Increased cyclooxygenase expression and thymine dimer formation after repeated exposures of humans to low doses of solar simulated radiation.

The impact of repeated doses of solar simulated radiation (SSR) has not been evaluated, particularly to determine if photoadaptation and photoprotection develop over time. In this study, erythema, pigmentation, cyclooxygenase (COX)-1 and 2 expression and thymine dimer (dTT) formation were evaluated in the skin of irradiated subjects of phototype II or III. Groups of 7-10 volunteers were whole-body irradiated with a low dose of SSR on each of 10 consecutive days followed by a single erythemal ultraviolet B (UVB) dose on a small body area, or irradiated only with the single erythemal UVB dose on a small body area, or irradiated with the low dose of SSR on each of 30 consecutive days, or were unirradiated. Erythema and pigmentation were measured 24 h after the final SSR or UVB, and skin biopsies collected for the assessment of COX(+) cells and dTT(+) nuclei. The repeated SSR exposures induced a small increase in pigmentation without erythema, and were slightly protective against the erythemal effects of the subsequent high UVB dose. The number of COX-1(+) and 2(+) cells increased as a result of 10-days SSR and rose still further after 30-days SSR, indicating that photoadaptation had not developed. The SSR exposures did not result in any protection against the further increase in COX-1 and 2 expression caused by the erythemal UVB dose. In contrast, for dTT formation, the repeated SSR exposures led to a limited degree of both photoadaptation and photoprotection.

Association of a long-chain fatty acid-CoA ligase 4 gene polymorphism with depression and with enhanced niacin-induced dermal erythema.

Hypotheses about relationships between changes in membrane lipids and mental illness have focused primarily on three long-chain polyunsaturated fatty acids: arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Membrane deficiencies of these fatty acids have been reported in schizophrenia (AA, EPA, and DHA) and in depression (EPA and DHA). Long-chain fatty acid-CoA ligase type 4 (FACL4; MIM 300157) is a key enzyme involved in the metabolism of AA, EPA, and DHA. FACL4 selectively esterifies these fatty acids with co-enzyme A, forming acyl-co-A, which can then be incorporated into membrane phospholipid. We used niacin-induced dermal erythema as one index of AA metabolism to identify a common C to T single nucleotide polymorphism (SNP) in the first intron of the FACL4 gene (Xq22.3), which is associated with enhanced dermal erythema in both schizophrenia and control subjects. Male subjects with the T0 genotype showed greater dermal erythema following topical application of methylnicotinate, suggesting that this polymorphism may be in linkage disequilibrium with a functional polymorphism of the FACL4 gene that modulates re-sequestration of agonist-released free AA. We also examined the allele frequency of this polymorphism in 555 European-Americans (EA), including 229 control subjects, 198 subjects with major depression, 58 with schizophrenia or schizoaffective disorder, and 70 with alcohol dependence without co-morbid psychiatric illness. We observed a significant excess of the T allele in subjects with major depression, as compared with controls (49% vs. 38%; P = 0.003) and a non-significant excess of the T allele in schizophrenia (44%; P = 0.29). The allele frequency for subjects with alcohol dependence did not differ from controls.

Photoprovocation test and immunohistochemical analysis of inducible nitric oxide synthase expression in patients with Sjögren's syndrome associated with photosensitivity.

BACKGROUND: Annular erythema (AE) in Sjögren's syndrome (SS) usually develops on areas of sun-exposed skin and is exacerbated during summer. OBJECTIVES: To evaluate photosensitivity in SS and to investigate the involvement of ultraviolet (UV) radiation in the development of AE in SS. METHODS: Phototesting with UVA and UVB was performed on 14 SS patients, including 10 with primary SS. Clinical and histological features as well as expression of inducible nitric oxide synthase (iNOS) in the evoked skin lesions were compared with those of lupus erythematosus (LE). Eleven SS patients had a history of photosensitive AE (n = 4), papules (n = 3) or other types (n = 4) of lesions on their sun-exposed skin that were induced or aggravated by sunlight exposure. RESULTS: Phototesting induced a prolonged erythematous response (n = 8), infiltrated erythema (IE) (n = 4) and/or papules (n = 3) in 11 of 14 SS patients, including one with primary SS without a history of photosensitivity. Histologically, the induced IE and papules showed coat-sleeve-like or sparse perivascular infiltration of lymphocytes similar to that in primary skin lesions of AE in SS. No epidermal changes characteristic for LE were found except for partial and mild liquefaction degeneration in three cases. In contrast, two cases were indistinguishable from the papular type of polymorphic light eruption in several aspects, including their primary skin lesions and early response to a photoprovocation test. Immunohistochemistry revealed diffuse expression of iNOS throughout the epidermis, which is characteristic for LE, in the three SS patients with minimal liquefaction degeneration, while the remaining seven SS patients examined exhibited no iNOS staining or a normal expression pattern. CONCLUSIONS: Our results indicate that photosensitivity exists in certain primary SS patients, and that UV is critical to the development of AE in SS, probably through a pathological mechanism distinct from that in LE.

Factor XIIIa+ dermal dendrocytes in erythema elevatum diutinum and ordinary cutaneous leukocytoclastic vasculitis lesions.

Factor XIIIa+ dermal dendrocytes belong to the dermal microvascular unit and are related to wound healing, angiogenic and fibrogenic processes. Erythema elevatum diutinum (EED) is a leukocytoclastic vasculitis followed by repair and fibrosis. In order to verify the involvement of fXIIIa+DD in the pathogenesis of EED and ordinary leukocytoclastic vasculitis (OLV) these cells were immune labeled with anti-factor XIIIa antibody and quantified in 15 biopsies of EED, 18 of OLV and compared with 11 fragments of normal skin (NS). The number of vessels was evaluated by endothelial cell staining with anti CD34 antibody. FXIIIa+DD appeared in both groups of vasculitis with hyperthophic dendrites, with no difference in their number at any level of the dermis. The number of fXIIIa+DD in the superficial dermis was higher in OLV than in NS (p<0.001). The number of dermal vessels in the EED group was higher at all dermis depths evaluated when compared with NS (p<0.05) and in the middle and deep dermis when compared with OLV (p<0.05). The results suggest the participation of fXIIIa+DD in the immunopathological mechanisms of both groups of vasculitis studied. However, there was no correlation between the number of fXIIIa+DD and angiogenesis and fibrogenesis in the EED lesions.

Increased synthesis of high-molecular-weight cPLA2 mediates early UV-induced PGE2 in human skin.

Ultraviolet light (UV) B-induced inflammation is characterized by dramatic increases in prostaglandin E2 (PGE2) synthesis due to enhanced arachidonate deacylation from the membrane. Therefore, the effect of UV on sythesis, mass, and distribution of the high-molecular-weight phospholipase A2 (cPLA2) in cultured human keratinocytes and human skin was studied. The 105-kDa cPLA2 was demonstrated to be the critical enzyme in UV-induced PGE2 synthesis and erythema in the first 6 h postirradiation. Immunoprecipitation of 35S-labeled protein showed cPLA2 synthesis increased three- to fourfold 6 h after irradiation. Immunoprecipitated 32P-labeled cPLA2 demonstrated phosphorylation of cPLA2 was concurrently induced, suggesting that UV also activates cPLA2. This increase in cPLA2 synthesis and activation also closely correlated with increased PGE2 synthesis and [3H]arachidonic acid release and was effectively blocked by both an S-oligonucleotide antisense to cPLA2 and methyl arachidonate fluorophosphate, a specific inhibitor of cPLA2. Biopsy and histochemical examination of erythematous sites expressed increased amounts of cPLA2 whereas nonerythematous irradiated sites did not. In contrast, cyclooxygenase-1 and -2 in cultures and skin explants were unaffected 6 h post-UV, and no change in cyclooxygenase activity was observed at this time. These results suggest that increased cPLA2 synthesis occurs only when skin is exposed to UV doses that are sufficient to cause erythema and indicate expression of cPLA2 participates in acute UV inflammation.

Immunohistochemical study of linear gingival erythema from HIV-positive patients.

Severe forms of periodontal disease are frequent in patients with acquired immunodeficiency syndrome (AIDS). Linear gingival erythema (LGE) is a progressive disease described in HIV-positive patients and is considered to be an early stage of necrotizing periodontitis. Although clinical and microbiological differences are reported in LGE and non-specific gingivitis (NSG), a comparative immunopathological approach of both has not been performed yet. The purpose of this study was to compare relative populations of T-lymphocytes, B-lymphocytes, neutrophils, macrophages and IgG bearing plasma cells in gingival biopsies from sites exhibiting LGE and from sites exhibiting NSG. A biotin-streptavidin amplified system was used for identification of the following antigens: CD3 (T-lymphocytes), CD20 (B-lymphocytes), elastase (neutrophils), CD68 (macrophages) and IgG (plasma cell's secretors of IgG). The results have demonstrated decrease proportions of T-lymphocytes, macrophages and high percentage of neutrophils and IgG bearing plasma cells in LGE. In contrast with NSG, many neutrophils cells in LGE were found inside oral gingival epithelium. Our results highlight the idea that progressive periodontal disease is not only characterized by increased tissue inflammation, but, in addition, by significant changes in the proportion of specific inflammatory cells. The high number of neutrophils along the gingival epithelium is probably associated with the severe gingival necrosis reported in AIDS patients.

The effects of sunscreens on UVB erythema and Langerhans cell depression.

Langerhans cells (LCs) are epidermal antigen-presenting cells capable of initiating a specific T lymphocyte-mediated immune response. It is a well known fact that ultraviolet light B (UVB) suppresses LC number and function. In this study, we confirmed that the sunscreens CITY BLOCK, and TOTAL SUN SHIELD 28 (Clinique Laboratories Tokyo, Japan) protected the epidermis against the depletion of LC number. We also investigated whether or not sunscreens could provide LC protection from ultraviolet ray (UVR) damage other than the prevention of the decrease in the total number of cells. Our data showed that the LC population was depressed after irradiation by 100 mJ/cm2 or 10 mJ/cm2 of UVB, but recovered to within normal levels after 16 days. Both sunscreens provided protection against erythema and LC depression due to UVB irradiation. However, despite the fact that these sunscreens had completely suppressed UVB erythema, shrinkage of LC dendrites was seen. Apparently, sunscreens prevent UVB erythema, but do not protect against functional changes in LC due to UVB. Recently, it has been reported that sunscreens are less effective in protecting against systemic immunosuppression that against inflammation. The shrinkage of LC dendrites despite sunscreen application may help explain this discrepancy.

Studies on the time course of dithranol-induced inflammation by quantification of alkaline phosphatase.

An inflammatory response of the skin to dithranol-induced free radicals seems to be essential for its clinical efficacy. In normal volunteers this response was evaluated at the level of the microvasculature following 30 min, 2 h and 24 h applications, using a functional parameter (erythema) and a biochemical parameter (alkaline phosphatase). The results of 'short contact' and 24 h applications were similar. In all schedules a maximum erythema was seen 2-3 days after the application which had resolved totally after 6-8 days. A marked discrepancy was established between the duration of functional and biochemical abnormalities; the alkaline phosphatase activity reached a maximum 1 day after the culmination of the erythema and persisted up to at least 7 days after disappearance of the erythema. These findings are discussed in the light of the day-to-day management of psoriasis with dithranol.

Alterations in colonic thymidine kinase enzyme activity induced by consumption of various dietary fibers.

Dietary fibers may tend to enhance or inhibit chemically induced experimental colon cancer, depending on the particular fiber consumed. This study examined the relationship between colonic thymidine kinase enzyme activity and mucin histochemistry and the reported effects of various dietary fibers on chemically induced colon carcinogenesis. Fiber-supplemented diets containing fibers reported to inhibit (wheat bran) or enhance (guar gum, carrageenan) chemically induced colon carcinogenesis in the rat were selected. Four groups of male Fischer 344 rats consumed 10% wheat bran, 5% guar gum, 5% carrageenan, or fiber-free diets ad libitum for 4 weeks. At the completion of the treatment period, the distal 12 cm of colonic mucosa was scraped off and homogenized for determination of thymidine kinase activity, and a 0.5-cm section of midcolon was processed by the high-iron diamine/Alcian blue method for mucin histochemistry. Final animal weights did not differ significantly among groups. Thymidine kinase enzyme specific activity (mumole thymidine phosphate formed x 10(6)/min/mg protein, means +/- SEMs) was not significantly different in the fiber-free, wheat bran, and guar gum groups (10.98 +/- 1.50, 7.41 +/- 1.09, and 9.11 +/- 2.04, respectively) but was markedly elevated at 41.84 +/- 4.65 in the carrageenan group (alpha less than 0.001). Mucin histochemistry failed to reveal any significant differences among dietary groups.

Quantification of alkaline phosphatase in lesions and uninvolved skin of psoriatic patients.

Alkaline phosphatase (ALP) has been quantified in psoriatic skin for the first time. The levels of both the soluble and the particulate forms of this enzyme were grossly elevated in psoriatic lesions; by contrast, levels in the clinically uninvolved skin of the patient were normal. The changes in the lesion cannot be explained solely in terms of vasodilatation, since UVR-induced erythema was accompanied only by a modest increase in soluble ALP activity.

Erythema dyschromicum perstans.

Erythema dyschromicum perstans (EDP) was first described in 1957, and electron microscopic studies were reported in 1969. Herein, we describe five cases and compare light and electron microscopic findings, direct and indirect immunofluorescence, and dopa-positive melanocyte counts between normal and affected skin. The results indicate that EDP is a clinically characteristic disorder with a lichenoid reaction in its active phase. This lichenoid reaction leads to a pronounced incontinence of pigment and to decreased numbers of melanocytes and of tyrosinase activity in the involved epidermis. These findings support the suggestion that EDP and lichen planus pigmentosus are possible the same entity. Direct inmunofluorescence and fine structural studies show similar findings to lichen plunus. Patients have low-titer antibodies to extranuclear basal cell components.