Cytogenetic effect of low dose γ-radiation in Hordeum vulgare seedlings: non-linear dose–effect relationship

The induction of chromosome aberrations in Hordeum vulgare germinated seeds was studied after ionizing irradiation with doses in the range of 10–1,000 mGy. The relationship between the frequency of aberrant cells and the absorbed dose was found to be nonlinear. A dose-independent plateau in the dose range from about 50 to 500 mGy was observed, where the level of cytogenetic damage was significantly different from the spontaneous level. The comparison of the goodness of the experimental data fitting with mathematical models of different complexity, using the most common quantitative criteria, demonstrated the advantage of a piecewise linear model over linear and polynomial models in approximating the frequency of cytogenetical disturbances. The results of the study support the hypothesis of indirect mechanisms of mutagenesis induced by low doses. Fundamental and applied implications of these findings are discussed. An erratum to this article can be found at     

Recent reports on the effect of low doses of ionizing radiation and its dose–effect relationship

Recently, the risk associated with low doses of ionizing radiation has gained new interest. Here, we analyze and discuss the major differences between two reports recently published on this issue; the report of the French Academy of Sciences and of the French Academy of Medicine published in March 2005, and the BEIR VII—Phase 2 Report of the American National Academy of Sciences published as a preliminary version in July 2005. The conclusion of the French Report is that the linear no-threshold relationship (LNT) may greatly overestimate the carcinogenic effect of low doses (<100 mSv) and even more that of very low doses (<10 mSv), such as those delivered during X-ray examinations. Conversely, the conclusion of the BEIR VII report is that LNT should be used for assessing the detrimental effects of these low and very low doses. The causes of these diverging conclusions should be carefully examined. They seem to be mostly associated with the interpretation of recent biological data. The point of view of the French Report is that these recent data are incompatible with the postulate on which LNT is implicitly based, namely the constancy of the carcinogenic effect per unit dose, irrespective of dose and dose rate.     

Ionizing radiation stimulates secretion of pro-inflammatory cytokines: dose–response relationship,mechanisms and implications

In previous studies we showed a marked increase in secretion of inflammatory cytokines TNFα and interleukin (IL)-1β by mouse macrophages in response to different doses of ionizing radiation (IR). Here we show the stimulation of IL-12 and IL-18 secretion by mouse peritoneal macrophages after whole-body irradiation with exploration of the possible mechanisms and implications in cancer radiotherapy. Both low (0.075 Gy) and high (2 Gy) doses of IR were found to cause sustained stimulation of IL-12 and IL-18 secretion by mouse macrophages; this paralleled the activation of NF-κB as well as up-regulated expression of CD14 and TLR4–MD2 on the macrophage surface and MyD88 in the cytoplasm. The expression of CD14, TLR4–MD2 and MyD88 increased in a dose-dependent manner from radiation doses between 0.05 and 2 Gy. The secretion of IL-12 and IL-18 showed a dose-dependent increase from doses between 0.05 and 4 Gy. It is concluded that IR can stimulate the secretion of IL-12 and IL-18 presumably via activation of the Toll signaling pathway in macrophages. The potential harmful effect of repeated doses of radiation used in radiotherapy for certain cancers is discussed. Yu-Xing Shan and Shun-Zi Jin contributed equally to the present work.     

Hill coefficients,dose–response curves and allosteric mechanisms

Hill coefficients (n _H) derived from four parameter logistic fits to dose–response curves were compared to calculated realistic reaction schemes and related to experimental data: (1) Hill coefficients may give information on the number of interacting sites but cannot distinguish between competitive, non-competitive or ortho-, iso-, or allosteric mechanisms. (2) For enzymatic dose–inhibition curves, Hill coefficients smaller than one do not indicate anticooperative binding but show that at least one ternary complex has enzymatic activity. (3) Hill coefficients different from one are proof for multiple ligand binding. The large variations of reported Hill coefficients corresponds to multiple allosteric binding, where induced conformational changes cause loss of the active conformation. Such a denaturation mechanism is in stark contrast to the desired specificity of drugs. The discussion is open.     

Scientific data and theories for salmonellosis dose–response assessment

An “expansive” risk assessment approach is illustrated, characterizing dose–response relationships for salmonellosis in light of the full body of evidence for human and murine superorganisms. Risk assessments often require analysis of costs and benefits for supporting public health decisions. Decision-makers and the public need to understand uncertainty in such analyses for two reasons. Uncertainty analyses provide a range of possibilities within a framework of present scientific knowledge, thus helping to avoid undesirable consequences associated with the selected policies. And, it encourages the risk assessors to scrutinize all available data and models, thus helping avoid subjective or systematic errors. Without the full analysis of uncertainty, decisions could be biased by judgments based solely on default assumptions, beliefs, and statistical analyses of selected correlative data. Alternative data and theories that incorporate variability and heterogeneity for the human and murine superorganisms, particularly colonization resistance, are emerging as major influences for microbial risk assessment. Salmonellosis risk assessments are often based on conservative default models derived from selected sets of outbreak data that overestimate illness. Consequently, the full extent of uncertainty of estimates of annual number of illnesses is not incorporated in risk assessments and the presently used models may be incorrect.     

Radiation risk estimates after radiotherapy: application of the organ equivalent dose concept to plateau dose–response relationships

Estimates of secondary cancer risk after radiotherapy are becoming more important for comparative treatment planning. Modern treatment planning systems provide accurate three-dimensional (3D) dose distributions for each individual patient. The dose distributions can be converted into organ equivalent doses to describe radiation-induced cancer after radiotherapy (OED_rad-ther) in the irradiated organs. The OED_rad-ther concept assumes that any two dose distributions in an organ are equivalent if they cause the same radiation-induced cancer risk. In this work, this concept is applied to dose–response relationships, which are leveling off at high dose. The organ-dependent operational parameter of this dose–response relationship was estimated by analyzing secondary cancer incidence data of patients with Hodgkin’s disease. The dose distributions of a typical radiotherapy treatment plan for treating Hodgkin’s disease was reconstructed. Dose distributions were calculated in individual organs from which cancer incidence data were available. The model parameter was obtained by comparing dose and cancer incidence rates for the individual organs.     

Effect of inorganic salts and glucose additives on dose–response,melting point and mass density of genipin gel dosimeters

Genipin gel dosimeters are hydrogels infused with a radiation-sensitive material which yield dosimetric information in three dimensions (3D). The effect of inorganic salts and glucose on the visible absorption dose–response, melting points and mass density of genipin gel dosimeters has been experimentally evaluated using 6-MV LINAC photons. As a result, the addition of glucose with optimum concentration of 10% (w/w) was found to improve the thermal stability of the genipin gel and increase its melting point (T_m) by 6 °C accompanied by a slight decrease of dose–response. Furthermore, glucose helps to adjust the gel mass density to obtain the desired tissue-equivalent properties. A drop of T_m was observed when salts were used as additives. As the salt concentration increased, gel T_m decreased. The mass density and melting point of the genipin gel could be adjusted using different amounts of glucose that improved the genipin gel suitability for 3D dose measurements without introducing additional toxicity to the final gel.     

The effect of the β-emitting yttrium-90 citrate on the dose–response of dicentric chromosomes in human lymphocytes: a basis for biological dosimetry after radiosynoviorthesis

The production of dicentric chromosomes in human lymphocytes by β-particles of yttrium-90 (Y-90) was studied in vitro to provide a basis of biological dosimetry after radiosynoviorthesis (RSO) of persistent synovitis by intra-articular administration of yttrium-90 citrate colloid. Since the injected colloid may leak into the lymphatic drainage exposing other parts of the body to radiation, the measurement of biological damage induced by β-particles of Y-90 is important for the assessment of radiation risk to the patients. A linear dose–response relationship (α = 0.0229 ± 0.0028 dicentric chromosomes per cell per gray) was found over the dose range of 0.2176–2.176 Gy. The absorbed doses were calculated for exposure of blood samples to Y-90 activities from 40 to 400 kBq using both Monte Carlo simulation and an analytical model. The maximum low-dose RBE, the RBE_M which is equivalent to the ratio of the α coefficients of the dose–response curves, is well in line with published results obtained earlier for irradiation of blood of the same donor with heavily filtered 220 kV X-rays (3.35 mm copper), but half of the RBE_M relative to weakly filtered 220 kV X-rays. Therefore, it can be concluded that for estimating an absorbed dose during RSO by the technique of biological dosimetry, in vitro and in vivo data for the same radiation quality are necessary.     

Iodine concentration of milk in a dose–response study with dairy cows and implications for consumer iodine intake

Most feed is poor in iodine and iodine supplementation of cow's diets must guarantee milk iodine concentrations for humans that contribute to prevention of the deficiency and minimize the risk of exceeding an upper limit of iodine intake. Five Holstein cows were fed four iodine doses (via Ca(ΙO₃)₂·6H₂O). In four sequential 14-d periods, doses of 0.2 (basal diet), 1.3, 5.1, and 10.1 mg iodine kg^?1 diet dry matter (DM) were administered. Samples of milk were collected during each period; blood was also sampled from each cow for each iodine dosage. In an 18-d depletion period, a non-supplemented diet was provided. Iodine was determined by inductively coupled plasma-mass spectrometry. The iodine content of milk and serum reflected the iodine dosages in feed significantly. The levels for the four doses tested in milk were 101±32, 343±109, 1215±222, and 2762±852 μg iodine kg^?1. The total amount of iodine in milk per day was 30–40% of ingested supplemental iodine. Omitting additional iodine resulted in a short-term reduction of serum and milk iodine following an exponential decay function. The iodine supplementation of 0.5–1.5 mg kg^?1 diet DM represents the requirement of the cow, resulting in 100–300 μg iodine L^?1 milk, which optimally contributes to human supply. The maximum dietary levels of former and present EU legislations (10 and 5 mg iodine kg^?1 cow feed) increase the risk of iodine excess in humans.     

Assessing bioavailability of the solubilization of organic compound in nonionic surfactant micelles by dose–response analysis

It is uncertain in some extent that organic compounds solubilized in micelles of a nonionic surfactant aqueous solution are bioavailable directly by the microbes in an extractive microbial transformation or biodegradation process. In this work, a dose–response method, where a bioequivalence concept is introduced to evaluate the synergic toxicity of the nonionic surfactants and the organic compounds, was applied to analyze the inhibition effect of organic compounds (naphthalene, phenyl ether, 2-phenylethanol, and 1-butanol) in nonionic surfactant Triton X-100 micelle aqueous solutions and Triton X-114 in aqueous solutions forming cloud point systems. Based on the result, a mole solubilization ratio of organic compounds in micelle was also determined, which consisted very well with those of classic semi-equilibrium dialysis experiments. The results exhibit that bioavailability of organic compounds solubilized in micelles to microbial cells is negligible, which provides a guideline for application of nonionic surfactant micelle aqueous solutions or cloud point systems as novel media for microbial transformations or biodegradations.     

Similarities and differences in the effect of cocaine on α-adrenergic and muscarinic response

Similarities and differences in the effect of cocaine on [alpha]-adrenergic and muscarinic receptors were shown in three experimental models. The postsynaptic stimulating effect of cocaine, mediated by [alpha]-adrenergic receptors was revealed in uninnervated chick amnion and innervated rat vas deferens. In vas deferens cocaine caused an increase of the amount of active [alpha]-adrenergic receptors, the appearance of an additional receptor pool, and change in the dimerization level. Cocaine acted as an antagonist on muscarinic receptors of the chick amnion. The inhibition by cocaine of muscarinic receptors in the rat brain cortex membranes led to a decrease in the number of receptors and their partial monomerization. Thus, cocaine influences both the [alpha]-adrenergic and the muscarinic response at the receptor level. Experiments on various objects have shown that cocaine activates the [alpha]-adrenergic response and inhibits the muscarinic one.     

Mathematical simulation of dose–effect relationships for fish eggs exposed chronically to ionizing radiation

A mathematical model which simulates the observed dose-effect relationships for fish eggs exposed to chronic irradiation is presented. The model assumes that the exposed fish eggs may exist in one of the following states: normally developing, reversibly damaged, and lethally damaged. Reversible damages may be recovered by repairing mechanisms which are spent for the repairing processes. The model was applied to describe the observed differences in effects of chronic exposure for quickly (2 weeks) and slowly (up to 20 weeks) developing fish eggs. Calculations were performed for dose rates of chronic irradiation ranging from 10 to 300 mGy/day. Two types of radiation effects were considered—the effect on eggs survival (percentage of survived eggs at time t), and the depletion of the repairing pool (in percentage of its maximal value). The model predictions have been compared with the experimental data from the EPIC database. This comparison showed that the model adequately describes the radiation effects in fish eggs of different species, within a wide range of chronic radiation exposures.     

Active immunization of post-pubertal heifers against prostaglandin F2α to suppress oestrous behaviour: effect of adjuvant and dose of immunogen

Two experiments were performed to develop an effective prostaglandin F_2α immunization protocol to suppress oestrous behaviour in beef heifers. In Experiment 1, a 3 × 2 factorial plan (n=4–5 per treatment) was used to test three doses (3.3, 10 and 30 mg) of a prostaglandin F_2α- human serum albumin (PGF-HSA) conjugate as the immunogen and two adjuvants, GNE (proprietary product; Intervet, The Netherlands) and diethylaminoethyl (DEAE)-dextran. Heifers (n=5) in a control group were untreated. Booster immunizations were given on Days 42 and 145 after the primary immunization (Day 0) and data collection for statistical purposes ended on Day 297. After Day 42 the incidence of oestrous behaviour was: (1) greater (P < 0.05) for control than immunized heifers (4.3 and 2.2, respectively), (2) greater (P < 0.05) for heifers immunized using GNE than for heifers immunized using DEAE-dextran (2.6 and 1.9, respectively), and (3) greater for heifers immunized with 30 mg of immunogen than for those immunized with either 3.3 or 10 mg (3.1, 1.7 and 1.9, respectively). Suppression of oestrous behaviour was accompanied by formation of a persistent corpus luteum (CL). Persistent CL were formed in ten of the 28 immunized heifers and the mean (± standard error of the mean) duration of persistence was 397 ± 85 days. In Experiment 2, a 2 × 2 factorial plan (n=6–7 per treatment) was used to test two doses (1 and 10 mg) of the PGF-HSA conjugate as the immunogen and two adjuvants, non-ulcerative Freund's adjuvant (NUFA) and DEAE-dextran. A control group was untreated (n=6). Booster immunization was given on Day 183 after the primary immunization (Day 0) and the experiment finished on Day 384. Antibody titres were higher (P < 0.05) in NUFA-treated heifers than in DEAE-dextran-treated (1 mg) heifers in the 183- to 283-day period. After Day 183, oestrous behaviour was suppressed in 26 out of the 27 immunized heifers. Persistent CL were maintained for longer (P < 0.05) in NUFA-treated heifers (245 days) than in DEAE-dextran-treated heifers (166 days) but there was no difference due to dose of immunogen (208 and 203 days, 1 and 10 mg, respectively). It is concluded that immunization against PGF-HSA results in suppression of oestrous behaviour in heifers due to prolongation of the life-span of the CL; however, efficacy of response is dependent on the immunization regime used.     

Cardiac troponins predict adverse clinical outcomes in stable coronary artery disease: a dose–response meta-analysis of prospective studies

Background: Predictive value of cardiac tropnins (cTns) in stable coronary artery disease (SCAD) has not been fully investigated.

Methods: We performed a meta-analysis to evaluate the dose–response relationship between serum detectable/rising cTns and adverse clinical outcomes, including all-cause mortality, cardiovascular (CV) mortality, myocardial infarction (MI), heart failure (HF) or major adverse cardiovascular events (MACEs) in SCAD.

Results: Sixteen studies involved 34,854 subjects were included. Compared with patients with negative/undetectable cTns, those with rising/detectable cTns were associated with increased risk of all-cause mortality, CV mortality, MI, HF and MACEs [the hazard ratio (HR) was 1.83 (95% confidence interval (CI) 1.61–2.08), 2.11 (1.80–2.48), 1.43 (1.26–1.62), 2.36 (1.97–2.83) and 1.99 (1.57–2.53), respectively]. Dose–response analysis have revealed that per 1-SD increment of cTnT was associated with increased risk of all-cause mortality, CV mortality, MI, HF and MACEs [the HR was 1.78 (1.20–2.63), 1.62 (1.41–1.85), 1.26 (1.12–1.42), 1.78 (1.17–2.69) and 1.26 (1.00–1.59), respectively].

Conclusion: Rising/detectable cTns was associated with increased risk of all-cause mortality, CV mortality, MI, HF and MACEs in SCAD in a dose–response manner.     

Synthesis and characterization of MMA–NaAlg/hydroxyapatite composite and the interface analyse with molecular dynamics

A novel composite of α-methyl methacrylate (MMA) grafted sodium alginate (NaAlg) and hydroxyapatite (HA) was prepared in this study. The compositions and chemical groups of materials were investigated by infrared spectra (IR), X-ray diffraction (XRD) and nuclear magnetic resonance (NMR). The results showed that MMA has been successfully grafted with the hydroxyl group of sodium alginate. Moreover many chemical bonds existed in the composite, including the “egg-box” structure and hydrogen bonding. Meanwhile, the chemical bondings between MMA and sodium alginate partly replaced the intermolecular hydrogen bonding or the intramolecular hydrogen bonding in sodium alginate. The composite had better water contact angle than sodium alginate, indicating the strong hydrophilic character of pure sodium alginate was improved. The molecular dynamics (MD) method was used to simulate and evaluate the interaction energies based on the theoretics, which suggested that the copolymer whose every monomer grafted with one MMA had a more stable structure.