Photoprotection in erythropoietic protoporphyria: mechanism of photoprotection by beta carotene.

Erythropoietic protoporphyria is a genetic disease caused by the accumulation of protoporphyrin IX. This molecule absorbs 400-nm light and its presence is at times associated with severe cutaneous photosensitivity. The only effective treatment for this disease is oral administration of beta carotene. Several possible mechanisms of photoprotection by beta carotene were investigated using the photohemolysis of red blood cells as an in vitro model. Additional studies were done in an in vivo model which involves lethal hematoporphyrin photosensitization of white mice. The photoprotective effects of beta carotene were compared with those of alpha tocopherol, an agent which possesses some but not all the properties that have been implicated in explaining the known effectiveness of beta carotene. In the photohemolysis model, both compounds demonstrated partial protection. In hematoporphyrin-photosensitized mice, tocopherol showed some protection at high doses, while beta carotene showed greater protection at lower concentrations. Although these results suggest that photoprotective was due to free radical scavenging or singlet oxygen quenching, properties common to both agents, they do not rule out the possible role of 400-nm light absorption, a property of beta carotene alone.

DNA repair processes protect human beings from premature solar skin damage: evidence from studies on xeroderma pigmentosum.

The repair of DNA damage by ultraviolet light is defective in the hereditary disease xeroderma pigmentosum. A deoxyribonucleotide excision-proficient form and several excision-deficient forms of xeroderma pigmentosum have been identified. Premature solar skin damage develops in all xeroderma pigmentosum patients. Some patients also have neurological abnormalities caused by premature death of nerve cells. This abnormal aging of the central nervous system and of sun-exposed skin appears to be the result of the abnormal DNA repair processes. Clinical, biological, and physicochemical studies on DNA-repair-dependent processes and on the DNA repair defects in xeroderma pigmentosum are elucidating the mechanisms by which such abnormal aging is prevented in normal human beings.

The post-UV colony-forming ability of normal fibroblast strains and of the xeroderma pigmentosum group G strain.

In xeroderma pigmentosum, an inherited disorder of defective DNA repair, post-UV colony-forming ability of fibroblasts from patients in complementation groups A through F correlates with the patients' neurological status. The first xeroderma pigmentosum patient assigned to the recently discovered group G had the neurological abnormalities of XP. We have determined the post-UV colony-forming ability of cultured fibroblasts from this patient and from 5 more control donors. Log-phase fibroblasts were irradiated with 254 nm UV light from a germicidal lamp, trypsinized, and replated at known densities. After 2 to 4 weeks' incubation the cells were fixed, stained and scored for colony formation. The strains' post-UV colony-forming ability curves were obtained by plotting the log of the percent remaining post-UV colony-forming ability as a function of the UV dose. The post-UV colony-forming ability of 2 of the 5 new normal strains was in the previously defined control donor zone, but that of the other 3 extended down to the level of the most resistant xeroderma pigmentosum strain. The post-UV colony-forming ability curve of the group G fibroblasts was not significantly different from the curves of the group D fibroblast strains from patients with clinical histories similar to that of the group G patient.

Morphogenesis and malformations of the skin NICHD/NIADDK research workshop.

Developmentally caused skin malformations constitute a spectrum of birth defects, some of which can be recognized prenatally by morphologic or biochemical means. The number of prenatally diagnosable skin diseases could be greatly expanded with an increased understanding of the molecular and cellular bases of skin development and the mechanisms that result in the generation of skin defects. The National Institute of Child Health and Human Development and the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases, therefore, sponsored a workshop that recommended basic biologic studies combined with clinical investigations of normal and abnormal cutaneous development set forth in this article. Investigations resulting from these research recommendations are intended to contribute to the knowledge that should aid in the prevention of developmentally caused skin deformities.

Lymphoblastoid lines and skin fibroblasts from patients with tuberous sclerosis are abnormally sensitive to ionizing radiation and to a radiomimetic chemical.

Lymphoblastoid lines, derived by transforming peripheral blood lymphocytes with Epstein-Barr virus, and skin fibroblast lines were established from two patients with tuberous sclerosis. The number of viable lymphoblastoid cells was determined by their ability to exclude the vital dye trypan blue after their irradiation with x-rays or 254 nm ultraviolet light. The growth of fibroblasts was determined by their ability to form colonies after treatment with the radiomimetic, DNA-damaging chemical N-methyl-N'-nitro-N-nitrosoguanidine. The tuberous sclerosis lymphoblastoid lines were hypersensitive to x-rays but had normal sensitivity to the ultraviolet radiation. The tuberous sclerosis fibroblast lines were hypersensitive to the N-methyl-N'-nitro-N-nitrosoguanidine. The hypersensitivity of tuberous sclerosis cells to x-rays and to N-methyl-N'-nitro-N-nitrosoguanidine is believed to reflect defective repair of DNA damaged by these agents and may provide the basis for in vitro, including prenatal, diagnostic tests for tuberous sclerosis.

Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989.

OBJECTIVE: To assess the incidence and natural history of alopecia areata (AA) among unselected patients from a community. DESIGN: We conducted a retrospective population-based descriptive study of AA among residents of Olmsted County, Minnesota, for the period from 1975 through 1989. MATERIAL AND METHODS: After identifying 292 Olmsted County residents first diagnosed with AA during the 15-year study period, we reviewed their complete (inpatient and outpatient) medical records in the community and statistically analyzed the effects of gender and age-group. RESULTS: The overall incidence of AA was 20.2 per 100,000 person-years and did not change with time. Rates were similar in the two genders and over all ages, and lifetime risk was estimated at 1.7%. Eighty-seven percent of patients were examined by a dermatologist who diagnosed AA, and 29% of cases were confirmed by biopsy. Most patients had mild or moderate disease, but alopecia totalis or universalis developed at some point during the clinical course in 21 patients. CONCLUSION: This study of the incidence and natural history of AA in a community shows that this disorder is fairly common and can be seen at all ages. Although spontaneous resolution is expected in most patients, a small but significant proportion of cases (probably approximately 7%) may evolve into severe and chronic hair loss, which may be psychosocially devastating for affected persons.

Prevention of skin cancer in xeroderma pigmentosum with oral isotretinoin.

To confirm reports that skin cancer can be prevented with retinoid treatment, a three-year controlled prospective study was conducted of oral isotretinoin in five patients with xeroderma pigmentosum who had a history of multiple cutaneous basal cell or squamous cell carcinomas. Patients were treated with isotretinoin, 2 mg/kg per day for two years, and then evaluated for an additional year without using the drug. Before, during, and after treatment, biopsy specimens of all suspicious lesions were examined, and skin cancers were removed surgically. The patients had a total of 121 tumors in the two years before treatment. During two years of treatment with isotretinoin, there were twenty-five tumors, with an average reduction in skin cancers of 63 percent (p = 0.019). After use of the drug was discontinued, the tumor frequency increased a mean of 8.5 times over the frequency during treatment (p = 0.007). Although all patients experienced mucocutaneous toxic effects, and abnormalities in triglyceride levels, results of liver function tests, or skeletal findings occurred in some, high-dosage oral isotretinoin was effective in the chemoprophylaxis of skin cancers in patients with xeroderma pigmentosum.

Evidence that lack of deoxyribonucleic acid repair causes death of neurons in xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is an autosomal recessive disorder with hypersensitivity to the lethal effects of ultraviolet radiation caused by inherited defects in deoxyribonucleic acid (DNA) repair processes. Some patients with XP develop a primary neuronal degeneration which has been thought to result from unrepaired damage in neuronal DNA. Five years ago we reported that cultured skin fibroblasts from a 12-year-old girl with XP, who then had only one major neurological abnormality of the disease, had a sensitivity to ultraviolet radiation intermediate between that of XP patients with numerous neurological abnormalities and those with none. Recent neurological studies reveal that she has a slowly but progressively developing sensorineural deafness as well as cerebellar and motor dysfunction typical of XP. The results support the postulate that defective DNA repair is associated with premature neuron death.

Clinically asymptomatic xeroderma pigmentosum neurological disease in an adult: evidence for a neurodegeneration in later life caused by defective DNA repair.

Xeroderma pigmentosum is a genetically heterogeneous disease caused by DNA repair defects resulting in skin cancer and, in some patients, a primary neuronal degeneration which has in all previous reports become symptomatic prior to age 21 years. A 47-year-old xeroderma pigmentosum patient is described who, although neurologically asymptomatic, has sensorineural hearing loss together with clinical signs and electrophysiologic evidence of a developing peripheral neuropathy. This case suggests that defective DNA repair may cause neurodegeneration in adults as well as in children.

Pemphigus vulgaris and drug reactions.

A retrospective study of patients with pemphigus vulgaris, drug eruptions, psoriasis, and normal controls was undertaken in an attempt to determine whether a significant difference in drug exposure and/or drug allergy existed between the various groups. A statistically significant difference in drug exposure was found between pemphigus vulgaris and drug eruption patients, as compared with psoriatics and normal patients. Representative case reports and some possible mechanisms for the induction or exacerbation of pemphigus patients is described and discussed.