Marselisborgcentret

BACKGROUND: Tacrolimus (FK 506) is an effective immunosuppressant drug for the prevention of rejection after organ transplantation, and preliminary studies suggest that topical application of tacrolimus is effective in the treatment of atopic dermatitis. METHODS: We conducted a randomized, doubleblind, multicenter study that compared 0.03 percent, 0.1 percent, and 0.3 percent tacrolimus ointment with vehicle alone in patients with moderate to severe atopic dermatitis. The ointment was applied twice daily to a defined, symptomatic area of 200 to 1000 cm2 of skin for three weeks. The primary end point was the change in the summary score for erythema, edema, and pruritus between the first and last days of treatment. RESULTS: After three weeks of treatment, the median percentage decrease in the summary score for dermatitis on the trunk and extremities was 66.7 percent for the 54 patients receiving 0.03 percent tacrolimus, 83.3 percent for the 54 patients receiving 0.1 percent tacrolimus, 75.0 percent for the 51 patients receiving 0.3 percent tacrolimus, and 22.5 percent for the 54 patients receiving vehicle alone (P<0.001). The results for the face and neck were similar. The differences among the three tacrolimus groups were not statistically significant. A sensation of burning at the site of application was the only adverse event that was significantly more frequent with tacrolimus than with vehicle alone (P<0.001). Throughout the study, most patients in all three tacrolimus groups had blood concentrations of tacrolimus below 0.25 ng per milliliter. The highest concentration was 4.9 ng per milliliter, which was reported in the group receiving 0.3 percent tacrolimus. CONCLUSIONS: The short-term application of tacrolimus ointment is effective in the treatment of atopic dermatitis, with the sensation of burning being the main side effect.

Detailed quantitative studies were performed on the generation and utilization of energy by resting and phagocytosing human neutrophils. The ATP content was 1.9 fmol/cell, was constant during rest, and was not influenced by the presence or absence of glucose in the medium. The intracellular content of phosphocreatine was less than 0.2 fmol/cell. In the presence of glucose, ATP was generated almost exclusively from lactate produced from glucose taken up from the surrounding medium. The amount of lactate produced could account for 85% of the glucose taken up by the cells, and the intracellular glycosyl store, glycogen, was not drawn upon. The rate of ATP generation as calculated from the rate of lactate production was 1.3 fmol/cell/min. During phagocytosis, there was no measurable increase in glucose consumption or lactate production, and the ATP content fell rapidly to 0.8 fmol/cell. This disappearance of ATP was apparently irreversible since no corresponding increase in ADP or AMP was observed. It therefore appears that this phagocytosis-induced fall in ATP concentration represents all the extra energy utilized in human neutrophils in the presence of glucose. In the absence of glucose, the rate of ATP generation in the resting cell was considerably smaller, 0.75 fmol/cell per min, as calculated from the rate of glycolysis, which is sustained exclusively by glycogenolysis. Under this condition, however, phagocytosis induces significant enhancement of glycogenolysis and the rate of lactate production is increased by 60%, raising the rate of ATP generation to 1.2 fmol/cell per min. Nonetheless, the ATP content drops significantly from 1.9 to 1.0 fmol/cell. Neutrophils from patients with chronic granulomatous disease have the same rate of glycolysis and the same ATP content as normal cells, thus confirming that the defective respiration of these cells does not affect their energy metabolism.

We have examined the expression of chemokines and their receptors in the atopic dermatitis-like (AD-like) lesions of NC/Nga mice. Such lesions develop when the mice are kept in conventional conditions, but not when they are kept isolated from specific pathogens. The thymus- and activation-regulated chemokine TARC is unexpectedly highly expressed in the basal epidermis of 14-week-old mice with lesions, whereas it is not expressed in the skin without lesions. Production of TARC by keratinocytes was confirmed by culturing murine keratinocytic cell line cells (PAM212) with TNF-alpha, IFN-gamma, or IL-1beta. Expression of another Th2 chemokine, macrophage-derived chemokine (MDC), was observed in the skin from mice kept in both conventional and pathogen-free conditions, but expression of MDC was increased severalfold in the skin with lesions. The cellular origin of MDC was identified to be dermal dendritic cells. Infiltration of the skin by IL-4-producing T cells and mast cells, and the increase of CCR4 mRNA in the skin, coincided with the development of AD lesions. These observations indicate that TARC and MDC actively participate in the pathogenesis of AD-like lesions in NC/Nga mice and that these Th2 chemokines could be novel targets for intervention therapy of AD in humans.

AIMS: To examine the medication adherence among old persons living in their own homes, to assess their knowledge of their medication, and to indicate target areas for intervention. METHODS: A cross-sectional study of data collected from randomly selected samples of 348 persons, aged 75 years recruited from a population-based register in the municipality of Aarhus, Denmark. Information on all drugs was collected from the subjects during a home visit, and their drug storage was examined. Information was collected from the general practitioners (GP). The measures of adherence were scores of agreements between the GPs' lists and the subjects' actual drug consumption. RESULTS: We found disagreement between the drug information collected from the study population and from the GPs: concerning drugs in 22% of the study-population, concerning doses in 71%, and concerning regimens prescribed by the GP in 66%. Twenty-four percent stated that they did not always follow prescriptions. Most of the deviations from prescriptions were toward lower doses and less frequent drug intake. The drugs most often involved in deviations were hypnotics, analgesics, bronchodilators and diuretics. Sixty percent of the participants knew the purpose of medication, and 21% knew the consequences of omission of the drugs. Less than 6% of the subjects knew about the toxic risks, side-effects, or potential drug interactions. The participants' knowledge of the drugs was positively associated with their adherence. We found a correlation between an increased number of prescribed frequency of drug intake per day and deviation from the regimen (r = 0.25, P = 0.01). There was a positive association between nonadherence and the use of three or more drugs (odds ratio (OR) 2.5; 95% confidence interval (CI) 1.5,4.1), prescriptions from more than one doctor (OR 2.5; 95% CI 1.3,4.8), and probability of dementia (OR 9.0; 95% CI 1.1,72.5). Moreover compliance aids facilitated adherence (OR 4.4; 95% CI 1.6,12.3). Persons living alone were more prone to medication errors (OR 2.0; 95% CI 1.1,3.5). CONCLUSIONS: A differentiated evaluation of adherence by considering the drug, the dose, and the regimen separately produced quantifiable data concerning the subjects' medication habits. Non-adherence ranged from 20 to 70% depending on the measuring method. The participants' knowledge of the treatment was poor. Our results suggest that better information on medication and the use of compliance aids may prevent nonadherence. Special attention should be paid to persons receiving three or more drugs, living alone, receiving drugs from other doctors, and to persons with predementia symptoms, as they are at higher risk of nonadherence.

BACKGROUND: Drug survival (time to drug discontinuation) has recently emerged as an important parameter reflecting the long-term therapeutic performance in a real-life setting. Biologic drug survival in psoriasis is mainly limited by a gradual loss of efficacy over time. Previous studies have been limited by small patient population size and short observation times and yielded discrepant survival times for different biologics. OBJECTIVES: To calculate the long-term drug survival for adalimumab, etanercept, infliximab and ustekinumab in a large cohort of real-life patients with psoriasis vulgaris and to analyse the factors that influence drug survival. PATIENTS AND METHODS: Data were extracted from the prospective registry DERMBIO covering all patients with psoriasis vulgaris treated with biologic agents in the academic centres in Denmark. Drug survival was analysed using the Kaplan-Meier method. The influence of different covariates on drug survival was analysed by Cox regression. RESULTS: Included in the analysis were 1867 treatment series (adalimumab n = 774, etanercept n = 449, infliximab n = 253, ustekinumab n = 391) administered in 1277 patients for up to 10 years. Drug survival was significantly longer for ustekinumab than for anti-tumour necrosis factor (TNF)-α agents (P < 0·001). Etanercept had the shortest survival time [median survival 30 months, 95% confidence interval (CI) 25·1-34·9] whereas adalimumab and infliximab had comparable survival rates (59 months, 95% CI 45·6-72·4; 44 months, 95% CI 33-54·9, respectively). Survival was longer in men [odds ratio (OR) 1·51, 95% CI 1·31-1·74 vs. women] and in patients who had not previously received any biologic agent (OR 1·24, 95% CI 1·05-1·46). Loss of efficacy accounted for 67% of all drug discontinuations. CONCLUSIONS: Ustekinumab has a significantly longer drug survival than the anti-TNF-α agents. Switching from one biologic to another is associated with an impairment of drug survival. Preventing loss of efficacy is a major area of medical need in the biologic therapy of psoriasis and the strategies that improve drug survival should be further investigated.

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor channel blocker known to inhibit "wind-up" and hence central hyperexcitability of dorsal horn neurons. We sought to assess the effect of ketamine on single and repeated nociceptive stimuli. A placebo-controlled, human (12 volunteers) experimental study was conducted in which several psychophysical (pain detection and tolerance thresholds, magnitude ratings) and electrophysiologic (withdrawal reflex) techniques were used 1) to investigate whether a ketamine (0.5 mg/kg) bolus followed by a 20-min infusion (9 micrograms.kg-1.min-1) inhibits central temporal summation to repeated nociceptive electrical stimuli, and 2) to assess quantitatively the hypoalgesic potency using several experimental nociceptive stimuli (argon laser, pressure, electrical). Facilitation of the withdrawal reflex to and pain rating of repeated electrical stimuli (five pulses at 2 Hz) were inhibited by ketamine. Reflex and pain rating to a single stimulus did not change. The pressure pain detection and tolerance thresholds were increased significantly by ketamine, whereas the laser heat pain and tolerance thresholds remained stable compared with placebo. The stimulus response function showed that ketamine reduced the responses to the highest electrical stimulus intensities (1.4, 1.6, and 1.8 times the reflex threshold). We conclude that ketamine inhibits central temporal summation in humans and has a marked hypoalgesic effect on high intensity nociceptive stimuli.

SUMMARY Seven hundred and sixty-four liver biopsies were performed in 328 psoriatics on treatment with methotrexate or being considered for systemic treatment either with methotrexate or with psoralens and long-wave ultraviolet light. The diagnosis of cirrhosis was established histologically in twenty-one patients. Two patients had cirrhosis in their premethotrexate biopsy and were not given methotrexate. The remainder all showed no signs of cirrhosis or fibrosis in their premethotrexate biopsy. The difference between the methotrexate treated psoriatics and the premethotrexate group was highly significant. Among thirty-nine patients treated for more than 5 years, ten developed cirrhosis (25.6%). Almost all patients were on a divided dose intermittent oral dosage schedule. The cumulative dose of methotrexate, when cirrhosis was first found, ranged from 590 to 8105 mg, with an average dosage of 2200 mg. Other factors contributing to cirrhosis in this study seem to be previous treatment with arsenic, a previous intake of alcohol, and lowered renal function. Data on later serial biopsies from fourteen patients, of which eleven continued to receive methotrexate due to very severe psoriasis, seem to indicate that methotrexate induced liver cirrhosis is not of a very aggressive nature. When evaluated blind no progression was found in most of the later biopsies, and a ‘cumulative cirrhosis index’ composed of the combined gradings for fibrosis, assessment of membrana limitans, fibrous destruction and regeneration showed a tendency to decrease. In three patients the latest of the serial biopsies showed no cirrhosis. The observation period on continued methotrexate therapy ranged from 1 to 7 years. None of the patients with cirrhosis differed from the remaining patients on methotrexate in their laboratory results for evaluating liver damage, and apart from transient increases in serum glutamic pyruvic transaminases no abnormalities were found. The data support the necessity of liver biopsies in the control of psoriatics treated with methotrexate. Liver biopsies should be performed at least in all psoriatics in whom a cumulative dosage of methotrexate exceeds 1.5g. The data also indicate that methotrexate can be continued at least for a while in patients where the indication is strong enough, if the dosage is maintained as low as possible and alcohol consumption avoided.

BACKGROUND: SDZ ASM 981 is a selective inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro. It is the first ascomycin macrolactam derivative under development for the treatment of inflammatory skin diseases. OBJECTIVES: This study was designed to determine the safety and efficacy of SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6% and 1.0% in the treatment of patients with atopic dermatitis and to select the concentration to be used in phase III studies. METHODS: This was a double-blind, randomized, parallel-group, multicentre dose-finding study. A total of 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6%, or 1.0%, matching vehicle cream, or the internal control 0.1% betamethasone-17-valerate cream (BMV). Treatment was given twice daily for up to 3 weeks. RESULTS: A clear dose-response relationship for SDZ ASM 981 was evident, with 0.2%, 0.6% and 1.0% SDZ ASM 981 creams all being significantly more effective than vehicle (P = 0.041, 0.001 and 0.008, respectively) in terms of baseline to end-point changes in the Eczema Area Severity Index (EASI) and pruritus score. The 1.0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. It appears that the efficacy plateau was not reached with the SDZ ASM 981 creams within 3 weeks treatment. SDZ ASM 981 was well tolerated. Burning or a feeling of warmth were the only adverse events reported more frequently in the 0.6% and 1.0% SDZ ASM 981 treatment groups than in the vehicle treatment group (42.9%, 48.9% and 34.9%, respectively). Few systemic adverse events were reported during the study (headache was the most frequent systemic event reported by 15 of 252 patients) and none was considered to be related to treatment. The local tolerability profile of the 1.0% cream was similar to that of the lower concentrations. CONCLUSIONS: 1.0% SDZ ASM 981 cream, which was shown to be safe, well tolerated and the most effective concentration in this study, was selected as the concentration to be further developed in phase III studies.

BACKGROUND: Long-term treatment for atopic dermatitis (AD) using low dose, intermittent, topical anti-inflammatory agents may control acute disease and prevent relapses. This 12-month, European, multicentre, randomized study investigated whether the proactive use of 0.1% tacrolimus ointment applied twice weekly can keep AD in remission and reduce the incidence of disease exacerbations (DE). METHODS: During the initial open-label period, 257 adults with AD applied 0.1% tacrolimus ointment twice daily (b.i.d.) for up to 6 weeks to affected areas. When an Investigator Global Assessment (IGA) score of <or=2 was achieved, the patient entered the disease control period (DCP) and was randomized to either proactive tacrolimus (n = 116) or vehicle ointment (n = 108) twice weekly for 12 months. Exacerbations were treated with 0.1% tacrolimus ointment b.i.d. until an IGA <or=2 was regained, then randomized treatment was restarted. The primary endpoint was the number of DEs during the DCP that required a substantial therapeutic intervention. RESULTS: Proactive tacrolimus 0.1% ointment application significantly reduced the number of DEs requiring substantial therapeutic intervention (median difference 2; P < 0.001; Wilcoxon rank sum test), the percentage of DE treatment days (median difference: 15.2%; P < 0.001; Wilcoxon rank sum test) and increased the time to first DE (median 142 vs 15 days; P < 0.001; stratified log-rank test). The adverse event profile was similar for the two treatment approaches. CONCLUSION: A 12-month, twice weekly proactive tacrolimus ointment application was an effective treatment in most study patients which prevented, delayed and reduced the occurrence of AD exacerbations

The effect of the non-calciotropic vitamin D3 analogue MC 903 on psoriasis vulgaris was assessed in a double-blind, placebo controlled trial in 30 patients. Lesions on one side of the body were treated for 6 weeks with a cream containing 10 μ/g, 33 μg//g or 100 μg/g MC 903 and lesions on the other side were treated with the cream base alone, according to a randomized design. Nine of the 10 patients in each treatment group completed the study. MC 903 cream gave a statistically significant decrease in erythema, thickness and scaling of the lesions, compared with the control. Overall assessment of psoriasis after 6 weeks showed moderate or excellent improvement in two of nine patients treated with 10 μg/g, in five of nine patients treated with 33 μ/g, and in seven of nine patients treated with 100 μ/g MC 903. Placebo treatment showed a moderate improvement in only one of the 27 patients. The histopathological picture of the psoriatic lesions corresponded with the clinical changes. The patients reported no adverse reactions, and laboratory tests did not show any significant changes; in particular there was no change in serum calcium levels. These results suggest that the vitamin D3 analogue MC 903 is an effective and safe topical treattnent for psoriasis.

BACKGROUND: Alterations in specific signal transduction pathways may explain the hyperproliferation and abnormal differentiation of the keratinocytes as well as the increased expression of inflammatory cytokines seen in psoriasis. Major signalling pathways used by eukaryotic cells to transduce extracellular signals into cellular responses impinge on the mitogen-activated protein kinases (MAPKs). OBJECTIVES: To investigate the expression of the MAPK p38, extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) in psoriatic skin. METHODS: Keratome biopsies were taken from patients with plaque-type psoriasis. Western blot analysis was used to determine p38, ERK and JNK activity and protein levels, whereas kinase assays were used to examine the kinase activity of p38. RESULTS: We demonstrated increased levels of the phosphorylated forms of p38 and ERK1/2 in lesional psoriatic skin compared with nonlesional psoriatic skin. No abnormality was found in the activation and expression of JNK1/2. Ex vivo kinase assays confirmed the increased activation of p38, and furthermore demonstrated increased kinase activity of the p38 isoforms p38alpha, p38beta and p38delta in lesional compared with nonlesional psoriatic skin. p38gamma was not detected in the psoriatic skin. Clearance of the psoriatic lesions, induced by climatotherapy at the Dead Sea for 4 weeks, led to a normalization in the activity of both p38 and ERK1/2. CONCLUSIONS: Taken together, our results demonstrate that the activity of the MAPKs p38alpha, p38beta and p38delta and ERK1/2 are increased in lesional psoriatic skin compared with nonlesional psoriatic skin, and that clearance of psoriasis normalizes the p38 and ERK1/2 activity. Thus, p38 and ERK1/2 might be potential targets in the treatment of psoriasis.

BACKGROUND: A standardized instrument is needed to rate the overall severity of chronic hand dermatitis (CHD), in particular during clinical trials. OBJECTIVES: To design and validate a photographic guide. METHODS: Initially, five experts were asked to grade 50 photographs of CHD, first individually, then as a consensus-building group, in order to select the photographs included in the guide. Then, a validation session with 11 different dermatologists evaluating 28 patients was conducted to assess the interrater reliability and test-retest reproducibility of the assessment of disease severity, relying on the photographic guide, on two consecutive days. Patient order was randomized, and only diseased hands were visible to prevent any bias in evaluation. RESULTS: The experts reached a consensus for development of a photographic guide composed of five severity levels and four photographs per severity level. Results of the validation session showed a high level of interrater reliability and test-retest reproducibility. CONCLUSIONS: The photographic guide is a reliable tool for assessing the morphological severity of hand dermatitis, and can be used as part of a comprehensive evaluation of disease in international multicentre clinical trials.

BACKGROUND AND AIM: Needle injections are used daily by millions of people around the world for the administration of various drugs (e.g., insulin), venepuncture, and some neurophysiological procedures. The aim of this paper was to study the influence of the outer needle diameter on the pain evoked by controlled needle insertion. METHODS: An automated needle injection system was used to perform a series of insertions where velocity, angle of insertion, and depth of injection were controlled. The frequency of pain following needle insertions (23G, 27G, 30G, 32G) was recorded together with the pain intensity (measured using the visual analogue scale--VAS) and the occurrence of bleeding. RESULTS: The outer needle diameter was positively and significantly correlated to the frequency of the insertion pain; for example, 63% of insertions with 23G needles caused pain, 53% of insertions with 27G and 31% of insertions with the thinnest (32G) needle (p < 0.0001) caused pain. The thickest needle caused most insertions associated with bleeding. Bleeding insertions were approximately 1.3 times more painful (as indicated by VAS scores) than insertions without concomitant bleedings (p = 0.004). CONCLUSION: By decreasing the outer diameter of a needle, the frequency of insertion pain can be reduced and may encourage patients to adhere to demanding injection regimens such as recurrent insulin administration.

Calcipotriol (the synthetic compound MC 903) is a structural analogue of naturally occurring, biologically active calcitriol. Calcipotriol and calcitriol (1,25-dihydroxy vitamin D3) show similar receptor binding and comparable effects on cell differentiation. However, calcipotriol seems to be at least 100 times less potent in its effects on calcium metabolism. In a double-masked study involving 50 patients with psoriasis vulgaris, the efficacy and tolerability of ointments containing various calcipotriol concentrations (25, 50, or 100 micrograms/g) or the vehicle alone were compared in a study involving a right-left, within-patient randomized design. Patients were treated twice daily for 8 weeks. Marked improvement was seen in 40% of the patients treated with the 25-micrograms/g concentration of calcipotriol in 63% of patients treated with the 50-micrograms/g concentration, and in 88% treated with the 100-micrograms/g concentration. No patient treated with placebo had more than slight improvement. Five patients developed facial dermatitis during the study. The serum levels of ionized calcium were unchanged. This study demonstrates that calcipotriol ointment provides an effective and well-tolerated treatment of psoriasis vulgaris.

Human IL-10 (hIL-10) is a newly described cytokine that was originally identified as a cytokine synthesis inhibitory factor regulating the production of several pro-inflammatory cytokines such as IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF-alpha, and IFN-gamma. Additionally, hIL-10 also inhibits the macrophage-dependent proliferative response of CD4+ T lymphocytes to Ag stimulation, and it down-regulates the constitutive class II MHC expression on human monocytes. We report hIL-10 to be a potent and specific chemotaxin for human T lymphocytes with optimum activity in the range between 10 and 100 U/ml. Checkerboard analysis shows the activity to be chemotactic and not chemokinetic. The chemotactic activity is directed toward CD8+ T lymphocytes and not towards CD(4+)-enriched cells. Also, hIL-10 lacks chemotactic activity toward human monocytes or neutrophil granulocytes. Further, we found that hIL-10 inhibits the chemotactic response of CD4+, but not CD8+, T cells toward IL-8. Because hIL-10 can be produced by several cells including CD4+ T cells of the Th2 type, our results suggest that hIL-10 participates in a complex regulatory circuit between CD4+ and CD8+ T cells with implications for the control of lymphocyte-mediated inflammatory responses.

BACKGROUND: Calcipotriol and betamethasone dipropionate are both widely used, effective treatments for psoriasis. Vitamin D analogues and topical corticosteroids have different mechanisms of action in the treatment of psoriasis. A new vehicle has been developed in order to contain both calcipotriol (50 micro g g-1) and betamethasone dipropionate (0.5 mg g-1) in an ointment form. By using calcipotriol and a corticosteroid together, greater efficacy may be achieved than by using either compound alone. OBJECTIVES: The present study was conducted in order to compare the clinical efficacy and safety of the combined ointment formulation used once daily with the vehicle ointment used twice daily, calcipotriol ointment used twice daily and the combined formulation used twice daily in psoriasis vulgaris. METHODS: This was an international, multicentre, prospective, randomized, double-blind, vehicle-controlled, parallel group, 4-week study in patients with psoriasis vulgaris amenable to topical treatment. Patients were randomized to one of four treatment groups: combined formulation once daily, combined formulation twice daily, calcipotriol twice daily or vehicle twice daily. Efficacy and safety were assessed. RESULTS: There was no statistically significant difference in the mean percentage change in the Psoriasis Area and Severity Index (PASI) from baseline to end of treatment between the two combined formulation groups, but the difference in PASI reduction was significantly higher in the combined formulation groups (68.6% once daily, 73.8% twice daily) than in both the twice daily calcipotriol group (58.8%) and the vehicle group (26.6%). Safety data showed the frequency of adverse events to be less in the combined formulation groups than in both the calcipotriol group and the vehicle group. The proportion of patients with lesional/perilesional adverse reactions was less in the combined formulation groups and vehicle group than in the calcipotriol group (9.9% combined formulation once daily, 10.6% combined formulation twice daily, 19.8% calcipotriol, 12.5% vehicle). CONCLUSIONS: No statistically significant nor clinically relevant difference in efficacy was seen between the combined formulation used once daily and twice daily. When compared to vehicle ointment or calcipotriol ointment alone, the combined formulation was shown to be clearly more efficacious.

11 widely used nickel alloys were investigated with respect to corrosion stability and reactivity in nickel-sensitive individuals. Alloys with a nickel release in synthetic sweat exceeding 1 microgram/cm2/week gave a strong patch test reaction in nickel-sensitive persons; those with a release below 0.5 microgram/cm2/week showed weak reactivity with one exception. Nickel allergy is a health problem. It may be minimized by using nickel alloys with a corrosion level below 0.5 microgram/cm2/week. Action should be taken by dermatologists, industry and authorities to solve this neglected problem.

Psoriasis is a chronic inflammatory disease of the skin characterized by epidermal hyperplasia, dermal angiogenesis, infiltration of activated T cells, and increased cytokine levels. One of these cytokines, IL-15, triggers inflammatory cell recruitment, angiogenesis, and production of other inflammatory cytokines, including IFN-gamma, TNF-alpha, and IL-17, which are all upregulated in psoriatic lesions. To investigate the role of IL-15 in psoriasis, we generated mAb's using human immunoglobulin-transgenic mice. One of the IL-15-specific antibodies we generated, 146B7, did not compete with IL-15 for binding to its receptor but potently interfered with the assembly of the IL-15 receptor alpha, beta, gamma complex. This antibody effectively blocked IL-15-induced T cell proliferation and monocyte TNF-alpha release in vitro. In a human psoriasis xenograft model, antibody 146B7 reduced the severity of psoriasis, as measured by epidermal thickness, grade of parakeratosis, and numbers of inflammatory cells and cycling keratinocytes. These results obtained with this IL-15-specific mAb support an important role for IL-15 in the pathogenesis of psoriasis.

The clinical applications of thermal sensory and pain thresholds have been very limited due to large intra-individual variations. In the present paper CO2 and argon lasers were used as thermal stimulators, and the different factors (stimulus parameters and skin conditions) affecting the thresholds are described. The intra-individual variations obtained in sensory (9.3%) and pain (4.3%) thresholds were very low, which suggests that the method can be applied for clinical purposes.

Psoriasis is a chronic inflammatory disease of the skin characterized by epidermal hyperplasia, dermal angiogenesis, infiltration of activated T cells, and increased cytokine levels. One of these cytokines, IL-15, triggers inflammatory cell recruitment, angiogenesis, and production of other inflammatory cytokines, including IFN-, TNF-, and IL-17, which are all upregulated in psoriatic lesions. To investigate the role of IL-15 in psoriasis, we generated mAb's using human immunoglobulin-transgenic mice. One of the IL-15-specific antibodies we generated, 146B7, did not compete with IL-15 for binding to its receptor but potently interfered with the assembly of the IL-15 receptor , , complex. This antibody effectively blocked IL-15-induced T cell proliferation and monocyte TNF- release in vitro. In a human psoriasis xenograft model, antibody 146B7 reduced the severity of psoriasis, as measured by epidermal thickness, grade of parakeratosis, and numbers of inflammatory cells and cycling keratinocytes. These results obtained with this IL-15-specific mAb support an important role for IL-15 in the pathogenesis of psoriasis.