Maider Pretel

An imbalance in Akt/mTOR is involved in the apoptotic and acantholytic processes in a mouse model of pemphigus vulgaris

Abstract:  Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by the presence of IgG autoantibodies against Dsg3. Our aim was to investigate the molecular events implicated in the development and localization of apoptosis and acantholysis in PV. We used a passive transfer mouse model together with immunohistochemical (IHC) techniques and the TUNEL assay, with quantification analysis in the basal layer of the epidermis. The activated signalling molecules analysed and apoptotic cells detected showed an identical localization. Herein, we found for the first time in vivo an increased expression of activated HER receptor isoforms in the basal layer in PV lesions. Besides, we observed the almost total lack of activated Akt compared with a higher level of activated mTOR within the basal cells of the epidermis. Our observations strongly support that the restriction of acantholysis to the basal layer may be due, at least in part, to the selective and increased presence of activated HER receptor isoforms in these cells. After phosphorylation of HER receptor isoforms, intracellular signalling pathways are activated in the basal layer. In addition, the imbalance in Akt/mTOR that takes place in the basal cells may provide intracellular signals necessary for the development of apoptosis and acantholysis.

Topical rapamycin combined with pulsed dye laser in the treatment of capillary vascular malformations in Sturge-Weber syndrome: Phase II, randomized, double-blind, intraindividual placebo-controlled clinical trial

BACKGROUND Sturge-Weber syndrome (SWS) is characterized by port-wine stains (PWS) affecting the face, eyes, and central nervous system. Pulsed dye laser (PDL) is the standard treatment for PWS. Unfortunately, recurrence is frequent because of reformation and reperfusion of blood vessels. OBJECTIVE We sought to assess the clinical efficacy of topical rapamycin combined with PDL in PWS of patients with SWS. METHODS We conducted a phase II, randomized, double-blind, intraindividual placebo-controlled, clinical trial. We recruited 23 patients with SWS and facial PWS (12 women; median age 33 years, age range 17-65 years) from the University Clinic of Navarra, Spain. Four interventions were evaluated: placebo, PDL + placebo, rapamycin, and PDL + rapamycin. Clinical and histologic responses were evaluated using a chromatographic computerized system, spectrometry, and histologic analyses at 6, 12, and 18 weeks after the intervention. RESULTS PDL + rapamycin yielded the lowest digital photographic image score and the lowest percentage of vessels in histologic analysis, and showed a statistically significant improvement compared with the other interventions. The treatment was generally well tolerated. LIMITATIONS PDL was only applied to the lateral parts of the PWS area. CONCLUSION Topical rapamycin associated with PDL seems to be an effective treatment for PWS in patients with SWS.

Lupus eritematoso inducido por fármacos

Drug-induced lupus erythematosus (DILE) refers to a condition whose clinical, histological, and immunological features are similar to those seen in idiopathic lupus erythematosus but that occurs when certain drugs are taken and resolves after their withdrawal. Over 90 drugs have been linked to DILE to date and the list is growing. Like idiopathic lupus erythematosus, DILE has systemic, subacute cutaneous, and chronic cutaneous forms. A correct diagnosis is very important, as this condition usually resolves after withdrawal of the offending drug.

Toxic epidermal necrolysis related to pemetrexed and carboplatin with vitamin B12 and folic acid supplementation for advanced non-small cell lung cancer.

Background: Pemetrexed is a multitargeted antifolate initially approved as a single agent for the second-line treatment of locally advanced or metastatic non-small cell lung cancer and more recently in the first-line setting combined with cisplatin. The combination of pemetrexed with carboplatin has been tested in several phase II clinical trials showing interesting antitumour activity with mild toxicity. Supplementation with folic acid and vitamin B12 during treatment with pemetrexed is recommended to reduce potential haematological and gastrointestinal adverse events. Case Report: A patient experienced cutaneous lesions including widespread erythema, epidermal detachment, and skin denudation, associated with deterioration of his general condition after the second cycle of this chemotherapy combination, which was clinically and histologically compatible with toxic epidermal necrolysis (Lyell’s syndrome). Treatment with systemic steroids, antihistamines, and antibiotics led to resolution of the skin lesions and improvement of his general condition. Conclusion: To our knowledge, this is the second case reported in the literature of this type of suspected adverse drug reaction associated with a pemetrexed-based chemotherapy combination.

Repigmentation of Gray Hair After Thyroid Hormone Treatment

BACKGROUND AND OBJECTIVES Darkening of gray and white hairs occurred in 2 patients with increased exogenous triiodothyronine (T3) due to treatment of myxedema coma in one case and iatrogenic hyperthyroidism in the other. We hypothesized that thyroid hormone may affect the homeostasis of hair follicles. To test our hypothesis and investigate the influence of thyroid hormone on the hair cycle, we used an in vivo murine model and an in vitro model based on culture of follicular units. METHODS We used the standard C57BL/6 murine model of the hair cycle. T3 (0.5 microg) dissolved in ethanol was applied topically once daily for 10 days to a depilated area in the telogen phase on the backs of the mice. Follicular units, obtained from hair transplant interventions, were cultured in vitro with different concentrations of T3. RESULTS On day 5, all T3-treated mice entered the anagen phase, whereas the anagen phase started spontaneously in control mice on day 9, and not until day 15 had all controls entered this phase. In the in vitro experiment, follicular units treated with 100 nmol/L T3 grew significantly larger compared to the control group. CONCLUSIONS These data suggest that follicles in the telogen phase can be induced to enter the anagen phase by the topical application of T3. This thyroid hormone may reverse graying of the terminal hair. In the in vitro experiments, T3 stimulated hair shaft growth. Follicular melanocytes may be the target cell for these actions.

Erythema gyratum repens-like eruption in a patient with epidermolysis bullosa acquisita associated with ulcerative colitis.

anocyte supernatants after 0Æ5, 6, 24, 48 and 72 h. A slight increase in S100b can be observed even in the controls, but the difference between control and irradiated cells increases over time after irradiation and is also dose dependent. We consider the slight increase of S100b level in controls to be caused either by the fact that cells could not be prepared in the total absence of light, resulting in melanocyte activation, or possibly by a cumulative increase of cell depletion. The cell doubling time was 45Æ6 h in both controls and irradiated cells, resulting in similar cell counts after each measurement. To our knowledge, we show for the first time that S100b levels in extracellular fluid derived from normal human skin melanocytes increase after irradiation with suberythemal as well as erythemal UVB doses. Taking this finding together with the observations of Tronnier et al., who found elevated serum S100b levels after UVB exposure in some individuals of a small group of volunteers, we conclude that UVB exposure of skin cells can indeed influence serum S100b levels. Further investigation is needed to provide correct interpretation of elevated S100b levels in dermatology as well as in neurology.

Dermoscopic “setting sun” pattern of juvenile xanthogranuloma

the Departments of Dermatology and Pathology, Univerty Clinic of Navarra, School of Medicine, Pamplona, Spain. ication of this article was supported by 3Gen. ing sources: None. licts of interest: None declared. spondence to: Maider Pretel, MD, PhD, Department of ermatology, University Clinic of Navarra, P io XII s/n, 31080 mplona, Spain. E-mail: maiderpretel@yahoo.es. J Am Acad Dermatol 2015;72:S73-5. 0190-9622/

Remisión clínica completa prolongada en pacientes con pénfigo vulgar grave después del tratamiento con ciclos intravenosos de ciclofosfamida

36.00 a 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.09.042

Prolonged Complete Clinical Remission in Patients With Severe Pemphigus Vulgaris After Cycles of Intravenous Cyclophosphamide

Background. Corticosteroids are the systemic treatment of choice in patients with pemphigus vulgaris, but chronic administration is associated with side effects. Intravenous treatment with cyclophosphamide can improve the clinical signs of pemphigus vulgaris. Material and methods. We prospectively studied 8 patients diagnosed with pemphigus vulgaris. Six of these had mucocutaneous pemphigus vulgaris and 2 had mucosal pemphigus vulgaris. Treatment consisted of 10 cycles of cyclophosphamide at a dose of 10-15 mg/kg separated by 15 days, while maintaining the initial corticosteroid and immunosuppressant dose. Clinical efficacy was assessed and the anti-epidermal intercellular substance (EIS) and anti-desmoglein (DSG) 3 and 1 antibody titers were monitored (by indirect immunofluorescence and enzyme-linked immunosorbent assay, respectively). Results. All patients with pemphigus vulgaris responded excellently to treatment. Five of the 8 patients achieved complete remission of pemphigus lesions after 10 cycles of cyclophosphamide. In the other 3 patients, the skin lesions disappeared a few weeks after the last cycle of cyclo- phosphamide. A substantial reduction in immuno suppres- sant dose was possible in all patients. Furthermore, an improved immunologic response was observed in all cases

Partial unilateral lentiginosis treated with alexandrite Q-switched laser: Case report and review of the literature

BACKGROUND Corticosteroids are the systemic treatment of choice in patients with pemphigus vulgaris, but chronic administration is associated with side effects. Intravenous treatment with cyclophosphamide can improve the clinical signs of pemphigus vulgaris. MATERIAL AND METHODS We prospectively studied 8 patients diagnosed with pemphigus vulgaris. Six of these had mucocutaneous pemphigus vulgaris and 2 had mucosal pemphigus vulgaris. Treatment consisted of 10 cycles of cyclophosphamide at a dose of 10-15 mg/kg separated by 15 days, while maintaining the initial corticosteroid and immunosuppressant dose. Clinical efficacy was assessed and the anti-epidermal intercellular substance (EIS) and anti-desmoglein (DSG) 3 and 1 antibody titers were monitored (by indirect immunofluorescence and enzyme-linked immunosorbent assay, respectively). RESULTS All patients with pemphigus vulgaris responded excellently to treatment. Five of the 8 patients achieved complete remission of pemphigus lesions after 10 cycles of cyclophosphamide. In the other 3 patients, the skin lesions disappeared a few weeks after the last cycle of cyclophosphamide. A substantial reduction in immuno suppressant dose was possible in all patients. Furthermore, an improved immunologic response was observed in all cases after cyclophosphamide treatment, with decreased anti-DSG1 and anti-DSG3 antibody titers and well as decreased circulating anti-EIS antibody titers. During the mean 15.1 month follow-up (range, 1-25 months), no new lesions appeared and no side effects of cyclophosphamide therapy were reported. CONCLUSIONS Fortnightly cycles of intravenous cyclophosphamide may be a useful therapeutic option in patients with severe pemphigus vulgaris. A reduction of corticosteroid dose was possible with this therapeutic approach and the cumulative cyclophosphamide dose was lower than with daily oral administration. Our findings also show that the therapeutic approach induces clinical and immunologic remission in most patients.