Personal solar ultraviolet radiation dosimetry in an\ua0occupational setting across Europe

Background: Work-related solar ultraviolet radiation (UVR) is an important factor in the pathogenesis of non-melanoma skin cancer (NMSC). The World Health Organization, through the International Agency for Research on Cancer, has classified solar UVR as a group 1 carcinogen since 2012. The main problems encountered so far in the study of occupationally induced skin cancer include the lack of accurate occupational UVR dosimetry as well as insufficient distinction between occupational and leisure UVR exposure and underreporting of NMSC. Objectives: The aim of this study was to collect long-term individual UVR measurements in outdoor workers across European countries. Methods: A prospective study was initiated through the European Academy of Dermatology and Venereology, Healthy Skin@Work Campaign, measuring UVR exposure doses at occupational settings of masons from five European countries. Measurements were performed for several consecutive months using the GENESIS-UV measurement system. Results: The results identified alarming UVR exposure data. Average daily UVR doses ranged 148.40–680.48 J/m2 in Romania, 342.4–640.8 J/m2 in Italy, 165.5–466.2 J/m2 in Croatia, 41.8–473.8 J/m2 in Denmark and 88.15–400.22 J/m2 in Germany. Results showed an expected latitude dependence with increasing UVR yearly dosage from the north to the south of Europe. Conclusions: This study shows that outdoor workers from EU countries included in this study are exposed to high levels of occupational solar UVR, vastly exceeding the occupational exposure limits for solar UVR exposure, considered to be 1–1.33 SED/day in the period from May to September. This finding may serve as an evidence-based recommendation to authorities on implementing occupational skin cancer prevention strategies

Metabolically stable bradykinin B2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half-life

<p>Abstract</p> <p>Background</p> <p>The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure. In this study we investigated the systemic actions of labradimil, as well as other bradykinin B2 receptor agonists with a range of metabolic stabilities, in context of the local actions of the respective B2 receptor agonists on the blood-brain tumor barrier of rodent malignant gliomas.</p> <p>Methods</p> <p>Using dynamic contrast-enhanced MRI, the pharmacokinetics of gadolinium-diethyltriaminepentaacetic acid (Gd-DTPA), a small MRI contrast agent, were imaged in rodents bearing orthotopic RG-2 malignant gliomas. Baseline blood and brain tumor tissue pharmacokinetics were imaged with the 1^stbolus of Gd-DTPA over the first hour, and then re-imaged with a 2^ndbolus of Gd-DTPA over the second hour, during which normal saline or a bradykinin B2 receptor agonist was infused intravenously for 15 minutes. Changes in mean arterial blood pressure were recorded. Imaging data was analyzed using both qualitative and quantitative methods.</p> <p>Results</p> <p>The decrease in systemic blood pressure correlated with the known metabolic stability of the bradykinin B2 receptor agonist infused. Metabolically stable bradykinin B2 agonists, methionine-lysine-bradykinin and labradimil, had differential effects on the transvascular flow rate of Gd-DTPA across the blood-brain tumor barrier. Both methionine-lysine-bradykinin and labradimil increased the blood half-life of Gd-DTPA sufficiently enough to increase significantly the tumor tissue Gd-DTPA area under the time-concentration curve.</p> <p>Conclusion</p> <p>Metabolically stable bradykinin B2 receptor agonists, methionine-lysine-bradykinin and labradimil, enhance the transvascular delivery of small chemotherapy drugs across the BBTB of malignant gliomas by increasing the blood half-life of the co-infused drug. The selectivity of the increase in drug delivery into the malignant glioma tissue, but not into normal brain tissue or skeletal muscle tissue, is due to the inherent porous nature of the BBTB of malignant glioma microvasculature.</p

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Modulation of Superconducting Transition Temperature in LaAlO₃SrTiO₃ by SrTiO₃ Structural Domains

The tetragonal domain structure in SrTiO3 (STO) is known to modulate the normal-state carrier density in LaAlO3/SrTiO3 (LAO/STO) heterostructures, among other electronic properties, but the effect of STO domains on the superconductivity in LAO/STO has not been fully explored. Using a scanning SQUID susceptometer microscope to map the superconducting response as a function of temperature in LAO/STO, we find that the superconducting transition temperature is spatially inhomogeneous and modulated in a pattern that is characteristic of structural domains in the STO. © 2018, The Author(s)

NMR structure of the transmembrane and cytoplasmic domains of human CD4 in micelles

The human cluster determinant 4 (CD4) is a type I transmembrane glycoprotein involved in T-cell signalling. It is expressed primarily on the surface of T helper cells but also on subsets of memory and regulatory T lymphocytes (CD4(+) cells). It serves as a coreceptor in T-cell receptor recognition of MHC II antigen complexes. Besides its cellular functions, CD4 serves as the main receptor for human immunodeficiency virus type I (HIV-1). During T-cell infection, the CD4 extracellular domain is bound by HIV-1 gp120, the viral surface glycoprotein, which triggers a number of conformational changes ultimately resulting in virion entry of the cell. Subsequently, CD4 is downregulated in infected cells by multiple strategies that involve direct interactions of the HIV-1 proteins VpU and Nef with the cytoplasmic part of CD4. In the present work, we describe the NOE-based solution structure of the transmembrane and cytoplasmic domains of the cystein-free variant of CD4 (CD4mut) in dodecylphosphocholine (DPC) micelles. Furthermore, we have characterized micelle-inserted CD4mut by paramagentic relaxation enhancement (PRE) agents and (1)H-(15)N heteronuclear NOE data. CD4mut features a stable and well-defined transmembrane helix from M372 to V395 buried in the micellar core and a cytoplasmic helix ranging from A404 to L413. Experimental data suggest the amphipathic cytoplasmic helix to be in close contact with the micellar surface. The role of the amphipathic helix and its interaction with the micellar surface is discussed with respect to the biological function of the full-length CD4 protein

Occupational solar UV exposure in construction workers in Italy: Results of a one-month monitoring with personal dosimeters

Occupational exposure to solar UV radiation (UVR) is relevant in the construction sector. We performed a one month monitoring period in late spring of direct individual solar UVR exposure measurements in a group of three construction workers from the Tuscany Italian region, using the GENESIS-UV system for personal dosimetry and for the collection of long-term exposure data in a centralized dataset. Then, we compared personal UVR exposure data with the environmental erythemal dose in the same days in clear-sky conditions. The individual solar UVR exposures of the construction workers in the period between 22nd May and 22nd June 2017 in Tuscany varied between 85.5 and 1556.8 J/m2, while the average daily exposure considering all the three workers resulted 573.3 J/m2. The percentage between individual vs environmental exposure varied from 2.7 up to 31.2%, resulting 12.2 on average. Of the total amount of 40 days/worker measured we detected exposure levels above the 100 J/m2 proposed limit value in 39 days/worker, with exceeding of the limit up to ten times per day, more than five times on average. In terms of cumulative UVR exposure, the construction workers received on average a total one month exposure, based on 21 working days, of 12 kJ/m2, and we estimated an annual exposure of about 70 kJ/m2, approximately corresponding to 700 Standard Erythemal Doses. Our data show that the exposure levels of the Italian construction workers are very high in late spring, systematically exceeding the limit values. These UVR exposure levels can be considered potentially dangerous, in particular if associated with relevant cumulative annual UV doses received at the body, which are related to an increased risk of adverse effects, including skin cancers. Accordingly, a big effort is needed, to urgently reduce occupational solar UVR exposure in the construction sector, improving the application of preventive measures