Biomedical subjects
Publications and source records attributed to J Alcalay.
An easy, convenient method of marking the borders of a cutaneous tumor before excision is presented. It enables the physician to see the preoperative clinical borders of a tumor without worry of erasing the inked borders with cleansing solution.
Although some psoralens are therapeutically active in the treatment of cutaneous hyperproliferative diseases when combined with UVA (320-400 nm) radiation, the toxic effects of these compounds have led physicians to seek new photochemotherapeutic agents. One such agent is 4,4',5'-trimethylazapsoralen (TMAP), a new bifunctional psoralen compound. We investigated the effects of repetitive treatments with TMAP plus UVA radiation on the number of dendritic immune cells in murine epidermis and on the induction of phototoxicity. Mice treated 3 times per week for 4 weeks with 129 microgram TMAP plus 10 kJ/m2 UVA radiation exhibited no gross or microscopic evidence of phototoxicity. During this treatment, the numbers of ATPase+, Ia+, and Thy-l+ dendritic epidermal cells were greatly reduced, and by the end of the treatment period, few dendritic immune cells could be detected. We conclude that morphological alterations of cutaneous immune cells can occur in the absence of overt phototoxicity, and that TMAP plus low-dose UVA radiation decreases the numbers of detectable Langerhans cells and Thy-1+ cells in murine skin.
The carcinogenic effect of a new monofunctional psoralen 4,4',6-trimethylangelicin (TMA) plus UVA radiation was examined in C3H/HeN mice and compared with that of the parent compound angelicin. TMA carcinogenic effects were also compared with the previously reported effects of 8-methoxypsoralen. Using 2 different doses of TMA (25 micrograms and 250 micrograms) combined with 1 J/cm2 of UVA radiation, we found that 42% and 52% of the mice (respectively) developed tumors on the treated site. A dose of angelicin (215 micrograms) equimolar to the highest dose of TMA combined with 1 J/cm2 of UVA radiation produced tumors in 28% of the mice (P greater than 0.05). All tumors were squamous cell carcinomas. No metastases were found in any of the mice. We conclude that, although TMA + UVA radiation is carcinogenic in mice, it seems to be an equally active, but less phototoxic and less carcinogenic psoralen than 8-methoxypsoralen. The parent compound angelicin is not significantly less carcinogenic, and its clinical efficacy is poor.
Skin disorders are often associated with pregnancy. Most of these disorders are physiologic but some are pathologic. The following review focuses on skin diseases that are unique to pregnancy.
A pigmented melanocytic tumor was induced on the treated site of a C3H/HeN female mouse given repeated topical applications of 8-methoxy-psoralen and subsequent exposures to ultraviolet A radiation (PUVA) over a 7-month period. The tumor invaded the subcutaneous tissue and muscle but produced no distant metastases. To our knowledge, this is the first report suggesting a direct relationship between PUVA treatment and the induction of cutaneous melanocytic tumor in mice.
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This study was conducted to explore the involvement of DNA damage in the suppression of contact hypersensitivity (CHS) by UV irradiation. The opossum, Monodelphis domestica, was used because cells of these marsupials have an enzyme that is activated by visible light (photoreactivating enzyme) and repairs ultraviolet radiation (UVR)-induced pyrimidine dimers in DNA. A single dose of 1,500 J/m2 of UVB (280-320 nm) radiation, representing 2 minimal erythema doses, was administered to the dorsal skin of opossums. This treatment prevented the opossums from developing a CHS response to dinitrofluorobenze (DNFB) applied either at the site of irradiation or an unirradiated site. In addition, this dose of UVR decreased the number of ATPase+ epidermal Langerhans cells in the dorsal epidermis to approximately 3% of that in unirradiated skin at the time of DNFB application. Treatment of the animals with wavelengths that activate the repair enzyme (320-500 nm, photoreactivating light, PRL) for 120 min immediately after UV irradiation inhibited the UVR-induced suppression of CHS almost completely. Exposure to PRL before UVR did not prevent UVR-induced suppression of CHS. PRL treatment after UV irradiation also prevented the decrease in the number of ATPase+ Langerhans cells. Measurements of lesions in DNA indicated that PRL treatment removed around 85% of the UVR-induced pyrimidine dimers. These data provide direct evidence that DNA, and most likely, the pyrimidine dimer, is the primary molecular target for the UVB-induced suppression of contact hypersensitivity to haptens applied to irradiated or unexposed skin.
To understand the role of cutaneous immune cells in host resistance to the induction and growth of skin cancer, we investigated the number and morphology of murine dendritic epidermal cells (dEC) during the evolution of ultraviolet (UVA) UV-induced skin cancers. Female C3H/HeN mice were treated topically with 8-methoxypsoralen followed by ultraviolet A (UVA) radiation 3 times/week or irradiated with UVB radiation 3 times/week. In both psoralen plus UVA- and UVB-treated mice, ATPase+ and Ia+ Langerhans cells almost completely disappeared from the treated skin during the early latency period of tumor development (4 weeks) but reappeared in the epidermis late in the latency period (between 15 and 22 weeks). The ATPase+ cells that reappeared in the epidermis had a rounder, less dendritic morphology than normal Langerhans cells. Thy-1+ dEC were totally depleted from the epidermis in both treatment groups at the end of first week of treatment and were nearly absent from the skin during the entire latency period. After tumors appeared (29 weeks), Thy-1+ dEC were still absent or detected only in small numbers in skin surrounding the tumors. ATPase+ and Ia+ cells present in skin around the tumors constituted 60 to 80% of the number in nonirradiated skin. Mice that received UVA radiation alone developed no tumors. ATPase+ and Ia+ Langerhans cells and Thy-1+ dEC were detected in UVA-treated epidermis after 22 weeks and 43 weeks, although the numbers were lower than those in unirradiated mice. Most psoralen plus UVA-induced tumors (81%) were squamous cell carcinomas, whereas only 24% of UVB-induced tumors were of this histological type. Our results demonstrate that UV-induced skin cancers developed in the presence of ATPase+ and Ia+ cells in the epidermis and in the absence of Thy-1+ dEC.
The successful use of phototherapy, especially psoralen plus UVA (PUVA) therapy, in the treatment of a variety of skin diseases is well known. Because the pathology of diseases such as vitiligo, alopecia and lichen planus is thought to involve immune mechanisms, the beneficial effect of PUVA may be due to immunosuppression. PUVA treatment can induce suppression in two ways. In the first (local suppression) psoralen is applied topically, the skin is irradiated with UVA and the contact allergen is applied directly to the irradiated skin. The induction of contact hypersensitivity (CHS) is suppressed and suppressor cells are found in the spleens of treated animals. Systemic suppression results from the injection of psoralen followed by exposure to UVA. The contact allergen is then applied at a distant non-irradiated site. CHS is suppressed and antigen-specific suppressor cells are found in the spleens of treated mice. The ability to induce specific immunosuppression may provide novel methods of inhibiting unwanted immune responses. We have demonstrated that graft rejection and the induction of graft-versus-host disease can be suppressed in an antigen-specific manner by UV radiation. Thus phototherapy may provide promising new treatments for suppressing graft rejection and perhaps may be beneficial in the treatment of autoimmune disease and allergic reactions.
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The role of Langerhans cells (LC) in host resistance against the induction and growth of nonmelanoma skin cancers is still obscure. The purpose of this study was to investigate the sensitivity of LC to simulated solar radiation in patients with basal cell carcinoma (BCC). Thirty-four patients (31-74 years old) with at least one histologically diagnosed BCC on a sun-exposed area and 21 healthy volunteers (29-62 years old) were included in the study. Patients and control subjects were given 10 graded doses of simulated solar UV radiation (10-75 mJ/cm2) on the lower back using a 12S solar simulator with a WG 320 filter. Twenty-four hours later, the minimal erythema dose (MED) was determined and shave biopsies were taken from the site given 1.25 X MED and from adjacent, unirradiated skin. Epidermal sheets were stained for LC using the ATPase method. The mean value of the MED of the BCC patients was 25 +/- 2 mJ/cm2 and that of controls was 29 +/- 3 mJ/cm2 (p greater than 0.05). The number of ATPase+ LC was significantly decreased (p less than 0.05), and their morphology was altered in the irradiated skin of nearly all individuals. However, there was no significant difference in the average reduction of LC in the patients (32% +/- 3%) compared with that of control subjects (32% +/- 4%). The depletion of LC ranged from 0% to 74% in different individuals, all of whom were given 1.25 MED. Furthermore, no correlation was found between the percentage decrease in ATPase+ cells and the dose of UV radiation required to produce erythema. Our results indicate that the ability of UV radiation to cause erythema was unrelated to the magnitude of its effects on LC number or morphology. Second, the morphologic alterations of LC in BCC patients after UV irradiation do not differ from those observed in normal individuals. Third, as a group, patients with BCC do not have a significantly lower MED than cancer-free subjects.
Monofunctional psoralens produce less phototoxicity than bifunctional psoralens after ultraviolet A (UVA) irradiation. We investigated the effect of repetitive treatments with angelicin (isopsoralen), a monofunctional psoralen, plus UVA radiation (IPUVA) on the number and morphology of dendritic epidermal cells (dEC). This effect was compared with that of 8-methoxypsoralen plus UVA radiation (PUVA), UVA alone, and UVB radiation. C3H/HeN mice were treated topically with the drugs three times/wk for 4 consecutive wk; followed each time by 1 or 2.5 J/cm2 of UVA radiation. Other groups of mice were treated with the drugs alone, UVA alone, or 0.81 J/cm2 of UVB. Epidermal sheets were stained for ATPase, Ia, and Thy-1 markers. Mice treated with PUVA and UVB exhibited severe phototoxicity, whereas no overt phototoxicity was observed in mice treated with IPUVA, UVA alone, or the drugs alone. Early during the PUVA and UVA treatments the ATPase marker was lost from dEC, followed by loss of the Ia marker; the Ia marker was lost before the ATPase marker from dEC in animals treated with IPUVA. At the end of the treatment, however, nearly total depletion of ATPase+, Ia+, and Thy-1+ dEC was observed in mice treated with PUVA and IPUVA. UVB radiation caused rapid depletion of Thy-1+ dEC as well as ATPase+ and Ia+ cells. During treatments with IPUVA, PUVA, UVA, and UVB, the Langerhans cells became rounded and lost their dendrites. These changes were quantitated by image analysis. We conclude that alterations of cutaneous immune cells can occur in the absence of overt phototoxicity, and that monofunctional and bifunctional psoralens plus low dose of UVA radiation may have different effects on dEC markers.
Monofunctional psoralens, plus UVA radiation are not erythemogenic and are less mutagenic than bifunctional psoralens plus UVA radiation. Thus, they have received considerable attention in recent years as potential therapeutic agents for various skin diseases. The purpose of this study was to examine the immunologic side effects following treatment of mice with a monofunctional psoralen plus UVA radiation. We report that angelicin plus UVA radiation suppressed the induction of contact hypersensitivity to dinitrofluorobenzene. This decreased immune response was associated with the presence of splenic suppressor cells that transferred suppression to normal recipients. Treatment with angelicin and UVA radiation also decreased the number of Thy-1+ and Ia+ dendritic epidermal cells in the treated site. We conclude that although this monofunctional psoralen is not phototoxic, it has immunosuppressive activity in mice.
We investigated the number and morphology of Langerhans' cells in the epidermal component of squamous cell carcinomas located on the sun-exposed skin of 10 patients. Using adenosine triphosphatase-stained epidermis from the tumors, we compared the Langerhans' cells in squamous cell carcinoma with those in nontumorous skin specimens from the same patient. The nontumorous skin specimen was obtained from either sun-exposed perilesional or non-sun-exposed sites. In three patients a normal number and almost normal morphology of Langerhans' cells were observed within the epidermal component of the tumor. One patient showed a normal number but a profound alteration of the morphology of the cells. In the remaining six patients, a significant decrease in the number of Langerhans' cells was observed. Langerhans' cells within the epidermal component of the tumors of these patients exhibited morphologic alterations in that they were mainly round or oval rather than highly dendritic. In none of our patients was the number of Langerhans' cells in the tumor increased. We conclude that a decreased number and altered morphology of Langerhans' cells occur in some, but not all, squamous cell carcinomas of the skin, and that there is no apparent difference between the number of Langerhans' cells in sun-exposed vs unexposed skin from the same individual.
We present a typical localized bullous pemphigoid (Brunsting-Perry) associated with positive Nikolski sign. To the best of our knowledge, this is the first report on positive Nikolski sign in localized bullous pemphidoid.
There is little insight into the pathogenesis of most of the dermatoses specifically associated with pregnancy. We evaluated the hormonal profile and the autoimmune background in 11 pregnant women with pruritic urticarial papules and plaques of pregnancy. No statistically significant difference was found between the serum levels of the beta-subunit of human chorionic gonadotropin, estradiol, cortisol, and urinary estriol of the patients and gestational age-matched control subjects. No autoantibodies were found in the patients' group. We conclude that patients with pruritic urticarial papules and plaques of pregnancy have no hormonal alterations when compared with normal pregnant women and that no known major autoimmune background plays a part in the pathogenesis of the disease.
We have recently demonstrated that in pruritic urticarial papules and plaques of pregnancy (PUPPP) there are multiple dermal fibroblasts with no deposition of mucin. We suggest that in the dermis of patients with PUPPP there is a deposition of a substance that induces fibroblasts proliferation. We assume that this substance (marked as F-substance) is a product of the placenta, which is released to the maternal circulation during pregnancy.
Three young and middle-aged patients developed severe bullous eruption after receiving various penicillins. The clinical findings included high fever, prostration, widespread bullous eruption mainly on the head, face, and extremities, targetlike lesions on the palms and soles, and severe erosions in almost all the mucous membranes. Direct and indirect immunofluorescence studies were those of bullous pemphigoid. Complete clearing of the eruption occurred with prednisone therapy. We conclude that drug-induced bullous pemphigoid is a different entity from the classic bullous pemphigoid.