralateral foot (212±68 PU), p<0.05. After revascularization a significant increase of the SBF in the forefoot (from 135±67 to 202±86 PU, p=0.001) and hindfoot (from 148±58 to 203±83, p=0.001) was observed on the treatment side. However, a large decrease of the SBF was seen in forefoot and hindfoot on the untreated side (from 250±123 PU to 176±83 and from 208±116 to 133±40, p=0.001, respectively). Conclusion This study confirms the benefits of revascularization in patients with nonhealing foot lesions due to critical limb ischemia. A significant increase of the SBF was observed on the treatment side. However, an unexpected decrease was observed on the untreated side.

Cicatrial cancer in the South-West of England: a regional plastic surgery unit's experience over a 20-year period.

Historical aspects of cicatrial cancer are presented and 18 cases of cicatrial cancer reviewed. The incidence of cicatrial cancer is increasing, paralleling other skin tumours. Survival is better than many series have suggested. Prevention and treatment is discussed in relation to the biological behaviour of scars and their tumours. A high index of suspicion for chronic non-healing lesions in scarred areas will increase survival.