Reproducibility and validity in the clinical diagnosis of the nonfamilial dysplastic nevus: work in progress.
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Biopsy↗
Biomedical subjects
A B Lerner
Publications and source records attributed to A B Lerner.
Delayed-amelanotic (DAM or Smyth) chicken: melanocyte dysfunction in vivo and in vitro.
Chickens of the autoimmune delayed-amelanotic (DAM or Smyth) line develop postnatal feather amelanosis and severe visual defects, both of which are presumed to be due to a dysfunction of melanocytes and a subsequent autoimmune response that eliminates pigment cells. In this report we elucidate further the melanocytic defect. We present a morphologic analysis of the mildly affected erratic (eDAM) group of Smyth chicken whose partial depigmentation and lack of visual impairment resemble human vitiligo more so than do the complete amelanosis and blindness in the classical Smyth line. Histologically, the sequential events leading to amelanosis in the young Smyth chicken occur simultaneously in the feathers of adult eDAM Smyth chickens, and the infiltration of the feather pulp with mononuclear leukocytes correlates with the extent of local pigmentary abnormality. Cytochemical localizations of dopa-oxidase and acid-phosphatase activities in eDAM feather melanocytes suggest that melanogenesis and autophagocytosis of melanosomes occur in tandem and that the rates of both are higher in these cells than in melanocytes of normally pigmented control chickens. Assays for tyrosinase activity in feather follicles indicate a hypermelanization in eDAM feathers and in the pigmented feathers of young Smyth chicks prior to the onset of depigmentation. Finally, we report on the establishment of pure, proliferative cultures of neural crest-derived melanocytes from control and Smyth chicken embryos. The degenerative events in Smyth chicken melanocyte cultures mimic in part those of the cells in vivo and are therefore indicative of a genetic defect that is independent of the immune system.
Animals↗
Human melanocytes cultured from nevi and melanomas.
The requirements for growth factors of human melanocytes in culture may be dependent on the stage of malignant transformation. Several factors synergistically promote the viability and proliferation of human neonatal melanocytes in culture. They are TPA (12-O-tetradecanoyl-phorbol-13-acetate), isobutylmethyl xanthine, cholera toxin, and as yet unidentified factors from extracts derived from several cell lines and human placenta. Neonatal melanocytes can maintain at least 50 population doublings during a period of 6 months, whereas melanocytes from adult skin proliferate only for 1 month and at less than 1% of the proliferative rate of melanocytes derived from newborn foreskins. In contrast, melanocytes from dysplastic and congenital nevi proliferate well in the presence of mitogens during the initial 4-6 weeks of culture, but then become quiescent. Melanocytes from primary melanomas are the most difficult to grow in culture. They need the mitogens, but their rate of proliferation is slow. Most of the metastatic melanocyte strains that do not need the mitogens in order to proliferate, are strongly inhibited by TPA, and to a lesser extent by WI-38 cell extract. We conclude that the acquisition of independence from mitogens in culture is a late event in the transformation of melanocytes to melanomas.
1-Methyl-3-isobutylxanthine↗
A mouse model for vitiligo.
As the result of a long search for a depigmenting mouse that could serve as a model for the study of vitiligo, we have located a strain that arose from the C57BL/6J. Its provisional genetic designation is C57BL/6J Ler-vit/vit. This vitiligo mouse has congenital dorsal and ventral white spots (piebaldism) as well as progressive replacement of pigmented hairs by white hairs with each spontaneous molt or after plucking. The lack of pigment is due to the absence of melanocytes from the amelanotic hair follicles and epidermis. As in human beings and the Smyth chicken model, there is also diminution of ocular pigment. Reciprocal skin transplants between C57BL/6J and vitiligo mice, and transplants into nude mice, suggest a programmed pigment cell death in the vitiligo mice. Like human beings with vitiligo, maximally depigmented vitiligo mice have a decreased contact sensitivity response in comparison to age-matched C57BL/6J controls. The resistance to injected B16 melanomas is lowered. Vitiligo mice show no signs of premature aging. Already at this early stage in the study of this new animal model, there are findings that open a range of new approaches to the study and treatment of patients with vitiligo and melanomas.
Animals↗
Dermatitis produced by applications of monobenzone in patients with active vitiligo.
Six patients with spreading vitiligo treated with applications of monobenzone developed a vesicular dermatitis. The eruption was restricted exclusively to the pigmented areas of the skin. Patch tests applied to pigmented and depigmented skin produced an inflammatory response only within the pigmented areas. The explanation for this puzzling phenomenon is not known.
Adult↗
Tyrosinase activity and abundance in Cloudman melanoma cells.
Rabbit anti-tyrosinase antibodies were used to study the abundance, processing, and degradation of tyrosinase in murine (Cloudman) melanoma cells. The polyclonal antibodies precipitated low-molecular-weight (68,000 and 70,000) and high-molecular-weight (78,000 and 80,000) tyrosinases that had a precursor-product relationship. Cells with high basal tyrosinase activity had high levels of newly synthesized tyrosinase. Cells with low tyrosinase activity synthesized less tyrosinase and degraded the enzyme at a faster rate than cells with high tyrosinase activity. Melanotropin (melanocyte stimulating hormone), dibutyryl cyclic adenosine monophosphate, and isobutylmethylxanthine caused an increase in the abundance of newly synthesized tyrosinase that was directly proportional to the increase in enzyme activity. This enzyme was not a phosphoprotein. Other changes in the culture conditions that increased the level of tyrosinase activity increased the abundance of newly synthesized enzyme. It is thus concluded that the level of tyrosinase activity in Cloudman melanoma cells is a direct reflection of the abundance of enzyme protein.
1-Methyl-3-isobutylxanthine↗
Vitiligo and melanoma: can genetically abnormal melanocytes result in both vitiligo and melanoma within a single family?
We found twelve families with melanoma who had close family members with halo nevi, early graying of hair, a halo primary melanoma, or ordinary vitiligo. On the basis of these findings and the observation of others in fish, horses, and pigs with melanomas, we suggest that the melanocytes of people with vitiligo or with a genetic background for vitiligo are predisposed to undergo a malignant transformation. The presence of vitiligo appears as a manifestation of host suppression of malignant melanocytes.
Adolescent↗
Optimization of a melanotropin-receptor binding assay by reversed-phase high-performance liquid chromatography.
We describe here a procedure, which should be generally applicable to a wide variety of polypeptide hormones, for analyzing with reversed-phase high-performance liquid chromatography the stability of radioiodinated ligands. Specifically, the integrity of mono [125I]beta-melanotropin during storage and under various assay conditions has been examined. The hormone was found to be quite stable during storage and when binding assays were conducted at 0-1 degree C. There was, however, a decrease in its stability when assays were conducted at higher temperatures (15, 25 and 37 degrees C), the instability increasing with temperature and being greater when cells were present. Employing heat-inactivated instead of untreated bovine serum albumin in the buffer used in the assay provided only a modest improvement in the stability of [125I]beta-melanotropin.
Animals↗
New observations on vitiligo and ocular disease.
We examined 223 consecutive patients with vitiligo for ocular disease and 154 consecutive patients with uveitis for vitiligo to better determine the nature of the relationship between vitiligo and ocular disease. Of the 129 patients whose uveitis had an unknown cause, seven (5.4%) had cutaneous depigmentation, poliosis, or early graying of hair. The incidence is 0.5% in the general population (P less than .02). None of the 25 patients whose uveitis had a known cause had vitiligo. Eleven (4.8%) of 223 patients with vitiligo had uveitis at the time of the study or had had it within the previous two years. Of 27 patients in whom vitiligo was associated with cutaneous melanoma, five (18.5%) had had uveitis within the previous two years. In three of these five, the uveitis began within one month of the appearance of cutaneous changes. Evidence of old chorioretinal scars were present in 69 of 223 patients with vitiligo (30.9%) but in only two of 148 control patients (P less than .001). Sixty of 223 patients with vitiligo (26.9%) had evidence of hypopigmentation or atrophy of the retinal pigment epithelium, or both, not related to old chorioretinitis or macular degeneration but only six of 148 controls did (P less than .001).
Adolescent↗
Vitiligo in patients with metastatic melanoma: a good prognostic sign.
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.
Adult↗
Regulation of tyrosinase in human melanocytes grown in culture.
Tyrosinase, the enzyme that controls the synthesis of melanin, is a unique product of melanocytes. Normal and malignant human melanocytes grown in culture were used to study the factors that regulate the expression of tyrosinase. Immunoprecipitation experiments showed that newly synthesized tyrosinase appeared as a protein with an apparent molecular weight of 70,000 that was processed to a protein with an apparent molecular weight of 80,000. Neither tunicamycin nor 2-deoxy-D-glucose inhibited this conversion, suggesting that O-glycosylation is the major biochemical event in the posttranslational modification of tyrosinase. Agents that stimulated the proliferation of normal melanocytes also stimulated tyrosinase activity. Melanocytes with low levels of tyrosinase activity synthesized less tyrosinase, processed the enzyme more slowly, and degraded it more rapidly than melanocytes with high levels of tyrosinase activity. We conclude that tyrosinase activity in cultures of human melanocytes derived from different donors is determined predominantly by its abundance.
Catechol Oxidase↗
Vitiligo and disorders of the retinal pigment epithelium.
The association of vitiligo with inflammation of the uveal tract is well established. The relationship between vitiligo and hypopigmentation and/or degeneration of the retinal pigment epithelium (RPE) not secondary to ocular inflammation has not been adequately investigated. Sixty (27%) of 223 consecutive patients with vitiligo were found to have some evidence of RPE hypopigmentation ranging from mild, focal areas of involvement in most cases to extensive RPE degeneration with a retinitis pigmentosa-like syndrome in one patient. Fifteen (25%) patients complained of night blindness. Only 6 (4%) of 148 patients in a control group had similar funduscopic findings (p less than 0.001). None of these patients were symptomatic. There have been isolated reports of vitiligo occurring with tapetoretinal degeneration. We report 2 patients with both vitiligo and retinitis pigmentosa.
Adolescent↗
Iodination of beta-melanotropin. Time course analysis of reaction mixtures by high pressure liquid chromatography and characterization of biologically active mono- and diiodo-beta-melanotropin.
The production of highly purified, chemically well defined, iodinated beta-melanotropin possessing full biological activity is described. beta-Melanotropin, purified by high pressure liquid chromatography, was iodinated using Iodogen as the oxidizing agent. Biological activity was recovered, following iodination, by incubating the iodinated peptide mixture in 0.75 M dithiothreitol at 37 degrees C for 18-24 h. The qualitative and quantitative effects of dithiothreitol and the changes that occurred in the iodination mixture with time were examined using high pressure liquid chromatography. This separation technique has proved to be a useful tool both for optimizing the iodination procedure and for the rapid, efficient purification of mono- and diiodinated beta-melanotropins. Amino acid analysis of these two peptides revealed modifications only of the one tyrosine residue (Tyr 5): the expected incorporation of iodine to form mono- or diiodo tyrosine. Monoiodo-beta-melanotropin had full biological activity, as measured by tyrosinase stimulation in Cloudman S91 melanoma cells, while diiodo-beta-melanotropin was an order of magnitude less active.
Animals↗
Extracellular granular material and degeneration of keratinocytes in the normally pigmented epidermis of patients with vitiligo.
Multiple biopsy specimens from the skin of 28 patients with common vitiligo were examined by light and electron microscopy. The patients were grouped according to the activity of their disease: progressing, stable, repigmenting, and resistant to treatment with psoralen plus sunlight. Three biopsy sites were sampled from each patient: (W) a white spot; (I) the pigmented and white interface; and (P) normally pigmented skin 1-15 cm away from I. Control specimens were obtained from 17 persons without vitiligo. Two microscopic abnormalities were observed in the epidermis of the patients with vitiligo: deposits of extracellular granular material, and foci of vacuolar degeneration of basal and parabasal keratinocytes. The extracellular granular material appeared to be derived from the cytoplasm of vacuolated keratinocytes. The abnormalities were observed in greatest abundance in the normally pigmented skin of patients with rapidly progressing or stable disease. They were absent from repigmenting skin and from the skin of healthy controls. Epidermal infiltrates of mononuclear leukocytes were seen only in the normal pigmented skin of the 2 patients whose vitiligo was resistant to treatment. Our observations indicate that cellular degeneration and the generation of debris in vitiligo are not limited to melanocytes but include keratinocytes and probably whole epidermal melanin units. Our findings also indicate that the fine structure of the epidermis in normal-appearing skin is markedly altered by the disease process in patients with vitiligo.
Adult↗
Action spectra of topical psoralens: a re-evaluation.
The action spectra for producing minimal phototoxic erythema with topical 0.I% trimethyl psoralen (TMP) and 8-methoxypsoralen (8-MOP) were determined with a double monochromator in the range of 295-380 nm. both psoralens induced photosensitivity in the range of 313-365 nm; TMP was 54% more effective than 8-MOP. There was no difference in the dose needed to produce minimal UV erythema or phototoxic erythema with 8-MOP and TMP at 295 and 305 nm, but at 313 nm with 8-MOP, photosensitivity was enhanced 3.5 times, and with TMP, sensitivity was enhanced 5.5 times. The peak sensitivity with 8-MOP was at 330 nm and for TMP it was 335 nm. No photosensitivity occurred above 380 nm. Results suggest that TMP and 8-MOP are significantly photoreactive at 320-335 nm. Commonly used UV-A light sources show peak emission around 360 nm. If there is a relationship between development of erythema and therapeutic effectiveness than this raises the possibility of alternative UV light sources for phototherapy with psoralens.
Furocoumarins↗
Vitiligo or halo nevi occurring in two patients with choroidal melanoma.
Vitiligo frequently develops in patients with cutaneous melanomas, especially those who have survived with metastases for prolonged periods. To our knowledge, only one patient with an ocular melanoma in whom vitiligo developed has been described. We have observed a second patient in whom vitiligo developed six to eight years after he had undergone an enucleation for ocular melanoma. Multiple hao nevi developed in a third patient who had an ocular melanoma. The association of vitiligo and ocular melanomas in these patients may not be the result of chance alone.
Adult↗