Absorption, Pharmacokinetics, and Urinary Excretion of Pyridines After Consumption of Coffee and Cocoa-Based Products Containing Coffee in a Repeated Dose, Crossover Human Intervention Study

Scope: The present study assesses the absorption, pharmacokinetics, and urinary excretion of coffee pyridines and their metabolites after daily regular exposure to specific dosages of coffee or cocoa-based products containing coffee (CBPCC), considering different patterns of consumption. Methods and results: In a three-arm, crossover, randomized trial, 21 volunteers are requested to randomly consume for 1 month: one cup of espresso coffee per day, three cups of espresso coffee per day, or one cup of espresso coffee plus two CBPCC twice per day. The last day of the one-month treatment, blood and urine samples are collected for 24 h. Trigonelline, N-methylpyridinium, N-methylnicotinamide, and N-methyl-4-pyridone-5-carboxamide are quantified. Trigonelline and N-methylpyridinium absorption curves and 24-h urinary excretion reflect the daily consumption of different servings of coffee or CBPCC, showing also significant differences in main pharmacokinetic parameters. Moreover, inter-subject variability due to sex and smoking is assessed, showing sex-related differences in the metabolism of trigonelline and smoking-related ones for N-methylpyridinium. Conclusion: The daily exposure to coffee pyridines after consumption of different coffee dosages in a real-life setting is established. This data will be useful for future studies aiming at evaluating the bioactivity of coffee-derived circulating metabolites in cell experiments, mimicking more realistic experimental conditions

Empirical comparison of high gradient achievement for different metals in DC and pulsed mode

For the SwissFEL project, an advanced high gradient low emittance gun is under development. Reliable operation with an electric field, preferably above 125 MV/m at a 4 mm gap, in the presence of an UV laser beam, has to be achieved in a diode configuration in order to minimize the emittance dilution due to space charge effects. In the first phase, a DC breakdown test stand was used to test different metals with different preparation methods at voltages up to 100 kV. In addition high gradient stability tests were also carried out over several days in order to prove reliable spark-free operation with a minimum dark current. In the second phase, electrodes with selected materials were installed in the 250 ns FWHM, 500 kV electron gun and tested for high gradient breakdown and for quantum efficiency using an ultra-violet laser.Comment: 25 pages, 13 figures, 5 tables. Follow up from FEL 2008 conference (Geyongju Korea 2008) New Title in JVST A (2010) : Vacuum breakdown limit and quantum efficiency obtained for various technical metals using DC and pulsed voltage source

The motivational interviewing skill code:Reliability and a critical appraisal

The Motivational Interviewing Skill Code (MISC) is a coding system developed to measure adherence to motivational interviewing (MI). MI is an effective clinical style used in different treatment situations. Counsellors practising MI have to follow general principles and avoid certain traps. In the present study, the content of the MISC is compared with the general principles of MI and the traps to avoid in MI. Investigation of the content validity raises some questions. All general principles are represented but the traps to avoid in MI are not fully covered. The consequences of this under-representation are shown in transcripts of a selection of well-conducted MI training sessions. The reliability of the MISC was investigated by having five independent coders code 39 MI training sessions of different counsellors. The reliability of the MISC is reasonable. The five coders agreed to a large extent on the absolute ratings but the intraclass correlations were low. Although the MISC can be a useful research tool for process research of MI, it remains a labour-intensive instrument and for teaching and practice audit development of a more simple coding system is recommended

Pioglitazone corrects dysregulation of skeletal muscle mitochondrial proteins involved in ATP synthesis in type 2 diabetes

Context: In this study, we aimed to identify the determinants of mitochondrial dysfunction in skeletal muscle (SKLM) of subjects with type 2 diabetes (T2DM), and to evaluate the effect of pioglitazone (PIO) on SKLM mitochondrial proteome. Methods: Two different groups of adults were studied. Group I consisted of 8 individuals with normal glucose tolerance (NGT) and 8 with T2DM, subjected to SKLM mitochondrial proteome analysis by 2D-gel electrophoresis followed by mass spectrometry-based protein identification. Group II included 24 individuals with NGT and 24 with T2DM, whose SKLM biopsies were subjected to immunoblot analysis. Of the 24 subjects with T2DM, 20 were randomized to receive placebo or PIO (15 mg daily) for 6 months. After 6 months of treatment, SKLM biopsy was repeated. Results: Mitochondrial proteomic analysis on Group I revealed that several mitochondrial proteins involved in oxidative metabolism were differentially expressed between T2DM and NGT groups, with a downregulation of ATP synthase alpha chain (ATP5A), electron transfer flavoprotein alpha-subunit (ETFA), cytochrome c oxidase subunit VIb isoform 1 (CX6B1), pyruvate dehydrogenase protein X component (ODPX), dihydrolipoamide dehydrogenase (DLDH), dihydrolipoamide-S-succinyltransferase (DLST), and mitofilin, and an up-regulation of hydroxyacyl-CoA-dehydrogenase (HCDH), 3,2-trans-enoyl-CoA-isomerase (D3D2) and delta3,5-delta2,4-dienoyl-CoA-isomerase (ECH1) in T2DM as compared to NGT subjects. By immunoblot analysis on SKLM lysates obtained from Group II we confirmed that, in comparison to NGT subjects, those with T2DM exhibited lower protein levels of ATP5A (−30%, P = 0.006), ETFA (−50%, P = 0.02), CX6B1 (−30%, P = 0.03), key factors for ATP biosynthesis, and of the structural protein mitofilin (−30%, P = 0.01). T2DM was associated with a reduced abundance of the enzymes involved in the Krebs cycle DLST and ODPX (−20%, P ≤ 0.05) and increased levels of HCDH and ECH1, enzymes implicated in the fatty acid catabolism (+30%, P ≤ 0.05). In subjects with type 2 diabetes treated with PIO for 6 months we found a restored SKLM protein abundance of ATP5A, ETFA, CX6B1, and mitofilin. Moreover, protein levels of HCDH and ECH1 were reduced by −10% and − 15% respectively (P ≤ 0.05 for both) after PIO treatment. Conclusion: Type 2 diabetes is associated with reduced levels of mitochondrial proteins involved in oxidative phosphorylation and an increased abundance of enzymes implicated in fatty acid catabolism in SKLM. PIO treatment is able to improve SKLM mitochondrial proteomic profile in subjects with T2DM

Loss of function and reduced levels of sphingolipid desaturase DEGS1 variants are both relevant in disease mechanism

The last step of ex novo ceramide biosynthesis consists of the conversion of dihydroceramide into ceramide catalyzed by sphingolipid Δ4-desaturase DEGS1. DEGS1 variants were found to be responsible for heterogeneous clinical pictures belonging to the family of hypomyelinating leukodystrophies. To investigate the mechanisms making such variants pathogenic, we designed a procedure for the efficient detection of desaturase activity in vitro using LC-MS/MS and prepared a suitable cell model knocking out DEGS1 in HEK-293T cells through CRISPR-Cas9 genome editing (KO-DES-HEK). Transfecting KO-DES-HEK cells with DEGS1 variants, we found that their transcripts were all overexpressed as much as the WT transcripts, while the levels of cognate protein were 40%-80% lower. In vitro desaturase activity was lost by many variants except L175Q and N255S, which maintain a catalytic efficiency close to 12% of the WT enzyme. Metabolic labeling of KO-DES-HEK with deuterated palmitate followed by LC-MS/MS analysis of the formed sphingolipids revealed that the ceramide/dihydroceramide and sphingomyelin/dihydrosphingomyelin ratios were low and could be reverted by the overexpression of WT DEGS1 as well as of L175Q and N255S variants, but not by the overexpression of all other variants. Similar analyses performed on fibroblasts from a patient heterozygous for the N255S variant showed very low variant DEGS1 levels and a low ratio between the same unsaturated and saturated sphingolipids formed upon metabolic labeling, notwithstanding the residual activity measured at high substrate and homogenate protein concentrations. We conclude that loss of function and reduced protein levels are both relevant in disease pathogenesis

A review of physical supply and EROI of fossil fuels in China

This paper reviews China’s future fossil fuel supply from the perspectives of physical output and net energy output. Comprehensive analyses of physical output of fossil fuels suggest that China’s total oil production will likely reach its peak, at about 230 Mt/year (or 9.6 EJ/year), in 2018; its total gas production will peak at around 350 Bcm/year (or 13.6 EJ/year) in 2040, while coal production will peak at about 4400 Mt/year (or 91.9 EJ/year) around 2020 or so. In terms of the forecast production of these fuels, there are significant differences among current studies. These differences can be mainly explained by different ultimately recoverable resources assumptions, the nature of the models used, and differences in the historical production data. Due to the future constraints on fossil fuels production, a large gap is projected to grow between domestic supply and demand, which will need to be met by increasing imports. Net energy analyses show that both coal and oil and gas production show a steady declining trend of EROI (energy return on investment) due to the depletion of shallow-buried coal resources and conventional oil and gas resources, which is generally consistent with the approaching peaks of physical production of fossil fuels. The peaks of fossil fuels production, coupled with the decline in EROI ratios, are likely to challenge the sustainable development of Chinese society unless new abundant energy resources with high EROI values can be found

Broad Spectrum project: Factors determining the quality of antibiotic use in primary care: An observational study protocol from Italy

Introduction The overuse of antibiotics is causing worldwide spread of antimicrobial resistance (AMR). Compared with other countries, Italy has both high antibiotic consumption rates and high rates of AMR. Due to the fact that around 90% of antibiotics are prescribed by general practitioners (GPs), this study aims to measure the impact of knowledge, attitudes and sociodemographic and workplace-related factors on the quality of antibiotic prescriptions filled by GPs in the Italian Region of Sardinia. Methods and analysis Knowledge, attitude, sociodemographic and workplace-related factors deemed to influence physicians prescribing behaviour will be evaluated in a cross-sectional study conducted among all GPs of the Italian Region of Sardinia (n=1200). A knowledge and attitudes questionnaire (Knowledge and Attitudes on Antibiotics and Resistance - Italian version: ITA-KAAR) accompanied by a sociodemographic form will be linked to drug prescription data reimbursed by the National Health System. European Surveillance of Antibiotic Consumption quality indicators for outpatient antibiotic use will be calculated from drug prescription records. Every GP will be deemed to have demonstrated an adequate quality of prescriptions of antibiotics if half of the indicator score plus one is better than the median of the region. A multivariate Poisson regression model with robust variance estimation will be used to evaluate the impact of the determinants of antibiotic prescriptions on the actual prescribing quality of each physician. Ethics and dissemination The project has been approved by the ethics committee of the Regional Health Trust of Sardinia (176/2019/CE, 24 September 2019). The results will be useful to inform evidence-based interventions to tackle irrational antibiotic use in the community

A Transfer Matrix Method for Resonances in Randall-Sundrum Models

In this paper we discuss in detail a numerical method to study resonances in membranes generated by domain walls in Randall-Sundrum-like scenarios. It is based on similar works to understand the quantum mechanics of electrons subject to the potential barriers that exist in heterostructures in semiconductors. This method was used recently to study resonances of a three form field and lately generalized to arbitrary forms. We apply it to a lot of important models, namely those that contain the Gauge, Gravity and Spinor fields. In many cases we find a rich structure of resonances which depends on the parameters involved.Comment: 25 pages, 17 figure

de Sitter Thick Brane Solution in Weyl Geometry

In this paper, we consider a de Sitter thick brane model in a pure geometric Weyl integrable five-dimensional space-time, which is a generalization of Riemann geometry and is invariant under a so-called Weyl rescaling. We find a solution of this model via performing a conformal transformation to map the Weylian structure into a familiar Riemannian one with a conformal metric. The metric perturbations of the model are discussed. For gravitational perturbation, we get the effective modified P$\ddot{\text{o}}$schl-Teller potential in corresponding Schr$\ddot{\text{o}}$dinger equation for Kaluza-Klein (KK) modes of the graviton. There is only one bound state, which is a normalizable massless zero mode and represents a stable 4-dimensional graviton. Furthermore, there exists a mass gap between the massless mode and continuous KK modes. We also find that the model is stable under the scalar perturbation in the metric. The correction to the Newtonian potential on the brane is proportional to $e^{-3 r \beta/2}/r^2$, where $\beta$ is the de Sitter parameter of the brane. This is very different from the correction caused by a volcano-like effective potential.Comment: 24 pages, 13 figures, published versio