The effect of ultra violet B (TL-01) phototherapy on epidermal expression of p53 protein in psoriatic plaques.

BACKGROUND: Psoriasis is a genetically determined inflammatory skin disease. It is now recognized that narrow band TL-01 phototherapy is an effective treatment for psoriasis. However, ultraviolet (UV) exposure induces p53 mutations in keratinocytes and repeated exposure of skin to UV radiation results in clonal expansion of these initiated p53-mutant cells within the epidermis. AIM: The present study aims to examine epidermal p53 expression in the skin of psoriatic patients at different time points following TL-01 phototherapy. METHODS: Skin samples from patients suffering from plaque-type psoriasis, collected before, during and at the final stages of TL-01 phototherapy were examined for p53 expression by immunohistochemistry. RESULTS/CONCLUSION: Our results showed an increase in p53 expressing keratinocytes following TL-01 phototherapy. Some of these cells were arranged spatially, as conical clones arising from putative stem cell compartments, suggesting that the chronic TL-01 treatment might have triggered cell growth and clonal expansion, an important step in initiating skin carcinogenesis.

Iatrogenic skin cancer: induction by psoralen/ultraviolet A and immunosuppression of organ transplant recipients.

Photochemotherapy (psoralen/UVA (PUVA)) is an efficient therapeutic tool for a wide range of skin diseases. Concern, however, exists regarding the long-term carcinogenic effects of this treatment modality and, as a consequence, is being used less frequently. PUVA remains an important treatment in our therapeutic armamentarium but must be used with caution in those patients with risk factors and cumulative dose exposure must be limited. PUVA-induced cancers show features in common with skin cancers induced by immunosuppressed organ transplant recipients. Tumours in the latter group of individuals are, however, much more aggressive and difficult to manage.

Combination TL01 ultraviolet B phototherapy and topical calcipotriol for psoriasis: a prospective randomized placebo-controlled clinical trial.

BACKGROUND: Previous studies have demonstrated the ultraviolet (UV)-sparing effect of combining topical calcipotriol with broadband UVB in the treatment of psoriasis. OBJECTIVES: To determine if the combination of narrowband TL01 UVB phototherapy and topical calcipotriol produces the same UVB-sparing effect. METHODS: This was a randomized, placebo-controlled, blinded clinical trial. Fifty psoriasis patients were recruited, 25 of whom were randomized into the active group who received TL01 phototherapy together with twice-daily application of calcipotriol cream 50 microg g(-1). The control group received TL01 phototherapy and twice-daily application of a topical emollient as placebo. TL01 phototherapy was given three times per week starting at 70% minimal erythema dose with 20% increments as tolerated for up to approximately 20 sessions. Patients were assessed using the Psoriasis Area and Severity Index (PASI) and Psoriasis Disability Index (PDI). They were evaluated at treatment sessions 8, 14 and 20, and followed up at 5 and 10 weeks post-treatment. Statistical analysis was performed using a two-tailed t-test. RESULTS: There were no significant differences in demographic characteristics and baseline PASI and PDI scores between the two groups. The mean PASI score declined significantly (P < 0.01) for both groups after treatment. The difference in mean PASI score reduction from baseline between the two groups was only significant during the first eight sessions, with a net reduction of 3.6 (95% confidence interval 1.0-6.2, P = 0.008) in the active group relative to the control group. The mean PDI score declined significantly (P < 0.05) for both groups, but there was no statistical difference in mean PDI score reduction between the two groups (P = 0.8) at the end of treatment. The mean cumulative UVB dose for the active group was significantly lower (P < 0.02) at 16 204 mJ cm-2 compared with 21 082 mJ cm-2 for the control group. CONCLUSIONS: We conclude that combining TL01 phototherapy with topical calcipotriol cream has a UVB-sparing effect.

The impact of psoriasis on the quality of life of patients from the 16-center PUVA follow-up cohort.

BACKGROUND: The impact of psoriasis on the quality of life of patients is likely to be principally related to alterations in individual appearance and consequent psychosocial disability. Quantifying the impact of psoriasis and related changes from therapy would help in the selection of optimal management. OBJECTIVE: Our purpose was to evaluate the impact of psoriasis on patients with severe disease who have had photochemotherapy (PUVA). METHODS: In 1979 we interviewed 877 of 988 still participating patients who were enrolled in 15 of 16 centers in the PUVA Follow-up Study. We determined the impact of psoriasis on quality of life with a questionnaire that had been modified to incorporate measures of impairment that are likely to be affected by cutaneous disease. RESULTS: Psoriasis had substantial impact on the quality of life. Women were more likely than men to report impairment in quality of life dimensions. The impact of disease decreased with increasing age. Moderate to high relative impact on total quality of life was more often reported by patients who had recently used UVB phototherapy than by those using PUVA or methotrexate. CONCLUSION: Psoriasis has a substantial impact on the quality of life. This impact seems to decrease with increasing age. Use of specific treatments are also associated with the extent to which psoriasis affects quality of life.

Cutaneous neoplasia following PUVA therapy for psoriasis.

To determine the risk of cutaneous neoplasia following photochemotherapy (PUVA), we reviewed patients with psoriasis treated at our unit between 1979 and 1991. Two hundred and forty-five patients were assessed, with a median duration of follow-up of 9.5 years. Fifty-nine per cent were male, and 41% female. The median number of exposures was 59, and the median total dose was 133 J/cm2 for the group as a whole. Non-melanoma skin cancers (NMSC) occurred in six individuals (2.4%). Basal cell carcinoma occurred in all six and one individual also developed four squamous cell carcinomas and Bowen's disease of the penis. No cases of malignant melanoma were recorded. Patients who developed NMSC received a median number of 225 exposures and a median cumulative dose of 654 J/cm2. Compared with a control study population in West Glamorgan, Wales, there was a 1.4 (95% confidence limits (CL) 0.5 and 3.1) times increased risk of NMSC. A statistically significant increased incidence of NMSC was found for patients who had received 100 or more exposures, and 250 or more J/cm2, with risks of 3.7 (95% CL 1.0 and 9.5), and 4.0 (95% CL 1.1 and 10), respectively. A PUVA dose of < 250 J/cm2 or < 100 exposures conferred a minimal increase in risk of NMSC in our study population.

Photosensitivity associated with combined UV-B and calcipotriene therapy.

BACKGROUND: Ultraviolet B phototherapy is an effective agent for the treatment of psoriasis; its most frequent acute side effect is burning of the skin. It has been combined with various other topical or systemic agents to augment therapeutic effect. Recently, UV-B therapy has been used with calcipotriene ointment (Dovonex, Westwood-Squibb, Buffalo, NY), a new vitamin D analogue. OBSERVATIONS: We report four cases of chronic plaque psoriasis that developed in patients who used UV-B phototherapy for a substantial period without ill effects and in whom photosensitivity reactions within psoriatic plaques developed after calcipotriene ointment was added, without changes in their UV-B dosage or frequency of treatment. The time from starting calcipotriene therapy to the development of photosensitivity ranged from 4 to 28 days, and the number of UV-B exposures during this period varied between one and 12 treatments. The mean UV-B dose at burning was 1114mJ/cm2. Twenty-two patients had used calcipotriene in combination with UV-B therapy of a total of 103 UV-B-treated patients during the period when the adverse events occurred. Half these patients started calcipotriene therapy prior to starting treatment with UV-B. However, cases of photosensitivity occurred only in the remaining half of the patients in whom calcipotriene therapy was added during UV-B therapy. Combined therapy was able to be continued or resumed in two patients by reduction of the UV-B dose. In three cases, phototesting, confirmed greater photosensitivity to calcipotriene-treated skin than to skin to which hydrated petrolatum was applied. CONCLUSIONS: Calcipotriene ointment should be introduced with caution in patients already receiving UV-B phototherapy, particularly those receiving high doses of UV-B. The mechanism of this photosensitivity reaction is unknown. This increased sensitivity to UV-B may be a result of the effect of calcipotriene on stratum corneum thickness, epidermal melanization, a result of its effect on the inflammatory reaction to UV-B irradiation, or, possibly, because it is a phototoxic agent.

PUVA and methotrexate therapy of psoriasis: how closely do dermatology departments follow treatment guidelines? Psoriasis Audit Workgroup of the British Association of Dermatologists.

Following publication of treatment guidelines for patients with psoriasis, a six-centre audit was undertaken to assess current therapeutic practice for two second-line treatments, PUVA and methotrexate. The audit consisted of random sampling of casenotes by external auditors from a paired dermatology department, and assessment by questionnaire. One hundred and eight PUVA and 118 methotrexate casenotes were audited. The commonest indications for treatment were: (a) failure of tropical therapy--PUVA (mean 81% of casenotes), methotrexate (84%); (b) repeated hospital admissions--PUVA (16%), methotrexate (25%). For both PUVA and methotrexate, some aspects of treatment were well documented: PUVA--psoralen dosage (91%), response to PUVA (89%), cumulative lifetime UVA dosage (81%); methotrexate--pretreatment assessment of full blood count (91%), urea and electrolytes (85%), liver function tests (84%). For other aspects documentation was less complete: PUVA--no documentation of presence/absence of skin cancer history (66%), note of photoactive drugs (32%); methotrexate--concurrent medication (69%), history of presence/absence of liver disease (36%). Another aspect which was poorly documented in both PUVA and methotrexate notes was whether advice on contraception/fertility had been given. There was no indication in 29 of 32 casenotes of females of child-bearing age receiving PUVA, and 52 of 63 case notes of relevant patients on methotrexate. This project has demonstrated that formal, multicentre audit based on published guidelines is a practical proposition.

Serotonergic neurotoxic lesions facilitate male sexual reflexes.

The effects of the neurotoxin 5,7 dihydroxytryptamine (5,7 DHT) on the urethrogenital reflex was examined in anesthetized male rats. Both ICV and intrathecal administration of 5,7 DHT produced a marked depletion (92%) of spinal 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HT IAA) levels. ICV but not intrathecal administration of 5,7 DHT also caused a moderate reduction in 5-HT and 5-HT IAA levels in the medulla and hypothalamus (40-48%). No reduction in adrenergic levels were observed. In spinally intact, vehicle-treated rats the urethrogenital reflex could not be evoked. However, the urethrogenital reflex could be evoked in rats pretreated with either ICV or intrathecal 5,7 DHT prior to section of the spinal cord. These data support the hypothesis that 5-HT mediates the descending inhibition of male sexual reflexes.

Stimulation of the hypothalamus initiates the urethrogenital reflex in male rats.

The urethrogenital (UG) reflex is a spinal sexual reflex which is tonically inhibited in the intact male rat by neurons in the nucleus paragigantocellularis (nPGi). The medial preoptic area of the hypothalamus (MPOA) is involved in the activation of male sexual behavior. The present study examines the effect of hypothalamic stimulation on the UG reflex in the intact male rat. Areas of the hypothalamus were stimulated bilaterally with either electrical stimulation or D,L-homocysteic acid (DLH) and the presence of the UG reflex examined. Stimulation of discrete aras of the hypothalamus evoked the UG reflex. The UG reflex could be initiated in the absence of genital stimulation. Microinjections of DLH into the MPOA also initiate the UG reflex. These data suggest that stimulation of neurons in the MPOA overcome the inhibition by the nPGi and facilitate spinal genital reflexes leading to ejaculation.

Central nervous system innervation of the penis as revealed by the transneuronal transport of pseudorabies virus.

Transneuronal tracing techniques were used in order to identify putative spinal interneurons and brainstem sites involved in the control of penile function. Pseudorabies virus was injected into the corpus cavernosus tissue of the penis in rats. After a four day survival period, rats were perfused with fixative and virus-labelled neurons were identified by immunohistochemistry. Postganglionic neurons were retrogradely labelled in the major pelvic ganglia. In the spinal cord, sympathetic and parasympathetic preganglionic neurons were labelled transneuronally. Presumptive interneurons were also labelled in the lower thoracic and lumbosacral spinal cord in locations consistent with what is currently known about such interneurons. In the brainstem, transneuronally labelled neurons were found in the medulla, pons and hypothalamus. Regions consistently labelled included the nucleus paragigantocellularis, parapyramidal reticular formation of the medulla, raphe pallidus, raphe magnus, A5 noradrenergic cell group, Barrington's nucleus and the paraventricular nucleus of the hypothalamus. This study confirmed previous studies from our lab and others concerning the preganglionic and postganglionic neurons innervating the penis. The number, morphology and location of these neurons were consistent with labelling seen following injection of conventional tracers into the penis. The brainstem nuclei labelled in this study were also consistent with what is currently known about the brainstem control of penile function. The labelling appeared to be highly specific, in that descending systems involved in other functions were not labelled. These results provide further evidence that the pseudorabies virus transneuronal tracing technique is a valuable method for identifying neural circuits mediating specific functions.

Determination of prostatic secretion in rats: effect of neurotransmitters and testosterone.

To study the neuronal and hormonal control of prostatic secretion, the prostatic urethra was cannulated in urethane anesthetized rats. The volume of prostatic secretion was measured following infusion of cholinergic and adrenergic agonists intact animals. Prostatic secretion was elicited by norepinephrine, phenylephrine and carbachol; but not by clonidine, isoproterenol, pilocarpine, or acetylcholine. Phenylephrine and norepinephrine infusions caused a high initial rate of secretion, which then declined rapidly. Carbachol infusion, in contrast, produced a low but constant rate of secretion that was maintained for up to 1 hour. Histological examination of the prostate revealed contraction of smooth muscle surrounding prostatic ducts after infusion of phenylephrine and norepinephrine, but not carbachol. Prostatic secretion was also measured in castrated rats supplemented with various doses of testosterone. Testosterone exerted a dose dependent control of prostatic weight and secretory volume. These results indicate 1) alpha 1 receptor agonists can cause contraction of smooth muscle to expel fluid from the rat prostate, 2) carbachol induces prostatic secretion through a mechanism other than contraction of gland, and 3) testosterone has a primary role in controlling prostatic size.