Janet H. Prystowsky

Acitretin plus UVB therapy for psoriasis. Comparisons with placebo plus UVB and acitretin alone

UVB radiation is beneficial for the treatment of psoriasis vulgaris. Patients with recalcitrant disease, however, are slow to respond to UVB phototherapy with and without the use of coal tars or emollients. Etretinate and, more recently, acitretin have proved useful, but clinical improvement is slow when they are used as monotherapy in plaque psoriasis. Each drug also produces side effects, some of which are dose related. This study was designed to compare results of treatment with UVB combined with either acitretin (50 mg/day) or placebo to determine if psoriasis would respond faster and to less cumulative exposure to UVB and acitretin. The psoriatic disease cleared to a greater degree in patients treated with acitretin-UVB with fewer treatments and smaller amounts of UVB radiation than in patients treated with either placebo-UVB or acitretin alone.

Pityriasis rubra pilaris: A review of diagnosis and treatment

The diagnosis of pityriasis rubra pilaris is based essentially on characteristic clinical features. Although the histologic features are not pathognomonic, a lesional skin biopsy for evaluation is important to rule out other papulosquamous and erythematous disorders. The presence of prominent seborrheic keratoses occurring in two cases of pityriasis rubra pilaris is presented. Our understanding of the relationship between vitamin A metabolism and pityriasis rubra pilaris is discussed. Currently available systemic therapeutic modalities for pityriasis rubra pilaris are reviewed. Although pityriasis rubra pilaris does not represent a vitamin A deficiency state, it is responsive to isotretinoin, etretinate, and vitamin A. Antimetabolites remain an alternative therapy.

Rat liver retinyl palmitate hydrolase activity. Relationship to cholesteryl oleate and triolein hydrolase activities

Studies were conducted to explore relationships in rat liver between retinyl palmitate hydrolase activity and the hydrolytic activities against cholesteryl oleate and triolein. Previous studies have shown positive correlations between these three lipid ester hydrolase activities. In order to extend this work, the hydrolase activities were further purified and characterized. The activities against cholesteryl oleate and triolein resembled retinyl palmitate hydrolase activity in showing great variability from rat to rat as assayed in vitro. The relative levels of the three activities were highly correlated with each other over a 50-fold range of activity in a series of 66 liver homogenates. Partial purification (approx. 200-fold) in the absence of detergents was achieved by sequential chromatography of an acetone powder extract of liver on columns of phenyl-Sepharose, DEAE-Sepharose and heparin-Sepharose. The three hydrolase activities copurified during each of these chromatographic steps. The properties of the three copurifying activities were similar with regard to stimulation of activity by trihydroxy bile salts, pH optimum (near 8.0), and observance of Michaelis-Menten-type saturation kinetics. The three activities were different in their sensitivity towards the serine esterase inhibitors diisopropylfluorophosphate and phenylmethanesulfonyl fluoride, and in their solubility properties in 10 mM sodium acetate, pH 5.0. Thus, triolein hydrolase activity was much less sensitive than the other two activities to the two inhibitors. In addition, the activity against cholesteryl oleate could be separated from the other two activities by extraction of an acetone powder with acetate buffer, pH 5.0. These results indicate that the three lipid hydrolase activities are due to at least three different catalytically active centers, and at least two distinct and separable enzymes. It is likely that three separate but similar enzymes, that appear to be coordinately regulated, are involved.

Effect of UVB phototherapy and oral calcitriol (1,25-dihydroxyvitamin D3) on vitamin D photosynthesis in patients with psoriasis

BACKGROUND Phototherapy and activated froms of vitamin D help clear psoriasis. OBJECTIVE The influence of UVB phototherapy and oral calcitriol (1,25-dihydroxyvitamin D3) on vitamin D photosynthesis was assessed in 16 patients. METHODS Patients were randomly selected to receive orally either placebo or calcitriol (0.5 to 2 micrograms daily) for the duration of the 8-week study; all patients received approximately 21 UVB treatments. Before and after treatment, serum levels of 25-hydroxyvitamin D and calcitriol were measured by high-pressure liquid chromatography. RESULTS Although calcitriol had no additive effect on phototherapy as a treatment modality, a significant increase in serum 25-hydroxyvitamin D levels occurred in both groups; in three patients extraordinarily high levels developed (> 120 ng/ml). Oral calcitriol significantly increased calcitriol serum levels. Increased serum calcitriol did not inhibit cutaneous synthesis of vitamin D or its hepatic conversion to serum 25-hydroxyvitamin D. CONCLUSION UVB induces high levels of vitamin D photosynthesis. Because oral or topical calcitriol alone helps clear psoriasis, studies to explore the possible influence of UVB phototherapy on its production should be considered. If UVB phototherapy induces cutaneous calcitriol synthesis this could explain the lack of added benefit to treatment when oral calcitriol is administered with phototherapy.

UVB radiation induces phosphorylation of the epidermal growth factor receptor, decreases EGF binding and blocks EGF induction of ornithine decarboxylase gene expression in SV40-transformed human keratinocytes

Abstract We previously demonstrated that epidermal growth factor (EGF) induces a several‐fold increase in ornithine decarboxylase (ODC) activity and the steady‐state level of ODC mRNA in cultured SV40‐transformed human keratinocytes (1). Pretreatment of cell cultures with ultraviolet B (UVB) radiation resulted in a reduction of EGF‐induced ODC activity. To determine whether UVB inhibits the accumulation of ODC mRNA by EGF, cells were pretreated with 20 mJ/cm2 UVB or sham‐irradiated and then incubated with 100 ng/ml EGF. Northern blot analysis revealed that UVB irradiation entirely blocked the EGF induction of ODC mRNA. Since the binding of EGF to its plasma membrane receptor is the first step in initiating a biological response, the effect of UVB on EGF binding was evaluated. UVB treatment of cultured keratinocytes resulted in an immediate and dose‐dependent reduction of EGF binding. Scatchard analysis revealed thai the reduction of EGF binding was due to a 52% decrease in the number of available receptors, from 6.2 × 104/cell to 3.0 × 104/cell. However, UVB decreased the EGF‐binding affinity very little (Kd = 0.60 nM in control and Kd=0.75 nM in UVB‐treated Z114 cells). In addition, UVB did not alter the rate of EGF internalization. These data suggest that UVB blocks the signal transduction pathway of EGF that is involved in regulation of ODC gene expression. Immunoblot analysis of extracts from irradiated cells showed that UVB induced tyro‐sine phosphorylation of EGFR and that the quantity of EGFR protein was unaffected by UVB treatment. Phosphorylation of EGFR may be responsible for decreased binding of EGF to its receptor.

Oral calcitriol (1,25-dihydroxyvitamin D3) does not augment UVB phototherapy for plaque psoriasis

as salicyclic acid in transdermal patches had a 3-month cure rate of 68%, whereas placebo with the occlusive patch material alone resulted in cleating in 28%. 4 Carbon dioxide laser has a cure rate of more than 95% after multiple treatments, but discomfort, risks of scarring, and cost make laser therapy a less optimal treatment in children. 6 In this small group of patients, our results were not as promising as those reported by Orlow and Paller. 1 One reason for this difference may be that they used cimetidine in conjunction with standard treatments in two thirds of their patients, all of w h o m had previously tried various topical agents alone without success. W e compared the effect of cimetidine alone with standard treatment in children who had, at most, one previous attempt with standard therapy. Although cimetidine might be helpful as adjuvant therapy for warts, we believe there is no compell ing evidence that it is effective by itself; in our view, it should not be used as a first-line treatment of common warts. Further studies comparing cimetidine with placebo (or other treatments) for recalcitrant warts may be warranted, but general prescribing of cimetidine for standard treatment of warts in children cannot be recommended on the basis o f the data available.

Epidermal growth factor induces ornithine decarboxylase in SV40-immortalized human keratinocytes.

Abstract The effect of epidermal growth factor (EGF) on the activity of ornithine decarboxylase (ODC) was evaluated and partially characterized in SV40‐transformed, immortalized cultured human keratinocytes. It was observed that the addition of fresh complete medium to confluent cultures resulted in a 10‐fold increase in ODC activity. Characterization of this activity using serum‐free medium revealed that the increase in ODC activity was primarily due to the presence of EGF (10 ng/ml). A dose‐dependent increase in ODC activity was observed when cultures were treated with EGF. Although near maximal induction occurred with EGF concentrations as low as 2.5–10 ng/ml, maximal induction of ODC (25‐fold) occurred with an EGF concentration of 50 ng/ml. The peak time for ODC induction was 10 hours following the addition of EGF to keratinocyte cultures. The induction of ODC by EGF was inhibited by pretreatment of cultures with either cycloheximide or actinomycin D, suggesting that both protein synthesis and gene transcription are important in the FGF induction of ODC. EGF significantly increased the steady stale levels of ODC mRNA with a peak at 4 hours, preceding the peak in observed enzyme activity as expected. Pretreatment of cultures with retinoic acid (10−5–10−7M) significantly inhibited the induction of ODC by EGF. Retinoic acid decreased the steady‐state levels of ODC mRNA. These data demonstrate that ODC is an enzyme that is induced by EGF in human keratinocytes; this induction probably involves both gene transcription and protein synthesis. Retinoic acid partially prevents the EGF induction of ornithine decarboxylase activity through a presently undefined mechanism(s), but appears to have effects that result in decreased ODC mRNA levels.

MD-PhDs in dermatology

A national survey was conducted to explore ways in which MD-PhDs in dermatology balance their research and clinical interests and the factors that influenced their career decisions. A questionnaire was mailed to all MD-PhDs who were affiliated with dermatology training programs as determined by a preliminary study. The survey consisted of a questionnaire about research background, career pathway, attitudes about personal and professional issues, and influence of residency training program on career decision making. From 60 MD-PhD dermatologists surveyed, 43 (72%) completed questionnaires. Eighty percent of the respondents (34 of 43) held positions in academic medicine; 76% entered dermatology with the intent to pursue academic medicine. Almost all (93%) held academic positions immediately after residency; 50% held positions with the title of assistant professor or higher as their first postresidency employment. Only 26% of the respondents received funding for their MD-PhD through the federally funded Medical Scientist Training Program. Fifty percent of the respondents completed their training with loans. Despite the long period of training and expense required for the dual career, a high percentage (80%) stayed in academic dermatology suggesting that they are an important source for supplying physician-scientists to the field of dermatology. The ability to limit patient care responsibilities and maintain protected time for research may be a factor responsible for the high percentage of MD-PhDs that stay in academic dermatology.