1,25-Dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the Fas receptor.

Beta cell loss occurs at the onset of type 1 diabetes and after islet graft. It results from the dysfunction and destruction of beta cells mainly achieved by apoptosis. One of the mediators believed to be involved in beta cell apoptosis is Fas, a transmembrane cell surface receptor transducing an apoptotic death signal and contributing to the pathogenesis of several autoimmune diseases. Fas expression is particularly induced in beta cells by inflammatory cytokines secreted by islet-infiltrating mononuclear cells and makes cells susceptible to apoptosis by interaction with Fas-ligand expressing cells. We have previously demonstrated that 1,25(OH)2D3, the active metabolite of vitamin D, known to exhibit immunomodulatory properties and prevent the development of type 1 diabetes in NOD mice, is efficient against apoptosis induced by cytokines in human pancreatic islets in vitro. The effects were mainly mediated by the inactivation of NF-kappa-B. In this study we demonstrated that 1,25(OH)2D3 was also able to counteract cytokine-induced Fas expression in human islets both at the mRNA and protein levels. These results were reinforced by our microarray analysis highlighting the beneficial effects of 1,25(OH)2D3 on death signals induced by Fas activation. Our results provides additional evidence that 1,25(OH)2D3 may be an interesting tool to help prevent the onset of type 1 diabetes and improve islet graft survival.

[Vinblastine treatment for extensive non-X histiocytosis (xanthoma disseminatum)]. / Histiocytose non langerhansienne (xanthoma disseminatum) extensive traitée par vinblastine.

INTRODUCTION: Xanthoma disseminatum is a non-Langerhans histiocyte proliferation, described by Montgomery in 1938. This rare entity is characterized by skin and mucous membrane xanthomatosis, associated with diabetes insipidus and normal lipid metabolism. In this case report, vinblastine produced the regression of the lesions. OBSERVATION: A 51 year-old man presented in 1999 with a four-year history of progressive xanthomatous papulonodular lesions of his trunk, axillary and inguinal folds, neck and face (leonin facies). Treatment with thalidomide for 6 months was ineffective. A rapid extension of the lesions to the pharynx, larynx and trachea with dyspnea occurred and required a tracheotomy. Histopathological study showed a dense histiocytic infiltrate within the upper and mid dermis with Touton giant cells and inflammatory cells. The histiocyte cells were positive for CD68. Neither lungs nor hypophysis were involved. A treatment with 6 cures of cyclophosphamide was insufficient. Vinblastine therapy (32 cycles: 0.1 mg/kg/cycle) produced a spectacular regression of the mucous-cutaneous papulonodular lesions leaving cheloid scars. The patient required a transitory tracheotomy and a bilateral commissuroplasty. DISCUSSION: Prognosis of xanthoma disseminatum is in related to the mucous membrane manifestations (50 p. 100 of cases) and involvement of the upper respiratory tract. The response to any form of therapy in xanthoma disseminatum is unsatisfactory. Surgical excision or laser therapy can improve physical and functional aspects but the evolution is characterized by very frequent relapses. Treatment with antimitotic drugs seems to be ineffective in many cases. In our patient, vinblastine induced a spectacular regression of mucocutaneous lesions without neurologic toxicity. To our knowledge, this is the first report of vinblastine efficacy in this rare and severe disorder.

[Tropical fish salesmen's knowledge and behaviour concerning "fish tank granuloma"]. / Les connaissances et le comportement des vendeurs de poissons exotiques concernant la maladie des aquariums

OBJECTIVES: Mycobacterium marinum is responsible for "fish tank granuloma", a chronic and sometimes disabling skin infection, which in France would be the most frequent "atypical" cutaneous mycobacteriosis. Tropical fish salesmen are concerned about this disease because they might sell contaminated fish and be infected themselves. A review of the literature indicated that one quarter of the patients were aquarium workers. This original study tested the salesmen's knowledge and behaviour regarding "fish tank granuloma". METHOD: This national study consisted in an anonymous questionnaire with 24 questions. RESULTS: Among forty salesmen, six of them (15 p. 100) knew this human disease well. Thirty (75 p. 100) ignored it. Among the few salesmen (22.5 p. 100) who had studied to become aquarium workers, only one third were taught about Mycobacterium marinum. Eight salesmen (20 p. 100) were concerned about the human disease: three of them were personally infected and five others had known infected colleagues or purchasers. Most of the aquarium workers immersed their hands without gloves in the fish tanks every day. Only a few destroyed all the fishes from a contaminated tank. CONCLUSIONS: Most of the tropical fish salesmen ignored "fish tank granuloma" although 20 p. 100 of them were concerned. This chronic disease, sometimes disabling, should be better known by aquarium salesmen. The national tropical fish salesmen were informed of the results of this study.

[Cutaneous necrosis is predictive of cancer in adult dermatomyositis]. / Les nécroses cutanées dans les dermatomyosites de l'adulte sont prédictives de l'association à une néoplasie.

INTRODUCTION: Adult dermatomyositis is associated with cancer in 15 p. 100 to 50 p. 100 of cases and, hence, investigations should be systematically performed to search for cancer. A number of predictive factors have been reported. The aim of our study was to search for predictive factors of cancer, among adults with dermatomyositis. METHODS: We prospectively assessed 26 adults presenting with dermatomyositis, hospitalised in our department of dermatology from January 1993 to June 2000. The parameters assessed were: association with a cancer, age, gender, cutaneous necrosis, muscular weakness, electromyographic abnormalities, erythrocyte sedimentation rate, and muscular enzyme levels. RESULTS: Mean age was of 52 years and sex ratio (M/F) was of 0.53. Cancers were diagnosed in eight cases (31 p. 100) (mean age: 59.5 years; sex ratio=1; cancer localization: lung (2), breast (2), ovary, endometrium, bladder, and melanoma). Five patients in the cancer group had cutaneous necrosis and only 2 in the without cancer (p=0.01; PPV=71.4 p.100). Elevation of muscular enzyme was also associated with cancer. CONCLUSION: Our report demonstrates that cutaneous necrosis is closely associated with cancer and it suggests that in selected patients with dermatomyositis and cutaneous necrosis, more exhaustive and repeated investigations should be performed to search for cancer. The interest of elevation in muscular enzyme as a predictive factor of cancer is discussed.

[Cutaneous lymphangitic carcinomatosis and acquired ichtyosis associated with prostatic carcinoma]. / Lymphangite carcinomateuse et ichtyose acquise associées à un adénocarcinome prostatique.

BACKGROUND: Prostatic adenocarcinoma is exceptionally associated with cutaneous lesions. We describe a patient with cutaneous lymphangitis and paraneoplastic ichtyosis related to prostatic cancer. CASE REPORT: A 92 year-old man had been treated for five years for a prostatic carcinoma. An angiomatous lesion developed with in 3 months near the right breast. Physical examination revealed axillary node enlargement, a large skin angiomatous lesion, and ichtyosis. The skin biopsy of the angiomatous skin lesion demonstrated its prostatic origin with carcinomatous metastases in the lymphatic vessels. The ichtyosis was considered as paraneoplastic. DISCUSSION: Cutaneous metastases from prostatic carcinoma are rare. Less than 1 p. 100 of cutaneous metastases are of prostate origin despite the high frequency of this cancer in the general population. The clinical aspects - angiomatous lesion and paraneoplastic ichtyosis - are exceptional.

[Pyoderma gangrenosum]. / Le pyoderma gangrenosum.

GENERAL CHARACTERISTICS: Rare cause of cutaneous ulceration, pyoderma gangrenosum is among the group of neutrophilic dermatites characterized by the richness of the mature neutrophilic polynuclear dermal infiltrate. The primary lesion is a pustule sitting on an inflammatory base; extremely painful, it rapidly ulcerates. The lesion rapidly extends to more than 10 cm in diameter, has a regular, sharp border and a peripheral roll of flesh exhibiting purulent channels on the inside and a red granulous surface often covered with a pustular coating. Little is known of this disease. CONCOMITANT AFFECTIONS: In more than 50% of cases, pyoderma gangrenosum is associated with other diseases, which must be systematically searched for. These may be digestive, essentially inflammatory enterocolitis with frequent development of peristomal ulceration, rheumatismal affections notably rheumatoid arthritis, hematological affections (benign monoclonal gammapathy, chronic myeloid hemopathy). FROM A PARACLINICAL POINT OF VIEW: There are no specific examinations. A cutaneous biopsy should be performed in all cases, notably to eliminate other causes of ulceration. Since concomitant disease can be subsequently revealed, it is essential to renew the paraclinical investigations, even after the disease has healed. NO CODIFIED TREATMENT: Treatment of the cause, if it can be cured, may be sufficient to permit regression of the lesions. Local treatments to provoke budding and hence avoid surinfection are mandatory. In the progressive and extensive forms, systemic treatment, notably high dose corticosteroids, is indicated. Surgery, a priori, is excluded.

[Retroperitoneal fibrosis secondary to metastatic neoplasm revealed by a leg lymphedema]. / Lymphoedème du membre inférieur révélant une fibrose rétropéritonéale d'origine métastatique.

INTRODUCTION: Diagnosis of retroperitoneal fibrosis is generally delayed and revealed by various non-specific signs. We report the case of an isolated lymphedema of the lower limb revealing retroperitoneal fibrosis complicating a metastatic squamous cell carcinoma. CASE REPORT: In an 83-year-old women, a lymphedema appeared that remained isolated for several months before being associated with alteration in general health. Morphological examinations showed bilateral compression of the urinary excretory tracts and led to the diagnosis of retroperitoneal fibrosis. Histological examination of a sub-clavicular adenopathy that had evolved over 9 months, confirmed the diagnosis of a metastatic squamous cell carcinoma of pulmonary cancer. DISCUSSION: Retroperitoneal fibrosis is an exceptional etiology that must be recognized in isolated lymphadomas of the lower limbs. In view of the possible tumoral origin of retroperitoneal fibrosis, any evocative sign accompanying the lymphedema must be searched for.

[Pemphigoid gestationis: treatment by topical class I corticosteroid]. / Pemphigoïde de la grossesse: traitement par corticothérapie locale de classe I.

BACKGROUND: Systemic corticosteroid is the main treatment of severe forms of pemphigoid gestationis. We report a case of generalised pemphigoid gestationis successfully treated with very potent topical corticosteroid. CASE: A 37-year-old woman developed during her third pregnancy with a new partner an urticated generalised eruption associated with bullous lesions. The diagnosis of pemphigoid gestationis was confirmed by direct immunofluorescence which detected a linear C3 deposition along the basement membrane zone and the positivity of Herpes Gestationis Factor (10 units). Local treatment with potent corticosteroid (betamethasone dipropionate 0.05 p. 100) failed and the patient was successfully treated by clobetasol propionate 0.05 p. 100 cream. The infant, in good health, was not delivered prematurely. DISCUSSION: Severe form of pemphigoid gestationis are currently treated with 0.5 to 1 mg/kg/day of systemic corticosteroids, with maternal and pediatric possible side effects. As in bullous pemphigoid, this observation underlines the efficiency and good tolerance of very potent corticosteroid in severe forms of pemphigoid gestationis.

Bullous pemphigoid in a leg affected with hemiparesia: a possible relation of neurological diseases with bullous pemphigoid?

We report a typical case of bullous pemphigoid (BP) associated with a neurological disorder and study a possible link between neurological disorders and BP. An 84-year-old hemiplegic woman presented with unilateral BP on the hemiparetic side. BP was confirmed by histological and immunofluorescence data. The medical records of the previous 46 consecutive patients with BP were retrospectively analyzed (average age: 79; median age: 85). Thirty of the 46 patients with BP had neurological disorders. These disorders included dementia, epilepsy, multiple sclerosis, cerebral stroke, Parkinson's disease, gonadotropic adenoma, trembling, dyskinesia, lumbar spinal stenosis. In a control group of the 46 consecutive oldest patients (older than 71; average age: 82,5; median age: 80) with another skin disease referred during the previous two-year-period to our one-day-unit only, 13 patients had a neurological disorder. This study demonstrates that there is a high prevalence of neurological disorders in patients with BP (p = 0.0004). A prospective case control study with neurological examination and psychometrical evaluation is warranted to confirm these data. We speculate that neuroautoimmunity associated with the aging process or neurological disorders may be involved in pemphigoid development via an autoimmune response against dystonin which shares homology with bullous pemphigoid antigen 1. Bullous pemphigoid could be considered to be a marker of neurological disorder.

[Mycobacterium kansasii skin infection at insulin injection sites]. / Infection cutanée à Mycobacterium kansasii aux sites d'injection d'insuline.

BACKGROUND: Insulin injection sites rarely become infected. We report a case of Mycobacterium kansasii infection at the sites of insulin injection. CASE REPORT: An 84-year-old woman with insulin-dependent diabetes consulted for lesions on the anterior aspect of the thighs. She had papulonodules at the sites of insulin injection. These lesions progressed to hard fibrinonecrotic ulcerations with a raised erythematous border. There were no enlarged nodes locally. Laboratory tests were normal. Bacteriological samples were negative at direct examination. Histology was not specific. The biopsy cultures finally found an atypical mycobacteria, Mycobacterium kansasii. The clinical course was favorable with clarithromycin alone. DISCUSSION: Only 35 cases of Mycobacterium kansasii skin infections have been reported in the literature. This is the first case observed in a diabetic subject and the first treated with clarithromycin alone. This case illustrates the potential, though exceptional, risk of insulin bottle contamination by an environmental germ.

Beneficial effect of 1,25 dihydroxyvitamin D3 on cytokine-treated human pancreatic islets.

We examined whether 1,25 dihydroxyvitamin D(3) (1,25 D(3)), the active form of vitamin D involved in the regulation of the immune system, may also protect human pancreatic islet cells from destruction induced by cytokines. In this study, we specifically investigated the effect of 1,25 D(3) on oxidative stress and major histocompatibility complex (MHC) induction, both implicated in cytokine-induced islet cell dysfunction and destruction. We also investigated the effects of 1,25 D(3) on interleukin (IL)-6, a pleiotropic cytokine implicated in the pathogenesis of immunoinflammatory disorders. Human pancreatic islets, isolated from heart-beating donors, were treated with a combination of three cytokines, IL-1beta+tumor necrosis factor alpha+interferon gamma, in the presence or absence of vitamin D, and compared with with untreated control cells. Metabolic activity was assessed by cell viability and insulin content. Oxidative stress was estimated by heat shock protein 70 (hsp70) expression, cell manganese superoxide dismutase (MnSOD) activity and nitrite release, a reflexion of nitric oxide (NO) synthesis. Variation of immunogenicity of islet preparations was determined by analysis of the MHC class I and class II transcripts. Inflammatory status was evaluated by IL-6 production. After 48 h of contact with cytokines, insulin content was significantly decreased by 40% but cell viability was not altered. MHC expression significantly increased six- to sevenfold as well as NO and IL-6 release (two- to threefold enhancement). MnSOD activity was not significantly induced and hsp70 expression was not affected by the combination of cytokines. The addition of 1,25 D(3) significantly reduced nitrite release, IL-6 production and MHC class I expression which then became not significantly different from controls. These results suggest that the effect of 1,25 D(3) in human pancreatic islets cells may be a reduction of the vulnerability of cells to cytotoxic T lymphocytes and a reduction of cytotoxic challenge. Hence, 1,25 D(3) might play a role in the prevention of type 1 diabetes and islet allograft rejection.

Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms.

BACKGROUND: There is a current debate regarding the association of human herpesvirus 6 (HHV-6) infection and drug reaction with eosinophilia and systemic symptoms (DRESS). METHODS: Seven consecutive patients hospitalized with DRESS were enrolled in a prospective study to evaluate evidence of active HHV-6 infection. OBSERVATIONS: The imputable drugs were carbamazepine (5 patients), ibuprofen (1 patient), and sulfasalazine (1 patient). All patients were seropositive for anti-HHV-6 IgG antibodies. Anti-HHV-6 IgM antibodies were detected in 4 of the 7 patients with a seroconversion in 2 patients. Neither anti-cytomegalovirus nor anti-Epstein-Barr virus early antigen IgM antibody was detected. Human herpesvirus 6 genome was not detected by polymerase chain reaction in the first serum sample of all patients. It was weakly detected in skin lesions in the last patient tested by polymerase chain reaction but was not found in uninvolved skin. CONCLUSIONS: The results suggest an association between HHV-6 active infection (primo-infection or reactivation) and severe DRESS. Absence of anti-cytomegalovirus or anti-Epstein-Barr virus early antigen IgM antibodies argues against a nonspecific viral reactivation. Human herpesvirus 6 infection may play a role in the development of DRESS in susceptible patients. Some drugs with reactive metabolites could favor reactivation and propagation of HHV-6.

[Mycobacterium malmoense cutaneous infection in an immunocompetent patient]. / Infection cutanée à Mycobacterium malmoense chez une malade immunocompétente.

BACKGROUND: Mycobacterium malmoense is a mycobacterium rarely described as a human pathogen. We report the first case of cutaneous infection in an immunocompetent patient. CASE REPORT: A 75-year-old woman presented with a cutaneous nodula on the back of her left hand. Histology of the node biopsy showed non caseating granuloma with giant and epithelioid cells. Acid-fast bacilli were isolated at direct smear and after culture. Mycobacterium malmoense was identified. The lesion has healed after surgery. DISCUSSION: Mycobacterium malmoense is an environmental mycobacterium isolated from soil and water. Typically, most patients with Mycobacterium malmoense infections are old people with previously lung disease. A few cervical lymphadenitis in children and rare cases of tenosynovitis of the hand have been reported. Disseminated infections with cutaneous lesions have been exceptionally described in immunocompromised patients. Mycobacterium malmoense is slow growing and its identification is hard, sometimes requiring molecular analysis. Probably it's the reason why we present the first description of a cutaneous infection in an immunocompetent patient. This case indicates that Mycobacterium malmoense is also a cutaneous pathogen.

Identification and purification of functional human beta-cells by a new specific zinc-fluorescent probe.

Pancreatic beta-cells contain large amounts of zinc. We took advantage of this to try to localize, quantify, and isolate insulin-producing cells from islet preparations. Our study was designed to identify a non-toxic zinc-sensitive fluorescent probe able to selectively label labile zinc in viable beta-cells and to exhibit excitation and emission wavelengths in the visible spectrum, making this technique exploitable by most instruments. We tested Newport Green, a probe excitable at 485 nm with a dissociation constant in the micromolar range corresponding to a low affinity for zinc. The loading of the lipophilic esterified form of Newport Green was easy, rapid, specific, and non-toxic to cells. Confocal microscopy highlighted an intense fluorescence associated with secretory granules. Regression analyses showed a good relationship between zinc fluorescence and islet number (r = 0.98) and between zinc fluorescence and insulin content (r = 0.81). The determination of Zn fluorescence per DNA enabled us to assess the quality of the different islet preparations intended for islet allografting in terms of both purity and viability. Cell sorting of dissociated Newport Green-labeled cells resulted in a clear separation of beta-cells, as judged by insulin content per DNA and immunocytochemical analysis. This zinc probe, the first able to specifically label living cells in the visible spectrum, appears very promising for beta-cell experimentation, both clinically and for basic research.

Chronic radiodermatitis after cardiac catheterization.

A woman presented with a chronic radiodermatitis after a percutaneous transluminal coronary angioplasty (PTCA) for unstable angina. Two PTCAs had already been performed previously. Although rare, these chronic radiodermatitis have been described after multiple cardiac catheterization procedures as a result of cumulative X-ray exposure. Prevention must therefore be implemented.