Effect of pioglitazone therapy on high sensitive C-reactive protein and lipid profile in diabetic patients with renal transplantation; a randomize clinical trial

Background: Inflammation has a major role in disease lead to renal failure and diabetes mellitus, controlling inflammation in diabetic kidney receivers could decrease morbidity and mortality. Objectives: This study designed for evaluating the efficacy of pioglitazone on C-reactive protein and lipid profile in diabetic kidney transplant receivers. Patients and Methods: In this double blinded clinical trial, 58 diabetic renal transplant receivers, in first month after transplantation, randomized into two groups; receiving insulin and pioglitazone (15 mg tablet daily, group A); and insulin and placebo (group B). Blood pressure, weight, body mass index (BMI) and laboratory data compared in before and after 4-month treatment in two groups by SPSS. Results: Fifty-eight patients with mean age of 44.15 ± 2 years included. There were no significant difference between groups in demographic data and other baseline measured variables (P > 0.05).The mean weigh and BMI were slightly increased in group A and decreased in group B. The mean hs-CRP was decreased 4.82 mg/dL in group A and 1.93 mg/dL in group B (P = 0.007). The mean total serum cholesterol was significantly decreased 34 mg/dL in group A and 18.07 mg/dL in group B (P = 0.027). The mean serum HDL-C was significantly increased 13.31 mg/dL in group A and 5.89 mg/dl in group B (P < 0.001). Conclusions: Pioglitazone seems to be a safe drug for reducing serum lipids and CRP in kidney transplant receivers with diabetes mellitus in short term. Long term effect of this drug could be evaluated in future studies. Copyright © 2015 The Author(s)

Comparison of Integrated Radiation Transport Models with TEPC Measurements for the Average Quality Factors in Spaceflights

The purpose of this work is to test our theoretical model for the interpretation of radiation data measured in space. During the space missions astronauts are exposed to the complex field of radiation type and kinetic energies from galactic cosmic rays (GCR), trapped protons, and sometimes solar particle events (SPEs). The tissue equivalent proportional counter (TEPC) is a simple time-dependent approach for radiation monitoring for astronauts on board the International Space Station. Another and a newer approach to Microdosimetry is the use of silicon-on-insulator (SOI) technology launched on the MidSTAR-1 mission in low Earth orbit (LEO). In the radiation protection practice, the average quality factor of a radiation field is defined as a function of linear energy transfer (LET), Q(sub ave)(LET). However, TEPC measures the average quality factor as a function of the lineal energy y, Q(sub ave)(y), defined as the average energy deposition in a volume divided by the average chord length of the volume. Lineal energy, y, deviates from LET due to energy straggling, delta-ray escape or entry, and nuclear fragments produced in the detector volume. Monte Carlo track structure simulation was employed to obtain the response of a TEPC irradiated with charged particle for an equivalent site diameter of 1 micron of wall-less counter. The calculated data of the energy absorption in the wall-less counter were compiled for various y values for several ion types at various discrete projectile energy levels. For the simulation of TEPC response from the mixed radiation environments inside a spacecraft, such as, Space Shuttle and International Space Station, the complete microdosimetric TEPC response, f( y, E, Z), were calculated with the Monte Carlo theoretical results by using the first order Lagrangian interpolation for a monovariate function at a given y value (y = 0.1 keV/micron 5000 keV/micron) at any projectile energy level (E = 0.01 MeV/u to 50,000 MeV/u) of each specific radiation type (Z = 1 to 28). Because the anomalous response has been observed at large event sizes in the experiment due to the escape of energy out of sensitive volume by delta-rays and the entry of delta-rays from the high-density wall into the low-density gas-volume cavity, Monte Carlo simulation was also made for the response of a walled-TEPC with wall thickness 2 mm and density 1 g/cm(exp 3). The radius of cavity was set to 6.35 mm and a gas density 7.874 x 10(exp -5) g/cm(exp 3). The response of the walled- and the wall-less counters were compared. The average quality factor Q(sub ave)(y) for trapped protons on STS-89 demonstrated the good agreement between the model calculations and flight TEPC data as shown. Using an integrated space radiation model (this includes the transport codes HZETRN and BRYNTRN, the quantum nuclear interaction model QMSFRG) and the resultant response distribution functions of walled-TEPC from Monte-Carlo track simulations, we compared model calculations with walled-TEPC measurements from NASA missions in LEO and made predictions for the lunar and the Mars missions. The Q(sub ave)(y) values for the trapped or the solar protons ranged from 1.9-2.5. This over-estimates the Qave(LET) values which ranged from 1.4-1.6. Both quantities increase with shield thickness due to nuclear fragmentation. The Q(sub ave)(LET) for the complete GCR spectra was found to be 3.5-4.5, while flight TEPCs measured 2.9-3.4 for Q(sub ave)(y). The GCR values are decreasing with the shield thickness. Our analysis for a proper interpretation of data supports the use of TEPCs for monitoring space radiation environment

X-irradiation of cells on glass slides has a dose doubling impact

Immunofluorescence detection of γH2AX foci is a widely used tool to quantify the induction and repair of DNA double-strand breaks (DSBs) induced by ionising radiation. We observed that X-irradiation of mammalian cells exposed on glass slides induced twofold higher foci numbers compared to irradiation with γ-rays. Here, we show that the excess γH2AX foci after X-irradiation are produced from secondary radiation particles generated from the irradiation of glass slides. Both 120 kV X-rays and 137Cs γ-rays induce ∼20 γH2AX foci per Gy in cells growing on thin (∼2 μm) plastic foils immersed in water. The same yield is obtained following γ-irradiation of cells growing on glass slides. However, 120 kV X-rays produce ∼40 γH2AX foci per Gy in cells growing on glass, twofold greater than obtained using cells irradiated on plastic surfaces. The same increase in γH2AX foci number is obtained if the plastic foil on which the cells are grown is irradiated on a glass slide. Thus, the physical proximity to the glass material and not morphological differences of cells growing on different surfaces accounts for the excess γH2AX foci. The increase in foci number depends on the energy and is considerably smaller for 25 kV relative to 120 kV X-rays, a finding which can be explained by known physical properties of radiation. The kinetics for the loss of foci, which is taken to represent the rate of DSB repair, as well as the Artemis dependent repair fraction, was similar following X- or γ-irradiation, demonstrating that DSBs induced by this range of treatments are repaired in an identical manner

Interpretation of TEPC Measurements in Space Flights for Radiation Monitoring

For the proper interpretation of radiation data measured in space, the results of integrated radiation transport models were compared with the tissue equivalent proportional counter (TEPC) measurements. TEPC is a simple, time-dependent approach to radiation monitoring for astronauts on board the International Space Station. Another and a newer approach to microdosimetry is the use of silicon-on-insulator (SOI) technology launched on the MidSTAR-1 mission in low Earth orbit (LEO). In the radiation protection practice, the average quality factor of a radiation field is defined as a function of linear energy transfer (LET), Qave(LET). However, TEPC measures the average quality factor as a function of the lineal energy y, Qave(y), defined as the average energy deposition in a volume divided by the average chord length of the volume. The deviation of y from LET is caused by energy straggling, delta-ray escape or entry, and nuclear fragments produced in the detector volume. The response distribution functions of the wall-less and walled TEPCs were calculated from Monte-Carlo track simulations. Using an integrated space radiation model (which includes the transport codes HZETRN and BRYNTRN, and the quantum nuclear interaction model QMSFRG) and the resultant response distribution functions from Monte-Carlo track simulations, we compared model calculations with the walled-TEPC measurements from NASA missions in LEO and made predictions for the lunar and the Mars missions. Good agreement was found for Qave(y) between the model and measured spectra from past NASA missions. The Qave(y) values for the trapped or the solar protons ranged from 1.9-2.5. This over-estimates the Qave(LET) values which ranged from 1.4-1.6. Both quantities increase with shield thickness due to nuclear fragmentation. The Qave(LET) for the complete GCR spectra was found to be 3.5-4.5, while flight TEPCs measured 2.9-3.4 for Qave(y). The GCR values are decreasing with the shield thickness. Our analysis of the measurements of TEPCs can be used for a proper interpretation of observed data of monitoring the space radiation environment

Electron Emission from Foils and Biological Materials after Proton Impact

Electron emission spectra from thin metal foils with thin layers of water frozen on them (amorphous solid water) after fast proton impact have been measured and have been simulated in liquid water using the event-by-event track structure code PARTRAC. The electron transport model of PARTRAC has been extended to simulate electron transport down to 1 eV by including low-energy phonon, vibrational and electronic excitations as measured by Michaud et al. (Radiat. Res. 159, 3–22, 2003) for amorphous ice. Simulated liquid water yields follow in general the amorphous solid water measurements at higher energies, but overestimate them significantly at energies below 50 eV. Originally published Radiation Physics and Chemistry, Vol. 77, No. 10-12, Oct-Dec 200

Electron scattering from molecules and molecular aggregates of biological relevance

In this Topical Review we survey the current state of the art in the study of low energy electron collisions with biologically relevant molecules and molecular clusters. We briefly describe the methods and techniques used in the investigation of these processes and summarise the results obtained so far for DNA constituents and their model compounds, amino acids, peptides and other biomolecules. The applications of the data obtained is briefly described as well as future required developments

Reactive Molecular Dynamics study on the first steps of DNA-damage by free hydroxyl radicals

We employ a large scale molecular simulation based on bond-order ReaxFF to simulate the chemical reaction and study the damage to a large fragment of DNA-molecule in the solution by ionizing radiation. We illustrate that the randomly distributed clusters of diatomic OH-radicals that are primary products of megavoltage ionizing radiation in water-based systems are the main source of hydrogen-abstraction as well as formation of carbonyl- and hydroxyl-groups in the sugar-moiety that create holes in the sugar-rings. These holes grow up slowly between DNA-bases and DNA-backbone and the damage collectively propagate to DNA single and double strand break.Comment: 6 pages and 8 figures. movies and simulations are available at: http://qmsimulator.wordpress.com

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair

Ataxia telangiectasia (ATM) mutated and Artemis, the proteins defective in ataxia telangiectasia and a class of Radiosensitive-Severe Combined Immunodeficiency (RS-SCID), respectively, function in the repair of DNA double strand breaks (DSBs), which arise in heterochromatic DNA (HC-DSBs) following exposure to ionizing radiation (IR). Here, we examine whether they have protective roles against oxidative damage induced and/or endogenously induced DSBs. We show that DSBs generated following acute exposure of G0/G1 cells to the oxidative damaging agent, tert-butyl hydroperoxide (TBH), are repaired with fast and slow components of similar magnitude to IR-induced DSBs and have a similar requirement for ATM and Artemis. Strikingly, DSBs accumulate in ATM−/− mouse embryo fibroblasts (MEFs) and in ATM or Artemis-defective human primary fibroblasts maintained for prolonged periods under confluence arrest. The accumulated DSBs localize to HC-DNA regions. Collectively, the results provide strong evidence that oxidatively induced DSBs arise in HC as well as euchromatic DNA and that Artemis and ATM function in their repair. Additionally, we show that Artemis functions downstream of ATM and is dispensable for HC-relaxation and for pKAP-1 foci formation. These findings are important for evaluating the impact of endogenously arising DNA DSBs in ATM and Artemis-deficient patients

Alpha-particle-induced complex chromosome exchanges transmitted through extra-thymic lymphopoiesis in vitro show evidence of emerging genomic instability

Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naïve T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure.This work was supported by the Department of Health, UK. Contract RRX95 (RMA NSDTG)