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Earlier experiments from our laboratory revealed that the medication most commonly used for depigmenting patients with vitiligo, monobenzyl ether of hydroquinone (MBEH), when applied to the skin of DBA/2 mice caused an increase in the population density (cells/mm2) of identifiable Ia+ and ATPase+ Langerhans cells. Further, this increase in Langerhans cell density could be correlated with an increase of contact hypersensitivity (CHS) reactivity to dinitrofluorobenzene (DNFB). The current experiments demonstrated that other compounds chemically similar to MBEH, such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), which are used as preservatives/antioxidants in many topical medications, cosmetics, food, and rubber products, can in five days significantly increase the population density of Thy-1+ dendritic epidermal cells. These compounds had no effects on Ia+ cells. This observation suggests that the Thy-1+ DEC cells may be more mobile and/or their surface markers may be readily expressed and are not a slowly mobile (trafficking) population of cells as suggested by the results of previous work. In addition, these parasubstituted phenolic compounds behaved like pertussis toxin and induced Thy-1 and Ia expression on keratinocytes. These changes in Thy-1 immune markers were not accompanied by functional alterations in the immune response to contact allergens as measured by the ear swelling technique.

Hydroa vacciniforme is a rare, chronic photodermatosis with onset in childhood. Multiple exposures to UV-A reproduced the symptoms and the vesicular and scarring lesions typical of the sun-induced disease in our patient. Treatment with hydroxychloroquine sulfate, but not indomethacin, reduced the photosensitivity both to sunlight and to artificial UV-A light. Serum complement levels were low while the disease was active and returned to normal after treatment of the patient with hydroxychloroquine.

Diseases that cause physical handicaps can seriously interfere with the life of a patient. Some disorders such as vitiligo cosmetically disfigure patients without producing any physical disabilities. The effects of such diseases as vitiligo on the life of a patient have not been widely investigated. The investigation reported here utilized a questionnaire survey to focus on emotional disturbances caused by vitiligo and on the factors that differentiated patients who cope well from those who cope poorly with this stress. The results indicate that the cosmetic disfigurement of a seemingly inconsequential skin disease also can seriously disrupt the lives of a large number of patients. Those who cope well with their disfigurement have higher self-esteem than a matched control group without the disorder. Those who cope poorly have significantly lower self-esteem, which suggests that response to disfiguring diseases is affected by basic ego strength. Younger patients and those individuals in the lower socioeconomic groups show especially poor adjustment. A number of suggestions for better patient care are offered.

One hundred twelve patients with vitiligo were examined for ocular abnormalities. Discrete areas of depigmentation with associated pigment hyperplasia clinically appearing to involve the choroid and retinal pigment epithelium were observed in 44 patients, and active uveitis was seen in nine patients. The changes observed suggest that the spectrum of diseases that includes Harada's disease and the Vogt-Koyanagi syndrome may be broader than previously appreciated. Patients with these syndromes may represent the most severe examples of vitiligo and uveal inflammation. The occurrence of symptoms of night blindness in 12 patients and a family history of retinitis pigmentosa in two of these may signify a possible malfunction of the retinal pigment epithelium. Further evidence for a pigment epithelium disorder is suggested by the high incidence of an unusually prominent choroidal pattern in these patients.

Waardenburg's syndrome and Hirschsprung's disease are both conditions involving a defect of migrating neural crest cells and may be seen together. We report a patient with the combination of these two diseases and review the literature on the subject. Physicians should be aware that deafness can be associated with pigmentary anomalies.

The role of cholecalciferol, 25(OH) D3, and 1,25(OH)2 D3, as modulators of melanocyte function and proliferation has been examined. Topical application of 100 micrograms cholecalciferol to the pinnal epidermis of DBA/2J mice for 5 or 10 days increased the number of L-dihydroxyphenylalanine-positive (DOPA-positive) melanocytes and had a synergistic effect with a low dose of ultraviolet B light (UVB). Application of 1 microgram 1,25(OH)2 D3 had a transient effect on epidermal melanocytes. Addition of cholecalciferol to pure cultures of human melanocytes did not alter their tyrosinase activity (therefore, melanin synthesis) or growth rate even after 72 hours of treatment. However, treatment of similar cultures with 1,25(OH)2 D3 at a concentration equal to or greater than 10(-8) M suppressed tyrosinase activity but did not affect proliferation. The effect of 25(OH) D3 was similar to, but lower in magnitude than, that of 1,25(OH)2 D3. We attempted to demonstrate the presence of specific receptors for 1,25(OH)2 D3 in normal human melanocytes using the monoclonal antibody (Mo Ab) 9A7 gamma raised against the receptor for 1,25(OH)2 D3. Melanocytes were exposed to 9A7 gamma and to a secondary biotinylated Ab and analyzed by the fluorescence activated cell sorter (FACS). An increase in the specific fluorescent signal was constantly observed. By using the immunoblotting technique, we observed a major immunoreactive species that migrated in the 53-kD region in normal melanocytes. The size of this major immunoreactive species was smaller in melanoma cells than in normal melanocytes. This correlates with the finding that the former cells were unresponsive to cholecalciferol, 25(OH) D3, or 1,25(OH)2 D3 treatment. These results predict a direct role for 1,25(OH)2 D3 as an effector of normal melanocyte function.

The prevalence of antibodies to melanocytes was determined by an immunofluorescence complement fixation technique in 294 patients with vitiligo, other pigmentary disorders, and unrelated dermatoses. Antimelanocyte antibodies were present in the sera of five (29%) of 17 patients with chronic mucocutaneous candidiasis. Only two of the five patients with antibodies had vitiligo. No antibodies to melanocytes were found in the sera of 31 patients with common vitiligo or of 38 patients with vitiligo associated with autoimmune diseases or melanoma. Nor were antibodies to melanocytes found in 129 patients with other diseases of pigment-producing cells or in a control group of 79 patients with nonpigmentary dermatoses. These results suggest that complement fixing antibodies to melanocytes are associated wih chronic mucocutaneous candidiasis but are not involved in the pathogenesis of common vitiligo.

A widely accepted notion is that an increasing cellular cyclic AMP (cAMP) concentration is prerequisite for increasing tyrosinase activity and melanin synthesis and for regulating proliferation of pigment cells. alpha-Melanocyte stimulating hormone (alpha-MSH) increases cAMP and tyrosinase activity in Cloudman melanoma cells. Prostaglandins (PGs) E1 and E2 increase melanoma cell tyrosinase activity and inhibit proliferation. Both PGs, but not alpha-MSH, block the progression of Cloudman melanoma cells from G2 phase of the cell cycle into M or G1. Only PGE1 and not PGE2 causes an elevation of cellular cAMP concentrations. The adenylate cyclase inhibitor 2',5'-dideoxyadenosine (DDA) at 5 x 10(-4) M effectively blocks the increased cAMP synthesis by cells treated with 10 micrograms/ml PGE1. The addition of DDA, however, enhances the melanogenic response of melanoma cells to 10 micrograms/ml PGE1 or PGE2, 10(-7) M alpha-MSH, 10(-4) M isobutylmethylxanthine, 10(-4) M dibutyryl cyclic AMP. DDA also augments the effects of PGE1 or PGE2 on the melanoma cell cycle. Moreover, when DDA is added concomitantly with alpha-MSH, more cells are recruited into G2 than observed in untreated controls. Neither alpha-MSH nor DDA alone has any effect on the cell cycle. These findings undermine the role of cAMP in the melanogenic process and suggest that blocking melanoma cells in G2 may be required for the remarkable stimulation of tyrosinase activity observed with PGE1 or PGE2 alone or in combination with DDA. The observed block in G2 may be essential for the synthesis of sufficient mRNA, which is required for stimulation of tyrosinase activity.

Epidermal melanocytes proliferate following a variety of physical stimuli, for example, mechanical injury to the skin or exposure to UV radiation. We suggest that some transducer in the epidermis converts the physical modality into a biochemical signal which is responsible for initiation of mitosis. Melanocyte stimulating hormone, both alpha and beta variants, administered parenterally for periods up to 4 weeks do not alter the number of melanocytes per mm2 in several strains of neonatal or adult mice. Ultraviolet B and arachidonic acid both stimulate proliferation of pigment cells. Indomethacin which inhibits cyclooxygenase and the formation of prostaglandins (PGs) blocks the proliferation induced by both agents. We tested a wide variety of PGs. We observed that PGD2 applied daily to the skin of a mouse causes a small increase in melanocyte density (cells/mm2). PGE2 in similar doses applied topically caused a large increase. PGE2 caused an increase in the uptake of tritiated thymidine by dopa-positive dendritic cells. This indicates that PGE2 stimulated some melanocytes to proliferate. Histologic studies indicate that PGE2 also enhances melanogenesis. PGE2 is synthesized in the skin and affects keratinocytes and Langerhans cells as well as pigment cells. We postulate that it is one compound that can modulate the interaction of these 3 main cells of the epidermis.

Prostaglandins (PGs) E1 and E2 stimulate tyrosinase activity and suppress the proliferation of Cloudman S91 melanoma cells by altering their progression through the cell cycle. Prostaglandin E1 and PGE2 have prolonged or residual effects on melanoma cells. Cells treated for 5 or 24 hours with 10 micrograms/ml PGE1 or cells treated for 8 or 24 hours with 10 micrograms/ml PGE2 demonstrated decreased proliferation and increased tyrosinase activity for 48 hours after removal of the PGs. The effects of PGs on the cell cycle were investigated by determining total DNA content in cells stained with propidium iodide (PI) and analyzed by a fluorescence activated cell sorter (FACS). Prostaglandin E1 blocked cells in G2 phase after 5 hours of treatment, corresponding to when inhibition of proliferation was first evident. Similarly, after 9 hours of treatment with PGE2, more cells were in late S, early G2 phase and less in G1 than their control counterparts. Also, melanoma cells were pulse-labeled with 5-bromo-2'-deoxyuridine (BrdUrd) prior to or at the end of PG treatment and then stained with a fluoresceinated monoclonal antibody to BrdUrd, and with PI. This allows one to observe how BrdUrd-labeled S-phase cells cycle with time. Both PGE1 and PGE2 inhibit proliferation by blocking cells in G2 phase of the cell cycle. The PG-induced block in G2 may be required by melanoma cells to synthesize mRNA and proteins that are essential for stimulation of tyrosinase activity. Ultrastructurally, only a subpopulation of the cells treated with PGE1 or PGE2 contained more mature melanosomes than control cells.

A 31-year-old man with familial dysplastic nevus syndrome presented with numerous histologically confirmed dysplastic nevi. Seven years before this, all of his nevi, numbering over 150, had been "prophylactically" removed. Despite the removal of all visible nevi, many new nevocellular nevi and atypical nevi appeared during the subsequent seven years. This case illustrates the natural history of dysplastic nevi and suggests that removal of all nevi to prevent melanoma may be futile.

In a 30-year-old homosexual man with a 3-year history of localized psoriasis, an oligoarthropathy and severe cutaneous lesions of Reiter's syndrome developed 6 months after acquired immunodeficiency syndrome (AIDS) was diagnosed. Reiter's syndrome and psoriasis may be a continuum of similarly expressed cutaneous diseases that develop in genetically predisposed individuals. We discuss the possible involvement of T lymphocytes and Langerhans cells in the cutaneous lesions of AIDS patients with psoriasis and Reiter's syndrome. In these AIDS patients, skin disease tends to be severe and recalcitrant to conventional therapy. Etretinate plus topical fluorinated steroids was an excellent treatment, producing near clearance of skin lesions and significant improvement in the oligoarthropathy.

Vitiligo presents an excellent opportunity to focus on the effect of impaired appearance on the lives of persons with this disease. We questioned 326 patients with vitiligo and obtained an overview of how they perceived others' reactions to them, their own reactions to the disease, and their experiences with physicians. Many patients are frightened and embarrassed by vitiligo, experience discrimination from others, and believe that they do not receive adequate support from their doctors. Implications of these findings for patient care are presented.

A study Of the uveas of white patients with known cutaneous melanoma and white control subjects showed that patients with cutaneous melanoma had a significantly higher frequency of iris nevi (101 of 197 patients, 51%) than control subjects (58 of 147 subjects, 39%). The frequency of choroidal nevi was also higher in the group with cutaneous melanoma but the number (eight of 197 patients compared with two of 147 control subjects) involved was too small for statistical significance to be assessed. Patients with cutaneous melanoma, particularly women, had more skin nevi than did control subjects.

Melanin is the major determinant of skin color in humans. Abnormalities and diseases affecting pigmentation interrupt the production of distribution of melanin. The authors discuss the many diseases of hyper- and hypopigmentation.

This report describes a method by which mitotic cells were isolated from nonsynchronized Cloudman melanoma cells that had been pulse labeled with 5-bromo-2'-deoxyuridine (BrdUrd) and double-stained with a fluoresceinated monoclonal antibody to BrdUrd and with propidium iodide (PI). In initial experiments, melanoma cells were first pulse labeled with BrdUrd, treated with prostaglandin E1 (PGE1 10 micrograms/m1) or vehicle (0.1% ethanol) for up to 24 hours, then stained with anti-BrdUrd and PI. PGE1-treated cells monitored at 3-hour intervals were observed to migrate from S phase to G2 phase, then, enigmatically, back into the late S phase region of the distribution. In other experiments, cells treated with PGE1 were pulse labeled with BrdUrd at the end of the treatment period and harvested. In these experiments, there was a small, discrete subpopulation of cells within the late S phase region of the DNA distribution that was negative for anti-BrdUrd. This subpopulation of cells was sorted and examined by light microscopy. We observed that 95% of these BrdUrd-negative "S phase" cells were mitotic cells. Since mitotic cells and G2 cells have equivalent amounts of DNA, the reduced red fluorescence exhibited by these cells may be due to a greater sensitivity to denaturation, which has been described for DNA of mitotic cells, and would account for the phenomenon of cells appearing to move "backwards" in the cell cycle. This report indicates that although the BrdUrd/PI method can further define the cell cycle into four compartments, it can also lead to over-estimation of S phase cells in kinetic studies because of contaminating mitotic cells.

Most pigment cells during embryogenesis arise from the cranial or truncal portion of the neural crest and migrate to the skin, hair bulbs, choroid of the eye, the inner ear, leptomeninges, and other tissues. Cells of the retinal pigment epithelium come from a different source, namely, the primitive forebrain, and are involved in the formation of the retina and the optic nerves and tracts. Most pigment cells in all parts of the body seem to be constant in number and function until approximately middle age (the fourth or fifth decade of life). Thereafter, the number of melanocytes in the skin, hair, and eyes and the number of nevi begin to decrease. One function of pigment cells may be to eradicate oxygen radicals that are responsible in part for inducing malignancies and are also involved in the aging process. Possibly one result of the loss of melanocytes from the various organs is acceleration of the aging process in a permissive environment for the development of malignancies.

During a 23-month period, 18 patients with facial or genital herpetic lesions were examined; culture specimens from each patient were obtained three times per week for virologic studies. The isolated viruses were identified, and the average duration of herpesvirus in lesions was determined. Herpes simplex virus type 1 (HSV-1) was isolated from facial lesions for a mean duration of 3 1/2 days. In contrast, herpes simplex virus type 2 (HSV-2) was isolated from genital lesions for a mean duration of 5 1/2 days. The duration of viral persistence in lesions of patients with mild primary infection did not seem to differ from that in patients with recurrent infection.

We have identified and studied twenty-seven patients with melanoma who also had vitiligo. Four patients had vitiligo before the diagnosis of melanoma, and twenty-three developed depigmentation after the diagnosis of malignancy. We also have reviewed published reports about twenty-four other patients with melanoma who developed vitiligo. The clinical course of the melanoma in the fifty-one patients was remarkably similar. Thirty-seven had a melanoma arising at a site which tends to carry a poor prognosis, for example, on the trunk, under the nail, or on the mucous membranes. Forty-nine patients had metastases in regional lymph nodes or at distal sites. Thirty-three patients survived 5 years, and twenty-five survived 10 years. These data suggest that the appearance of vitiligo in patients with metastatic melanoma portends a longer survival than expected. The patients with vitiligo are not necessarily cured and eventually may succumb to metastatic disease. We were unable to determine whether the vitiligo caused retardation of tumor growth or whether the melanoma caused vitiligo.

A 12-year-old boy with vitiligo, chronic thrombocytopenia, and a Coombs's positive autoimmune hemolytic anemia was treated with oral psoralens and exposure to ultraviolet light. An acute hemolytic crisis developed and he died. The association of autoimmune hemolytic anemia and vitilligo should be looked for in other cases. Until more information is available, patients with vitiligo and thrombocytopenia should not be treated with psoralens and exposure to ultraviolet light.

Choroidal melanocytes and the retinal pigmented epithelium (RPE) were studied morphologically and histochemically in the Smyth chicken, an avian model for human vitiligo. The sequence of cytological events occurring in the ocular tissue of minimally depigmented Smyth birds was determined. Abnormalities of melanocytes and the associated inflammation was least severe in peripheral areas of the choroid and most pronounced in the back of the eye at the base of the optic nerve head. In the peripheral choroid, morphologically normal melanocytes and an occasional mononuclear leukocyte were observed. However, some of these morphologically normal melanocytes histochemically demonstrated atypical tyrosinase activity at the trans area of the Golgi apparatus. Toward the back of the eye, the melanocytes first appeared swollen and had retracting dendrites. Ultrastructurally these melanocytes demonstrated an increase in extramelanosomal cytoplasm. Later, melanocytes became spherical and had membrane bound, autophagosome-like compartments of pigment granules. As the melanocyte injury progressed, macrophages invaded the tissue and phagocytized melanocytic dendrites. These were followed by numerous plasma cells. Eventually, the back of the eye contained no pigment and was infiltrated with numerous mononuclear inflammatory cells. The retinal pigment epithelium also demonstrated a gradient in the degree of destruction, related to its topography. These cytological features consisted of the retraction of apical RPE processes, the disappearance of the basal plasma membrane infoldings, and the replacement of Bruch's membrane by collagen-like fibrils. These results demonstrate that the uveitis which develops in vitiligo appears to be a consequence of an inherent choroidal melanocyte defect.

Hypomelanosis of Ito appears to be a disorder of hypopigmentation. Findings from histochemical and electronmicroscopic studies indicate that pigment cells from the hypopigmented areas have short dendrites and synthesize less than normal amounts of melanin. The syndrome may have two forms; a cutaneous and neurocutaneous variety. In the more severe neurocutaneous variety, the phenotypic pigmentary abnormalities probably reflect a biochemical defect in all tissues derived from the neuro-ectodermal anlage.

Release of the protein molecule, leukocytic pyrogen, is one of the many reactions exhibited by leukocytes after phagocytosis. After the ingestion of heat-killed S. albus, a 3-4 hr latent period exists, during which human peripheral leukocytes release no pyrogen, yet cellular metabolism is altered in such a way that pyrogen output may subsequently occur in the absence of further phagocytosis. Transcription of messenger RNA and translation of new protein are initial events in the. activation process, since addition of the inhibitors, actinomycin D, and cycloheximide or puromycin, during this period markedly depressed or abolished subsequent pyrogen release. These effects were noted to be dependent upon the time of addition of the inhibitors. None of the inhibitor drugs interfered with cell viability as measured by phagocytosis and hexose monophosphate shunt activity, nor did they alter the pyrogenicity of preformed leukocytic pyrogen. Vincristine did not inhibit pyrogen formation, consistent with its reported failure to alter RNA synthesis in mature human granulocytes. The glycolytic inhibitor, sodium fluoride, blocked pyrogen release both when added prior to particle ingestion or 1 hr after the initiation of phagocytosis. Whereas inhibition of phagocytosis would explain the sodium fluoride effect prior to 1 hr, this was not observed in leukocyte preparations incubated for 1 hr with S. albus before adding sodium fluoride. When sodium fluoride was added to preparations 2 hr after the start of incubation, the LP production was unimpaired. Potassium cyanide had no effect on cell activation or pyrogen release. These findings suggest that the primary energy supply for the activation process is derived from high energy phosphate bonds provided by anaerobic glycolysis. Since the major amount of cell activation appears to occur in the 1st hr after phagocytosis, this energy might be involved in the induction of a genome leading to the transcription of m-RNA and its translation into new protein or is required for polysome integrity during protein synthesis. It is suggested that this new protein may be leukocytic pyrogen itself, or an enzyme responsible for cleaving it from an inactive precursor.