Smoking and γ-Glutamyltransferase: Opposite Interactions with Alcohol Consumption and Body Mass Index

BACKGROUND: Smoking has recently been suggested to synergistically interact with alcohol intake as a determinant of serum gamma-glutamyltransferase (γ-GT), an emergent powerful predictor of disease and mortality. This study investigated whether this also applies to higher smoking and alcohol exposure ranges and to body mass index (BMI), which likewise is strongly associated with γ-GT. METHODOLOGY/PRINCIPAL FINDINGS: Analyses were based on occupational health examinations of more than 15,000 German male workers aged 16-64 years, predominantly from the construction industry. Sociodemographics and other health-related information were collected during the exam. Joint associations of smoking and alcohol consumption or BMI with elevated or log-transformed γ-GT were examined by tabulation and multiple adjusted regression models. Cigarette smoking exerted no effect on γ-GT in teetotalers, but there was a statistically significant effect of smoking among participants with higher alcohol consumption intensity, odds of elevated γ-GT being increased by 24% and 27% per additional 10 cigarettes smoked per day in subjects drinking 61-90 and >90 gram alcohol per day, respectively (P for interaction = 0.039). The interaction was opposite for BMI, where no association was seen in obese subjects, whereas odds of elevated γ-GT were increased by 24% per 10 cigarettes below 25 kg/m(2) (P for interaction = 0.040). This novel interaction was replicable in an independent cohort. CONCLUSION: The evidence for opposite interactions of smoking with alcohol and BMI as determinants of serum γ-GT suggests that different physiological pathways are responsible for the associations between these factors

Automatic Verification of Application-Tailored OSEK Kernels

The OSEK industrial standard governs the design of embedded real-time operating systems in the automotive domain. We report on efforts to develop verification methods for OSEK-conformant compilers, specifically of a code generator that weaves system calls and application code using a static configuration file, producing a stand-alone application that incorporates the relevant parts of the kernel. Our methodology involves two verification steps: On the one hand, we extract an OS-application interaction graph during the compilation phase and verify that it conforms to the standard, in particular regarding prioritized scheduling and interrupt handling. To this end, we generate from the configuration file a temporal specification of standard-conformant behaviour and model check the arising formulas on a labelled transition system extracted from the interaction graph. On the other hand, we verify that the actual generated code conforms to the interaction graph; this is done by graph isomorphism checking of the interaction graph against a dynamically-explored state-transition graph of the generated system

Analysis of Mrgprb2 Receptor-Evoked Ca2+ Signaling in Bone Marrow Derived (BMMC) and Peritoneal (PMC) Mast Cells of TRPC-Deficient Mice

Mast cells are a heterogeneous group of immune cells. The simplest and commonly accepted classification divides them in two groups according to their protease content. We have compared the action of diverse secretagogues on bone marrow derived (BMMC) and peritoneal (PMC) mast cells which represent classical models of mucosal and connective tissue type mast cells in mice. Whereas, antigen stimulation of the FcεRI receptors was similarly effective in triggering elevations of free intracellular Ca2+ concentration ([Ca2+]i) in both BMMC and PMC, robust [Ca2+]i rise following Endothelin-1 stimulation was observed only in a fraction of BMMC. Leukotriene C4 activating cysteinyl leukotriene type I receptors failed to evoke [Ca2+]i rise in either mast cell model. Stimulation of the recently identified target of many small-molecule drugs associated with systemic pseudo-allergic reactions, Mrgprb2, with compound 48/80, a mast cell activator with unknown receptor studied for many years, triggered Ca2+ oscillations in BMMC and robust [Ca2+]i rise in PMCs similarly to that evoked by FcεRI stimulation. [Ca2+]i rise in PMC could also be evoked by other Mrgprb2 agonists such as Tubocurarine, LL-37, and Substance P. The extent of [Ca2+]i rise correlated with mast cell degranulation. Expression analysis of TRPC channels as potential candidates mediating agonist evoked Ca2+ entry revealed the presence of transcripts of all members of the TRPC subfamily of TRP channels in PMCs. The amplitude and AUC of compound 48/80-evoked [Ca2+]i rise was reduced by ~20% in PMC from Trpc1/4/6−/− mice compared to Trpc1/4−/− littermatched control mice, whereas FcεRI-evoked [Ca2+]i rise was unaltered. Whole-cell patch clamp recordings showed that the reduction in compound 48/80-evoked [Ca2+]i rise in Trpc1/4/6−/− PMC was accompanied by a reduced amplitude of Compound 48/80-induced cation currents which exhibited typical features of TRPC currents. Together, this study demonstrates that PMC are an appropriate mast cell model to study mechanisms of Mrgprb2 receptor-mediated mast cell activation, and it reveals that TRPC channels contribute at least partially to Mrgprb2-mediated mast cellactivation but not following FcεRI stimulation. However, the channels conducting most of the Ca2+ entry in mast cells triggered by Mrgprb2 receptor stimulation remains to be identified

A rare case of neuroleptic malignant syndrome presenting with serious hyperthermia treated with a non-invasive cooling device: a case report

<p>Abstract</p> <p>Introduction</p> <p>A rare side effect of antipsychotic medication is neuroleptic malignant syndrome, mainly characterized by hyperthermia, altered mental state, haemodynamic dysregulation, elevated serum creatine kinase and rigor. There may be multi-organ dysfunction including renal and hepatic failure as well as serious rhabdomyolysis, acute respiratory distress syndrome and disseminated intravascular coagulation. The prevalence of neuroleptic malignant syndrome is between 0.02% and 2.44% for patients taking neuroleptics and it is not necessary to fulfil all cardinal features characterizing the syndrome to be diagnosed with neuroleptic malignant syndrome. Because of other different life-threatening diseases matching the various clinical findings, the correct diagnosis can sometimes be hard to make. A special problem of intensive care treatment is the management of severe hyperthermia. Lowering of body temperature, however, may be a major clinical problem because hyperthermia in neuroleptic malignant syndrome is typically unresponsive to antipyretic agents while manual cooling proves difficult due to peripheral vasoconstriction.</p> <p>Case presentation</p> <p>A 22-year-old Caucasian man was admitted unconscious with a body temperature of 42°C, elevated serum creatine phosphokinase, tachycardia and hypotonic blood pressure. In addition to intensive care standard therapy for coma and shock, a non-invasive cooling device (Arctic Sun 2000^®, Medivance Inc., USA), originally designed to induce mild therapeutic hypothermia in patients after cardiopulmonary resuscitation, was used to lower body temperature. After successful treatment it became possible to obtain information from the patient about his recent ambulant treatment with Olanzapin (Zyprexa®) for schizophrenia.</p> <p>Conclusion</p> <p>Numerous case reports have been published about patients who developed neuroleptic malignant syndrome due to Olanzapin (Zyprexa®) medication. Frequently hyperthermia has been observed in these cases with varying outcomes. In our case the only residual impairment for the patient is dysarthria with corresponding symmetric cerebellar pyramidal cell destruction demonstrated by increased signal intensity in T2-weighted magnetic resonance imaging, most likely caused by the excessive hyperthermia.</p

Analysis of Mrgprb2 Receptor-Evoked Ca2+ Signaling in Bone Marrow Derived (BMMC) and Peritoneal (PMC) Mast Cells of TRPC-Deficient Mice

Mast cells are a heterogeneous group of immune cells. The simplest and commonly accepted classification divides them in two groups according to their protease content. We have compared the action of diverse secretagogues on bone marrow derived (BMMC) and peritoneal (PMC) mast cells which represent classical models of mucosal and connective tissue type mast cells in mice. Whereas, antigen stimulation of the FcεRI receptors was similarly effective in triggering elevations of free intracellular Ca2+ concentration ([Ca2+]i) in both BMMC and PMC, robust [Ca2+]i rise following Endothelin-1 stimulation was observed only in a fraction of BMMC. Leukotriene C4 activating cysteinyl leukotriene type I receptors failed to evoke [Ca2+]i rise in either mast cell model. Stimulation of the recently identified target of many small-molecule drugs associated with systemic pseudo-allergic reactions, Mrgprb2, with compound 48/80, a mast cell activator with unknown receptor studied for many years, triggered Ca2+ oscillations in BMMC and robust [Ca2+]i rise in PMCs similarly to that evoked by FcεRI stimulation. [Ca2+]i rise in PMC could also be evoked by other Mrgprb2 agonists such as Tubocurarine, LL-37, and Substance P. The extent of [Ca2+]i rise correlated with mast cell degranulation. Expression analysis of TRPC channels as potential candidates mediating agonist evoked Ca2+ entry revealed the presence of transcripts of all members of the TRPC subfamily of TRP channels in PMCs. The amplitude and AUC of compound 48/80-evoked [Ca2+]i rise was reduced by ~20% in PMC from Trpc1/4/6−/− mice compared to Trpc1/4−/− littermatched control mice, whereas FcεRI-evoked [Ca2+]i rise was unaltered. Whole-cell patch clamp recordings showed that the reduction in compound 48/80-evoked [Ca2+]i rise in Trpc1/4/6−/− PMC was accompanied by a reduced amplitude of Compound 48/80-induced cation currents which exhibited typical features of TRPC currents. Together, this study demonstrates that PMC are an appropriate mast cell model to study mechanisms of Mrgprb2 receptor-mediated mast cell activation, and it reveals that TRPC channels contribute at least partially to Mrgprb2-mediated mast cellactivation but not following FcεRI stimulation. However, the channels conducting most of the Ca2+ entry in mast cells triggered by Mrgprb2 receptor stimulation remains to be identified.Fil: Tsvilovskyy, Volodymyr. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Solis Lopez, Alejandra. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Almering, Julia. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Richter, Christin. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Dietrich, Alexander. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Freichel, Marc. Ruprecht Karls Universitat Heidelberg; Alemani

Ultraviolet Fe II Emission in Fainter Quasars: Luminosity Dependences, and the Influence of Environments

We investigate the strength of ultraviolet Fe II emission in fainter quasars com- pared with brighter quasars for 1.0 :( z :( 1.8, using the SDSS (Sloan Digital Sky Survey) DR7QSO catalogue and spectra of Schneider et al., and the SFQS (SDSS Faint Quasar Survey) catalogue and spectra of Jiang et al. We quantify the strength of the UV Fe II emission using the W 2400 equivalent width of Weymann et al., which is defined between two rest-frame continuum windows at 2240–2255 and 2665–2695 ˚A. The main results are the following. (1) We find that for W 2400 2: 25 ˚A there is a universal (i.e. for quasars in general) strengthening of W 2400 with decreasing intrinsic luminosity, L3000. (2) In conjunction with previous work by Clowes et al., we find that there is a further, differential, strengthening of W 2400 with decreasing L3000 for those quasars that are members of Large Quasar Groups (LQGs). (3) We find that increasingly strong W 2400 tends to be associated with decreasing FWHM of the neighbouring Mg II λ2798 broad emission line. (4) We suggest that the dependence of W 2400 on L3000 arises from Lyα fluorescence. (5) We find that stronger W 2400 tends to be associated with smaller virial estimates from Shen et al. of the mass of the central black hole, by a factor ∼ 2 between the ultrastrong emitters and the weak. Stronger W 2400 emission would correspond to smaller black holes that are still growing. The differential effect for LQG members might then arise from preferentially younger quasars in the LQG environments

The mass-metallicity relation of SDSS quasars

Active galactic nuclei (AGNs) are characterized by a clear correlation between luminosity and metallicity (L_AGN-Z_AGN relation). The origin of this correlation is not clear. It may result from a relation between the black hole mass (M_BH) and metallicity, or from a relation between the accretion rate (L/L_Edd) and metallicity. To investigate the origin of the L_AGN-Z_AGN relation, we use optical spectra of 2383 quasars at 2.3 < z < 3.0 from the Sloan Digital Sky Survey. By using this data set, we have constructed composite spectra of 33 subsamples in intervals of both M_BH and L/L_Edd. From these composite spectra we measure emission-line flux ratios that are sensitive to the metallicity of the broad line region (BLR); specifically, NV/CIV, NV/HeII, (SiIV+OIV])/CIV, and AlIII/CIV. We find that there is a significant correlation between M_BH and Z_BLR as inferred from all four metallicity-sensitive emission-line flux ratios. This result strongly suggests that the observed L_AGN-Z_AGN relation is mostly a consequence of the M_BH-Z_AGN relation. The relation between M_BH and Z_BLR is likely a consequence of both the M_BH-M_bul relation and of the mass-metallicity relation in the host galaxy. We also find that L/L_Edd correlates with the emission line flux ratios involving NV (more specifically, NV/CIV and NV/HeII), while it does not correlate with the other two metallicity sensitive emission line flux ratios, i.e., (SiIV+OIV])/CIV and AlIII/CIV. These correlations indicate that the emission-line flux ratios involving NV depend on both metallicity and relative abundance of nitrogen. We suggest that the relation between L/L_Edd and those line ratios involving nitrogen, is caused by a delay of the black hole accretion rate relative to the onset of nuclear star formation of about 10^8 years, which is the timescale required for the nitrogen enrichment.Comment: Accepted for publication in A&A, 16 pages, 6 figure

ISO-SWS spectroscopy of NGC 1068

We present ISO-SWS spectroscopy of NGC 1068 for the wavelength range 2.4 to 45um, detecting a total of 36 emission lines. Most of the observed transitions are fine structure and recombination lines originating in the narrow line region. We compare the line profiles of optical lines and reddening-insensitive infrared lines to constrain the dynamical structure and extinction properties of the NLR. The considerable differences found are most likely explained by two effects. (1) The spatial structure of the NLR is a combination of a highly ionized outflow cone and lower excitation extended emission. (2) Parts of the NLR, mainly in the receding part at velocities above systemic, are subject to extinction that is significantly suppressing optical emission. Line asymmetries and net blueshifts remain, however, even for infrared fine structure lines suffering very little obscuration. This may be either due to an intrinsic asymmetry of the NLR, or due to a very high column density obscuring component which is hiding part of the NLR even from infrared view. Mid-infrared emission of molecular hydrogen in NGC 1068 arises in a dense molecular medium at temperatures of a few hundred Kelvin that is most likely closely related to the warm and dense components seen in the near-infrared H2 transitions, and in millimeter wave tracers of molecular gas. Any emission of the putative pc-scale molecular torus is likely overwhelmed by this larger scale emission.Comment: aastex (V4), 9 eps figures. Accepted by Ap

Angiotensin-II-Evoked Ca2+ Entry in Murine Cardiac Fibroblasts Does Not Depend on TRPC Channels

TRPC proteins form cation conducting channels regulated by different stimuli and are regulators of the cellular calcium homeostasis. TRPC are expressed in cardiac cells including cardiac fibroblasts (CFs) and have been implicated in the development of pathological cardiac remodeling including fibrosis. Using Ca2+ imaging and several compound TRPC knockout mouse lines we analyzed the involvement of TRPC proteins for the angiotensin II (AngII)-induced changes in Ca2+ homeostasis in CFs isolated from adult mice. Using qPCR we detected transcripts of all Trpc genes in CFs; Trpc1, Trpc3 and Trpc4 being the most abundant ones. We show that the AngII-induced Ca2+ entry but also Ca2+ release from intracellular stores are critically dependent on the density of CFs in culture and are inversely correlated with the expression of the myofibroblast marker α-smooth muscle actin. Our Ca2+ measurements depict that the AngII- and thrombin-induced Ca2+ transients, and the AngII-induced Ca2+ entry and Ca2+ release are not affected in CFs isolated from mice lacking all seven TRPC proteins (TRPC-hepta KO) compared to control cells. However, pre-incubation with GSK7975A (10 µM), which sufficiently inhibits CRAC channels in other cells, abolished AngII-induced Ca2+ entry. Consequently, we conclude the dispensability of the TRPC channels for the acute neurohumoral Ca2+ signaling evoked by AngII in isolated CFs and suggest the contribution of members of the Orai channel family as molecular constituents responsible for this pathophysiologically important Ca2+ entry pathway