Comparative studies on the tolerance to photoinduced cutaneous inflammatory reactions by psoralen and rose bengal.

The photochemotherapeutic value of topical 8-methoxypsoralen (8-MOP) plus UVA irradiation has been well recognized. The phototoxicity associated with psoralen plus UVA (PUVA) therapy is hallmarked by an increase in vascular permeability (iVP), the accumulation of polymorphonuclear leukocytes (aPMN) and erythema formation in situ. Rose bengal (RB) plus UVA-VIS light (320-700 nm) produces a similar acute inflammatory response, but without immediate or delayed erythema and perceptible edema. This study describes some of the parameters involved in inflammatory reactions evoked by PUVA and the results are compared with RB-induced phototoxic reactions. The rates of iVP and aPMN with a 3 h pulse were quantified using 125I-albumin and 51Cr-labelled PMNs respectively. The erythemal response was graded visually. 8-MOP cream was applied topically, while RB was injected intradermally in rabbit skin before UVA-VIS (9.4 J cm-2) irradiation. The data show that there is no significant difference in the rates of iVP, aPMN and erythema formation between normal skin sites and mast cell-depleted skin sites when challenged with 8-MOP plus light. These results suggest that in situ mast cells do not play a significant role in 8-MOP-photoinduced acute cutaneous inflammatory reactions, in contrast with RB-photoinduced reactions. The iVP and aPMN responses are minimal or absent in sites subjected to repeated exposure to 8-MOP plus light for three or more consecutive days, suggesting the establishment of a desensitized/unresponsive state. Moreover, 8-MOP-photo-desensitized sites do not produce iVP and aPMN of the same magnitude as the normal (naive) skin sites when challenged with RB plus light. Similarly, RB-photo-desensitized sites do not produce iVP and aPMN of the same magnitude as the native skin sites when challenged with 8-MOP plus light. The desensitization and cross-desensitization of skin sites to 8-MOP- or RB-photoinduced reactions suggest that there is either direct attack on the target cell(s), thereby removing the ability to express adhesion molecules, such as endothelial leukocyte adhesion molecule 1 (ELAM-1) or intercellular adhesion molecule 1 (ICAM-1), involved in the accumulation of inflammatory cells, or downregulation of the secretion/release of putative agent(s), such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), responsible for the initiation and progression of cutaneous inflammations.

Modulation of 8-methoxypsoralen-photoinduced cutaneous inflammatory reactions by various chemotherapeutic agents in vivo.

Exposure of albino rabbits to UVA-VIS (320-700 nm) radiation after the topical application of 8-methoxypsoralen (8-MOP) cream is associated with acute cutaneous inflammatory reactions in situ. In the present studies the effects of various agents on 8-MOP plus light induced cutaneous inflammatory response viz. increase in vascular permeability (iVP), accumulation of polymorphonuclear leukocytes (aPMN) and erythema formation were investigated. The inflammatory reactions were induced by a single exposure of 8-MOP-sensitized sites to UVA-VIS (9.4J/cm2) light. Indomethacin, p-bromophenacyl bromide (BPAB), MK886 (trade name of Merck Sharpe & Dome), ibuprofen (IB), nordihydroguaiaretic acid (NDGA) or quinacrine were applied topically in cream base at various times prior to 8-MOP application. The iVP and aPMN were quantitated 24 h postirradiation using 125I-HSA and 51Cr-labeled PMN respectively, while erythema was graded visually. The rate of iVP, aPMN and erythema was inhibited almost completely by indomethacin (7.5-10%) when applied twice, 18 h and 3 h prior to 8-MOP. At lower concentrations of indomethacin (< or = 5%) iVP was inhibited whereas aPMN was augmented. The BPAB (0.25%) inhibited more than 90% of 8-MOP-photoinduced iVP and aPMN while there was partial reduction in erythema. The MK886 (0.1%) cream inhibited about 50% of iVP and aPMN but erythema persisted. The agents that are somewhat nonspecific such as IB, quinacrine and NDGA inhibited 8-MOP-photoinduced inflammation only marginally at the concentrations tested. The fact that iVP, aPMN and erythema can be dissociated suggests that there are independent variables in 8-MOP-photoinduced reactions, which involve multifactorial mechanisms probably controlled by different cell-signalling pathways and mediators.

Endogenous porphyrins in murine skin and transplanted PAM-212 squamous cell carcinoma tissues after injection of delta-aminolevulinic acid.

After intraperitoneal (IP) injection of delta-aminolevulinic acid (ALA), the endogenous porphyrins in murine skin and tumor tissues were determined by a method involving solvent and acid extractions. The results showed that the total amount of porphyrins in the tumor tissues after ALA injection was much higher than that in the skin from the same mice, although the amount of porphyrins in the skin from the ALA-injected mice was higher than that from the saline-injected (control) mice. The porphyrins in the tumor were mostly protoporphyrin and coproporphyrin, with only a small amount of uroporphyrin. The optimum period for porphyrin accumulation in the tumor as well as in the skin was 1 hour after the injection of ALA. As the period was extended to 3 and 6 hours, the amount of porphyrins in these tissues decreased considerably. These findings could be valuable for further application of ALA in the photodynamic therapy of skin cancer.

Photoinduced cutaneous inflammatory response by psoralens.

Our studies describe the inflammatory response in rabbit skin induced by topical application of 8-methoxypsoralen (8-MOP) and UVA-visible irradiation (320-700 nm). Increase in vascular permeability (iVP) and accumulation of polymorphonuclear leucocytes (aPMN) at the test sites were quantitated using 125I-albumin and 51Cr-labelled PMNs respectively. Erythema was graded visually. 8-MOP cream was applied topically and irradiated. The erythemal response, aPMN and iVP at the test sites were quantitated at 6, 24, 48 and 72 h post-irradiation. The iVP and aPMN were maximal at 24 h; the erythemal response was the same at 24-48 h. The responses were dependent on 8-MOP concentration and irradiation dose. Topical application of 200 micrograms 8-MOP cream followed by irradiation for 2 h (9.4 J cm-2) produced 3-7 times iVP, 2-4 times aPMN and intense erythema at the test sites after 24 h. Neither aPMN nor iVP was detected before 6 h and erythemal response was not observable up to 16 h after irradiation. The aPMN and iVP gradually subsided in 72 h, although the erythemal response was still present. The repeated exposure of 8-MOP-treated sites for three consecutive days 24 h apart did not produce appreciable iVP or aPMN at 72 h or 24 h after the last exposure; however, erythema persisted. The 8-MOP-treated sites previously exposed for three consecutive days on reapplication of 8-MOP cream plus irradiation showed significantly less response compared with non-pretreated sites. Our results suggest that the erythemal response is not directly related to either iVP or aPMN.

Identifying effective treatments for uremic pruritus.

The identification of effective treatments for uremic pruritus used a literature search of MEDLINE (1966 to March 1991), Index Medicus (1978 to March 1991), bibliographic reviews of textbooks, and pertinent articles. Only randomized controlled clinical trials were selected for analysis. Assessment of study quality was performed independently by two observers with specific methodologic criteria. A clinically significant therapeutic effect was defined as a statistically significant result in the proportion of patients improving and a reduction in pruritus score of at least 50%. Clinically significant outcomes were obtained for two of three whole-body ultraviolet B trials. Meta-analysis of the ultraviolet B trials retained the significant effect in analysis of proportions (pooled odds ratio 18; 95% confidence interval 4, 161). Trials of lidocaine, charcoal, and nicergoline demonstrated either statistically significant improvement in pruritus score or in proportions, but not both. Ultraviolet B phototherapy is the treatment of choice in moderate to severe uremic pruritus.

Role of iron in the photosensitization by uroporphyrin.

The role of iron in the mechanism of photosensitivity due to uroporphyrin was investigated. There is frequently increased levels of Fe in the serum from patients with porphyria cutanea tarda, where the photosensitivity is due to uroporphyrin. It has been reported that H2O2 has a major role in the uroporphyrin induced photosensitivity. Hence we examined the hypothesis that Fe would catalyze the production of OH from H2O2 and the OH thus formed may have a significant role in the uroporphyrin photosensitivity. This was examined by studying the effects of the Fe chelating compound deferoxamine in an in vitro system. Our results show that deferoxamine inhibited the uroporphyrin photosensitivity, but not the photosensitivity due to protoporphyrin. This indicates that Fe may play a role in the uroporphyrin photosensitization in the skin, by accelerating the formation of OH, which may be a major reactive species responsible for the photosensitization in porphyria cutanea tarda.

Characterization of the pigment from homogentisic acid and urine and tissue from an alkaptonuria patient.

When urine samples from alkaptonuria patients are allowed to stand, they turn black, presumably owing to the oxidation of homogentisic acid to a melanin-like substance. We report the characterization of the pigments formed by polymerization of (a) the components in the urine from a patient with alkaptonuria and (b) homogentisic acid. The absorption spectra and electron spin resonance signals of these pigments are similar to those of eumelanins. Irradiation of the pigments with nitroblue tetrazolium caused reduction of the tetrazolium; this was partially inhibited by superoxide dismutase. Irradiation of Ehrlich ascites carcinoma cells with the pigments from homogentisic acid or urine caused cell lysis. Since this lysis was inhibited by catalase, we have concluded that it was mediated by H2O2. A similar pigment was also extracted from the tissue from an alkaptonuria patient. It is suggested that the degeneration of tissue in vivo may be due to the deposition of melanin-like pigments in the tissues, probably in combination with metal ions.

Quantitation of hydrogen peroxide formed during UV-visible irradiation of protoporphyrin, coproporphyrin and uroporphyrin.

Free porphyrins are strong photosensitizers. Previously reported findings indicate that the in vitro cell lysis induced by irradiation in the presence of coproporphyrin (CP) and uroporphyrin (UP) is mediated by H2O2 and that induced by irradiation with protoporphyrin (PP) is not mediated by H2O2. In the present study the possible role of H2O2 in the porphyrin photosensitization was investigated by direct measurement of the H2O2 formed during the irradiation of PP, CP and UP. Our results show that the amount of H2O2 formed decreased in the following order: UP, CP, PP. The amounts of H2O2 formed during irradiation of CP and PP were approximately 86% and 38% respectively in comparison to the H2O2 formed during the irradiation of UP. The formation of H2O2 was inhibited by sodium azide, a strong quencher of singlet oxygen. These observations are in good agreement with the previous report that the in vitro photolysis of Ehrlich ascites carcinoma cells by UP and CP, but not that by PP, was inhibited by catalase and clinical findings with patients with erythropoietic protoporphyria (EPP) and porphyria cutanea tarda (PCT). The patients with EPP, where the photosensitivity is due to PP, respond well to beta-carotene while beta-carotene does not protect against the photosensitivity in PCT, in which case the photosensitivity is due to uroporphyrin.

Granuloma annulare in patients with human immunodeficiency virus infections.

We present four cases of granuloma annulare occurring in patients with human immunodeficiency virus (HIV) infection. These patients had either an extensive localized form or generalized granuloma annulare. The patient with generalized granuloma annulare was clinically reminiscent of the previously described papular eruption seen in HIV-positive patients. In several patients with the localized form, Kaposi's sarcoma was considered in the differential diagnosis. In all patients, however, the eruptions were surprisingly transient. The similarity of the localized form of granuloma annulare to Kaposi's sarcoma and the generalized micropapular form to the papular eruption of acquired immunodeficiency syndrome seen in HIV-positive patients illustrates the usefulness of skin biopsies in these patients.

Ultrastructural changes produced in Ehrlich ascites carcinoma cells by ultraviolet-visible radiation in the presence of melanins.

Irradiation of Ehrlich ascites carcinoma (EAC) cells in the presence of pheomelanin, i.e., red hair melanin (RHM), has been reported to produce extensive cell lysis. Irradiation in the presence of eumelanin, i.e., black hair melanin (BHM), or irradiation in the absence of either type of melanin did not produce this effect. We observed that RHM particles penetrated the cell membrane without apparent structural damage to the cell or the cell membrane. Irradiation of the cells in the absence of melanin did not produce any changes in the ultrastructure of the cells. Incubation of the cells in the dark in the presence of RHM produced only minor structural, mainly cytoplasmic changes. Irradiation of the cells in the presence of RHM produced extensive ultrastructural changes prior to complete cell lysis; these changes were more severe than the effects of incubation of the cells in the dark in the presence of RHM. When the cells incubated in the dark or irradiated in the presence of latex particles or either one of the eumelanins particles, viz. BHM or synthetic dopa melanin, these particles did not penetrate into the cells or produce any ultrastructural changes. These particles were in fact not even ingested by the cells.

Dermatologic signs in anorexia nervosa and bulimia nervosa.

The dermatologic changes in anorexia nervosa and bulimia nervosa may be the first signs to give the clinician a clue that an eating disorder is present, as many of these patients either deny their symptoms or secretly refuse to comply with treatment. The dermatologic signs are a result of (1) starvation or malnutrition, eg, lanugolike body hair, asteatotic skin, brittle hair and nails, and carotenodermia; (2) self-induced vomiting, eg, hand calluses, dental enamel erosion, gingivitis, and a Sjögrenlike syndrome; (3) use of laxatives, diuretics, or emetics and their dermatologic side effects; and (4) other concomitant psychiatric illness, eg, hand dermatitis from compulsive handwashing. Further, as most of the cutaneous signs are not specific to anorexia nervosa and bulimia nervosa, failure to include eating disorders in the differential diagnosis may lead to misdiagnosis of the cutaneous symptoms.

Psoriasis and psychiatry: an update.

Psychosocial factors are important in the onset and/or exacerbation of psoriasis in 40%-80% of cases. Yet psoriasis has received little attention in the recent psychiatric literature. A subgroup of psoriatics appear to be "stress reactors" and these patients may have a better long-term prognosis. Identification of such patients early in the course of treatment and incorporation of specific psychosocial interventions in their overall treatment regimen may improve the course of illness. Psoriasis has also been associated with suicide and an increased prevalence of alcoholism. The disturbances in body image perception and the effect of psoriasis on interpersonal, social, and occupational functioning can further contribute to the overall morbidity, especially if psoriasis first occurs during a developmentally critical period like adolescence. Certain biochemical and physiologic correlates of psoriasis of interest to the psychiatrist such as exacerbation of psoriasis with lithium therapy and increased cutaneous blood flow are discussed. Finally, some practical guidelines are provided for psychosocial interventions in psoriasis.

The self-inflicted dermatoses: a critical review.

The self-inflicted dermatoses, namely dermatitis artefacta, neurotic excoriations, and trichotillomania, have been reported to be associated with various degrees of psychopathology in the dermatologic literature, but have received surprisingly little emphasis in the psychiatric literature. This probably reflects, firstly the fact that most of these patients initially deny any psychologic problems and hence may not receive psychiatric interventions, and secondly a lack of adequate collaboration between the psychiatrist and dermatologist. These disorders may be associated with serious sequelae, such as suicide and repeated major surgical procedures. Their treatment is also primarily psychiatric. This article critically reviews the literature and comments upon the salient clinical features and treatments for these disorders, which are relevant for the psychiatrist doing consultation-liaison work. Knowledge of these disorders is important in the evaluation of any psychiatric patient, as these disorders are essentially a cutaneous sign of psychopathology.

Sarcoidosis with extensive cutaneous ulceration. Unusual clinical presentation.

A 70-year-old white woman with sarcoidosis and insulin-resistant diabetes mellitus presented with extensive cutaneous ulcerations. Both the cutaneous lesions and the systemic features of sarcoidosis showed a dramatic improvement during oral corticosteroid therapy. When extensive cutaneous ulcerations are present, it is important to consider sarcoidosis, as these may be the only presenting sign of the disease. Unlike ulcerated necrobiosis lipoidica diabeticorum, sarcoidal ulcerations may respond well to treatment with oral corticosteroids.

Cutaneous malignant neoplasms in patients with renal transplants.

There is an increased risk of developing cutaneous neoplasms in patients with renal transplants who are receiving immunosuppressive therapy. We studied 523 consecutive white patients who had received renal transplants at a Canadian medical center. Malignant neoplasms developed in 7.5% of these patients, and 72% of these neoplasms were cutaneous in origin. Compared with the general population, the rate of development of all skin cancers, squamous cell carcinoma, and basal cell carcinoma was 3.2, 18.4, and 1.4 times, respectively. In our study the squamous cell carcinoma to basal cell carcinoma ratio was 2.3:1, compared with 0.2:1 in the general population. There was no significant difference in the site of development of skin cancer in patients with renal transplants compared with the general population. There was, however, a propensity for the development of multiple skin cancers at an earlier age, especially on sun-exposed areas. The results of this study have been compared with those of other world medical centers.