Ciclosporin compared to prednisolone therapy for patients with pyoderma gangrenosum: cost-effectiveness analysis of the STOP GAP trial

Background Pyoderma gangrenosum (PG) is a painful, ulcerating skin disease with poor evidence for management. Prednisolone and ciclosporin are the most commonly used treatments, although not previously compared within a randomised controlled trial (RCT) Objectives To compare the cost-effectiveness of ciclosporin and prednisolone-initiated treatment for patients with PG. Methods Quality-of-life (EuroQoL EQ-5D-3L) and resource data were collected as part of the STOP-GAP trial: a multicentre, parallel-group, observer-blind RCT. Within-trial analysis used bivariate regression of costs and QALYs, with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective. Results In the base case analysis, when compared with prednisolone, ciclosporin was cost-effective due to a reduction in costs (net cost: -£1160; 95%CI: (-2991 to 672) and improvement in quality of life (net QALYs: 0.055; 95%CI: 0.018 to 0.093). However, this finding appears driven by a minority of patients with large lesions (≥20cm2) (net cost: -£5310; 95%CI: -9729 to -891; net QALYs: 0.077; 95%CI: 0.004 to 0.151). The incremental cost-effectiveness of ciclosporin for the majority of patients with smaller lesions was £23,374/QALY although the estimate is imprecise: the probability of being cost-effective at a willingness to pay of £20,000/QALY was 43%. Conclusions Consistent with the clinical findings of the STOP-GAP trial, patients with small lesions should receive treatment guided by the side effect profiles of the drugs and patient preference - neither strategy is clearly a preferred use of NHS resources. However, ciclosporin-initiated treatment may be more cost-effective for patients with large lesions

Lipid-soluble Vitamins A, D, and E in HIV-Infected Pregnant women in Tanzania.

There is limited published research examining lipid-soluble vitamins in human immunodeficiency virus (HIV)-infected pregnant women, particularly in resource-limited settings. This is an observational analysis of 1078 HIV-infected pregnant women enrolled in a trial of vitamin supplementation in Tanzania. Baseline data on sociodemographic and anthropometric characteristics, clinical signs and symptoms, and laboratory parameters were used to identify correlates of low plasma vitamin A (<0.7 micromol/l), vitamin D (<80 nmol/l) and vitamin E (<9.7 micromol/l) status. Binomial regression was used to estimate risk ratios and 95% confidence intervals. Approximately 35, 39 and 51% of the women had low levels of vitamins A, D and E, respectively. Severe anemia (hemoglobin <85 g/l; P<0.01), plasma vitamin E (P=0.02), selenium (P=0.01) and vitamin D (P=0.02) concentrations were significant correlates of low vitamin A status in multivariate models. Erythrocyte Sedimentation Rate (ESR) was independently related to low vitamin A status in a nonlinear manner (P=0.01). The correlates of low vitamin D status were CD8 cell count (P=0.01), high ESR (ESR >81 mm/h; P<0.01), gestational age at enrollment (nonlinear; P=0.03) and plasma vitamins A (P=0.02) and E (P=0.01). For low vitamin E status, the correlates were money spent on food per household per day (P<0.01), plasma vitamin A concentration (nonlinear; P<0.01) and a gestational age <16 weeks at enrollment (P<0.01). Low concentrations of lipid-soluble vitamins are widely prevalent among HIV-infected women in Tanzania and are correlated with other nutritional insufficiencies. Identifying HIV-infected persons at greater risk of poor nutritional status and infections may help inform design and implementation of appropriate interventions

Exploring Problematic Mobile Phone Attachment and Associations to Anxiety and Inhibitory Control After a Short-Term Smartphone Separation

This study investigates problematic smartphone attachment under conditions of short-term smartphone separation. Two experimental studies with randomized group allocation were designed to investigate effects of smartphone separation on anxiety and inhibitory control. Problematic smartphone use pathways were explored using a self-report measure. In the first experiment (N= 85) smartphone addicted participants showed an increase in state anxiety after 20 min of separation from their smartphones compared to a control group of non-addicted participants. There was no evidence for impaired inhibitory control based on a period of smartphone separation. In the second experiment the methodology was slightly varied, and the participants (N= 95) were provided with a task during a smartphone separation of 15 min. This led to a reduction of state anxiety for problematic attached participants but did not result in a change for unproblematic attached participants. Problematic attached participants showed a larger disturbance in inhibitory control undergoing a separation period than unproblematic attached participants. Moreover, the results provide supplementary evidence for the existence of specific problematic smartphone attachment pathways and further variables

A Critical Appraisal of Strategies to Optimize Vitamin D Status in Germany, a Population with a Western Diet

During the last decade, our scientific knowledge of the pleiotropic biological effects of vitamin D metabolites and their relevance to human health has expanded widely. Beyond the well-known key role of vitamin D in calcium homeostasis and bone health, it has been shown that vitamin D deficiency is associated with a broad variety of independent diseases, including several types of cancer, and with increased overall mortality. Moreover, recent findings have demonstrated biological effects of the vitamin D endocrine system that are not mediated via activation of the classical nuclear vitamin D receptor (VDR) by binding with high affinity to its corresponding ligand, the biologically active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D). In contrast, many of these new biological effects of vitamin D compounds, including regulation of the circadian clock and many metabolic functions, are mediated by other vitamin D metabolites, including 20-hydroxyvitamin D and 20,23-dihydroxyvitamin D, and involve their binding to the aryl hydrocarbon receptor (AhR) and retinoid-orphan receptor (ROR). In most populations, including the German population, UVB-induced cutaneous vitamin D production is the main source for fulfilling the human body’s requirements of vitamin D. However, this causes a dilemma because solar or artificial UVR exposure is associated with skin cancer risk. In addition to UVB-induced vitamin D production in skin, in humans, there are two other possible sources of vitamin D: from diet and supplements. However, only a few natural foods contain substantial amounts of vitamin D, and in most populations, the dietary source of vitamin D cannot fulfill the body´s requirements. Because an increasing body of evidence has convincingly demonstrated that vitamin D deficiency is very common worldwide, it is the aim of this paper to (i) give an update of the vitamin D status in a population with a western diet, namely, the German population, and to (ii) develop strategies to optimize the vitamin D supply that consider both the advantages as well as the disadvantages/risks of different approaches, including increasing vitamin D status by dietary intake, by supplements, or by UVB-induced cutaneous synthesis of vitamin D

Live Longer with Vitamin D?

The global burden of vitamin D deficiency or insufficiency is of great concern for public health. According to recent studies, vitamin D deficiency is an important etiological factor in the pathogenesis of many chronic diseases. Whether or not there is a connection between 25-hydoxyvitamin D (25(OH)D) status and overall mortality is a matter of considerable debate. A new meta-analysis confirmed that low 25(OH)D levels were associated with a significant increased risk for all-cause mortality. Individuals with severe vitamin D deficiency have almost twice the mortality rate as those with 25(OH)D level ≥ 30 ng/mL, (≥75 nmol/L). Unlike previous meta-analyses which suggested that serum 25(OH)D > 50 ng/mL was associated with increased mortality, this new analysis found that there was no increased risk even when 25(OH)D levels were ≥70 ng/mL. In general, closer attention should be paid to vitamin D deficiency in medical and pharmaceutical practice than has been the case hitherto. The results of these studies are consistent with the recommendation to improve the general vitamin D status in children and adults by means of a healthy approach to sunlight exposure, consumption of foods containing vitamin D and supplementation with vitamin D preparations

Neue Interaktionen der Notch- und p53/63/73-Signalwege beim Glioblastom: Jagged1 als direktes p73-Zielgen

Neue Forschungsergebnisse unterstreichen die Bedeutung der funktionell teilweise überlappenden Notch- und p53/p63/p73-Signalwege für Pathogenese, Wachstumsverhalten und Therapie des Glioblastoms. Die dafür verantwortlichen molekularen Mechanismen sind jedoch bislang weitestgehend unbekannt. Ziel dieser Arbeit war es einen möglichen cross-talk zwischen dem Notch-Signalweg und der Transkriptionsfaktorfamilie p53/p63/p73 in Glioblastomzellen zu untersuchen. Wir charakterisierten die Expression wichtiger Komponenten des Notch-Signalwegs (Notch-Rezeptoren1-4; Notch-Liganden: Dll1, 3, 4; Jagged1,2) in humanen Glioblastomzelllinien (Tx3868, Tx3095, U373, U118, U87), wobei die Proteinexpression von Notch1 und Jagged1 mit dem p53-Status der Zelle korrelierte. Notch1 wurde ausschließlich, und Jagged1 wesentlich stärker, in Zellen mit mutiertem p53 (U373) exprimiert, verglichen mit Wildtyp-p53-Zellen (U87). In U373 Zellen war p73 stark exprimiert, dagegen war dieses Protein in Zellen mit Wildtyp-p53 (U87) nicht nachweisbar. Behandlung mit ionisierender Strahlung oder Doxorubicin selegierte eine Zellpopulation mit starker Jagged1-Expression und verändertem Wachstumsverhalten. Die siRNA-vermittelte Hemmung der p73-Expression reduzierte in U373 Zellen die Proteinexpression von Jagged1. Mittels Chromatinimmunpräzipitation zeigten wir in U373-Zellen eine direkte Bindung des p73 Proteins an die Promotorregion des Jagged1-Gens. Deren Intensität nahm nach Behandlung mit ionisierender Strahlung deutlich ab. Unsere Ergebnisse in Glioblastomzellen stehen somit im Einklang mit folgenden Hypothesen: (I) Abhängig vom p53-Status werden wichtige Komponenten des Notch-Signalwegs (u.a. Jagged1) differentiell exprimiert. (II) Behandlung mit ionisierender Strahlung oder Doxorubicin stimuliert die Jagged1-Expression, welche mit verändertem Wachstumsverhalten assoziiert ist. (III) In Zellen mit mutiertem p53 wird die Jagged1-Expression durch das p53-verwandte p73 Protein auf Transkriptionsebene induziert. (IV) Die nach Behandlung mit ionisierender Strahlung nur schwach nachweisbare Bindung des p73 Proteins an die Jagged1-Promotorregion spricht für eine Beteiligung anderer Faktoren an der Regulation dieses Gens. Wir konnten Jagged1 als direktes p73-Zielgen identifizieren und neue Interaktionen zwischen Notch- und p53-Signalwegen nachweisen. Die Relevanz dieser Ergebnisse für Pathogenese, Wachstumsverhalten und Therapie von Glioblastomzellen muss in zukünftigen Untersuchungen geklärt werden.In recent years, scientific progress has convincingly demonstrated an important role of notch and p53/p63/p73 that are in part functionally overlapping, for pathogenesis, growth behaviour and therapy of glioblastomas. However, the underlying molecular mechanism are to date unknown. The aim of this work was to examine a possible cross-talk between Notch-signaling and the transcription factor family p53/p63/p73 in glioblastoma cells. We characterised the expression of important components of the Notch-signaling pathway (Notch receptors 1-4; Notch ligands: Dll1,3,4; Jagged1,2) in human glioblastoma cells (Tx3868, Tx3095, U373, U118, U87) in vitro and could show that the protein expression of Notch1 and Jagged1 correlated with the p53 status of the cells. Notch1 was exclusively, and Jagged1 substantially stronger, expressed in cells with mutant p53 (U373), compared to wild type p53 cells (U87). In U373 cells, p73 was strongly expressed, while this protein was not detected in cells with wild type-p53 (U87). Treatment with ionising radiation or doxorubicin resulted in a cell population with increased Jagged1 expression and modulated growth behaviour. The siRNA-induced suppression of p73 expression reduced the protein expression of Jagged1 in U373 cells. Using chromatinimmunoprecipitation (ChIP) we could prove in U373 cells a direct binding of the p73 protein to the promotor region of the Jagged1 gene. The intensity of this binding decreased after treatment with ionising radiation clearly. Our results in glioblastoma cells are in agreement with the following hypotheses: (I) Depending on the p53 status, important components of the Notch-signaling pathway (including Jagged1) are differentially expressed. (II) Treatment with ionising radiation or doxorubicin stimulates the Jagged1 expression, which is associated with changed growth behaviour. (III) In cells with mutant p53, the Jagged1 expression is induced by p53-related p73 protein at the transcription level. (IV) After treatment with ionising radiation, only weak binding of the p73 protein to the Jagged1-promotor region was shown, indicating a participation of other factors in the regulation of this gene. In conclusion, we succeeded in identifying Jagged1as a direct p73-target gene and in proving new interactions between Notch- and p53/p63/p73-signaling pathways. The relevance of these results for pathogenesis and growth behaviour, as well as for the therapy of glioblastoma, must be confirmed in future investigations

Atopic dermatitis and vitamin D: facts and controversies

Patients with atopic dermatitis have genetically determined risk factors that affect the barrier function of the skin and immune responses that interact with environmental factors. Clinically, this results in an intensely pruriginous and inflamed skin that allows the penetration of irritants and allergens and predisposes patients to colonization and infection by microorganisms. Among the various etiological factors responsible for the increased prevalence of atopic diseases over the past few decades, the role of vitamin D has been emphasized. As the pathogenesis of AD involves a complex interplay of epidermal barrier dysfunction and dysregulated immune response, and vitamin D is involved in both processes, it is reasonable to expect that vitamin D's status could be associated with atopic dermatitis' risk or severity. Such association is suggested by epidemiological and experimental data. in this review, we will discuss the evidence for and against this controversial relationship, emphasizing the possible etiopathogenic mechanisms involved.Univ Brasilia UNB, Brasilia, DF, BrazilFed Dist Hlth State Dept SES DF, Brasilia, DF, BrazilUniv Brasilia HUB UNB, Brasilia Univ Hosp, Brasilia, DF, BrazilSão Paulo Fed Univ UNIFESP, Brasilia, DF, BrazilSão Paulo Fed Univ UNIFESP, Brasilia, DF, BrazilWeb of Scienc