Ultraviolet-induced dna repair synthesis in lymphocytes from patients with actinic keratosis.

Actinic keratosis is an epidermal cancer in situ. Extensive exposure to sunlight is considered as a contributing factor to the etiology of this tumor. Ultraviolet (UV) light of solar radiation induces structural damage in DNA, which may give rise to mutations and transformed cells if the damage is not repaired. Repair of UV-induced DNA lesions is an essential property of human cells. The conditions so far reported to have defective DNA repair are all associated with an increased incidence of malignancy. Do patients with actinic keratosis also exhibit a reduced capacity to repair UV-induced DNA lesions? DNA repair synthesis in peripheral leukocytes was studied in 10 patients with actinic keratosis and 10 healthy subjects of corresponding age. After irradiation with various doses of UV light the leukocytes were incubated for 2 hr with [3H]thymidine in the presence of hydroxyurea. A dose-response relationship for the UV-induced DNA repair synthesis was established for each individual. The average repair capacity in the patients with actinic keratosis was about 30% below that of the controls. The difference is statistically significant (p less than 0.02). Reduced DNA repair synthesis may therefore be an important factor in the etiology of actinic keratosis.

Decreased urinary histamine metabolite after successful PUVA treatment of urticaria pigmentosa.

The effect of PUVA therapy on pruritus, the skin mast cell population and histamine metabolism has been studied in 3 patients with urticaria pigmentosa and manifestations of systemic mastocytosis. Relief of itch was found concomitant with a significant decrease of the major histamine metabolite 1-methyl-4-imidazoleacetic acid in the urine. The decrease occurred during the first 2 mo after starting PUVA therapy and was sustained during an observation period of 3 mo after discontinuation of the treatment. At this time a reduction of the number of mast cells was found in skin biopsy specimens. No evidence of acute histamine release in association with PUVA treatment was obtained. These results suggest that this effective new treatment for urticaria pigmentosa reduces the histamine turnover in the skin by inhibiting mast cell proliferation.

HLA-antigens and contact hypersensitivity.

The HLA-A, -B -C typing of 100 bricklayers was performed. 50 bricklayers had developed contact allergy to chromium while 50 were healthy bricklayers. The distribution of HLA antigens were equal in the 2 groups.

Axon-reflex-mediated vasodilatation in the psoriatic plaque?

Blood flow in the psoriatic plaque is increased, but the underlying mechanisms are not known. The aim of the present study was to examine whether neurogenic factors are important for blood flow regulation in the plaque. Local neurogenic mechanisms were inhibited by surface anesthesia and central nervous control by conduction anesthesia of nerves to the psoriatic plaque. The differences in skin perfusion before and after anesthesia were measured with a laser Doppler perfusion imager. The skin perfusion in psoriatic plaques located in hairy skin was unaffected by conduction anesthesia, but surface anesthesia of the plaque evoked a marked blood flow reduction. The perfusion in ultraviolet-B-irradiated skin, used as a control for nonspecific phenomena, was reduced after local application of indomethacin but was unaffected or increased after surface anesthesia. The results are compatible with the idea that a local neurogenic mechanism (axon-reflex) contributes to the high blood flow in the psoriatic plaque.

Studies of DNA and chromosome damage in skin fibroblasts and blood lymphocytes from psoriasis patients treated with 8-methoxypsoralen and UVA irradiation.

Exposure of human lymphocytes and skin fibroblasts in vitro to a single, clinically used dose of PUVA, i.e., 0.1 micrograms/ml of 8-methoxypsoralen (8-MOP) plus 0.9-4 J/cm2 of longwave ultraviolet radiation (UVA), lead to the formation of DNA damage as determined by alkaline elution, and to chromosome aberrations and sister chromatid exchanges (SCE). When lymphocyte-enriched plasma was obtained from psoriasis patients 2 h after oral intake of 8-MOP and then UVA irradiated (1.8-3.6 J/cm2) in vitro, an increased frequency of chromosome aberrations and SCE was observed. Normal levels of chromosome aberrations and SCE were found in lymphocytes of psoriasis patients after 3-30 weeks of PUVA treatment in vivo. A small but statistically significant increase in the SCE frequency was observed in the lymphocytes of psoriasis patients treated for 1-6 years with PUVA (mean 18.0 SCE/cell) as compared with before PUVA (mean 15.8, p less than 0.05). Skin fibroblasts of psoriasis patients analyzed 5 years after the start of PUVA treatment showed a normal number of SCE but a high fraction of filter-retained DNA in the alkaline elution assay, suggesting the presence of cross-linked DNA.

S gene (Corneodesmosin) diversity and its relationship to psoriasis; high content of cSNP in the HLA-linked S gene.

Psoriasis is a heterogeneous disease in which several reports suggest the presence of a susceptibility gene in or in the proximity of the human leukocyte antigen complex in chromosome 6p. There is an association between HLA-Cw6 and young onset of the disease. The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its reportedly exclusive expression in differentiating keratinocytes. We have studied this gene in a large Swedish psoriasis population and we report a strikingly high degree of polymorphism in the coding parts of the gene, 1 every 100 base pairs. We used a stratified approach to compare the polymorphic variants in patients and controls. A single nucleotide polymorphism in the coding region leading to an amino acid exchange (Ser-->Phe) that differed significantly between patients and controls was identified (position 619). Owing to a high allele frequency in a larger control group, however, and an insignificant influence of the variant on the age at onset distribution curve based on a large psoriasis population, we could not confirm that this coding single nucleotide polymorphism was involved in disease etiology. We also examined the single nucleotide polymorphism in position 1243, recently proposed to have an influence on the pathogenesis of the disease. This polymorphism showed less association to the disease as compared with the single nucleotide polymorphism at positions 619 and 722. Such a high degree of variation present also in an HLA gene which is not involved in immune response indicates the difficulty involved in assessing the role of a specific allele in the pathogenesis of a complex disease in this region. A strong association effect due to linkage disequilibrium in an extended region in the HLA complex is also a complicating factor.

No evidence for involvement of the growth hormone/insulin-like growth factor-1 axis in psoriasis.

We have examined whether alterations in the growth hormone/insulin-like growth factor-1 axis play a role in the pathogenesis of psoriasis. Serum, urine, full skin biopsies, and suction blister roofs were obtained from patients with psoriasis and from healthy controls. Serum concentrations of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 were measured by radioimmunoassay. Growth hormone-binding protein was measured by ligand-mediated immunofunctional assay. Growth hormone concentration in urine was measured by an immunometric assay, and growth hormone receptor-gene expression was measured by RNase protection assay or by quantitative reverse transcriptase polymerase chain reaction in total RNA isolated from epidermal suction blister roofs. Serum concentrations of insulin-like growth factor-1 (249 +/- 12 micrograms per liter, mean +/- SEM, n = 42, and 277 +/- 21 micrograms per liter, n = 9, for psoriatic patients and controls, respectively), insulin-like growth factor binding protein-3 (3.1 +/- 0.08 mg per liter, n = 42, and 3.3 +/- 0.22 mg per liter, n = 9), growth hormone-binding protein (344 +/- 65 pmol per liter, n = 10, and 311 +/- 83 pmol per liter, n = 9), urinary growth hormone excretion during 24 h (12.8 +/- 2.7 microIU per 24 h, n = 12, and 12.3 +/- 1.6 microIU per 24 h, n = 9), and epidermal growth hormone receptor gene expression [32 +/- 12 x 10(3) mRNA transcripts per microgram total RNA (involved skin), n = 11, and 47 +/- 14 x 10(3) mRNA transcripts per microgram total RNA, n = 9] were similar in patients and controls. For insulin-like growth factor-1 and insulin-like growth factor binding protein-3 the values in psoriatic patients were also similar to those in larger control groups, n = 195 and n = 400, respectively. In addition, we found no evidence of local expression of growth hormone or prolactin in full skin punch biopsies from psoriatic involved skin by reverse transcriptase polymerase chain reaction. In conclusion, our results suggest that alterations in the growth hormone/ insulin-like growth factor-1 axis do not play a major role in the pathogenesis of psoriasis.

Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden.

We have performed a pair-wise linkage study in the search for psoriasis susceptibility regions. A preliminary scan was performed on 20 families. In this set we obtained indications of linkage on chromosome 3q21. This region was further investigated using material from a total of 104 families (set 1B) resulting in a non-parametric linkage (NPL) of 1.77. The material was stratified in families whose parental origin is in southwest Sweden (set 1C). A maximum NPL value of 2.77 was obtained in this group. A transmission disequilibrium test (TDT) was performed on the stratified material (set 1C) and a significant P value of 0.005 was obtained, at marker D3S1269. The locus was confirmed with TDT in replicate material consisting of 148 families in which a single member was affected (P value 0.0007) at marker D3S1551. Thus, we have observed a significant P value using TDT in the vicinity of markers D3S1269/D3S1551, suggesting a novel psoriasis susceptibility region.

Cytogenetic analysis of 477 psoriatics revealed an increased frequency of aberrations involving chromosome region 11q.

Psoriasis is an inflammatory skin disorder affecting approximately 3% of the population. Genetic studies published so far have shown a complex genetic inheritance with heterogeneity and a putative major susceptibility locus in the HLA region on chromosome 6. We have collected a large amount of material consisting mostly of small nuclear families in order to perform a genome-wide scan for psoriasis-associated genes. In order to focus the scan properly on possible candidate regions, we performed a cytogenetic analysis of 477 unrelated psoriatics. We divided our findings into sporadic, affecting a minor fraction of the cells, and constitutional, i.e. they were present in all cells examined. We found three cases of balanced translocation, all of which involved chromosome 11q. Two of these had a breakpoint in q12-13, whilst one involved the telomeric part of chromosome 11q. In order to characterise further the breakpoint on 11q12-13, we used bacterial artificial chromosomes (BACs) analysed by fluorescent in situ hybridisation (FISH). We were able to show that the persons had a close, but not identical breakpoints; they were separated by at least 5 cM. The major atopy locus is located in this region, as well as a locus for insulin-dependent diabetes mellitus, both being conditions with a pathogenetic mechanism involving antigen presentation.

Serum concentration and phototoxic effect of methoxsalen in patients with psoriasis.

The correlation between serum concentration of methoxsalen (8-methoxypsoralen; 8-MOP) and phototoxic effect using long-wave ultraviolet light has been studied in 5 psoriatic patients. The maximum serum concentration occurred between 0.5 and 2 hr after oral administration of 0.6 mg/kg of methoxsalen. The lowest value for the minimum phototoxic dose (MPD), i.e., highest photosensitivity, was obtained between 1 and 2 hr. There was a significant negative correlation between the logarithm of the serum concentration and minimum phototoxic dose (MPD) (r = 0.780). Hence, the degree of photosensitivity appears to be related to the serum level of methoxsalen.

PUVA, etretinate, and PUVA-etretinate therapy for pustulosis palmoplantaris. A placebo-controlled comparative trial.

Thirty patients with severe pustulosis palmoplantaris completed a placebo-controlled comparative trial. Patients were randomly allocated to placebo or etretinate therapy; after two weeks, psoralen plus long-wave ultraviolet light (PUVA) treatment was instituted on one hand or foot, while the other hand or foot served as an untreated control. Fourteen of 18 hands or feet cleared with the combined treatment, compared with three of 18 with etretinate treatment and three of 12 with PUVA treatment. Follow-up showed a high relapse rate. Treatment of severe pustulosis palmoplantaris must be individualized to minimize short- and long-term side effects.

A mother and two children with nonbullous congenital ichthyosiform erythroderma.

A mother and her two daughters were all afflicted by congenital nonbullous ichthyosis. The clinical and ultrastructural picture are in accordance with recessive congenital ichthyosiform erythroderma. The mode of inheritance for the children is assumed to be by pseudo-dominance. Nonbullous congenital ichthyosiform erythroderma and lamellar ichthyosis are probably heterogeneous.

Cutaneous drug reactions. An attempt to quantitative estimation.

The drugs taken by patients with suspected cutaneous drug reactions (CDR) were recorded during a 4-year period at Sahlgren Hospital in Gotenburg in a prospective study. A total of 440 patients were included. By dividing the frequency of occurrence of the recorded drugs by the number of sold defined daily doses (SDDD) for the city during the same period of time, figures for the CDR risk for different drugs corrected for frequency of use were obtained. The risk of CDR seemed to be highest for gold compounds, trimethoprim with and without sulphonamides, cephalosporins and penicillins. The most common types of CDR were macular and mucalopapular eruptions, followed by urticaria and cutaneous vasculitis. The results correlate well with those of the Boston Collaborative Drug Surveillance Program.

Stronger association with HLA-Cw6 than with corneodesmosin (S-gene) polymorphisms in Swedish psoriasis patients.

Psoriasis vulgaris is strongly associated with certain human leukocyte antigens, especially in early onset. The purpose of this study was to study the HLA-Cw6 allele and its contribution to disease susceptibility in a set of 104 families with at least two affected siblings. A sequencing method was utilized to examine the two exons that build up the antigen binding site of the C locus receptor. DNA from patients homozygous for Cw6 based on haplotype information were sequenced. The results confirmed the identity of the Cw6 allele in affected individuals with the consensus sequence for Cw*0602. We screened the set of families for psoriasis patients homozygous for Cw6 and found 11 individuals with a mean age at onset of 16.1 years. The corresponding figure for the Cw6 heterozygotes was 18.45 years and for the Cw6-negatives 22.36 years. This is indicative of a gene dose effect. We performed a transmission disequilibrium test (TDT) on the Cw6 allele per se, used as a biallelic marker. The analysis resulted in a P-value of 5.3 x 10(-17) (t167/nt45). This greatly exceeds our previous results of a TDT in the region, including microsatellite markers and single nucleotide polymorphisms (SNPs) in the coding part of the S gene (corneodesmosin), which is a suggested candidate gene in the region. The maximum nonparametric linkage (NPL) value was also reached using HLA-C as a marker. We conclude that Cw6 is the allele which shows the highest degree of association with psoriasis in our set of families and we propose that it directly influences the age at onset of the disease rather than increasing the genetic load in accordance with a polygenic theory.

The ichthyosis.

This review discusses the classification of generalized, hereditary forms of ichthyosis. The present state of knowledge of the mode of inheritance for the different forms of ichthyosis is briefly discussed in relation to genetic counselling. The different therapeutic principles are touched upon as well as other measures aimed at helping these patients to cope with some problems of everyday life.

Urea in the treatment of dry skin.

Urea is a unique physiological substance. It has frequently been used in dermatological therapy for more than 20 years. The relevant properties of urea with regard to its use in dermatological preparations are discussed in this brief review. Urea's natural presence in the horny layer, its water solubility, dipolar character and relation to concentrated solutions of electrolytes, are highlighted. The clinical use of urea creams is discussed with respect to indications, side-effects and combinations with other substances.