Lifetime excess absolute risk for lung cancer due to exposure to radon: results of the pooled uranium miners cohort study PUMA.

The Pooled Uranium Miners Analysis (PUMA) study is the largest uranium miners cohort with 119,709 miners, 4.3 million person-years at risk and 7754 lung cancer deaths. Excess relative rate (ERR) estimates for lung cancer mortality per unit of cumulative exposure to radon progeny in working level months (WLM) based on the PUMA study have been reported. The ERR/WLM was modified by attained age, time since exposure or age at exposure, and exposure rate. This pattern was found for the full PUMA cohort and the 1960 + sub-cohort, i.e., miners hired in 1960 or later with chronic low radon exposures and exposure rates. The aim of the present paper is to calculate the lifetime excess absolute risk (LEAR) of lung cancer mortality per WLM using the PUMA risk models, as well as risk models derived in previously published smaller uranium miner studies, some of which are included in PUMA. The same methods were applied for all risk models, i.e., relative risk projection up to <95 years of age, an exposure scenario of 2 WLM per year from age 18-64 years, and baseline mortality rates representing a mixed Euro-American-Asian population. Depending upon the choice of model, the estimated LEAR per WLM are 5.38 × 10-4 or 5.57 × 10-4 in the full PUMA cohort and 7.50 × 10-4 or 7.66 × 10-4 in the PUMA 1960 + sub-cohort, respectively. The LEAR per WLM estimates derived from risk models reported for previously published uranium miners studies range from 2.5 × 10-4 to 9.2 × 10-4. PUMA strengthens knowledge on the radon-related lung cancer LEAR, a useful way to translate models for policy purposes.

Updated risk models for lung cancer due to radon exposure in the German Wismut cohort of uranium miners, 1946-2018.

UNSCEAR recently recommended that future research on the lung cancer risk at low radon exposures or exposure rates should focus on more contemporary uranium miners. For this purpose, risk models in the German Wismut cohort of uranium miners were updated extending the follow-up period by 5 years to 1946-2018. The full cohort (n = 58,972) and specifically the 1960 + sub-cohort of miners first hired in 1960 or later (n = 26,764) were analyzed. The 1960 + sub-cohort is characterized by low protracted radon exposure of high quality of measurements. Internal Poisson regression was used to estimate the excess relative risk (ERR) for lung cancer per cumulative radon exposure in Working Level Months (WLM). Applying the BEIR VI exposure-age-concentration model, the ERR/100 WLM was 2.50 (95% confidence interval (CI) 0.81; 4.18) and 6.92 (95% CI < 0; 16.59) among miners with attained age < 55 years, time since exposure 5-14 years, and annual exposure rates < 0.5 WL in the full (n = 4329 lung cancer deaths) and in the 1960 + sub-cohort (n = 663 lung cancer deaths), respectively. Both ERR/WLM decreased with older attained ages, increasing time since exposure, and higher exposure rates. Findings of the 1960 + sub-cohort are in line with those from large pooled studies, and ERR/WLM are about two times higher than in the full Wismut cohort. Notably, 20-30 years after closure of the Wismut mines in 1990, the estimated fraction of lung cancer deaths attributable to occupational radon exposure is still 26% in the full Wismut cohort and 19% in the 1960 + sub-cohort, respectively. This demonstrates the need for radiation protection against radon.

PROPERTIES OF THE BEOSL DOSIMETRY SYSTEM IN THE FRAMEWORK OF A LARGE-SCALE PERSONAL MONITORING SERVICE.

The Individual Monitoring Service of the Helmholtz Zentrum München is currently using the BeOSL dosimetry system for monitoring ∼15 000 persons per month. This dosimetry system has a modular structure and represents a complete new concept on handling dosemeters in a large-scale dosimetry service. It is based on optically stimulated luminescence dosemeters made of beryllium oxide. The dosimetric and operational properties of the system are shown and discussed.

Effects of RRR-alpha-tocopherol on leukocyte expression of HSP72 in response to exhaustive treadmill exercise.

Previous research revealed an increased expression of HSP72 in leukocytes after vigorous endurance exercise. We questioned whether more intensive but shorter exercise also induces leukocyte HSP72 synthesis. To delineate the role of reactive oxygen species (ROS) in exercise-related HSP72 induction, we additionally examined the effect of RRR-alpha-tocopherol (alpha-toc) on HSP72 expression using a double-blind placebo (P) controlled cross-over design. After supplementation with alpha-toc (500 I.U. daily) or P for 8 days, 9 male subjects performed a combined exhaustive treadmill protocol (total duration 29.4 +/- 2.0 min). HSP72 was assessed on mRNA (RT-PCR) and protein levels (flow cytometry). HSP72 mRNA rose 3 h after exercise only in the P group, but individual differences (alpha-toc - P) did not reveal significant treatment effects. A moderate but significant rise of HSP72 protein occurred in granulocytes up to 48 h after exercise. Three hours post-exercise, granulocyte HSP72 protein was lower when subjects received alpha-toc, but this effect vanished 24 and 48 h post-exercise. Exhaustive treadmill exercise augments HSP72 mRNA in leukocytes and induced a moderate but prolonged response of granulocyte HSP72 protein. These exercise effects are lower when compared to earlier findings obtained after vigorous endurance exercise. ROS seem to be involved, but do not play the major role in the induction of granulocyte HSP72 synthesis after exhaustive exercise.

Piracetam affects facilitatory I-wave interaction in the human motor cortex.

OBJECTIVE: To investigate by means of transcranial magnetic stimulation (TMS) the effect of a single oral dose of the GABA derivate piracetam on intracortical facilitatory I-wave interaction. METHODS: The study was performed in 8 healthy volunteers. Before, 1, 3, 6, and 24 h after intake of 4000 mg piracetam, MEPs in the relaxed abductor digiti minimi muscle were elicited by a recently introduced double pulse TMS technique with a suprathreshold first and a subthreshold second stimulus. From interstimulus intervals of 0.5-5.1 ms 3 periods were observed in which MEP facilitation showed maxima - so-called peaks of I-wave interaction - and which were separated by two troughs with no facilitation. We studied the changes in timing and size of the peaks over time. RESULTS: With piracetam, I-wave peaks showed a reduction in size as well as a shortening of the latencies at which the peaks occurred. Both changes were significant at 6 h after drug intake compared to baseline. The effects were partially reversible after 24 h. CONCLUSIONS: The mode of action of piracetam within the nervous system is almost unknown. The peak size reduction was similar to effects that were seen under GABAergic drugs, although GABAergic properties of piracetam have not been observed so far. Shortening of the I-wave peak latencies is a new phenomenon. The results are discussed on the basis of the known therapeutic effects of piracetam in cortical myoclonus and as nootropic agent.

Reduced phosphodiesters and high-energy phosphates in the frontal lobe of schizophrenic patients: a (31)P chemical shift spectroscopic-imaging study.

BACKGROUND: (31)Phosphorous magnetic resonance spectroscopy has been widely used to evaluate schizophrenic patients in comparison to control subjects, because it allows the investigation of both phospholipid and energy metabolism in vivo; however, the results achieved so far are inconsistent. Chemical shift imaging (CSI) has the advantage that instead of only one or a few preselected voxels the tissue of a whole brain slice can be examined. The aim of the present investigation was to determine whether the results of previous studies of our group, showing that phosphodiesters (PDE) are decreased in the frontal lobe of schizophrenic patients as compared to control subjects, might be confirmed in an independent unmedicated patient sample using the CSI technique. METHODS: A carefully selected new cohort including 11 neuroleptic-free schizophrenic patients and 11 age- and gender-matched healthy control subjects was recruited. CSI was applied and an innovative analysis method for CSI data based on a general linear model was used. RESULTS: PDE, phosphocreatine, and adenosine triphosphate (ATP) were found to be significantly decreased in the frontal lobe of patients with schizophrenia. CONCLUSIONS: Because PDE was decreased in schizophrenic patients, the membrane phospholipid hypothesis of schizophrenia could not be corroborated. Further results indicate decreased ATP production in the frontal lobe of patients with schizophrenia.

Molecular and biochemical characterization of rat gamma-trimethylaminobutyraldehyde dehydrogenase and evidence for the involvement of human aldehyde dehydrogenase 9 in carnitine biosynthesis.

The penultimate step in carnitine biosynthesis is mediated by gamma-trimethylaminobutyraldehyde dehydrogenase (EC 1.2.1.47), a cytosolic NAD(+)-dependent aldehyde dehydrogenase that converts gamma-trimethylaminobutyraldehyde into gamma-butyrobetaine. This enzyme was purified from rat liver, and two internal peptide fragments were sequenced by Edman degradation. The peptide sequences were used to search the Expressed Sequence Tag data base, which led to the identification of a rat cDNA containing an open reading frame of 1485 base pairs encoding a polypeptide of 494 amino acids with a calculated molecular mass of 55 kDa. Expression of the coding sequence in Escherichia coli confirmed that the cDNA encodes gamma-trimethylaminobutyraldehyde dehydrogenase. The previously identified human aldehyde dehydrogenase 9 (EC 1.2.1.19) has 92% identity with rat trimethylaminobutyraldehyde dehydrogenase and has been reported to convert substrates that resemble gamma-trimethylaminobutyraldehyde. When aldehyde dehydrogenase 9 was expressed in E. coli, it exhibited high trimethylaminobutyraldehyde dehydrogenase activity. Furthermore, comparison of the enzymatic characteristics of the heterologously expressed human and rat dehydrogenases with those of purified rat liver trimethylaminobutyraldehyde dehydrogenase revealed that the three enzymes have highly similar substrate specificities. In addition, the highest V(max)/K(m) values were obtained with gamma-trimethylaminobutyraldehyde as substrate. This indicates that human aldehyde dehydrogenase 9 is the gamma-trimethylaminobutyraldehyde dehydrogenase, which functions in carnitine biosynthesis.

Physical exercise-induced expression of inducible nitric oxide synthase and heme oxygenase-1 in human leukocytes: effects of RRR-alpha-tocopherol supplementation.

This study evaluated the effects of RRR-alpha-tocopherol (500 IU/day, 8 days) on in vivo cytokine response and cytoplasmic expression of inducible nitric oxide synthase (iNOS) and the antioxidant stress protein heme oxygenase-1 (HO-1) in human leukocytes after exhaustive exercise. Thirteen men were investigated in a double-blind, placebo-controlled, cross-over study with a wash-out period of 28 days. The exercise procedure consisted of an incremental treadmill test followed by a continuous run until exhaustion at 110% of the individual anaerobic threshold (total duration 28.5 +/- 0.8 min). HO-1 and iNOS protein were assessed in mono- (M), lympho-, and granulocytes (G) using flow cytometry. Plasma interleukin-6 (IL-6) and IL-8 were measured by ELISA. IL-6 rose significantly whereas IL-8 did not exhibit significant changes after exercise. Changes of IL-6 were not affected by RRR-alpha-tocopherol. Exercise induced an increase of iNOS protein primarily in M and G. A small, but significant, increase of HO-1 protein was measured in M and G. RRR-alpha-Tocopherol did not show any significant effects on cytoplasmic expression of iNOS and HO-1 at rest and after exercise. In conclusion, exhaustive exercise induces expression of iNOS and HO-1 in human leukocytes by a mechanism that is not sensitive to RRR-alpha-tocopherol supplementation.

Dopamine receptor subtypes modulate olfactory bulb gamma-aminobutyric acid type A receptors.

The gamma-aminobutyric acid type A (GABAA) receptor is the predominant Cl- channel protein mediating inhibition in the olfactory bulb and elsewhere in the mammalian brain. The olfactory bulb is rich in neurons containing both GABA and dopamine. Dopamine D1 and D2 receptors are also highly expressed in this brain region with a distinct and complementary distribution pattern. This distribution suggests that dopamine may control the GABAergic inhibitory processing of odor signals, possibly via different signal-transduction mechanisms. We have observed that GABAA receptors in the rat olfactory bulb are differentially modulated by dopamine in a cell-specific manner. Dopamine reduced the currents through GABA-gated Cl- channels in the interneurons, presumably granule cells. This action was mediated via D1 receptors and involved phosphorylation of GABAA receptors by protein kinase A. Enhancement of GABA responses via activation of D2 dopamine receptors and phosphorylation of GABAA receptors by protein kinase C was observed in mitral/tufted cells. Decreasing or increasing the binding affinity for GABA appears to underlie the modulatory effects of dopamine via distinct receptor subtypes. This dual action of dopamine on inhibitory GABAA receptor function in the rat olfactory bulb could be instrumental in odor detection and discrimination, olfactory learning, and ultimately odotopic memory formation.

Inhibition of mitogen-activated proliferation of human lymphocytes in vitro by high concentrations of glutamine

We invetigated the influence of hogh concentrations of glutamine and aspargine on in vitro cellular growth of lymphocytes stimulated with phytohaemaglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM), a recognized test of cellular immunocompetence. Human peripheral lymphocytes were cultured in flat-bottomed 96-well microplates at 37§ C for 96 (PHA and Con A) or 144 hours (PWM) in the presence of a mitogen at different concentrations and either glutamine or asparagine supplemented at doses of 2, 4 or 8 mM. Lymphocyte reactivity, meas ured by the incorporation of tritiated thymidine into cellular DNA, was compared to identical cultures in the absence of supplemented amino acids (controls). We found that glutamine in doses of 2 mM and higher inhibited lymphocyte proliferation of mitogen-stimulated human lymphocyes, whereas asparagine caused no effect. These results demonstrate that, although necessary for cellular division in moderate amounts, glutamine in high concentrations has the reverse effect

[Tensile strength of dental porcelains]. / Festigkeit dentalkeramisicher Massen.

Flexural, compressive and tensile strength as well as the modulus of elasticity of 15 different dental ceramics were evaluated. Conventional dental ceramics differed insignificantly in their mechanical properties. By testing new products like Cerec 2 and especially In-Ceram there was found an evident increase in inner strength. For comparison the strength of some other new ceramics as Dicor increased slightly related to conventional ceramics.