Agonists of peroxisome proliferator-activated receptor gamma inhibit cell growth in malignant melanoma

Peroxisome proliferator-activated receptor gamma is a member of the nuclear receptor superfamily involved in adipocyte differentiation and glucose homeostasis. There is evidence that peroxisome proliferator-activated receptor gamma may also act as a tumor suppressor. Here, we demonstrate expression of peroxisome proliferator-activated receptor gamma in benign melanocytic naevi, different variants of primary cutaneous melanomas, and melanoma metastases. Peroxisome proliferator-activated receptor gamma protein and peroxisome proliferator-activated receptor gamma1 mRNA were also detected in human melanoma cell lines. The peroxisome proliferator-activated receptor gamma specific agonists 15-deoxy-Delta12,14-prostaglandin J2, troglitazone, and rosiglitazone dose-dependently inhibited cell proliferation in four melanoma cell lines, whereas a specific agonist of peroxisome proliferator-activated receptor alpha had no such effect. At a concentration of 50 microM rosiglitazone, the most potent peroxisome proliferator-activated receptor gamma agonist tested suppressed cell growth by approximately 90%. Apoptosis could be induced in melanoma cell lines by incubation with tumor-necrosis-factor-related apoptosis-inducing ligand. In contrast, the growth inhibitory effect of peroxisome proliferator-activated receptor gamma activation was independent of apoptosis and seemed to occur primarily through induction of cell cycle arrest. Our data indicate that melanoma cell growth may be modulated through peroxisome proliferator-activated receptor gamma.     

Skin symptoms among workers in the fish processing industry are caused by high molecular weight compounds

Scratch tests were performed with fish juice containing high and low molecular weight compounds obtained by ultrafiltration and with degradation compounds known to accumulate in fish stored on ice. 75 volunteers were tested. The peptide pattern in raw fish juice and its high and low molecular weight fractions were analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and the concentration of protein in the various fractions was determined. Fish products were analysed for bacteria and algae and the concentration of degradation compounds was measured. Mainly high molecular weight compounds (polypeptides) of fish juice were found to be responsible for the skin symptoms.     

Stable incidence of atopic dermatitis among children in Denmark during the 1990s

An increase in the prevalence of atopic dermatitis (AD) has been reported since the 1960s. The increase could be due to many factors including a genuine increase of incidence or duration of AD. We decided to study if the increasing trend persisted during the 1990s by comparing the cumulative incidence of AD in 1993 and 1998. Further, we studied the severity and management of AD among children. Two samples of children born in Denmark were drawn from the Danish Medical Birth Register. In the 1993 and 1998 studies a mailed questionnaire with identical questions concerning AD was sent out. In the 1998 follow-up study the questionnaire included a severity score and questions concerning management of AD. In the 1993 study the cumulative incidence of AD at age 7 was 18.9% and in 1998 it was 19.6%. There was no difference in the age-adjusted AD incidence in the 5-year observation period. In the 1998 study, 81% had mild to moderate AD, 90% had been seen by a doctor at least once, 36% had mainly been treated by a dermatologist, and 2% had been hospitalized. It should be kept in mind that we base most of our common knowledge of the disease on AD patients selected for management in dermatology clinics and departments.     

Differential Changes in Inflammatory Mononuclear Phagocyte and T-Cell Profiles within Psoriatic Skin during Treatment with Guselkumab vs. Secukinumab

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Adalimumab Efficacy in Patients with Psoriasis Who Received or Did Not Respond to Prior Systemic Therapy: A Pooled Post Hoc Analysis of Results from Three Double-Blind,Placebo-Controlled Clinical Trials

Introduction

There are limited data from randomized controlled clinical trials on the outcomes of biologics after discontinuation of a different systemic therapy. To determine the efficacy of adalimumab in patients who previously received systemic therapy (including failed therapy), we performed a pooled post hoc analysis of Psoriasis Area and Severity Index (PASI) response data from three double-blind, placebo-controlled clinical trials in patients with moderate to severe psoriasis.

Methods

Patients from the M02-528, REVEAL, and CHAMPION studies who were previously exposed to systemic treatment were categorized based on their response. The efficacy of adalimumab compared with placebo was analyzed at the end of the double-blind treatment period for the overall pooled intent-to-treat population (N = 1469) and subgroups that received (n = 780) or did not respond to (n = 229) previous systemic pretreatments.

Results

Rates for an improvement of ≥75 % from baseline in the PASI score (PASI75 response) were significantly greater (p < 0.001) at week 16 in patients treated with adalimumab compared with patients who received placebo in the overall (72.1 vs. 8.0 %, respectively), previously treated (72.7 vs. 8.5 %), and previously failed treatment (70.4 vs. 8.1 %) groups. PASI75 response rates were similar in the overall group and in patients who did not respond to methotrexate, cyclosporine, or psoralen plus ultraviolet A therapy. Improvements of ≥90 or ≥100 % from baseline PASI score were also higher with adalimumab vs. placebo in previously treated patients. Adverse events were similar among subgroups.

Conclusions

Adalimumab was efficacious for the treatment of moderate to severe psoriasis regardless of prior exposure to systemic therapies or failure of those prior therapies.

ClinicalTrials.gov identifiers

NCT00645814, NCT00237887, NCT00235820.

     

Cost-effectiveness analysis of palivizumab as respiratory syncytial virus prophylaxis in preterm infants in Sweden

Aim: To investigate the cost‐effectiveness of palivizumab vs. no prophylaxis for respiratory syncytial virus (RSV) infection in preterm infants in Sweden. Methods: A probabilistic Markov model was populated using a nationwide register linkage and data from the literature. Cost‐effectiveness was investigated from a societal perspective over a lifetime for infants born at <29 weeks of gestation. Palivizumab was modelled using assumptions for its direct effect on RSV hospitalization risk and an indirect effect (via decreased RSV hospitalization) on subsequent asthma and mortality during the epidemic. Costs and effects were discounted by 3%. Results: In the base case, prophylaxis resulted in an additional 0.102 quality‐adjusted life‐year (QALY) at a cost of 20 000 SEK relative to no prophylaxis (incremental cost‐effectiveness ratio [ICER] 195 000 SEK/QALY). The probability of prophylaxis being cost–effective was 99% at a willingness‐to‐pay of 500 000 SEK/QALY. Assumptions about a causal association between RSV infection and subsequent asthma had a moderate impact, while exclusion of the indirect prophylaxis effect on mortality increased the ICER to 492 000 SEK/QALY. When excluding both of these, prophylaxis was not cost–effective. Conclusion: Based on a willingness‐to‐pay of 500 000 SEK/QALY, palivizumab was found to be cost–effective compared with no prophylaxis for infants born at <29 weeks if severe RSV infection was assumed to increase subsequent asthma or mortality risk.     

Anatomic single- versus double-bundle ACL reconstruction: a meta-analysis

Purpose

To determine whether anatomic double-bundle anterior cruciate ligament (ACL) reconstruction compared to anatomic single-bundle ACL reconstruction more effectively restored antero–posterior (A–P) laxity, rotatory laxity and reduced frequency of graft rupture. Our hypothesis was that anatomic double-bundle ACL reconstruction results in superior rotational knee laxity and fewer graft ruptures due to its double-bundle tension pattern, compared with anatomic single-bundle ACL reconstruction.

Methods

An electronic search was performed using the PubMed, EMBASE and Cochrane Library databases. All therapeutic trials written in English reporting knee kinematic outcomes and graft rupture rates of primary anatomic double- versus single-bundle ACL reconstruction were included. Only clinical studies of levels I–II evidence were included. Data regarding kinematic tests were extracted and included pivot-shift test, Lachman test, anterior drawer test, KT-1000 measurements, A–P laxity measures using navigation and total internal–external (IRER) laxity measured using navigation, as well as graft failure frequency.

Results

A total of 7,154 studies were identified of which 15 papers (8 randomized controlled trials and 7 prospective cohort studies, n = 970 patients) met the eligibility criteria. Anatomic ACL double-bundle reconstruction demonstrated less anterior laxity using KT-1000 arthrometer with a standard mean difference (SMD) = 0.36 (95 % CI 0.214–0.513, p < 0.001) and less A–P laxity measured with navigation (SMD = 0.29 95 % CI 0.01–0.565, p = 0.042). Anatomic double-bundle ACL reconstruction did not lead to significant improvements in pivot-shift test, Lachman test, anterior drawer test, total IRER or graft failure rates compared to anatomic single-bundle ACL reconstruction.

Conclusion

Anatomic double-bundle ACL reconstruction is superior to anatomic single-bundle reconstruction in terms of restoration of knee kinematics, primarily A–P laxity. Whether these improvements of laxity result in long-term improvement of clinical meaningful outcomes remains uncertain.

Level of evidence

II.