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Notes: The early morphological changes induced by lithium carbonate, a well-known psoriasis-provoking drug, were studied on cultured skin.Normal human skin from patients undergoing mastectomy was cultured in the presence of 3 m m, 6 m m and 10 m m of Li2CO3 for 4 days. The morphological changes were then evaluated by three observers in a blind manner and their reports were matched and collated.The cultured skin in the presence of Li2CO3 showed cell crowding of keratinocytes in the lower part of the epidermis, indicating epidermal hyperplasia. Another striking finding was intercellular oedema and vacuolar alteration with formation of small cavities in the upper dermis. There was no evidence of parakeratosis or any other histological characteristic of psoriasis, except hyperproliferation of the epidermis.Based on our knowledge of mechanisms of lithium action, we proposed two competitive explanations for its action on the epidermis: i) that lithium acts directly on dividing cells of the epidermis; and ii) that it acts indirectly by altering epidermal barrier function.Although we lack definite proof, we suggest that the observed morphological changes, in particular the non-specific stimulus to epidermal proliferation, are the primary events which initiate the process that will ultimately lead to the development of psoriatis in a predisposed patient.

Notes: Background: Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and mucosa due to the presence of autoantibodies against the components of desmosomes. To date, less is known about the expression levels of β- and γ-catenins in blistering diseases. The objective of this study was to evaluate the role of β- and γ-catenins in the pathogenesis of acantholysis in pemphigus vulgaris.Methods: β- and γ-catenin expression was evaluated by immunohistochemistry in 30 cases of PV at various stages of the disease and, as controls, in 18 specimens of the skin/oral mucosa of healthy patients.Results: Healthy skin and normal oral mucosa showed a strong β- and γ-catenin expression in basal and spinous layers with a prevalent cellular membrane distribution; the intensity of staining progressively decreased toward the superficial layers of epithelium. In PV patients, cytoplasmic expression of γ-catenin was detected in 28/30 cases, and in 19/30 cases of PV for β-catenin. Moreover, a progressive displacement of the signal toward the nucleus was found in 14/30 cases for β-catenin, with dyslocalization toward the nucleus, particularly in areas with intense acantholysis, and in 22/30 cases of PV for γ-catenin.Conclusions: Abnormal distribution of γ-catenin, consequent to PV IgG, may be considered a direct consequence of Dg3 dissociation from catenin. γ-catenin likely plays a direct role in PV pathogenesis through its dyslocalization toward the nucleus or indirectly through the β-catenin dyslocalization toward the nucleus, which is thought to induce transcription of selected target genes, such as uPAR.

Notes: AbstractBackground  There have been reports suggesting the involvement of environmental factors in the disease process of pemphigus. Factors suggested include exposure to pesticides or certain drugs.Objective  To analyze the association of pemphigus with environmental exposure to various agents, including smoking, recreational and occupational insults, drugs, and food.Design and setting In-person interviews of pemphigus patients and control subjects were conducted by trained medical investigators using a structured questionnaire. Questions included occupational, behavioral, medical, and qualitative food frequency details. The multicenter study was conducted at outpatient services of teaching hospitals in Bulgaria, Brazil, India, Israel, Italy, Spain, and the USA.Participants  A total of 126 pemphigus patients (55 men, 71 women; age, 54 ± 17 years) and 173 healthy controls (87 men, 86 women; age 50 ± 19 years) were interviewed in the period between October 1, 1999 and March 31, 2000. The diagnosis of pemphigus was based on clinical, histologic, immunohistologic, and immunohistochemical criteria. The disease duration was 2–27 years (8.4 ± 7.2 years). Individuals with skin diseases other than pemphigus were selected as control subjects.Main outcome measure  Information on drugs, foods, and occupational, environmental, constitutional, and other possible risk factors was analyzed by t-tests and chi-squared tests as applicable. A multivariate logistic regression model was applied to the data to study simultaneously the independent relationship between each risk factor and pemphigus vulgaris.Results  The risk for pemphigus vulgaris was lower for ex-smokers and current smokers than for patients who had never smoked. Exposure to pesticides and occupational exposure to metal vapor were associated with an increased risk of pemphigus. Pemphigus patients had more pregnancies than controls. There were differences in environmental factors between countries, with exposure to gardening materials and pesticides being highest among patients from Bulgaria, followed by Israel. Disease characteristics also exhibited differences between countries. Bulgarian patients less frequently had oral mucous membrane lesions: 66% compared to 92% for Israeli patients and 83% for Italians. The distribution of the disease in skin and mucous membranes was similar among patients from all countries. Exclusive skin involvement was seen in 50% of patients, mucous membranes alone in 23% of patients, and both skin and mucous membranes in 27% of patients.Conclusions  The beneficial effect of smoking on pemphigus might be explained by its effect on the immune system. In addition, smoking has an antiestrogenic effect, while pesticides have an estrogenic effect. The lower numbers of smokers among patients, the higher exposure rates to pesticides, and the higher number of female patients who had been pregnant may point to the contribution of estrogens to the disease process. It remains to be determined whether measures, such as avoiding exposure to pesticides or metal vapor, may be beneficial in the clinical context. As the present study was a survey, more definitive studies should be conducted to validate the results.

Notes: A 53-year-old man presented with a crop of papular and somewhat warty lesions on the internal aspect of his prepuce ( 〈link href="#f3-1"〉Fig. 1). They had appeared over the last 3 months and lately had been enlarging; this persuaded the patient to seek dermatovenereologic advice. The patient, who was uncircumcised, denied any extramarital intercourse, but reported a clear medical history of recurrent herpes progenitalis that had afflicted him and his spouse for many years. Recurrent attacks of this infection, each lasting about 2 weeks, had occurred with variable frequency in his forties, and the last episode could be dated exactly to the age of 49 years. The herpetic infection had been managed with topical and sometimes oral acyclovir, but no considerable therapeutic benefit had been noticed. On admission, the patient's main concern was that the new lesions could represent a relapse of the herpes progenitalis. Although they were completely different from the herpetic lesions objectively (solid and not vesicular), subjectively (asymptomatic and not tingling or painful), and in their course (lasting unmodified for months and not evolving into erosions), they had arisen in the area in which the herpetic vesicles had appeared in the past.〈figure xml:id="f3-1"〉1〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD035-3:IJD_035_3_f1"/〉Papular lesions, in a ring-like arrangement, at the site of a prior recurrent herpes simplexDespite the obvious clinical diagnosis of genital warts and in compliance with the patient's explicit request, a punch biopsy was made. The epithelium showed moderate parakeratosis, pronounced acanthosis, diffuse cell vacuolization, and no signs of nuclear dysplasia ( 〈link href="#f3-2"〉Fig. 2). Mild edematous changes, dilated capillaries, and a discrete lymphocytic infiltrate were observed in the dermis.〈figure xml:id="f3-2"〉2〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD035-3:IJD_035_3_f2"/〉Histologic examination of a papular lesion. Acanthotic epithelium with diffuse perinuclear vacuolization (hematoxylin and eosin staining, × 200)The diagnosis of genital warts was made and the lesions were successfully treated with liquid nitrogen.

Notes: Abstract Background  Exogenous factors, such as certain drugs, may be involved in the induction of pemphigus. Other offenders sharing a similar chemical composition to these drugs may also play a role. Tannins with their considerable biologic activity were suggested as possible factors. To substantiate the role of tannins in the pathomechanism of pemphigus, the present study examined the acantholytic potential of tannins in vitro.Methods  Normal human breast skin from patients without any bullous disease was cultured for 3 days in the presence of tannic acid at concentrations of 0.02, 0.05, 0.1, 0.25, 0.5, 1.0, and 2.0 m m. The effect of the tannic acid was microscopically examined in a blind fashion by three independent investigators.Results  In addition to the cytotoxic effect, tannic acid caused marked acantholytic changes, with a clear suprabasal cleavage and intraepidermal acantholytic cells. The acantholytic changes were the most constant and specific effects. They were constantly observed at 1.0 and 2.0 m m, whereas lower concentrations showed changes only in some of the explants. The concentrations needed to exert this effect were notably low. There was a remarkable variability among the subjects who had provided the explants.Conclusions  The results suggest a possible role of tannin in the disease process of pemphigus. The tannin acantholytic potential was much greater than the potential of known acantholytic drugs, such as penicillamine and captopril. The interindividual variability in susceptibility to acantholysis may explain the variability in the individual potential for developing pemphigus.

Notes: Background A variety of drugs have been implicated in the onset and exacerbation of pemphigus and bullous pemphigoid. The demonstration of biochemical acantholysis in skin explants to various drugs in the absence of autoantibodies, in which the tested drugs evoke a biochemical reaction that leads to desmosomal function loss, may be a valuable adjunct to patient management by confirming the suspicion of drug-related pemphigus or bullous pemphigoid. Objective To determine whether a skin explant model might serve as a possible in vitro correlate of drug-induced pemphigus and pemphigoid-like effects related to the calcium channel blocker nifedipine. Methods Normal human breast skin obtained from nonpemphigus and nonpemphigoid patients undergoing mastectomy was cultured with nifedipine at final concentrations of 2, 4, and 8 mm. The drug effect on skin explants evidenced by morphologic changes was evaluated by microscopy by three observers. Results Five out of seven explants cultured with nifedipine at concentrations ranging from 2 to 8 mm exhibited obvious morphologic changes of two types: intraepithelial (or pemphigus-type) splittings and subepithelial (or pemphigoid-type) splittings. Two explants showed no acantholysis and no subepithelial splittings. Control cultures without polyethylene glycol 200 (PEG) showed no changes. Skin control samples cultured in medium supplemented with 10% PEG displayed vacuolar degeneration throughout the entire epidermis, but no sign of cell–cell dyshesion or dermo-epidermal detachment. Conclusions A type of skin susceptibility to nifedipine may be genetically determined, with some nifedipine-treated patients developing an acantholytic reaction and others a subepidermal bullous eruption.

Notes: Background The factors that contribute to a preferential anatomic localization of pemphigus lesions are not well known. In particular, the question arises as to whether certain skin areas may be more acantholysis-prone than others. ObjectiveTo verify whether, in pemphigus patients, a different susceptibility to acantholysis exists among different cutaneous regions, the technique of tissue cultures was used. MethodsNormal human skin explants from two distinct anatomic regions (back and buttocks) of two former pemphigus patients were cultured in vitro in the presence of enalapril (6 mM) or cystamine (10 mM), two substances with a proven biochemical acantholytic effect. After 4 days of culture, the tissues were processed for standard histology. ResultsDiffuse acantholysis, with large intraepidermal splits, was observed in the explants taken from the backs of both subjects and cultured with either enalapril or cystamine. Mild to moderate acantholytic changes were detected in the explants taken from the buttocks of both subjects and cultured with either enalapril or cystamine. No structural changes were seen in the control cultures. ConclusionsPemphigus patients present different thresholds of acantholysis in different areas of their bodies. This might explain, at least in part, certain preferential anatomic localizations of pemphigus lesions.