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Sample records for dose-response relationship hormesis

  1. A Method to Evaluate Hormesis in Nanoparticle Dose-Responses

    OpenAIRE

    Nascarella, Marc A.; Calabrese, Edward J.

    2012-01-01

    The term hormesis describes a dose-response relationship that is characterized by a response that is opposite above and below the toxicological or pharmacological threshold. Previous reports have shown that this relationship is ubiquitous in the response of pharmaceuticals, metals, organic chemicals, radiation, and physical stressor agents. Recent reports have also indicated that certain nanoparticles (NPs) may also exhibit a hormetic dose-response. We describe the application of three previo...

  2. Preconditioning is hormesis part I: Documentation, dose-response features and mechanistic foundations.

    Science.gov (United States)

    Calabrese, Edward J

    2016-08-01

    This article provides the first extensive documentation of the dose response features of pre- and postconditioning. Pre- and postconditioning studies with rigorous study designs, using multiple doses/concentrations along with refined dose/concentration spacing strategies, often display hormetic dose/concentration response relationships with considerable generality across biological model, inducing (i.e., conditioning) agent, challenging dose treatment, endpoint, and mechanism. Pre- and postconditioning hormesis dose/concentration-response relationships are reported for 154 diverse conditioning agents, affecting more than 550 dose/concentration responses, across a broad range of biological models and endpoints. The quantitative features of the pre- and postconditioning-induced protective responses are modest, typically being 30-60% greater than control values at maximum, findings that are consistent with a large body (>10,000) of hormetic dose/concentration responses not related to pre- and postconditioning. Regardless of the biological model, inducing agent, endpoint or mechanism, the quantitative features of hormetic dose/concentration responses are similar, suggesting that the magnitude of response is a measure of biological plasticity. This paper also provides the first documentation that hormetic effects account for preconditioning induced early (1-3h) and delayed (12-72h) windows of protection. These findings indicate that pre- and postconditioning are specific types of hormesis.

  3. The notion of hormesis and the dose-response theory: a unified approach.

    Science.gov (United States)

    Murado, M A; Vázquez, J A

    2007-02-07

    According to an opinion which is vigorous and insistently defended for approximately one decade, hormesis (the response of a biological entity to an effector, with stimulatory results at low doses and inhibitory results at high doses) radically puts into question the classic theory of dose-response (DR) relationships and demands a profound revision of environmental protection policies. Herein we show that DR theory, with the modifications which we propose, allows the modelling of various kinds of biphasic responses which are phenomenologically similar to hormetic ones and of well-defined origin, as well as responses which have been treated as genuinely hormetic. Our descriptive approach may also represent a useful resource for experimental design, directed towards identifying some of the potentially heterogeneous mechanisms which underlie the hormetic phenomenon. Finally, it also allows to discuss some factors which prevent the use of the notion of hormesis-perhaps useful in a clinical context, under strictly controlled conditions-to make decisions on environmental protection measures.

  4. Interpreting 'dose-response' curves using homeodynamic data: with an improved explanation for hormesis.

    Science.gov (United States)

    Stebbing, A R D

    2009-04-15

    A re-interpretation of the 'dose-response' curve is given that accommodates homeostasis. The outcome, or overall effect, of toxicity is the consequence of toxicity that is moderated by homeodynamic responses. Equilibrium is achieved by a balance of opposing forces of toxic inhibition countered by a stimulatory response. A graphical model is given consisting of two linked curves (response vs concentration and effect vs concentration), which provide the basis for a re-interpretation of the 'dose-response' curve. The model indicates that such relationships are non-linear with a threshold, which is due to homeodynamic responses. Subthreshold concentrations in 'dose-response' curves provide the sum of toxic inhibition minus the homeodynamic response; the response itself is unseen in serving its purpose of neutralizing perturbation. This interpretation suggests why the alpha- and beta-curves are non-linear. The beta-curve indicates adaptive overcorrection to toxicity that confers greater resistance to subsequent toxic exposure, with hormesis as an epiphenomenon.

  5. Effect of Photon Hormesis on Dose Responses to Alpha Particles in Zebrafish Embryos

    Science.gov (United States)

    Ng, Candy Yuen Ping; Cheng, Shuk Han; Yu, Kwan Ngok

    2017-01-01

    Photon hormesis refers to the phenomenon where the biological effect of ionizing radiation with a high linear energy transfer (LET) value is diminished by photons with a low LET value. The present paper studied the effect of photon hormesis from X-rays on dose responses to alpha particles using embryos of the zebrafish (Danio rerio) as the in vivo vertebrate model. The toxicity of these ionizing radiations in the zebrafish embryos was assessed using the apoptotic counts at 20, 24, or 30 h post fertilization (hpf) revealed through acridine orange (AO) staining. For alpha-particle doses ≥ 4.4 mGy, the additional X-ray dose of 10 mGy significantly reduced the number of apoptotic cells at 24 hpf, which proved the presence of photon hormesis. Smaller alpha-particle doses might not have inflicted sufficient aggregate damages to trigger photon hormesis. The time gap T between the X-ray (10 mGy) and alpha-particle (4.4 mGy) exposures was also studied. Photon hormesis was present when T ≤ 30 min, but was absent when T = 60 min, at which time repair of damage induced by alpha particles would have completed to prevent their interactions with those induced by X-rays. Finally, the drop in the apoptotic counts at 24 hpf due to photon hormesis was explained by bringing the apoptotic events earlier to 20 hpf, which strongly supported the removal of aberrant cells through apoptosis as an underlying mechanism for photon hormesis. PMID:28208665

  6. Effect of Photon Hormesis on Dose Responses to Alpha Particles in Zebrafish Embryos

    Directory of Open Access Journals (Sweden)

    Candy Yuen Ping Ng

    2017-02-01

    Full Text Available Photon hormesis refers to the phenomenon where the biological effect of ionizing radiation with a high linear energy transfer (LET value is diminished by photons with a low LET value. The present paper studied the effect of photon hormesis from X-rays on dose responses to alpha particles using embryos of the zebrafish (Danio rerio as the in vivo vertebrate model. The toxicity of these ionizing radiations in the zebrafish embryos was assessed using the apoptotic counts at 20, 24, or 30 h post fertilization (hpf revealed through acridine orange (AO staining. For alpha-particle doses ≥ 4.4 mGy, the additional X-ray dose of 10 mGy significantly reduced the number of apoptotic cells at 24 hpf, which proved the presence of photon hormesis. Smaller alpha-particle doses might not have inflicted sufficient aggregate damages to trigger photon hormesis. The time gap T between the X-ray (10 mGy and alpha-particle (4.4 mGy exposures was also studied. Photon hormesis was present when T ≤ 30 min, but was absent when T = 60 min, at which time repair of damage induced by alpha particles would have completed to prevent their interactions with those induced by X-rays. Finally, the drop in the apoptotic counts at 24 hpf due to photon hormesis was explained by bringing the apoptotic events earlier to 20 hpf, which strongly supported the removal of aberrant cells through apoptosis as an underlying mechanism for photon hormesis.

  7. Paradigm lost, paradigm found: The re-emergence of hormesis as a fundamental dose response model in the toxicological sciences

    Energy Technology Data Exchange (ETDEWEB)

    Calabrese, Edward J. [Environmental Health Sciences, School of Public Health, Morrill I, N344, University of Massachusetts, Amherst, MA 01003 (United States)]. E-mail: edwardc@schoolph.umass.edu

    2005-12-15

    This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted. - The quantitative features of the hormetic dose/response are described and placed within the context of toxicology.

  8. Historical blunders: how toxicology got the dose-response relationship half right.

    Science.gov (United States)

    Calabrese, E J

    2005-12-14

    Substantial evidence indicates that reliable examples of hormetic dose responses in the toxicological literature are common and generalizable across biological model, endpoint measured and chemical class. Further evaluation revealed that the hormetic dose response model is more common than the threshold dose response model in objective, head-to-head comparisons. Nonetheless, the field of toxicology made a profound error by rejecting the use of the hormetic dose response model in its teaching, research, risk assessment and regulatory activities over nearly the past century. This paper argues that the hormetic dose response model (formerly called the Arndt-Schulz Law) was rejected principally because of its close historical association with the medical practice of homeopathy as a result of the prolonged and bitter feud between traditional medicine and homeopathy. Opponents of the concept of hormesis, making use of strong appeals to authority, were successful in their misrepresentation of the scientific foundations of hormesis and in their unfair association of it with segments of the homeopathic movement with extreme and discreditable views. These misrepresentations became established and integrated within the pharmacology and toxicology communities as a result of their origins in and continuities with traditional medicine and subsequently profoundly impacted a broad range of governmental risk assessment activities further consolidating the rejection of hormesis. This error of judgment was reinforced by toxicological hazard assessment methods using only high and few doses that were unable to assess hormetic responses, statistical modeling processes that were constrained to deny the possibility of hormetic dose response relationships and by the modest nature of the hormetic stimulatory response itself, which required more rigorous study designs to evaluate possible hormetic responses.

  9. Dose-response relationships for carcinogens: a review.

    OpenAIRE

    Zeise, L; Wilson, R.; Crouch, E A

    1987-01-01

    We review the experimental evidence for various shapes of dose-response relationships for carcinogens and summarize those experiments that give the most information on relatively low doses. A brief review of some models is given to illustrate the shapes of dose-response curve expected from them. Our major interest is in the use of dose-response relationships to estimate risks to humans at low doses, and so we pay special attention to experimentally observed and theoretically expected nonlinea...

  10. Defining hormesis: evaluation of a complex concentration response phenomenon.

    Science.gov (United States)

    Kendig, Eric L; Le, Hoa H; Belcher, Scott M

    2010-01-01

    Hormesis describes dose-response relationships characterized by a reversal of response between low and high doses of chemicals, biological molecules, physical stressors, or other initiators of a response. Acceptance of hormesis as a viable dose-response theory has been limited until recently, in part, because of poor conceptual understanding, ad hoc and inappropriate use, and lack of a defined mechanism. By examining the history of this dose-response theory, it is clear that both pharmacological and toxicological studies provide evidence for hormetic dose responses, but retrospective examination of studies can be problematic at best. Limited scientific evidence and lack of a common lexicon with which to describe these responses have left hormesis open to inappropriate application to unrelated dose-response relationships. Future studies should examine low-dose effects using unbiased, descriptive criteria to further the scientific understanding of this dose response. A clear, concise definition is required to further the limited scientific evidence for hormetic dose responses.

  11. Historical foundations of hormesis.

    Science.gov (United States)

    Calabrese, Edward J

    2015-04-01

    The present paper provides an historical assessment of the concept of hormesis and its relationship to homeopathy and modern medicine. It is argued that the dose-response concept was profoundly influenced by the conflict between homeopathy and traditional medicine and that decisions on which dose-response model to adopt were not based on "science" but rater on historical antipathies. While the historical dispute between homeopathy and traditional medicine has long since subsided, their impact upon the field has been enduring and generally unappreciated, profoundly adversely affecting current drug development, therapeutic strategies and environmental risk assessment strategies and policies.

  12. Curious cases: Altered dose-response relationships in addiction genetics.

    Science.gov (United States)

    Uhl, George R; Drgonova, Jana; Hall, F Scott

    2014-03-01

    Dose-response relationships for most addictive substances are "inverted U"-shaped. Addictive substances produce both positive features that include reward, euphoria, anxiolysis, withdrawal-relief, and negative features that include aversion, dysphoria, anxiety and withdrawal symptoms. A simple model differentially associates ascending and descending limbs of dose-response curves with rewarding and aversive influences, respectively. However, Diagnostic and Statistical Manual (DSM) diagnoses of substance dependence fail to incorporate dose-response criteria and don't directly consider balances between euphoric and dysphoric drug effects. Classical genetic studies document substantial heritable influences on DSM substance dependence. Linkage and genome-wide association studies identify modest-sized effects at any locus. Nevertheless, clusters of SNPs within selected genes display 10(-2)>p>10(-8) associations with dependence in many independent samples. For several of these genes, evidence for cis-regulatory, level-of-expression differences supports the validity of mouse models in which levels of expression are also altered. This review documents surprising, recently defined cases in which convergent evidence from humans and mouse models supports central influences of altered dose-response relationships in mediating the impact of relevant genomic variation on addiction phenotypes. For variation at loci for the α5 nicotinic acetylcholine receptor, cadherin 13, receptor type protein tyrosine phosphatase Δ and neuronal cell adhesion molecule genes, changed dose-response relationships conferred by gene knockouts in mice are accompanied by supporting human data. These observations emphasize desirability of carefully elucidating dose-response relationships for both rewarding and aversive features of abused substances wherever possible. They motivate consideration of individual differences in dose-response relationships in addiction nosology and therapeutics.

  13. Radiation Dose-Response Relationships and Risk Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Strom, Daniel J.

    2005-07-05

    The notion of a dose-response relationship was probably invented shortly after the discovery of poisons, the invention of alcoholic beverages, and the bringing of fire into a confined space in the forgotten depths of ancient prehistory. The amount of poison or medicine ingested can easily be observed to affect the behavior, health, or sickness outcome. Threshold effects, such as death, could be easily understood for intoxicants, medicine, and poisons. As Paracelsus (1493-1541), the 'father' of modern toxicology said, 'It is the dose that makes the poison.' Perhaps less obvious is the fact that implicit in such dose-response relationships is also the notion of dose rate. Usually, the dose is administered fairly acutely, in a single injection, pill, or swallow; a few puffs on a pipe; or a meal of eating or drinking. The same amount of intoxicants, medicine, or poisons administered over a week or month might have little or no observable effect. Thus, before the discovery of ionizing radiation in the late 19th century, toxicology ('the science of poisons') and pharmacology had deeply ingrained notions of dose-response relationships. This chapter demonstrates that the notion of a dose-response relationship for ionizing radiation is hopelessly simplistic from a scientific standpoint. While useful from a policy or regulatory standpoint, dose-response relationships cannot possibly convey enough information to describe the problem from a quantitative view of radiation biology, nor can they address societal values. Three sections of this chapter address the concepts, observations, and theories that contribute to the scientific input to the practice of managing risks from exposure to ionizing radiation. The presentation begins with irradiation regimes, followed by responses to high and low doses of ionizing radiation, and a discussion of how all of this can inform radiation risk management. The knowledge that is really needed for prediction of

  14. Linearity of dose-response relationships for human carcinogenic exposures

    Energy Technology Data Exchange (ETDEWEB)

    Smith, A.H. (Univ. of California, Berkeley (USA))

    The shape of dose-response relationships is a critical factor in considering cancer risks for the work place and environmental exposure to carcinogens. Markedly different risk estimates result from assumptions of linearity versus sublinear and threshold assumptions. This paper presents evidence that the relationship between the relative risk of development of cancer and the dose rate to carcinogenic exposures is frequently linear with no evidence for thresholds. Dose-response relationships from four studies of asbestos and lung cancer were examined, all of which were consistent with a linear relationship. Analysis of the relationship between the relative risk of lung cancer and exposure to nickel in a smelter study, selected because of relatively good exposure data, demonstrated a close agreement with a linear relationship. The relationship between the level of arsenic in drinking wter and the prevalence of skin cancer also was linear for males in the highest prevalence age group in Taiwan, although there was some evidence of sublinearity for females and younger persons. Also, the relationships between the number of cigarettes smoked per day and the relative risk of lung cancer was very close to linear in many studies. The analysis of these and other studies involving human exposure to carcinogens provides empirical evidence for linearity when the response variable is a rate ratio measure, rather than a risk difference measure. Linearity in dose-response is biologically plausible, without invoking a one-hit model. Except in special circumstances. the epidemiological evidence supports linear extrapolation of cancer relative risks.

  15. Using machine learning to model dose-response relationships.

    Science.gov (United States)

    Linden, Ariel; Yarnold, Paul R; Nallamothu, Brahmajee K

    2016-12-01

    Establishing the relationship between various doses of an exposure and a response variable is integral to many studies in health care. Linear parametric models, widely used for estimating dose-response relationships, have several limitations. This paper employs the optimal discriminant analysis (ODA) machine-learning algorithm to determine the degree to which exposure dose can be distinguished based on the distribution of the response variable. By framing the dose-response relationship as a classification problem, machine learning can provide the same functionality as conventional models, but can additionally make individual-level predictions, which may be helpful in practical applications like establishing responsiveness to prescribed drug regimens. Using data from a study measuring the responses of blood flow in the forearm to the intra-arterial administration of isoproterenol (separately for 9 black and 13 white men, and pooled), we compare the results estimated from a generalized estimating equations (GEE) model with those estimated using ODA. Generalized estimating equations and ODA both identified many statistically significant dose-response relationships, separately by race and for pooled data. Post hoc comparisons between doses indicated ODA (based on exact P values) was consistently more conservative than GEE (based on estimated P values). Compared with ODA, GEE produced twice as many instances of paradoxical confounding (findings from analysis of pooled data that are inconsistent with findings from analyses stratified by race). Given its unique advantages and greater analytic flexibility, maximum-accuracy machine-learning methods like ODA should be considered as the primary analytic approach in dose-response applications. © 2016 John Wiley & Sons, Ltd.

  16. Dose response relationship in local radiotherapy for hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hee Chul; Seong, Jin Sil; Han, Kwang Hyub; Chon, Chae Yoon; Moon, Young Myoung; Song, Jae Seok; Suh, Chang Ok [College of Medicine, Yonsei Univ., Seoul (Korea, Republic of)

    2001-06-01

    In this study, it was investigated whether dose response relation existed or not in local radiotherapy for primary hepatocellular carcinoma. From January 1992 to March 2000, 158 patients were included in present study. Exclusion criteria included the presence of extrahepatic metastasis, liver cirrhosis of Child's class C, tumors occupying more than two thirds of the entire liver, and performance status on the ECOG scale of more than 3. Radiotherapy was given to the field including tumor with generous margin using 6, 10-MV X-ray. Mean tumor dose was 48.2{+-}7.9 Gy in daily 1.8 Gy fractions. Tumor response was based on diagnostic radiologic examinations such as CT scan, MR imaging, hepatic artery angiography at 4-8 weeks following completion of treatment. Statistical analysis was done to investigate the existence of dose response relationship of local radiotherapy when it was applied to the treatment of primary hepatocellular carcinoma. An objective response was observed in 106 of 158 patients, giving a response rate of 67. 1%. Statistical analysis revealed that total dose was the most significant factor in relation to tumor response when local radiotherapy was applied to the treatment of primary hepatocellular carcinoma. Only 29.2% showed objective response in patients treated with dose less than 40 Gy, while 68.6% and 77.1 % showed major response in patients with 40-50 Gy and more than 50 Gy, respectively. Child-Pugh classification was significant factor in the development of ascites, overt radiation induced liver disease and gastroenteritis. Radiation dose was an important factor for development of radiation induced gastroduodenal ulcer. Present study showed the existence of dose response relationship in local radiotherapy for primary hepatocellular carcinoma. Only radiotherapy dose was a significant factor to predict the objective response. Further study is required to predict the maximal tolerance dose in consideration of liver function and non

  17. Confidence bounds for nonlinear dose-response relationships.

    Science.gov (United States)

    Baayen, C; Hougaard, P

    2015-11-30

    An important aim of drug trials is to characterize the dose-response relationship of a new compound. Such a relationship can often be described by a parametric (nonlinear) function that is monotone in dose. If such a model is fitted, it is useful to know the uncertainty of the fitted curve. It is well known that Wald confidence intervals are based on linear approximations and are often unsatisfactory in nonlinear models. Apart from incorrect coverage rates, they can be unreasonable in the sense that the lower confidence limit of the difference to placebo can be negative, even when an overall test shows a significant positive effect. Bootstrap confidence intervals solve many of the problems of the Wald confidence intervals but are computationally intensive and prone to undercoverage for small sample sizes. In this work, we propose a profile likelihood approach to compute confidence intervals for the dose-response curve. These confidence bounds have better coverage than Wald intervals and are more precise and generally faster than bootstrap methods. Moreover, if monotonicity is assumed, the profile likelihood approach takes this automatically into account. The approach is illustrated using a public dataset and simulations based on the Emax and sigmoid Emax models. Copyright © 2015 John Wiley & Sons, Ltd.

  18. Insecticide-induced hormesis and arthropod pest management.

    Science.gov (United States)

    Guedes, Raul Narciso C; Cutler, G Christopher

    2014-05-01

    Ecological backlashes such as insecticide resistance, resurgence and secondary pest outbreaks are frequent problems associated with insecticide use against arthropod pest species. The last two have been particularly important in sparking interest in the phenomenon of insecticide-induced hormesis within entomology and acarology. Hormesis describes a biphasic dose-response relationship that is characterized by a reversal of response between low and high doses of a stressor (e.g. insecticides). Although the concept of insecticide-induced hormesis often does not receive sufficient attention, or has been subject to semantic confusion, it has been reported in many arthropod pest species and natural enemies, and has been linked to pest outbreaks and potential problems with insecticide resistance. The study of hormesis remains largely neglected in entomology and acarology. Here, we examined the concept of insecticide-induced hormesis in arthropods, its functional basis and potential fitness consequences, and its importance in arthropod pest management and other areas.

  19. Dose-response relationship in multistage carcinogenesis: promoters.

    OpenAIRE

    Kitchin, K T; Brown, J. L.; Setzer, R.W.

    1994-01-01

    Published dose-response curves of promoters of multistage carcinogenesis were selected that met the combined criteria of long study times, multiple doses, and low doses. In rat liver, 12 dose-response studies of 7 different promoters (phenobarbital, 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], clophen A-50 (a polychlorinated biphenyl), alpha-, beta-, and gamma-hexachlorocyclohexane [HCH], and chloroform) were selected. These promoters were studied for 7-86 weeks and either altered hepatic foci...

  20. Cardiac dose-response relationships of oral and intravenous pindolol

    OpenAIRE

    Carruthers, S. George

    1982-01-01

    1 The dose-response curve of pindolol on exercise heart rate has been constructed from observations in healthy male subjects studied 2 h after oral doses of pindolol 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg and 20 mg. This dose-response curve has been compared with historical controls who received atenolol, oxprenolol, practolol, propranolol and sotalol.

  1. Chronic periodontitis and smoking Prevalence and dose-response relationship

    Science.gov (United States)

    Khan, Shahrukh; Khalid, Taimur; Awan, Kamran H.

    2016-01-01

    Objectives: To determine the prevalence and dose-response relationship of chronic periodontitis among smokers in Pakistan. Methods: This is a cross-sectional study among participants seeking dental care in Karachi Medical and Dental College, Karachi, Pakistan. A total of 443 participants with a mean age of 44.3 (±6.5) participated in the study from April 2011 to December 2011. Males comprised 64.7%, and females comprised 35.2%. Participants were interviewed on social demographics and oral habits. Participants with shallow pockets (3.5-5.5 mm) and deep pockets (>5.5 mm) were considered suffering from chronic periodontitis. The characteristics of participants were assessed using frequency distribution for categorical variables and mean (standard deviation) for continuous variables. Results: Among 443 participants, smokers were distributed as 55.1% and non-smokers as 44.9%. Smoking was found to be significantly related to young adults (p<0.007), male gender (p<0.001), and lower education level (p<0.01). Overall prevalence of chronic periodontitis among smokers was estimated at 81.6%. Heavy smoking was found to have significantly high prevalence (p<0.001) and severity (p<0.001) of periodontitis as compared with moderate and light smokers. The multivariate unadjusted model depicted 3.5 times higher risk of chronic periodontitis among smokers (p<0.001). Conclusion: Chronic periodontitis had a high prevalence among smokers. Heavy smoking was found to have a higher risk for having periodontitis. PMID:27464867

  2. Dose-response relationships and threshold levels in skin and respiratory allergy

    NARCIS (Netherlands)

    Arts, J.H.E.; Mommers, C.; Heer, C.de

    2006-01-01

    A literature study was performed to evaluate dose-response relationships and no-effect levels for sensitization and elicitation in skin- and respiratory allergy. With respect to the skin, dose-response relationships and no-effect levels were found for both intradermal and topical induction, as well

  3. Health damage of air pollution : an estimate of a dose-response relationship for The Netherlands

    NARCIS (Netherlands)

    Nentjes, A; Schneider, T

    1998-01-01

    This paper estimates the dose-response relationship between air pollution and the number of work loss days for The Netherlands. The study is based on illness data (work loss days) for the Dutch labor population and average year concentrations of air pollution in 29 districts. The dose-response

  4. Confidence bounds for nonlinear dose-response relationships

    DEFF Research Database (Denmark)

    Baayen, C; Hougaard, P

    2015-01-01

    . It is well known that Wald confidence intervals are based on linear approximations and are often unsatisfactory in nonlinear models. Apart from incorrect coverage rates, they can be unreasonable in the sense that the lower confidence limit of the difference to placebo can be negative, even when an overall...... test shows a significant positive effect. Bootstrap confidence intervals solve many of the problems of the Wald confidence intervals but are computationally intensive and prone to undercoverage for small sample sizes. In this work, we propose a profile likelihood approach to compute confidence...... intervals for the dose-response curve. These confidence bounds have better coverage than Wald intervals and are more precise and generally faster than bootstrap methods. Moreover, if monotonicity is assumed, the profile likelihood approach takes this automatically into account. The approach is illustrated...

  5. Bayesian Dose-Response Modeling in Sparse Data

    Science.gov (United States)

    Kim, Steven B.

    This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a

  6. Concord grape juice polyphenols and cardiovascular risk factors: dose-response relationships

    Science.gov (United States)

    Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship ...

  7. Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships

    Directory of Open Access Journals (Sweden)

    Jeffrey B. Blumberg

    2015-12-01

    Full Text Available Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid content in the context of results from randomized clinical trials of other polyphenol-rich foods and beverages describing the same outcomes but covering a broader range of intake. We selected established biomarkers determined by similar methods for measuring flow-mediated vasodilation (FMD, blood pressure, platelet aggregation, and the resistance of low density lipoprotein cholesterol (LDL to oxidation. Despite differences among the clinical trials in the treatment, subjects, and duration, correlations were observed between the dose and FMD. Inverse dose-response relationships, albeit with lower correlation coefficients, were also noted for the other outcomes. These results suggest a clear relationship between consumption of even modest serving sizes of Concord grape juice, flavonoid intake, and effects on risk factors for cardiovascular disease. This approach to dose-response relationships may prove useful for testing other individual foods and beverages.

  8. Exploring the dose-response relationship between resistance exercise intensity and cognitive function.

    Science.gov (United States)

    Chang, Yu-Kai; Etnier, Jennifer L

    2009-10-01

    The purpose of this study was to explore the dose-response relationship between resistance exercise intensity and cognitive performance. Sixty-eight participants were randomly assigned into control, 40%, 70%, or 100% of 10-repetition maximal resistance exercise groups. Participants were tested on Day 1 (baseline) and on Day 2 (measures were taken relative to performance of the treatment). Heart rate, ratings of perceived exertion, self-reported arousal, and affect were assessed on both days. Cognitive performance was assessed on Day 1 and before and following treatment on Day 2. Results from regression analyses indicated that there is a significant linear effect of exercise intensity on information processing speed, and a significant quadratic trend for exercise intensity on executive function. Thus, there is a dose-response relationship between the intensity of resistance exercise and cognitive performance such that high-intensity exercise benefits speed of processing, but moderate intensity exercise is most beneficial for executive function.

  9. Epidemiological methods for assessing dose-response and dose-effect relationships

    DEFF Research Database (Denmark)

    Kjellström, Tord; Grandjean, Philippe

    2007-01-01

    of the Toxic Effects of Metals Aluminum Antimony Arsenic Barium Beryllium Bismuth Cadmium Chromium Cobalt Copper Gallium and Semiconductor Compounds Germanium Indium Iron Lead Manganese Mercury Molybdenum Nickel Palladium Platinum Selenium Silver Tellurium Thallium Tin Titanium Tungsten Uranium Vanadium Zinc...... and their compounds. An entirely new structure and illustrations represent the vast array of advancements made since the last edition. Special emphasis has been placed on the toxic effects in humans with chapters on the diagnosis, treatment and prevention of metal poisoning. This up-to-date reference provides easy...... Selected Molecular Mechanisms of Metal Toxicity and Carcinogenicity General Considerations of Dose-Effect and Dose-Response Relationships Interactions in Metal Toxicology Epidemiological Methods for Assessing Dose-Response and Dose-Effect Relationships Essential Metals: Assessing Risks from Deficiency...

  10. Perception and annoyance due to wind turbine noise--a dose-response relationship.

    Science.gov (United States)

    Pedersen, Eja; Waye, Kerstin Persson

    2004-12-01

    Installed global wind power increased by 26% during 2003, with U.S and Europe accounting for 90% of the cumulative capacity. Little is known about wind turbines' impact on people living in their vicinity. The aims of this study were to evaluate the prevalence of annoyance due to wind turbine noise and to study dose-response relationships. Interrelationships between noise annoyance and sound characteristics, as well as the influence of subjective variables such as attitude and noise sensitivity, were also assessed. A cross-sectional study was performed in Sweden in 2000. Responses were obtained through questionnaires (n = 351; response rate 68.4%), and doses were calculated as A-weighted sound pressure levels for each respondent. A statistically significant dose-response relationship was found, showing higher proportion of people reporting perception and annoyance than expected from the present dose-response relationships for transportation noise. The unexpected high proportion of annoyance could be due to visual interference, influencing noise annoyance, as well as the presence of intrusive sound characteristics. The respondents' attitude to the visual impact of wind turbines on the landscape scenery was found to influence noise annoyance.

  11. Quantitative structure-activity relationships of selected phenols with non-monotonic dose-response curves

    Institute of Scientific and Technical Information of China (English)

    GAO ChangAn; ZHANG AiQian; LIN Yuan; YIN DaQiang; WANG LianSheng

    2009-01-01

    Particular non-monotonic dose-response curves of many endocrine disrupting chemicals (EDCs) suggest the existence of diverse toxicity mechanisms at different dose levels. As a result, the biologi-cal activities of EDCs cannot be simply exhibited by unique EC/LD<,50. values, and the quantitative structure-activity relationship (QSAR) analysis for non-monotonic dose-response relationship be-comes an unknown field in the environmental science. In this paper, nine phenols with inverted U-shaped dose-response curves in lymphocyte proliferation test of Carassius auratus were selected. The binding interactions between the phenols and several typical EDCs-related receptors were then explored in a molecular simulation study. The estrogen receptor (ER), androgen receptor (AR), thyroid hormone receptor (TR), bacterial O2 sensing FixL protein (FixL), aryl hydrocarbon receptor (AhR), and the peroxisome proliferator-activated receptor (PPAR) were the target receptors in the study. Linear regression QSAR models for the low and high exposure levels of the compounds were developed separately. The results indicated that the lymphocyte proliferation in the low-dose range might involve ER-mediated process, while the proliferation inhibition in the high dose range was dominated by the acute toxicity of phenols due to receptor occupancy and cell damage.

  12. INFLUENCE OF SUCCINYLCHOLINE ON THE DOSE-RESPONSE RELATIONSHIP OF SUBSEQUENTLY ADMINISTERED ROCURONIUN

    Institute of Scientific and Technical Information of China (English)

    陈锡明; 闻大翔; 杭燕南; 孙大金

    2005-01-01

    Objective To investigate the effect of succinylcholine on the dose-response relationship of subsequently administered rocuronium in healthy patients. Methods Forty-eight ASA physical status Ⅰ-Ⅱ patients,aged 17 -65 years, scheduled for elective general surgery, were randomly assigned to either the rocuronium treatment group (R) or succinylcholine-rocuronium treatment group (SR). General anesthesia was induced with thiopental 4 to 6mg/kg and fentanyl 2 to 5μg/kg intravenously and maintained with 60% nitrous oxide in oxygen. Additional doses of thiopental or fentanyl were administered as required. The dose-response relationship of rocuronium was determined by the single dose-response technique. In R group ( n =24) , rocuronium was given after induction of anesthesia. In SR group (n =24 ) , patients were intubated after 1.5mg/kg of succinylcholine and rocuronium was given after the complete recovery of neuromuscular blockade from succinylcholine. Patients were further randomly divided into 4 subgroups receiving 150, 200, 250 or 300μg/kg of rocuronium respectively in both groups. Neuromuscular function was assessed accelographically with train-of-four (TOF) stimulation at the wrist every 12s (using the TOF Guard(R) accelerometer). The relationship between probit-tranformed percentage depression of first twitch height (Th) of train-of-four stimulation and logarithm dose of rocuronium was analyzed using linear regression.Results The dose-response curve of rocuronium after succinylcholine was shifted to the left in a parallel fashion compared with that of rocuronium given alone. ED50 and ED95 of rocuronium were 193 ±69 and 367 ± 73μg/kg respectively in R group, and 158 ± 35 and 317 ± 80μg/kg respectively in SR group ( P < 0. 05 ). Conclusion Succinylcholine shifts the dose-response curve of rocuronium to the left and potentiates the effects of the neuromuscular blockade by about 15% of subsequently administered rocuronium. Lower doses of rocuronium are

  13. Dose-response relationship between periodontal inflamed surface area and HbA1c in type 2 Diabetics

    NARCIS (Netherlands)

    Nesse, Willem; Linde, Annemiek; Abbas, Frank; Spijkervet, Frederik Karst Lucien; Dijkstra, Pieter Ubele; de Brabander, Eric Carl; Gerstenbluth, Izzy; Vissink, Arjan

    2009-01-01

    Nesse W, Linde A, Abbas F, Spijkervet FKL, Dijkstra PU, de Brabander EC, Gerstenbluth I, Vissink A. Dose-response relationship between periodontal inflamed surface area and HbA1c in type 2 diabetics. J Clin Periodontol 2009; 36: 295-300. doi: 10.1111/j.1600-051X.2009.01377.x. A dose-response relatio

  14. Dose-response relationship between periodontal inflamed surface area and HbA1c in type 2 Diabetics

    NARCIS (Netherlands)

    Nesse, Willem; Linde, Annemiek; Abbas, Frank; Spijkervet, Frederik Karst Lucien; Dijkstra, Pieter Ubele; de Brabander, Eric Carl; Gerstenbluth, Izzy; Vissink, Arjan

    Nesse W, Linde A, Abbas F, Spijkervet FKL, Dijkstra PU, de Brabander EC, Gerstenbluth I, Vissink A. Dose-response relationship between periodontal inflamed surface area and HbA1c in type 2 diabetics. J Clin Periodontol 2009; 36: 295-300. doi: 10.1111/j.1600-051X.2009.01377.x. A dose-response

  15. Alanine aminotransferase and risk of the metabolic syndrome: a linear dose-response relationship.

    Directory of Open Access Journals (Sweden)

    Setor K Kunutsor

    Full Text Available BACKGROUND: Elevated baseline circulating alanine aminotransferase (ALT level has been demonstrated to be associated with an increased risk of the metabolic syndrome (MetS, but the nature of the dose-response relationship is uncertain. METHODS: We performed a systematic review and meta-analysis of published prospective cohort studies to characterize in detail the nature of the dose-response relationship between baseline ALT level and risk of incident MetS in the general population. Relevant studies were identified in a literature search of MEDLINE, EMBASE, and Web of Science up to December 2013. Prospective studies in which investigators reported relative risks (RRs of MetS for 3 or more categories of ALT levels were eligible. A potential nonlinear relationship between ALT levels and MetS was examined using restricted cubic splines. RESULTS: Of the 489 studies reviewed, relevant data were available on 29,815 non-overlapping participants comprising 2,125 incident MetS events from five prospective cohort studies. There was evidence of a linear association (P for nonlinearity=0.38 between ALT level and risk of MetS, characterised by a graded increase in MetS risk at ALT levels 6-40 U/L. The risk of MetS increased by 14% for every 5 U/L increment in circulating ALT level (95% CI: 12-17%. Evidence was lacking of heterogeneity and publication bias among the contributing studies. CONCLUSIONS: Baseline ALT level is associated with risk of the MetS in a linear dose-response manner. Studies are needed to determine whether the association represents a causal relationship.

  16. Dose-response relationship between physical activity and dyslipidemia in youth.

    Science.gov (United States)

    LeBlanc, Allana G; Janssen, Ian

    2010-01-01

    The minimal and optimal amount of physical activity associated with cardiovascular health benefits in young people is unknown. To determine the dose-response relationship between moderate-to-vigorous physical activity (MVPA) with high-risk low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride values in youth. The study sample consisted of 1235 adolescents (12 to 19 years of age) from the 20032004 and 20052006 cycles of the United States National Health and Nutrition Examination Survey. Objective measures of MVPA were obtained over seven days with accelerometers. LDL cholesterol, HDL cholesterol and triglycerides were measured from a fasting blood sample. High-risk values for these lipidslipoproteins were determined using age- and sex-specific thresholds. Logistic regression models were used to determine the dose-response relationships between MVPA and high-risk lipid levels. ORs for high-risk HDL cholesterol and triglyceride values decreased in a curvilinear manner with increasing minutes of MVPA. Compared with no MVPA (0 min), the ORs for high-risk HDL cholesterol values at 15 min, 30 min and 60 min per day of MVPA were 0.29 (95% CI 0.13 to 0.67), 0.24 (95% CI 0.10 to 0.64) and 0.21 (95% CI 0.07 to 0.61), respectively. The corresponding ORs for high-risk triglyceride values were 0.40 (95% CI 0.18 to 0.76), 0.22 (95% CI 0.06 to 0.66) and 0.10 (95% CI 0.01 to 0.51). There was no discernible dose-response relationship between MVPA and LDL cholesterol. Small amounts of MVPA were associated with a large reduction in the likelihood of having high-risk HDL cholesterol and triglyceride values in this representative sample of adolescents.

  17. The dose-response relationship for cardiovascular disease is not necessarily linear.

    Science.gov (United States)

    Schneider, Uwe; Ernst, Marina; Hartmann, Matthias

    2017-04-27

    The probability for a complication after radiotherapy is usually a function of dose and volume in the organ or tissue of interest. In most epidemiological studies the risk for a complication is stratified in terms of dose, but not irradiated volume. We show that the obtained risk cannot generally be applied to radiotherapy patients.The epidemiological data of Darby et al. (N Engl J Med 368:2527, 2013) who found a linear relationship between the excess relative risk of major coronary events as function of mean heart dose in patients treated with tangential breast irradiation are analyzed. We have used the relative seriality model for a partly irradiated heart ("a lot to a little") which models radiation therapy using two tangential fields. The relative seriality model was then used to predict NTCP of cardiovascular disease for a homogenously irradiated heart ("a little to a lot"). The relative seriality model was fitted to the data of Darby et al. (N Engl J Med 368:2527, 2013) for tangential breast irradiation. For the situation "a little to a lot" it was found that the dose-response relationship is sigmoidal and contradicts the findings of Darby et al. (N Engl J Med 368:2527, 2013). It was shown in this work that epidemiological studies which predict a linear dose-response relationship for cardiovascular disease can be reproduced by bio-physical models for normal tissue complication. For irradiation situations which were not included in the epidemiological studies, e.g. a homogenous irradiation of the heart ("a little to a lot") the dose-response curve can be different. This could have consequences whether or not IMRT should be used for treating breast cancer. We believe that the results of epidemiological studies should not be generally used to predict normal tissue complications. It is better to use such data to optimize bio-physical models which can then be applied (with caution) to general treatment situations.

  18. Hormesis: why it is important to biogerontologists.

    Science.gov (United States)

    Calabrese, Edward J; Iavicoli, Ivo; Calabrese, Vittorio

    2012-06-01

    This paper offers a broad assessment of the hormetic dose response and its relevance to biogerontology. The paper provides detailed background information on the historical foundations of hormesis, its quantitative features, mechanistic foundations, as well as how the hormesis concept could be further applied in the development of new therapeutic advances in the treatment of age-related diseases. The concept of hormesis has direct application to biogerontology not only affecting the quality of the aging process but also experimental attempts to extend longevity.

  19. The dose-response relationship between in-ear occupational noise exposure and hearing loss.

    Science.gov (United States)

    Rabinowitz, Peter M; Galusha, Deron; Dixon-Ernst, Christine; Clougherty, Jane E; Neitzel, Richard L

    2013-10-01

    Current understanding of the dose-response relationship between occupational noise and hearing loss is based on cross-sectional studies prior to the widespread use of hearing protection, and with limited data regarding noise exposures below 85 dBA. We report on the hearing loss experience of a unique cohort of industrial workers, with daily monitoring of noise inside of hearing protection devices. At an industrial facility, workers exhibiting accelerated hearing loss were enrolled in a mandatory programme to monitor daily noise exposures inside of hearing protection. We compared these noise measurements (as time-weighted LAVG) to interval rates of high-frequency hearing loss over a 6-year period using a mixed-effects model, adjusting for potential confounders. Workers' high-frequency hearing levels at study inception averaged more than 40 dB Hearing threshold level (HTL). Most noise exposures were less than 85 dBA (mean LAVG 76 dBA, IQR 74-80 dBA). We found no statistical relationship between LAvg and high-frequency hearing loss (p=0.53). Using a metric for monthly maximum noise exposure did not improve model fit. At-ear noise exposures below 85 dBA did not show an association with risk of high-frequency hearing loss among workers with substantial past noise exposure and hearing loss at baseline. Therefore, effective noise control to below 85 dBA may lead to significant reduction in occupational hearing loss risk in such individuals. Further research is needed on the dose-response relationship of noise and hearing loss in individuals with normal hearing and little prior noise exposure.

  20. Mass shootings: a meta-analysis of the dose-response relationship.

    Science.gov (United States)

    Wilson, Laura C

    2014-12-01

    A meta-analysis was conducted to examine the dose-response theory as it relates to posttraumatic stress symptoms (PTSSs) following mass shootings. It was hypothesized that greater exposure to a mass shooting would be associated with greater PTSSs. Trauma exposure in the current study was broadly defined as the extent to which a person experienced or learned about a mass shooting. The meta-analysis identified 11 qualifying studies that included 13 independent effect sizes from a total of 8,047 participants. The overall weighted mean effect size, based on a random effects model, was r = .19, p < .001, 95% CI [.13, .25]. Maximum likelihood meta-regressions revealed no significant linear effects of participant gender, participant age, or time elapsed since the shooting on the relationship between exposure and PTSSs. Because so few studies satisfied the inclusion criteria, the present study also documents that this area of the literature is underresearched.

  1. New flux based dose-response relationships for ozone for European forest tree species.

    Science.gov (United States)

    Büker, P; Feng, Z; Uddling, J; Briolat, A; Alonso, R; Braun, S; Elvira, S; Gerosa, G; Karlsson, P E; Le Thiec, D; Marzuoli, R; Mills, G; Oksanen, E; Wieser, G; Wilkinson, M; Emberson, L D

    2015-11-01

    To derive O3 dose-response relationships (DRR) for five European forest trees species and broadleaf deciduous and needleleaf tree plant functional types (PFTs), phytotoxic O3 doses (PODy) were related to biomass reductions. PODy was calculated using a stomatal flux model with a range of cut-off thresholds (y) indicative of varying detoxification capacities. Linear regression analysis showed that DRR for PFT and individual tree species differed in their robustness. A simplified parameterisation of the flux model was tested and showed that for most non-Mediterranean tree species, this simplified model led to similarly robust DRR as compared to a species- and climate region-specific parameterisation. Experimentally induced soil water stress was not found to substantially reduce PODy, mainly due to the short duration of soil water stress periods. This study validates the stomatal O3 flux concept and represents a step forward in predicting O3 damage to forests in a spatially and temporally varying climate.

  2. The Shape of the Dose-Response Relationship between Sugars and Caries in Adults.

    Science.gov (United States)

    Bernabé, E; Vehkalahti, M M; Sheiham, A; Lundqvist, A; Suominen, A L

    2016-02-01

    Dental caries is considered a diet-mediated disease, as sugars are essential in the caries process. However, some gaps in knowledge about the sugars-caries relationship still need addressing. This longitudinal study aimed to explore 1) the shape of the dose-response association between sugars intake and caries in adults, 2) the relative contribution of frequency and amount of sugars intake to caries levels, and 3) whether the association between sugars intake and caries varies by exposure to fluoride toothpaste. We used data from 1,702 dentate adults who participated in at least 2 of 3 surveys in Finland (Health 2000, 2004/05 Follow-up Study of Adults' Oral Health, and Health 2011). Frequency and amount of sugars intake were measured with a validated food frequency questionnaire. The DMFT index was the repeated outcome measure. Data were analyzed with fractional polynomials and linear mixed effects models. None of the 43 fractional polynomials tested provided a better fit to the data than the simpler linear model. In a mutually adjusted linear mixed effects model, the amount of, but not the frequency of, sugars intake was significantly associated with DMFT throughout the follow-up period. Furthermore, the longitudinal association between amount of sugars intake and DMFT was weaker in adults who used fluoride toothpaste daily than in those using it less often than daily. The findings of this longitudinal study among Finnish adults suggest a linear dose-response relationship between sugars and caries, with amount of intake being more important than frequency of ingestion. Also, daily use of fluoride toothpaste reduced but did not eliminate the association between amount of sugars intake and dental caries.

  3. Dose-response relationship for breast cancer induction at radiotherapy dose

    Directory of Open Access Journals (Sweden)

    Gruber Günther

    2011-06-01

    Full Text Available Abstract Purpose Cancer induction after radiation therapy is known as a severe side effect. It is therefore of interest to predict the probability of second cancer appearance for the patient to be treated including breast cancer. Materials and methods In this work a dose-response relationship for breast cancer is derived based on (i the analysis of breast cancer induction after Hodgkin's disease, (ii a cancer risk model developed for high doses including fractionation based on the linear quadratic model, and (iii the reconstruction of treatment plans for Hodgkin's patients treated with radiotherapy, (iv the breast cancer induction of the A-bomb survivor data. Results The fitted model parameters for an α/β = 3 Gy were α = 0.067Gy-1 and R = 0.62. The risk for breast cancer is according to this model for small doses consistent with the finding of the A-bomb survivors, has a maximum at doses of around 20 Gy and drops off only slightly at larger doses. The predicted EAR for breast cancer after radiotherapy of Hodgkin's disease is 11.7/10000PY which can be compared to the findings of several epidemiological studies where EAR for breast cancer varies between 10.5 and 29.4/10000PY. The model was used to predict the impact of the reduction of radiation volume on breast cancer risk. It was estimated that mantle field irradiation is associated with a 3.2-fold increased risk compared with mediastinal irradiation alone, which is in agreement with a published value of 2.7. It was also shown that the modelled age dependency of breast cancer risk is in satisfying agreement with published data. Conclusions The dose-response relationship obtained in this report can be used for the prediction of radiation induced secondary breast cancer of radiotherapy patients.

  4. Youth suicide attempts and the dose-response relationship to parental risk factors: a population-based study

    DEFF Research Database (Denmark)

    Christiansen, E; Goldney, R D; Beautrai, A L;

    2011-01-01

    illness and low level of income were all significant independent risk factors for offspring's suicide attempts. CONCLUSIONS: Knowledge of the effect of multiple risk factors on the likelihood of suicide attempts in children and adolescents is important for risk assessment. Dose-response effects......BACKGROUND: There is a lack of specific knowledge about the dose-response effect of multiple parental risk factors for suicide attempts among children and adolescents. The aim of this study was to determine the dose-response effect of multiple parental risk factors on an offspring's risk...... to each case and a link to the offspring's biological parents was established. RESULTS: There was a dose-response relationship between the number of exposures and the risk of suicide attempts, with the increased risk seeming to be a multiplicative effect. Parental suicide, suicide attempt, psychiatric...

  5. Herbicide hormesis to segregate a weed population? – A case study with Tripleurospermum perforatum (Mérat Lainz

    Directory of Open Access Journals (Sweden)

    Belz, Regina G.

    2016-02-01

    Full Text Available Weed populations feature within-population genetic differences. Thus, evaluating mean responses in herbicide treated populations may miss ecologically significant individual responses. Since hormesis can likewise vary between individuals, this study investigated the hypothesis that herbicide hormesis within a high-density weed population is different among slowly-growing individuals, as compared to fast-growing individuals. In a dose-response experiment, Tripleurospermum perforatum (Mérat Lainz was exposed to 12 doses of Atlantis WG (mesosulfuron + iodosulfuron in 24 replicates (50 plants/replicate. Root/shoot growth responses were evaluated as dose-response relationships for the population mean, the 90-97th percentile of the population (fast-growing individuals, and the 5-10th percentile (slow-growing individuals. Growth responses were generally biphasic. Slow-growing individuals had more pronounced hormesis that occurred partially at lower doses as compared to the population mean. With fast-growing individuals, hormesis was instead less pronounced and partially shifted to higher doses. Hence, hormesis was primarily associated with a stimulation of slow-growing individuals, while fast-growing individuals contributed to a lesser extent to the hormetic population response in a dense stand in vitro. This discrepancy may have the potential to segregate an herbicide exposed population and alter its sensitivity in the long-run.

  6. An alternate method for estimating the dose-response relationships of neuromuscular blocking drugs.

    Science.gov (United States)

    Kopman, A F; Klewicka, M M; Neuman, G G

    2000-05-01

    Slopes of the dose-response relationships for all available neuromuscular blocking drugs appear to be essentially parallel and to approximate a log-dose/logit value of 4.75. We tested the possibility of estimating both 50% effective dose (ED(50)) and 95% effective dose (ED(95)) values from a single dose-response data point when that slope is postulated. We compared the ED(50) and ED(95) values of rocuronium and succinylcholine calculated by using traditional log-dose/logit regression analysis with the same values obtained by averaging individual estimates of potency as determined by using the Hill equation. After the induction of anesthesia (propofol/alfentanil), tracheal intubation was accomplished without the administration of neuromuscular blocking drugs. Anesthesia was maintained with nitrous oxide and propofol. The evoked electromyographic response to 0.10-Hz single stimuli was continuously recorded. After baseline stabilization, a single IV bolus of succinylcholine (0.08-0.26 mg/kg, n = 50) or rocuronium (0. 13-0.30 mg/kg, n = 40) was administered and the peak effect noted. By using log-dose/logit regression analysis, we calculated ED(50) and ED(95) values for rocuronium of 0.17 and 0.33 mg/kg and 0.14 and 0.27 mg/kg for succinylcholine. When potency was calculated from the Hill equation, the resultant ED(50) and ED(95) values did not differ by more than +/-4% from those obtained by using regression analysis. Averaging of single-dose estimates of neuromuscular potency provides a useful adjunct and reasonable alternative to conventional regression analysis.

  7. Dose-response relationships using brain-computer interface technology impact stroke rehabilitation.

    Science.gov (United States)

    Young, Brittany M; Nigogosyan, Zack; Walton, Léo M; Remsik, Alexander; Song, Jie; Nair, Veena A; Tyler, Mitchell E; Edwards, Dorothy F; Caldera, Kristin; Sattin, Justin A; Williams, Justin C; Prabhakaran, Vivek

    2015-01-01

    Brain-computer interfaces (BCIs) are an emerging novel technology for stroke rehabilitation. Little is known about how dose-response relationships for BCI therapies affect brain and behavior changes. We report preliminary results on stroke patients (n = 16, 11 M) with persistent upper extremity motor impairment who received therapy using a BCI system with functional electrical stimulation of the hand and tongue stimulation. We collected MRI scans and behavioral data using the Action Research Arm Test (ARAT), 9-Hole Peg Test (9-HPT), and Stroke Impact Scale (SIS) before, during, and after the therapy period. Using anatomical and functional MRI, we computed Laterality Index (LI) for brain activity in the motor network during impaired hand finger tapping. Changes from baseline LI and behavioral scores were assessed for relationships with dose, intensity, and frequency of BCI therapy. We found that gains in SIS Strength were directly responsive to BCI therapy: therapy dose and intensity correlated positively with increased SIS Strength (p ≤ 0.05), although no direct relationships were identified with ARAT or 9-HPT scores. We found behavioral measures that were not directly sensitive to differences in BCI therapy administration but were associated with concurrent brain changes correlated with BCI therapy administration parameters: therapy dose and intensity showed significant (p ≤ 0.05) or trending (0.05 stroke rehabilitation, therapy frequency may be less important than dose and intensity.

  8. A method to adjust radiation dose-response relationships for clinical risk factors

    DEFF Research Database (Denmark)

    Appelt, Ane Lindegaard; Vogelius, Ivan R

    2012-01-01

    Several clinical risk factors for radiation induced toxicity have been identified in the literature. Here, we present a method to quantify the effect of clinical risk factors on radiation dose-response curves and apply the method to adjust the dose-response for radiation pneumonitis for patients...

  9. Structured Development and Promotion of a Research Field: Hormesis in Biology, Toxicology, and Environmental Regulatory Science.

    Science.gov (United States)

    Mushak, Paul; Elliott, Kevin C

    2015-12-01

    The ability of powerful and well-funded interest groups to steer scientific research in ways that advance their goals has become a significant social concern. This steering ability is increasingly being recognized in the peer-reviewed scientific literature and in findings of deliberative scientific bodies. This paper provides a case study that illustrates some of the major strategies that can be used to structure and advance a controversial research field. It focuses on hormesis, described as a type of dose-response relationship in toxicology and biology showing low-dose stimulation but high-dose inhibition, or the reverse. Hormesis proponents tout its significance, arguing that substances toxic at high doses and beneficial at lower doses should be regulated less stringently. We identify five strategies employed by hormesis proponents to foster its acceptance: (1) creating institutions focused on supporting hormesis; (2) developing terminology, study designs, and data interpretations that cast it in a favorable light; (3) using bibliometric techniques and surveys to attract attention; (4) aggressively advocating for the phenomenon and challenging critics; and (5) working with outside interest groups to apply the hormesis phenomenon in the economic and political spheres. We also suggest a number of oversight strategies that can be implemented to help promote credible and socially responsible research in cases like this one.

  10. Dose - response relationship between noise exposure and the risk of occupational injury

    Directory of Open Access Journals (Sweden)

    Jin-Ha Yoon

    2015-01-01

    Full Text Available Many workers worldwide experience fatality and disability caused by occupational injuries. This study examined the relationship between noise exposure and occupational injuries at factories in Korea. A total of 1790 factories located in northern Gyeonggi Province, Korea was evaluated. The time-weighted average levels of dust and noise exposure were taken from Workplace Exposure Assessment data. Apart occupational injuries, sports events, traffic accidents, and other accidents occurring outside workplaces were excluded. The incidences of occupational injury in each factory were calculated by data from the Korea Workers′ Compensation and Welfare Services. Workplaces were classified according to the incidence of any occupational injuries (incident or nonincident workplaces, respectively. Workplace dust exposure was classified as 90 dB. Workplaces with high noise exposure were significantly associated with being incident workplaces, whereas workplaces with high dust exposure were not. The odds ratios (95% confidence intervals derived from a logistic regression model were 1.68 (1.27-2.24 and 3.42 (2.26-5.17 at 80-89 dB and ≥90 dB versus <80 dB. These associations remained significant when in a separate analysis according to high or low dust exposure level. Noise exposure increases the risk of occupational injury in the workplace. Furthermore, the risk of occupational injury increases with noise exposure level in a dose-response relationship. Therefore, strategies for reducing noise exposure level are required to decrease the risk of occupational injury.

  11. Dose - response relationship between noise exposure and the risk of occupational injury.

    Science.gov (United States)

    Yoon, Jin-Ha; Hong, Jeong-Suk; Roh, Jaehoon; Kim, Chi-Nyon; Won, Jong-Uk

    2015-01-01

    Many workers worldwide experience fatality and disability caused by occupational injuries. This study examined the relationship between noise exposure and occupational injuries at factories in Korea. A total of 1790 factories located in northern Gyeonggi Province, Korea was evaluated. The time-weighted average levels of dust and noise exposure were taken from Workplace Exposure Assessment data. Apart occupational injuries, sports events, traffic accidents, and other accidents occurring outside workplaces were excluded. The incidences of occupational injury in each factory were calculated by data from the Korea Workers' Compensation and Welfare Services. Workplaces were classified according to the incidence of any occupational injuries (incident or nonincident workplaces, respectively). Workplace dust exposure was classified as noise exposure as 90 dB. Workplaces with high noise exposure were significantly associated with being incident workplaces, whereas workplaces with high dust exposure were not. The odds ratios (95% confidence intervals) derived from a logistic regression model were 1.68 (1.27-2.24) and 3.42 (2.26-5.17) at 80-89 dB and ≥ 90 dB versus Noise exposure increases the risk of occupational injury in the workplace. Furthermore, the risk of occupational injury increases with noise exposure level in a dose-response relationship. Therefore, strategies for reducing noise exposure level are required to decrease the risk of occupational injury.

  12. Western red cedar dust exposure and lung function: a dose-response relationship.

    Science.gov (United States)

    Noertjojo, H K; Dimich-Ward, H; Peelen, S; Dittrick, M; Kennedy, S M; Chan-Yeung, M

    1996-10-01

    The relationship between levels of cumulative red cedar dust exposure and decline in lung function was explored in an 11-yr follow-up study of 243 sawmill workers who participated in at least two occasions. We also studied 140 office workers in a similar manner as control subjects. Workers with asthma were excluded from the analysis. During the period of the study, 916 personal and 216 area samples of dust were collected from the sawmill. Cumulative wood dust exposure was calculated for each sawmill worker according to the duration and exposure in each job, based on the geometric mean of all dust measurements for that job. Average daily dust exposure was calculated by dividing the total cumulative exposure by the number of days of work. Workers were divided into low-, medium-, and high-exposure groups with mean daily level of exposure of 0.4 mg/m3, respectively. Sawmill workers had significantly greater declines in FEV1 and FVC compared with office workers adjusted for age, smoking, and initial lung function. A dose-response relationship was observed between the level of exposure and the annual decline in FVC. We conclude that exposure to Western red cedar dust is associated with a greater decline in lung function which may lead to development of chronic airflow limitation.

  13. Generation of dose-response relationships to assess the effects of acidity in precipitation on growth and productivity of vegetation

    Energy Technology Data Exchange (ETDEWEB)

    Evans, L.S.

    1981-01-01

    Experiments were performed with several plant species in natural environments as well in a greenhouse and/or tissue culture facilities to establish dose-response functions of plant responses to simulated acidic rain in order to determine environmental risk assessments to ambient levels of acidic rain. Response functions of foliar injury, biomass of leaves and seed of soybean and pinto beans, root yields of radishes and garden beets, and reproduction of bracken fern are considered. The dose-response function of soybean seed yields with the hydrogen ion concentration of simulated acidic rainfalls was expressed by the equation y = 21.06-1.01 log x where y = seed yield in grams per plant and x = the hydrogen concentration if ..mu..eq l/sup -1/. The correlation coefficient of this relationship was -0.90. A similar dose-response function was generated for percent fertilization of ferns in a forest understory. When percent fertilization is plotted on logarithmic scale with hydrogen ion concentration of the simulated rain solution, the Y intercept is 51.18, slope -0.041 with a correlation coefficient of -0.98. Other dose-response functions were generated that assist in a general knowledge as to which plant species and which physiological processes are most impacted by acidic precipitation. Some responses did not produce convenient dose-response relationships. In such cases the responses may be altered by other environmental factors or there may be no differences among treatment means.

  14. Examining the exercise-affect dose-response relationship: does duration influence frontal EEG asymmetry?

    Science.gov (United States)

    Woo, Minjung; Kim, Sungwoon; Kim, Jingu; Petruzzello, Steven J; Hatfield, Bradley D

    2009-05-01

    The "feel better" effect of exercise has been well established, but the specific influence of exercise duration on affect has not been systematically studied from a multi-level measurement approach. Such an approach offers the opportunity to assess psychophysiological responses that relate to psychological state. One relevant response is the change in frontal brain processes indexed by anterior EEG asymmetry, which is related to approach-withdrawal orientation and affective state [Davidson, R.J., 1993. Cerebral asymmetry and emotion: conceptual and methodological conundrums. Cogn. Emot. 7, 138; Davidson, R.J., 1998. Anterior electrophysiological asymmetries, emotion, and depression: Conceptual and methodological conundrums. Psychophysiology 35(5), 607-614.]. To examine the relationship between exercise duration and affective response, as well as the role of frontal brain processes in this relationship, female undergraduate students (N=16, VO(2) max=35.93 ml kg(-1) min(-1), aged 19-23 yrs) were assessed for frontal EEG and self-reported affective responses, as measured by the Profile of Mood States (POMS), following rest and three different durations of exercise (15, 30 and 45 min) performed at a standardized intensity (i.e., just below the ventilatory threshold (VT)). Psychological vigor and frontal EEG asymmetry following exercise of 30 min were elevated compared to that observed following rest and other exercise durations (i.e., 15, 45 min). The results support a dose-response relationship between exercise duration and affect characterized by an inverted-U. Furthermore, the covariance analysis, conducted to assess the role of cortical activation at the homologous sites in the post-exercise affective response, suggests that the enhanced vigor observed after 30 min of exercise results from the reduction of withdrawal-oriented processes rather than the facilitation of approach-oriented processes.

  15. Standard error of inverse prediction for dose-response relationship: approximate and exact statistical inference.

    Science.gov (United States)

    Demidenko, Eugene; Williams, Benjamin B; Flood, Ann Barry; Swartz, Harold M

    2013-05-30

    This paper develops a new metric, the standard error of inverse prediction (SEIP), for a dose-response relationship (calibration curve) when dose is estimated from response via inverse regression. SEIP can be viewed as a generalization of the coefficient of variation to regression problem when x is predicted using y-value. We employ nonstandard statistical methods to treat the inverse prediction, which has an infinite mean and variance due to the presence of a normally distributed variable in the denominator. We develop confidence intervals and hypothesis testing for SEIP on the basis of the normal approximation and using the exact statistical inference based on the noncentral t-distribution. We derive the power functions for both approaches and test them via statistical simulations. The theoretical SEIP, as the ratio of the regression standard error to the slope, is viewed as reciprocal of the signal-to-noise ratio, a popular measure of signal processing. The SEIP, as a figure of merit for inverse prediction, can be used for comparison of calibration curves with different dependent variables and slopes. We illustrate our theory with electron paramagnetic resonance tooth dosimetry for a rapid estimation of the radiation dose received in the event of nuclear terrorism.

  16. Influence of image slice thickness on rectal dose-response relationships following radiotherapy of prostate cancer

    Science.gov (United States)

    Olsson, C.; Thor, M.; Liu, M.; Moissenko, V.; Petersen, S. E.; Høyer, M.; Apte, A.; Deasy, J. O.

    2014-07-01

    When pooling retrospective data from different cohorts, slice thicknesses of acquired computed tomography (CT) images used for treatment planning may vary between cohorts. It is, however, not known if varying slice thickness influences derived dose-response relationships. We investigated this for rectal bleeding using dose-volume histograms (DVHs) of the rectum and rectal wall for dose distributions superimposed on images with varying CT slice thicknesses. We used dose and endpoint data from two prostate cancer cohorts treated with three-dimensional conformal radiotherapy to either 74 Gy (N = 159) or 78 Gy (N = 159) at 2 Gy per fraction. The rectum was defined as the whole organ with content, and the morbidity cut-off was Grade ≥2 late rectal bleeding. Rectal walls were defined as 3 mm inner margins added to the rectum. DVHs for simulated slice thicknesses from 3 to 13 mm were compared to DVHs for the originally acquired slice thicknesses at 3 and 5 mm. Volumes, mean, and maximum doses were assessed from the DVHs, and generalized equivalent uniform dose (gEUD) values were calculated. For each organ and each of the simulated slice thicknesses, we performed predictive modeling of late rectal bleeding using the Lyman-Kutcher-Burman (LKB) model. For the most coarse slice thickness, rectal volumes increased (≤18%), whereas maximum and mean doses decreased (≤0.8 and ≤4.2 Gy, respectively). For all a values, the gEUD for the simulated DVHs were ≤1.9 Gy different than the gEUD for the original DVHs. The best-fitting LKB model parameter values with 95% CIs were consistent between all DVHs. In conclusion, we found that the investigated slice thickness variations had minimal impact on rectal dose-response estimations. From the perspective of predictive modeling, our results suggest that variations within 10 mm in slice thickness between cohorts are unlikely to be a limiting factor when pooling multi-institutional rectal dose data that include slice thickness

  17. Dose-response relationship between sports activity and musculoskeletal pain in adolescents.

    Science.gov (United States)

    Kamada, Masamitsu; Abe, Takafumi; Kitayuguchi, Jun; Imamura, Fumiaki; Lee, I-Min; Kadowaki, Masaru; Sawada, Susumu S; Miyachi, Motohiko; Matsui, Yuzuru; Uchio, Yuji

    2016-06-01

    Physical activity has multiple health benefits but may also increase the risk of developing musculoskeletal pain (MSP). However, the relationship between physical activity and MSP has not been well characterized. This study examined the dose-response relationship between sports activity and MSP among adolescents. Two school-based serial surveys were conducted 1 year apart in adolescents aged 12 to 18 years in Unnan, Japan. Self-administered questionnaires were completed by 2403 students. Associations between time spent in organized sports activity and MSP were analyzed cross-sectionally (n = 2403) and longitudinally (n = 374, students free of pain and in seventh or 10th grade at baseline) with repeated-measures Poisson regression and restricted cubic splines, with adjustment for potential confounders. The prevalence of overall pain, defined as having pain recently at least several times a week in at least one part of the body, was 27.4%. In the cross-sectional analysis, sports activity was significantly associated with pain prevalence. Each additional 1 h/wk of sports activity was associated with a 3% higher probability of having pain (prevalence ratio = 1.03, 95% confidence interval = 1.02-1.04). Similar trends were found across causes (traumatic and nontraumatic pain) and anatomic locations (upper limbs, lower back, and lower limbs). In longitudinal analysis, the risk ratio for developing pain at 1-year follow-up per 1 h/wk increase in baseline sports activity was 1.03 (95% confidence interval = 1.02-1.05). Spline models indicated a linear association (P adolescents played sports, the more likely they were to have and develop pain.

  18. Dose-Response Relationships of Resistance Training in Healthy Old Adults : A Systematic Review and Meta-Analysis

    NARCIS (Netherlands)

    Borde, Ron; Hortobagyi, Tibor; Granacher, Urs

    2015-01-01

    Background Resistance training (RT) is an intervention frequently used to improve muscle strength and morphology in old age. However, evidence-based, dose-response relationships regarding specific RT variables (e.g., training period, frequency, intensity, volume) are unclear in healthy old adults. O

  19. Dose-Response Relationships of Balance Training in Healthy Young Adults : A Systematic Review and Meta-Analysis

    NARCIS (Netherlands)

    Lesinski, Melanie; Hortobagyi, Tibor; Muehlbauer, Thomas; Gollhofer, Albert; Granacher, Urs

    2015-01-01

    Background Balance training (BT) has been used for the promotion of balance and sports-related skills as well as for prevention and rehabilitation of lower extremity sport injuries. However, evidence-based dose-response relationships in BT parameters have not yet been established. Objective The obje

  20. European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'

    DEFF Research Database (Denmark)

    Calderón, M A; Larenas, D; Kleine-Tebbe, J

    2011-01-01

    For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen prod...

  1. Continuous Dose-Response Response Relationship of the LDL-Cholesterol-Lowering Effect of Phytosterol Intake 1,2

    NARCIS (Netherlands)

    Demonty, I.; Ras, R.T.; Knaap, van der H.C.M.; Duchateau, G.S.M.J.E.; Meijer, L.; Zock, P.L.; Geleijnse, J.M.; Trautwein, E.A.

    2009-01-01

    Phytosterols (plant sterols and stanols) are well known for their LDL-cholesterol (LDL-C)¿lowering effect. A meta-analysis of randomized controlled trials in adults was performed to establish a continuous dose-response relationship that would allow predicting the LDL-C¿lowering efficacy of different

  2. Intraspecies variability in the dose-response relationship for Salmonella Enteritidis associated with genetic differences in cellular immune response.

    NARCIS (Netherlands)

    Havelaar, A.H.; Garssen, J.; Takumi, K.; Koedam, M.I.; Ritmeester, W.; Fonteyne, L. de la; Bousema, T.; Vos, J.

    2004-01-01

    To evaluate the effects of differences in host cellular immunity, we studied the dose-response relationship for infection with Salmonella enterica serovar Enteritidis (SE) in two different rat strains, skewed towards T helper 1 (Th1, Lewis rats) or T helper 2 (Th2, Brown Norway rats) immunoregulatio

  3. Dose-Response Relationships of Balance Training in Healthy Young Adults : A Systematic Review and Meta-Analysis

    NARCIS (Netherlands)

    Lesinski, Melanie; Hortobagyi, Tibor; Muehlbauer, Thomas; Gollhofer, Albert; Granacher, Urs

    Background Balance training (BT) has been used for the promotion of balance and sports-related skills as well as for prevention and rehabilitation of lower extremity sport injuries. However, evidence-based dose-response relationships in BT parameters have not yet been established. Objective The

  4. Isobolographic analysis of interaction between drugs with nonparallel dose-response relationship curves: a practical application.

    Science.gov (United States)

    Luszczki, Jarogniew J

    2007-04-01

    The objective of this study was to characterize the anticonvulsant and acute adverse-effect potentials of topiramate (TPM) and gabapentin (GBP)-two second-generation antiepileptic drugs administered alone and in combination in the maximal electroshock (MES)-induced seizures and chimney test in mice. The anticonvulsant and acute adverse effects of the combination of TPM with GBP at the fixed ratio of 1:1 were determined using the type I isobolographic analysis for nonparallel dose-response relationship curves (DRRCs). To ascertain any pharmacokinetic contribution to the observed interaction between TPM and GBP, total brain concentrations of both drugs were determined. The isobolographic analysis of interaction for TPM and GBP, whose DRRCs were not parallel in both MES and chimney tests, was accompanied with a presentation of all required calculations allowing the determination of lower and upper lines of additivity. The isobolographic analysis revealed that TPM combined with GBP at the fixed-ratio combination of 1:1 interacted supraadditively (synergistically) in terms of suppression of MES-induced seizures, and simultaneously, the combination produced additive interaction with respect to motor coordination impairment (adverse effects) in the chimney test. The evaluation of pharmacokinetic characteristics of interaction for the combination of TPM with GBP revealed that neither TPM nor GBP affected their total brain concentrations in experimental animals, and thus, the observed interaction in the MES test was pharmacodynamic in nature. In conclusion, the combination of TPM with GBP, because of supraadditivity in the MES test and additivity in terms of motor coordination impairment in the chimney test as well as lack of pharmacokinetic interactions between drugs, fulfilled the criterion of a favorable combination, worthy of recommendation in further clinical practice.

  5. Dose-response relationship for light intensity and ocular and electroencephalographic correlates of human alertness

    Science.gov (United States)

    Cajochen, C.; Zeitzer, J. M.; Czeisler, C. A.; Dijk, D. J.

    2000-01-01

    Light can elicit both circadian and acute physiological responses in humans. In a dose response protocol men and women were exposed to illuminances ranging from 3 to 9100 lux for 6.5 h during the early biological night after they had been exposed to dose response curve. Half of the maximum alerting response to bright light of 9100 lux was obtained with room light of approximately 100 lux. This sensitivity to light indicates that variations in illuminance within the range of typical, ambient, room light (90-180 lux) can have a significant impact on subjective alertness and its electrophysiologic concomitants in humans during the early biological night.

  6. Hormesis: a fundamental concept in biology

    Science.gov (United States)

    Calabrese, Edward J.

    2014-01-01

    This paper assesses the hormesis dose response concept, including its historical foundations, frequency, generality, quantitative features, mechanistic basis and biomedical, pharmaceutical and environmental health implications. The hormetic dose response is highly generalizable, being independent of biology model (i.e. common from plants to humans), level of biological organization (i.e. cell, organ and organism), endpoint, inducing agent and mechanism, providing the first general and quantitative description of plasticity. The hormetic dose response describes the limits to which integrative endpoints (e.g. cell proliferation, cell migration, growth patterns, tissue repair, aging processes, complex behaviors such as anxiety, learning, memory, and stress, preconditioning responses, and numerous adaptive responses) can be modulated (i.e., enhanced or diminished) by pharmaceutical, chemical and physical means. Thus, the hormesis concept is a fundamental concept in biology with a wide range of biological implications and biomedical applications.

  7. Hormesis: a fundamental concept in biology

    Directory of Open Access Journals (Sweden)

    Edward J. Calabrese

    2014-04-01

    Full Text Available This paper assesses the hormesis dose response concept, including its historical foundations, frequency, generality, quantitative features, mechanistic basis and biomedical, pharmaceutical and environmental health implications. The hormetic dose response is highly generalizable, being independent of biology model (i.e. common from plants to humans, level of biological organization (i.e. cell, organ and organism, endpoint, inducing agent and mechanism, providing the first general and quantitative description of plasticity. The hormetic dose response describes the limits to which integrative endpoints (e.g. cell proliferation, cell migration, growth patterns, tissue repair, aging processes, complex behaviors such as anxiety, learning, memory, and stress, preconditioning responses, and numerous adaptive responses can be modulated (i.e., enhanced or diminished by pharmaceutical, chemical and physical means. Thus, the hormesis concept is a fundamental concept in biology with a wide range of biological implications and biomedical applications.

  8. Ozone acting on human blood yields a hormetic dose-response relationship

    Directory of Open Access Journals (Sweden)

    Travagli Valter

    2011-05-01

    Full Text Available Abstract The aim of this paper is to analyze why ozone can be medically useful when it dissolves in blood or in other biological fluids. In reviewing a number of clinical studies performed in Peripheral Arterial Diseases (PAD during the last decades, it has been possible to confirm the long-held view that the inverted U-shaped curve, typical of the hormesis concept, is suitable to represent the therapeutic activity exerted by the so-called ozonated autohemotherapy. The quantitative and qualitative aspects of human blood ozonation have been also critically reviewed in regard to the biological, therapeutic and safety of ozone. It is hoped that this gas, although toxic for the pulmonary system during prolonged inhalation, will be soon recognized as a useful agent in oxidative-stress related diseases, joining other medical gases recently thought to be of therapeutic importance. Finally, the elucidation of the mechanisms of action of ozone as well as the obtained results in PAD may encourage clinical scientists to evaluate ozone therapy in vascular diseases in comparison to the current therapies.

  9. Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder

    Directory of Open Access Journals (Sweden)

    Cardozo Linda

    2010-08-01

    Full Text Available Abstract Background Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI, usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine. Methods Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models. Results The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively. Conclusions A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials. Trial Registration The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723.

  10. Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder.

    Science.gov (United States)

    Cardozo, Linda; Khullar, Vik; El-Tahtawy, Ahmed; Guan, Zhonghong; Malhotra, Bimal; Staskin, David

    2010-08-19

    Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine. Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models. The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively. A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials. The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723).

  11. Hormesis [Biological Effects of Low Level Exposures (Belle)] and Dermatology

    OpenAIRE

    Thong, Haw-Yueh; Maibach, Howard I.

    2008-01-01

    Hormesis, or biological effects of low level exposures (BELLE), is characterized by nonmonotonic dose response which is biphasic, displaying opposite effects at low and high dose. Its occurrence has been documented across a broad range of biological models and diverse type of exposure. Since hormesis appears to be a relatively common phenomenon in many areas, the objective of this review is to explore its occurrence related to dermatology and its public health and risk assessment implication....

  12. [Occlusion treatment for amblyopia. Age dependence and dose-response relationship].

    Science.gov (United States)

    Fronius, M

    2016-04-01

    Based on clinical experience and studies on animal models the age of 6-7 years was regarded as the limit for treatment of amblyopia, although functional improvement was also occasionally reported in older patients. New technical developments as well as insights from clinical studies and the neurosciences have attracted considerable attention to this topic. Various aspects of the age dependence of amblyopia treatment are discussed in this article, e. g. prescription, electronic monitoring of occlusion dosage, calculation of indicators for age-dependent plasticity of the visual system, and novel, alternative treatment approaches. Besides a discussion of the recent literature, results of studies by our "Child Vision Research Unit" in Frankfurt are presented: results of a questionnaire about prescription habits concerning age limits of patching, electronic recording of occlusion in patients beyond the conventional treatment age, calculation of dose-response function and efficiency of patching and their age dependence. The results of the questionnaire illustrate the uncertainty about age limits of prescription with significant deviations from the guideline of the German Ophthalmological Society (DOG). Electronic recording of occlusion allowed the quantification of declining dose-response function and treatment efficiency between 5 and 16 years of age. Reports about successful treatment with conventional and novel methods in adults are at variance with the notion of a rigid adult visual system lacking plasticity. Electronic recording of patching allowed new insights into the age-dependent susceptibility of the visual system and contributes to a more evidence-based treatment of amblyopia. Alternative approaches for adults challenge established notions about age limits of amblyopia therapy. Further studies comparing different treatment options are urgently needed.

  13. Dose-response relationship of {gamma}-H2AX foci induction in human lymphocytes after X-rays exposure

    Energy Technology Data Exchange (ETDEWEB)

    Mandina, Tania [Centro de Proteccion e Higiene de las Radiaciones, Calle 20 No. 4113 e/41y 47 Miramar, AP 6195 C. Habana (Cuba); Roch-Lefevre, Sandrine H.; Voisin, Pascale [Institut de Radioprotection et de Surete Nucleaire (IRSN), DRPH, SRBE, LDB, BP17, 92262 Fontenay-aux-Roses (France); Gonzalez, Jorge E.; Lamadrid, Ana I.; Romero, Ivonne [Centro de Proteccion e Higiene de las Radiaciones, Calle 20 No. 4113 e/41y 47 Miramar, AP 6195 C. Habana (Cuba); Garcia, Omar, E-mail: omar@cphr.edu.cu [Centro de Proteccion e Higiene de las Radiaciones, Calle 20 No. 4113 e/41y 47 Miramar, AP 6195 C. Habana (Cuba); Voisin, Philippe; Roy, Laurence [Institut de Radioprotection et de Surete Nucleaire (IRSN), DRPH, SRBE, LDB, BP17, 92262 Fontenay-aux-Roses (France)

    2011-09-15

    Biological dosimeters are recommended for dose estimation in case of human overexposure to ionising radiation. Rapid measurement of {gamma}-H2AX foci as a marker of DNA double-strand breaks (DSB) induction has been recently tested with this purpose. Here we reported a dose-response relationship after X-ray irradiation at different times post-exposure. Blood samples were obtained from several healthy donors and exposed to doses between 0 and 2 Gy. After irradiation, blood samples were incubated at 37 deg. C during 0.5 h, 5 h, and 8 h. Scoring of cells and {gamma}-H2AX foci was performed by software. The dose-response curves for different incubation times were as follows: Y{sub (0.5h)} = 11.66D + 0.15 (R{sup 2} = 0.99), Y{sub (5h)} = 2.44D + 0.15 (R{sup 2} = 0.99), Y{sub (8h)} = 1.57D + 0.22 (R{sup 2} = 0.99). At 0.5 h post-exposure, the dose-response relationship for X-irradiated lymphocytes was similar to the one obtained after gamma-irradiation using the same protocol. On the other hand, the results were not similar after 8 h due to different kinetics after gamma- and X-irradiation. Our results confirm the possibilities of using {gamma}-H2AX foci method for dose estimation in a period from 0.5 h up to 8 h post X-irradiation and support the hypothesis of differences in {gamma}-H2AX foci kinetics after gamma- and X-irradiation in vitro.

  14. Mechanisms of Action and Dose-Response Relationships Governing Biological Control of Fusarium Wilt of Tomato by Nonpathogenic Fusarium spp.

    Science.gov (United States)

    Larkin, R P; Fravel, D R

    1999-12-01

    ABSTRACT Three isolates of nonpathogenic Fusarium spp. (CS-1, CS-20, and Fo47), previously shown to reduce the incidence of Fusarium wilt diseases of multiple crops, were evaluated to determine their mechanisms of action and antagonist-pathogen inoculum density relationships. Competition for nutrients, as represented by a reduction in pathogen saprophytic growth in the presence of the biocontrol isolates, was observed to be an important mechanism of action for isolate Fo47, but not for isolates CS-1 and CS-20. All three biocontrol isolates demonstrated some degree of induced systemic resistance in tomato (Lycopersicon esculentum) and watermelon (Citrullus lanatus) plants, as determined by split-root tests, but varied in their relative abilities to reduce disease. Isolate CS-20 provided the most effective control (39 to 53% disease reduction), while Fo47 provided the least effective control (23 to 25% reduction) in split-root tests. Dose-response relationships also differed considerably among the three biocon-trol isolates, with CS-20 significantly reducing disease incidence at antagonist doses as low as 100 chlamydospores per g of soil (cgs) and at pathogen densities up to 10(5) cgs. Isolate CS-1 also was generally effective at antagonist densities of 100 to 5,000 cgs, but only when pathogen densities were below 10(4) cgs. Isolate Fo47 was effective only at antagonist densities of 10(4) to 10(5) cgs, regardless of pathogen density. Epidemiological dose-response models (described by linear, negative exponential, hyperbolic saturation [HS], and logistic [LG] functions) fit to the observed data were used to quantify differences among the biocontrol isolates and establish biocontrol characteristics. Each isolate required a different model to best describe its dose-response characteristics, with the HS/HS, LG/HS, and LG/LG models (pathogen/biocontrol components) providing the best fit for isolates CS-1, CS-20, and Fo47, respectively. Model parameters (defining effective

  15. The dose-response relationship between the patch test and ROAT and the potential use for regulatory purposes.

    Science.gov (United States)

    Fischer, Louise Arup; Voelund, Aage; Andersen, Klaus Ejner; Menné, Torkil; Johansen, Jeanne Duus

    2009-10-01

    Allergic contact dermatitis is common and can be prevented. The relationship between thresholds for patch tests and the repeated open application test (ROAT) is unclear. It would be desirable if patch test and ROAT data from already sensitized individuals could be used in prevention. The aim was to develop an equation that could predict the response to an allergen in a ROAT based on the dose-response curve derived by patch testing. Results from two human experimental elicitation studies with non-volatile allergens, nickel and the preservative methyldibromo glutaronitrile (MDBGN), were analysed by logistic dose-response statistics. The relation for volatile compounds was investigated using the results from experiments with the fragrance chemicals hydroxyisohexyl 3-cyclohexene carboxaldehyde and isoeugenol. For non-volatile compounds, the outcome of a ROAT can be estimated from the patch test by: ED(xx)(ROAT) = 0.0296 ED(xx)(patch test). For volatile compounds, the equation predicts that the response in the ROAT is more severe than the patch test response, but it overestimates the response. This equation may be used for non-volatile compounds other than nickel and MDBGN, after further validation. The relationship between the patch test and the ROAT can be used for prevention, to set safe levels of allergen exposure based on patch test data.

  16. Dose-response relationship for lifetime excess mortality and temporal pattern of manifestation in mice irradiated neonatally with gamma rays

    Energy Technology Data Exchange (ETDEWEB)

    Sasaki, Shunsaku; Fukuda, Nobuo [National Inst. of Radiological Sciences, Chiba (Japan)

    2002-09-01

    The dose-response relationships for the lifetime excess mortality and temporal distribution of excess mortality were analysed using a data set from an experiment on the long-term effects of gamma irradiation in neonatal mice. The excess mortality was calculated based on an assumption that any increase in the mortality rate was attributable to radiation exposure. The dose-response relationship for the lifetime excess mortality was convex upward, whereas the shortening of the mean life span was proportional to the dose. The excess mortality at 1 Gy was estimated to be 35.6%. The relative risk decreased markedly with increasing age. However, the mortality rate in the irradiated group was persistently higher than the background rate of death, and the absolute risk increased with age. A logistic specification was used to analyze the temporal distribution of the excess mortality. The results of the analysis indicated a dose-dependent shortening of the latent period and a broadening of the distribution. (author)

  17. Is There a Dose-Response Relationship for Heart Disease With Low-Dose Radiation Therapy?

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Eugene [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Corbett, James R. [Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Moran, Jean M. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Griffith, Kent A. [Department of Biostatistics, University of Michigan, Ann Arbor, Michigan (United States); Marsh, Robin B.; Feng, Mary; Jagsi, Reshma; Kessler, Marc L. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Ficaro, Edward C. [Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Pierce, Lori J., E-mail: ljpierce@umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    2013-03-15

    Purpose: To quantify cardiac radiation therapy (RT) exposure using sensitive measures of cardiac dysfunction; and to correlate dysfunction with heart doses, in the setting of adjuvant RT for left-sided breast cancer. Methods and Materials: On a randomized trial, 32 women with node-positive left-sided breast cancer underwent pre-RT stress single photon emission computed tomography (SPECT-CT) myocardial perfusion scans. Patients received RT to the breast/chest wall and regional lymph nodes to doses of 50 to 52.2 Gy. Repeat SPECT-CT scans were performed 1 year after RT. Perfusion defects (PD), summed stress defects scores (SSS), and ejection fractions (EF) were evaluated. Doses to the heart and coronary arteries were quantified. Results: The mean difference in pre- and post-RT PD was −0.38% ± 3.20% (P=.68), with no clinically significant defects. To assess for subclinical effects, PD were also examined using a 1.5-SD below the normal mean threshold, with a mean difference of 2.53% ± 12.57% (P=.38). The mean differences in SSS and EF before and after RT were 0.78% ± 2.50% (P=.08) and 1.75% ± 7.29% (P=.39), respectively. The average heart Dmean and D95 were 2.82 Gy (range, 1.11-6.06 Gy) and 0.90 Gy (range, 0.13-2.17 Gy), respectively. The average Dmean and D95 to the left anterior descending artery were 7.22 Gy (range, 2.58-18.05 Gy) and 3.22 Gy (range, 1.23-6.86 Gy), respectively. No correlations were found between cardiac doses and changes in PD, SSS, and EF. Conclusions: Using sensitive measures of cardiac function, no clinically significant defects were found after RT, with the average heart Dmean <5 Gy. Although a dose response may exist for measures of cardiac dysfunction at higher doses, no correlation was found in the present study for low doses delivered to cardiac structures and perfusion, SSS, or EF.

  18. Evaluation of the Comet Assay for Assessing the Dose-Response Relationship of DNA Damage Induced by Ionizing Radiation

    Directory of Open Access Journals (Sweden)

    Qiang Liu

    2013-11-01

    Full Text Available Dose- and time-response curves were combined to assess the potential of the comet assay in radiation biodosimetry. The neutral comet assay was used to detect DNA double-strand breaks in lymphocytes caused by γ-ray irradiation. A clear dose-response relationship with DNA double-strand breaks using the comet assay was found at different times after irradiation (p < 0.001. A time-response relationship was also found within 72 h after irradiation (p < 0.001. The curves for DNA double-strand breaks and DNA repair in vitro of human lymphocytes presented a nice model, and a smooth, three-dimensional plane model was obtained when the two curves were combined.

  19. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework.

    Science.gov (United States)

    Calabrese, Edward J; Bachmann, Kenneth A; Bailer, A John; Bolger, P Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M George; Chiueh, Chuang C; Clarkson, Thomas W; Cook, Ralph R; Diamond, David M; Doolittle, David J; Dorato, Michael A; Duke, Stephen O; Feinendegen, Ludwig; Gardner, Donald E; Hart, Ronald W; Hastings, Kenneth L; Hayes, A Wallace; Hoffmann, George R; Ives, John A; Jaworowski, Zbigniew; Johnson, Thomas E; Jonas, Wayne B; Kaminski, Norbert E; Keller, John G; Klaunig, James E; Knudsen, Thomas B; Kozumbo, Walter J; Lettieri, Teresa; Liu, Shu-Zheng; Maisseu, Andre; Maynard, Kenneth I; Masoro, Edward J; McClellan, Roger O; Mehendale, Harihara M; Mothersill, Carmel; Newlin, David B; Nigg, Herbert N; Oehme, Frederick W; Phalen, Robert F; Philbert, Martin A; Rattan, Suresh I S; Riviere, Jim E; Rodricks, Joseph; Sapolsky, Robert M; Scott, Bobby R; Seymour, Colin; Sinclair, David A; Smith-Sonneborn, Joan; Snow, Elizabeth T; Spear, Linda; Stevenson, Donald E; Thomas, Yolene; Tubiana, Maurice; Williams, Gary M; Mattson, Mark P

    2007-07-01

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

  20. Nitrogen dose-response relationships: benthic algae and macroinvertebrates in running water

    OpenAIRE

    R Wright; Eriksen, T.; Schneider, S.

    2013-01-01

    Nitrogen deposition affects freshwater biodiversity in two ways: by contributing to acidification via nitrate in runoff, and by acting as a nutrient. We used data for two organism groups, benthic algae (224 sites) and benthic invertebrates (62 sites), to test if N as a nutrient affects the species numbers of these groups in running water. Neither of these groups showed significant relationships with nitrogen, except for a positive relationship between nitrate concentration and the number of b...

  1. Nutritional Hormesis and Aging

    OpenAIRE

    Hayes, Daniel P.

    2009-01-01

    Nutritional hormesis has the potential to serve as a pro-healthy aging intervention by reducing the susceptibility of the elderly to various chronic degenerative diseases and thereby extending human healthspan. Supportive evidence for nutritional hormesis arising from essential nutrients (vitamins and minerals), dietary pesticides (natural and synthetic), dioxin and other herbicides, and acrylamide will be reviewed and discussed.

  2. Nutritional hormesis and aging.

    Science.gov (United States)

    Hayes, Daniel P

    2009-11-16

    Nutritional hormesis has the potential to serve as a pro-healthy aging intervention by reducing the susceptibility of the elderly to various chronic degenerative diseases and thereby extending human healthspan. Supportive evidence for nutritional hormesis arising from essential nutrients (vitamins and minerals), dietary pesticides (natural and synthetic), dioxin and other herbicides, and acrylamide will be reviewed and discussed.

  3. Drug therapy: dose-response relationship of oral mesalazine in inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    C. J. J. Mulder

    1998-01-01

    Full Text Available Mesalazine is widely used in the treatment of inflammatory bowel disease. Little is known about the doseresponse relationship and about possible dose related side effects. In ulcerative colitis higher dosages of mesalazine (3 g are more effective in maintaining a remission than lower dosages (1.5 g. In mild to moderately active ulcerative colitis, studies also indicate that higher dosages might be more effective in inducing remission. Dose-comparing studies in Crohn's disease are even more sparse, but the available results indicate higher efficacy at higher dose levels.

  4. Teenage and adult tonsillectomy: dose-response relationship between diathermy energy used and morbidity.

    Science.gov (United States)

    Cardozo, A A J; Hallikeri, C; Lawrence, H; Sankar, V; Hargreaves, S

    2007-10-01

    To determine whether an increase in the use of bipolar diathermy energy to perform a tonsillectomy is associated with an increase in postoperative pain and haemorrhage. Prospective study. District General Hospital. In all, 101 patients above the age of 13 years who underwent a tonsillectomy that involved the use of bipolar diathermy during the study period were included. The cumulative amount of diathermy energy used to perform each tonsillectomy was calculated with the help of a digital stop clock timing device connected to the diathermy foot-pedal. Postoperative pain scores and the incidence of secondary haemorrhage were recorded for each patient at four points in time following surgery, up to the tenth postoperative day. The haemorrhage rates were categorised into three groups (no bleeding, minor bleeding and major bleeding) according to severity. Associations between the diathermy energy used to perform each tonsillectomy and the corresponding postoperative pain scores and secondary bleeding rates were investigated. There was a statistically significant positive relationship between the total amount of bipolar diathermy energy used per tonsillectomy and the pain scores at all the four recorded points in time (r(s) = 0.44-0.72, P relationship between diathermy energy and postoperative bleeding is less clear. This suggests that there could be other important factors such as surgical instrument characteristics and degree of tonsillar adherence that have an additional influence and are therefore possible areas for future research.

  5. Prenatal irradiation and spatial memory in mice: investigation of dose-response relationship

    Energy Technology Data Exchange (ETDEWEB)

    Sienkiewicz, Z.J.; Haylock, R.G.E.; Saunders, R.D. (National Radiological Protection Board, Chilton (United Kingdom))

    1994-05-01

    Pregnant CD1 mice were exposed on gestational day 18 to 250 kV X-rays at 0.1, 0.25, 0.35 and 0.5 Gy. The performances of 10 adult male offspring from each exposure condition were investigated on a spatial discrimination learning task in a radial arm maze. An impairment in the performance of this task was found which showed a correlation with dose. Compared with sham exposed control mice, performance was not significantly affected with irradiation at 0.1 Gy and was slightly but non-significantly reduced at 0.25 Gy. Irradiation at 0.35 Gy caused a significant impairment in performance, and exposure at 0.5 Gy resulted in a still larger impairment. The overall association between dose and behavioural impairment was best described by a linear relationship without a threshold, although at doses lower than about 0.25 Gy any impairment would appear to be too small to be detectable. (Author).

  6. Exposure dose response relationships of the freshwater bivalve Hyridella australis to cadmium spiked sediments

    Energy Technology Data Exchange (ETDEWEB)

    Marasinghe Wadige, Chamani P.M., E-mail: chamani.marasinghe.wadige@canberra.edu.au; Maher, William A.; Taylor, Anne M.; Krikowa, Frank

    2014-07-01

    Highlights: • The exposure–dose–response approach was used to assess cadmium exposure and toxicity. • Accumulated cadmium in H. australis reflected the sediment cadmium exposure. • Spill over of cadmium into the biologically active pool was observed. • Increased cadmium resulted in measurable biological effects. • H. australis has the potential to be a cadmium biomonitor in freshwater environments. - Abstract: To understand how benthic biota may respond to the additive or antagonistic effects of metal mixtures in the environment it is first necessary to examine their responses to the individual metals. In this context, laboratory controlled single metal-spiked sediment toxicity tests are useful to assess this. The exposure–dose–response relationships of Hyridella australis to cadmium-spiked sediments were, therefore, investigated in laboratory microcosms. H. australis was exposed to individual cadmium spiked sediments (<0.05 (control), 4 ± 0.3 (low) and 15 ± 1 (high) μg/g dry mass) for 28 days. Dose was measured as cadmium accumulation in whole soft body and individual tissues at weekly intervals over the exposure period. Dose was further examined as sub-cellular localisation of cadmium in hepatopancreas tissues. The biological responses in terms of enzymatic and cellular biomarkers were measured in hepatopancreas tissues at day 28. H. australis accumulated cadmium from spiked sediments with an 8-fold (low exposure organisms) and 16-fold (high exposure organisms) increase at day 28 compared to control organisms. The accumulated tissue cadmium concentrations reflected the sediment cadmium exposure at day 28. Cadmium accumulation in high exposure organisms was inversely related to the tissue calcium concentrations. Gills of H. australis showed significantly higher cadmium accumulation than the other tissues. Accumulated cadmium in biologically active and biologically detoxified metal pools was not significantly different in cadmium exposed

  7. The definition of hormesis and its implications for in vitro to in vivo extrapolation and risk assessment

    NARCIS (Netherlands)

    Woude, van der H.; Alink, G.M.; Rietjens, I.M.C.M.

    2005-01-01

    This article comments on some of the basic questions put forward in state-of-the-art discussions on hormesis. There seems to be a need for a better definition of the concept itself and reconsideration of whether all biphasic dose-response curves should be considered representative for hormesis.

  8. Hormesis on life-history traits: is there such thing as a free lunch?

    Science.gov (United States)

    Jager, Tjalling; Barsi, Alpar; Ducrot, Virginie

    2013-03-01

    The term "hormesis" is used to describe dose-response relationships where the response is reversed between low and high doses of a stressor (generally, stimulation at low doses and inhibition at high ones). A mechanistic explanation is needed to interpret the relevance of such responses, but there does not appear to be a single universal mechanism underlying hormesis. When the endpoint is a life-history trait such as growth or reproduction, a stimulation of the response comes with costs in terms of resources. Organisms have to obey the conservation laws for mass and energy; there is no such thing as a free lunch. Based on the principles of Dynamic Energy Budget theory, we introduce three categories of explanations for hormesis that obey the conservation laws: acquisition (i.e., increasing the input of energy into the individual), allocation (i.e., rearranging the energy flows over various traits) and medication (e.g., the stressor is an essential element or acts as a cure for a disease or infection). In this discussion paper, we illustrate these explanations with cases where they might apply, and elaborate on the potential consequences for field populations.

  9. Dose response relationship of disturbed migration of Purkinje cells in the cerebellum due to X-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Darmanto, W.; Inouye, Minoru; Hayasaka, Shizu; Takagishi, Yoshiko; Aolad, H.; Murata, Yoshiharu [Nagoya Univ. (Japan). Research Inst. of Environmental Medicine

    1998-10-01

    Pregnant rats were exposed to 2.0, 2.25 or 2.5 Gy X-irradiation on gestation day 21. Pups were sacrificed 12 hr after exposure, and on postnatal day 5 (P5), P7 and P9. Their cerebella were observed immunohistochemically using anti-inositol 1,4,5 triphosphate (IP3) receptor antibody to identify Purkinje cells. These cells were disturbed to migrate and remained in the internal granular layer and white matter of the cerebellum. They had short dendrites, and some showed an abnormal direction of dendrites in rats exposed to 2.25 or 2.5 Gy. Alignment of Purkinje cells was also disturbed when examined either on P5, P7 or P9 especially by doses of 2.25 and 2.5 Gy. There was a relationship between X-ray doses and the number of cells piling up in the Purkinje cell layer of the cerebellum. The dose-response relationship with the number of ectopic Purkinje cells was noted in the anterior lobes of the cerebellum. (author)

  10. Dose-response relationship between alcohol use and blood pressure among drivers of commercial vehicles in Calabar, Southern Nigeria

    Directory of Open Access Journals (Sweden)

    Segun Bello

    2010-08-01

    Full Text Available Alcohol is a sedative/hypnotic with effects similar to those of barbiturates.1 The type of alcoholic beverages consumed depends on the social context and financial capability. Alcoholic beverages may be in form of beer, wine, dry gin. Drinking alcohol is an activity that many people enjoy; taking a few drinks occasionally is generally harmless. Most people do not have problems as a result of drinking alcohol in this manner, although this may predispose to heavy use. Heavy alcohol consumption has been shown in observational studies to have a strong positive association with elevated blood pressure.2-4 Further evidence have been shown by clinical trials5,6 that have demonstrated that reduction in alcohol intake among individuals who drink heavily (i.e. three or more drinks per day can lower blood pressure in normotensive and hypertensive men. Some studies have recorded a linear dose-response relationship sometimes starting with a consumption threshold of three drinks per day (30 g of ethanol.7-13 In others, the relationship has been non-linear especially in women, and some authors have speculated that ingestion of small quantities may reduce blood pressure.14-22 These discrepancies may reflect differences in investigational design, methods and populations.23 Many studies have been done in this area in developed countries like the United States, United Kingdom and Australia. This is however, not a commonly researched area in this part of the world. The aim of this study was to assess the relationship between alcohol consumption and blood pressure of drivers of commercial vehicles.

  11. Hormesis in aging.

    Science.gov (United States)

    Rattan, Suresh I S

    2008-01-01

    Hormesis in aging is represented by mild stress-induced stimulation of protective mechanisms in cells and organisms resulting in biologically beneficial effects. Single or multiple exposure to low doses of otherwise harmful agents, such as irradiation, food limitation, heat stress, hypergravity, reactive oxygen species and other free radicals have a variety of anti-aging and longevity-extending hormetic effects. Detailed molecular mechanisms that bring about the hormetic effects are being increasingly understood, and comprise a cascade of stress response and other pathways of maintenance and repair. Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, the chain of events following initial hormesis leads to biologically amplified effects that are much larger, synergistic and pleiotropic. A consequence of hormetic amplification is an increase in the homeodynamic space of a living system in terms of increased defence capacity and reduced load of damaged macromolecules. Hormetic strengthening of the homeodynamic space provides wider margins for metabolic fluctuation, stress tolerance, adaptation and survival. Hormesis thus counter-balances the progressive shrinkage of the homeodynamic space, which is the ultimate cause of aging, diseases and death. Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The established scientific foundations of hormesis are ready to pave the way for new and effective approaches in aging research and intervention.

  12. The Occurrence of Hormesis in Plants and Algae

    DEFF Research Database (Denmark)

    Cedergreen, Nina; Streibig, Jens C; Kudsk, Per

    2007-01-01

    fungicide and binary mixtures thereof. In total 687 dose-response curves were included in the database. The study showed that both the frequency and the magnitude of the hormetic response depended on the endpoint being measured. Dry weight at harvest showed a higher frequency and a larger hormetic response...... compared to relative growth rates. Evaluating hormesis for relative growth rates for all species showed that 25% to 76% of the curves for each species had treatments above 105% of the control. Fitting the data with a dose-response model including a parameter for hormesis showed that the average growth...... for acifluorfen and terbuthylazine. The concentration ranges of the hormetic part of the dose-response curves corresponded well with literature values....

  13. Dose response biology: the case of resveratrol.

    Science.gov (United States)

    Calabrese, Edward J; Mattson, Mark P; Calabrese, Vittorio

    2010-12-01

    Resveratrol often displays hormesis-like biphasic dose responses. This occurs in a broad range of biological models and for numerous endpoints of biomedical interest and public health concern. Recognition of the widespread occurrence of the hormetic nature of many of the responses of resveratrol is important on multiple levels. It can help optimize study design protocols by investigators, create a dose-response framework for better addressing dose-related biological complexities and assist in the development of public health and medical guidance with respect to considerations for what is an optimal dose not just for an agent such as resveratrol, but also for the plethora of agents that also act via hormetic mechanisms.

  14. Home dampness, childhood asthma, hay fever, and airway symptoms in Shanghai, China: associations, dose-response relationships, and lifestyle's influences.

    Science.gov (United States)

    Hu, Y; Liu, W; Huang, C; Zou, Z J; Zhao, Z H; Shen, L; Sundell, J

    2014-10-01

    Numerous studies of associations between dampness and respiratory diseases have been conducted, but their implications remain inconclusive. In this study of 13,335 parent-reported questionnaires (response rate: 85.3%), we analyzed associations between home dampness and asthma and related symptoms in 4- to 6-year-old children in a cross-sectional study of Shanghai. Indicators of home dampness were strongly and significantly associated with dry cough, wheeze, and rhinitis symptoms. In the current residence, children with visible mold spots (VMS) exposure had 32% higher risk of asthma (adjusted OR, 95% CI: 1.32, 1.07-1.64); damp clothing and/or bedding (frequently) was strongly associated with dry cough (1.78, 1.37-2.30); condensation on windows was strongly associated with hay fever (1.60, 1.27-2.01). In the early-life residence, VMS or damp stains (frequently) were strongly associated with dry cough (2.20, 1.55-3.11) and rhinitis ever (1.57, 1.11-2.21). Associations between dampness and diseases among children with or without family history of atopy were similar. The total number of dampness indicators had strong dose-response relationships with investigated health outcomes. Actions, including opening windows of the child's room at night and cleaning the child's room frequently, could potentially mitigate 25% of home VMS, thereby preventing more than 1.5% of attributable risk of the studied symptoms. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. The 10th anniversary of the publication of genes and environment: memoir of establishing the Japanese environmental mutagen society and a proposal for a new collaborative study on mutagenic hormesis.

    Science.gov (United States)

    Sutou, Shizuyo

    2017-01-01

    The Japanese Environmental Mutagen Society (JEMS) was established in 1972 by 147 members, 11 of whom are still on the active list as of May 1, 2016. As one of them, I introduce some historic topics here. These include 1) establishment of JEMS, 2) the issue of 2-(2-furyl)-3-(3-nitro-2-furyl)acrylamide (AF-2), 3) the Mammalian Mutagenicity Study Group (MMS) and its achievements, and 4) the Collaborative Study Group of the Micronucleus Test (CSGMT) and its achievements. In addition to these historic matters, some of which are still ongoing, a new collaborative study is proposed on adaptive response or hormesis by mutagens. There is a close relationship between mutagens and carcinogens, the dose-response relationship of which has been thought to follow the linear no-threshold model (LNT). LNT was fabricated on the basis of Drosophila sperm experiments using high dose radiation delivered in a short period. The fallacious 60 years-old LNT is applied to cancer induction by radiation without solid data and then to cancer induction by carcinogens also without solid data. Therefore, even the smallest amount of carcinogens is postulated to be carcinogenic without thresholds now. Radiation hormesis is observed in a large variety of living organisms; radiation is beneficial at low doses, but hazardous at high doses. There is a threshold at the boundary between benefit and hazard. Hormesis denies LNT. Not a few papers report existence of chemical hormesis. If mutagens and carcinogens show hormesis, the linear dose-response relationship in mutagenesis and carcinogenesis is denied and thresholds can be introduced.

  16. Dose-Response Relationship between Dietary Magnesium Intake and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Regression Analysis of Prospective Cohort Studies

    Directory of Open Access Journals (Sweden)

    Xin Fang

    2016-11-01

    Full Text Available The epidemiological evidence for a dose-response relationship between magnesium intake and risk of type 2 diabetes mellitus (T2D is sparse. The aim of the study was to summarize the evidence for the association of dietary magnesium intake with risk of T2D and evaluate the dose-response relationship. We conducted a systematic review and meta-analysis of prospective cohort studies that reported dietary magnesium intake and risk of incident T2D. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to February 2016. We included cohort studies that provided risk ratios, i.e., relative risks (RRs, odds ratios (ORs or hazard ratios (HRs, for T2D. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. A total of 25 studies met the eligibility criteria. These studies comprised 637,922 individuals including 26,828 with a T2D diagnosis. Compared with the lowest magnesium consumption group in the population, the risk of T2D was reduced by 17% across all the studies; 19% in women and 16% in men. A statistically significant linear dose-response relationship was found between incremental magnesium intake and T2D risk. After adjusting for age and body mass index, the risk of T2D incidence was reduced by 8%–13% for per 100 mg/day increment in dietary magnesium intake. There was no evidence to support a nonlinear dose-response relationship between dietary magnesium intake and T2D risk. The combined data supports a role for magnesium in reducing risk of T2D, with a statistically significant linear dose-response pattern within the reference dose range of dietary intake among Asian and US populations. The evidence from Europe and black people is limited and more prospective studies are needed for the two subgroups.

  17. The six year report: Acidification of surface water in Europe and North America. Dose/response relationships and long-term trends

    Energy Technology Data Exchange (ETDEWEB)

    Skjelkvaale, B.L.; Newell, A.D.; Raddum, G.; Johannessen, M.; Hovind, H.; Tjomsland, T.; Wathne, B.M.

    1994-12-31

    This report discusses The International Cooperative Programme on Assessment and Monitoring of Acidification of Rivers and Lakes, which is designed to (1) establish degree and extent of acidification of surface waters, (2) evaluate dose/response relationships and (3) define long-term trends and variations in aquatic chemistry and biota attributable to atmospheric pollution. Data from 200 sites in 14 countries of Europe and North America are available. Dose/response relationships show that the fauna is adapted to different water qualities in different regions, and that critical limits for the fauna must be calculated according to data for the specific region. Long-term trends of water chemistry show decreases in SO{sub 4}{sup 2-} and Ca{sup 2+} at many sites. Nitrate shows no consistent trends. 66 refs., 26 figs., 16 tabs.

  18. The incidence of radioepidermitis and the dose-response relationship in parotid gland cancer patients treated with 125I seed brachytherapy. Incidence of radioepidermitis and the dose-response relationship

    Energy Technology Data Exchange (ETDEWEB)

    Mao, Ming-Hui; Zheng, Lei; Gao, Hong; Zhang, Jie; Liu, Shu-ming; Huang, Ming-wei; Shi, Yan [Peking University School and Hospital of Stomatology, Department of Oral and Maxillofacial Surgery, Beijing (China); Zhang, Jian-Guo [Peking University School and Hospital of Stomatology, Department of Oral and Maxillofacial Surgery, Beijing (China); Fujian Provincial Hospital, Fujian (China)

    2014-09-09

    We studied the incidence and dose-response relationship of radioepidermitis in parotid gland carcinoma patients treated with [{sup 125}I] seed brachytherapy in the hopes of designing an optimized pre-implant treatment plan that would reduce the incidence and severity of radioepidermitis in patients receiving this therapy. Between January 2007 and May 2010, 100 parotid gland cancer patients were treated postoperatively with [{sup 125}I] seed brachytherapy. The matched peripheral dose (MPD) was 80-140 Gy, and [{sup 125}I] seed activity was 0.7-0.8 mCi. The mean dose delivered to the skin was calculated in the post-implant CT on day 0 following implantation. Grades of acute and late dermatitis were evaluated at 2, 6, 12, and 18 months post-implantation. Most patients experienced grade 0-2 acute and late skin side effects (86 and 97 %, respectively), though a small subset developed severe complications. Most grade 1-3 effects resolved within 6 months of implantation, though some grade 1-3 effects and all grade 4 effects remained unchanged throughout the 18-month follow-up period. Grade 3 and 4 effects were most prominent (75 and 25 %, respectively) with doses of 110-140 Gy; doses higher than 140 Gy produced only grade 4 effects. [{sup 125}I] seed brachytherapy produced acceptable levels of acute and late radioepidermitis with a good clinical outcome. A mean dose under 100 Gy delivered to the skin was safe, though doses of 110-140 Gy should be given with caution and extra monitoring; doses greater than 140 Gy are dangerous and likely to produce grade 4-5 effects. (orig.) [German] Wir untersuchten die Inzidenz und die Dosis-Wirkung-Beziehung bei Patienten mit Ohrspeicheldruesenkrebs, die mit [{sup 125}I]-Seed-Brachytherapie behandelt wurden, in der Hoffnung, eine optimierte praeimplantologische Behandlung zu entwickeln, welche die Inzidenz und Schwere der Radioepidermitis bei Patienten, die diese Therapie erhalten haben, reduziert. Zwischen Januar 2007 und Mai 2010

  19. The Role of Target and Bystander Cells in Dose-Response Relationship of Radiation-Induced Bystander Effects in Two Cell Lines

    Science.gov (United States)

    Soleymanifard, Shokouhozaman; Bahreyni Toossi, Mohammad Taghi; Sazgarnia, Ameneh; Mohebbi, Shokoufe

    2013-01-01

    Objective(s): Radiation effect induced in nonirradiated cells which are adjacent or far from irradiated cells is termed radiation-induced bystander effect (RIBE). Published data on dose-response relationship of RIBE is controversial. In the present study the role of targeted and bystander cells in RIBE dose-response relationship of two cell lines have been investigated. Materials and Methods: Two cell lines (QU-DB and MRC5) which had previously exhibited different dose-response relationship were selected. In the previous study the two cell lines received medium from autologous irradiated cells and the results showed that the magnitude of damages induced in QU-DB cells was dependent on dose unlike MRC5 cells. In the present study, the same cells irradiated with 0.5, 2 and 4 Gy gamma rays and their conditioned media were transferred to nonautologous bystander cells; such that the bystander effects due to cross-interaction between them were studied. Micronucleus assay was performed to measure the magnitude of damages induced in bystander cells (RIBE level). Results: QU-DB cells exhibited a dose-dependent response. RIBE level in MRC5 cells which received medium from 0.5 and 2 Gy QU-DB irradiated cells was not statistically different, but surprisingly when they received medium from 4Gy irradiated QU-DB cells, RIBE was abrogated. Conclusion: Results pertaining to QU-DB and MRC5 cells indicated that both target and bystander cells determined the outcome. Triggering the bystander effect depended on the radiation dose and the target cell-type, but when RIBE was triggered, dose-response relationship was predominantly determined by the bystander cell type. PMID:24298387

  20. Systematic review using meta-analyses to estimate dose-response relationships between iodine intake and biomarkers of iodine status in different population groups.

    Science.gov (United States)

    Ristić-Medić, Danijela; Dullemeijer, Carla; Tepsić, Jasna; Petrović-Oggiano, Gordana; Popović, Tamara; Arsić, Aleksandra; Glibetić, Marija; Souverein, Olga W; Collings, Rachel; Cavelaars, Adriënne; de Groot, Lisette; van't Veer, Pieter; Gurinović, Mirjana

    2014-03-01

    The objective of this systematic review was to identify studies investigating iodine intake and biomarkers of iodine status, to assess the data of the selected studies, and to estimate dose-response relationships using meta-analysis. All randomized controlled trials, prospective cohort studies, nested case-control studies, and cross-sectional studies that supplied or measured dietary iodine and measured iodine biomarkers were included. The overall pooled regression coefficient (β) and the standard error of β were calculated by random-effects meta-analysis on a double-log scale, using the calculated intake-status regression coefficient (β) for each individual study. The results of pooled randomized controlled trials indicated that the doubling of dietary iodine intake increased urinary iodine concentrations by 14% in children and adolescents, by 57% in adults and the elderly, and by 81% in pregnant women. The dose-response relationship between iodine intake and biomarkers of iodine status indicated a 12% decrease in thyroid-stimulating hormone and a 31% decrease in thyroglobulin in pregnant women. The model of dose-response quantification used to describe the relationship between iodine intake and biomarkers of iodine status may be useful for providing complementary evidence to support recommendations for iodine intake in different population groups.

  1. Dose-response relationship of physical activity to premature and total all-cause and cardiovascular disease mortality in walkers.

    Directory of Open Access Journals (Sweden)

    Paul T Williams

    Full Text Available PURPOSE: To assess the dose-response relationships between cause-specific mortality and exercise energy expenditure in a prospective epidemiological cohort of walkers. METHODS: The sample consisted of the 8,436 male and 33,586 female participants of the National Walkers' Health Study. Walking energy expenditure was calculated in metabolic equivalents (METs, 1 MET = 3.5 ml O2/kg/min, which were used to divide the cohort into four exercise categories: category 1 (≤ 1.07 MET-hours/d, category 2 (1.07 to 1.8 MET-hours/d, category 3 (1.8 to 3.6 MET-hours/d, and category 4 (≥ 3.6 MET-hours/d. Competing risk regression analyses were use to calculate the risk of mortality for categories 2, 3 and 4 relative to category 1. RESULTS: 22.9% of the subjects were in category 1, 16.1% in category 2, 33.3% in category 3, and 27.7% in category 4. There were 2,448 deaths during the 9.6 average years of follow-up. Total mortality was 11.2% lower in category 2 (P = 0.04, 32.4% lower in category 3 (P<10(-12 and 32.9% lower in category 4 (P = 10(-11 than in category 1. For underlying causes of death, the respective risk reductions for categories 2, 3 and 4 were 23.6% (P = 0.008, 35.2% (P<10(-5, and 34.9% (P = 0.0001 for cardiovascular disease mortality; 27.8% (P = 0.18, 20.6% (P = 0.07, and 31.4% (P = 0.009 for ischemic heart disease mortality; and 39.4% (P = 0.18, 63.8% (P = 0.005, and 90.6% (P = 0.002 for diabetes mortality when compared to category 1. For all related mortality (i.e., underlying and contributing causes of death combined, the respective risk reductions for categories 2, 3 and 4 were 18.7% (P = 0.22, 42.5% (P = 0.001, and 57.5% (P = 0.0001 for heart failure; 9.4% (P = 0.56, 44.3% (P = 0.0004, and 33.5% (P = 0.02 for hypertensive diseases; 11.5% (P = 0.38, 41.0% (P<10(-4, and 35.5% (P = 0.001 for dysrhythmias: and 23.2% (P = 0.13, 45.8% (P = 0.0002, and 41.1% (P

  2. An update on modeling dose-response relationships: Accounting for correlated data structure and heterogeneous error variance in linear and nonlinear mixed models.

    Science.gov (United States)

    Gonçalves, M A D; Bello, N M; Dritz, S S; Tokach, M D; DeRouchey, J M; Woodworth, J C; Goodband, R D

    2016-05-01

    Advanced methods for dose-response assessments are used to estimate the minimum concentrations of a nutrient that maximizes a given outcome of interest, thereby determining nutritional requirements for optimal performance. Contrary to standard modeling assumptions, experimental data often present a design structure that includes correlations between observations (i.e., blocking, nesting, etc.) as well as heterogeneity of error variances; either can mislead inference if disregarded. Our objective is to demonstrate practical implementation of linear and nonlinear mixed models for dose-response relationships accounting for correlated data structure and heterogeneous error variances. To illustrate, we modeled data from a randomized complete block design study to evaluate the standardized ileal digestible (SID) Trp:Lys ratio dose-response on G:F of nursery pigs. A base linear mixed model was fitted to explore the functional form of G:F relative to Trp:Lys ratios and assess model assumptions. Next, we fitted 3 competing dose-response mixed models to G:F, namely a quadratic polynomial (QP) model, a broken-line linear (BLL) ascending model, and a broken-line quadratic (BLQ) ascending model, all of which included heteroskedastic specifications, as dictated by the base model. The GLIMMIX procedure of SAS (version 9.4) was used to fit the base and QP models and the NLMIXED procedure was used to fit the BLL and BLQ models. We further illustrated the use of a grid search of initial parameter values to facilitate convergence and parameter estimation in nonlinear mixed models. Fit between competing dose-response models was compared using a maximum likelihood-based Bayesian information criterion (BIC). The QP, BLL, and BLQ models fitted on G:F of nursery pigs yielded BIC values of 353.7, 343.4, and 345.2, respectively, thus indicating a better fit of the BLL model. The BLL breakpoint estimate of the SID Trp:Lys ratio was 16.5% (95% confidence interval [16.1, 17.0]). Problems with

  3. Second Solid Cancers After Radiation Therapy: A Systematic Review of the Epidemiologic Studies of the Radiation Dose-Response Relationship

    Energy Technology Data Exchange (ETDEWEB)

    Berrington de Gonzalez, Amy, E-mail: berringtona@mail.nih.gov [Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States); Gilbert, Ethel; Curtis, Rochelle; Inskip, Peter; Kleinerman, Ruth; Morton, Lindsay; Rajaraman, Preetha; Little, Mark P. [Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States)

    2013-06-01

    Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studies of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques.

  4. Ecological versus case-control studies for testing a linear-no threshold dose-response relationship.

    Science.gov (United States)

    Cohen, B L

    1990-09-01

    The two basic problems with ecological studies are (A) individuals studied are not necessarily the individuals who are at risk, and (B) they are very vulnerable to confounding factors. It is shown that where the study is designed to test a linear-no threshold dose-response theory, (A) does not apply. Where the ecological study deals with the average dose and response in a large number of US counties, the available data and computer capability for reducing effects of confounders are so powerful that (B) may be no more important for the ecological than for a case-control study. The migration problem is treated and found to be relatively unimportant.

  5. Dose-response relationships for the onset of avoidance of sonar by free-ranging killer whales.

    Science.gov (United States)

    Miller, Patrick J O; Antunes, Ricardo N; Wensveen, Paul J; Samarra, Filipa I P; Alves, Ana Catarina; Tyack, Peter L; Kvadsheim, Petter H; Kleivane, Lars; Lam, Frans-Peter A; Ainslie, Michael A; Thomas, Len

    2014-02-01

    Eight experimentally controlled exposures to 1-2 kHz or 6-7 kHz sonar signals were conducted with four killer whale groups. The source level and proximity of the source were increased during each exposure in order to reveal response thresholds. Detailed inspection of movements during each exposure session revealed sustained changes in speed and travel direction judged to be avoidance responses during six of eight sessions. Following methods developed for Phase-I clinical trials in human medicine, response thresholds ranging from 94 to 164 dB re 1 μPa received sound pressure level (SPL) were fitted to Bayesian dose-response functions. Thresholds did not consistently differ by sonar frequency or whether a group had previously been exposed, with a mean SPL response threshold of 142 ± 15 dB (mean ± s.d.). High levels of between- and within-individual variability were identified, indicating that thresholds depended upon other undefined contextual variables. The dose-response functions indicate that some killer whales started to avoid sonar at received SPL below thresholds assumed by the U.S. Navy. The predicted extent of habitat over which avoidance reactions occur depends upon whether whales responded to proximity or received SPL of the sonar or both, but was large enough to raise concerns about biological consequences to the whales.

  6. Site-specific dose-response relationships for cancer induction from the combined Japanese A-bomb and Hodgkin cohorts for doses relevant to radiotherapy

    Directory of Open Access Journals (Sweden)

    Sumila Marcin

    2011-07-01

    Full Text Available Abstract Background and Purpose Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation induced solid cancer. Materials and methods For various organs and tissues the analysis of cancer induction was extended by an attempted combination of the linear-no-threshold model from the A-bomb survivors in the low dose range and the cancer risk data of patients receiving radiotherapy for Hodgkin's disease in the high dose range. The data were fitted using organ equivalent dose (OED calculated for a group of different dose-response models including a linear model, a model including fractionation, a bell-shaped model and a plateau-dose-response relationship. Results The quality of the applied fits shows that the linear model fits best colon, cervix and skin. All other organs are best fitted by the model including fractionation indicating that the repopulation/repair ability of tissue is neither 0 nor 100% but somewhere in between. Bone and soft tissue sarcoma were fitted well by all the models. In the low dose range beyond 1 Gy sarcoma risk is negligible. For increasing dose, sarcoma risk increases rapidly and reaches a plateau at around 30 Gy. Conclusions In this work OED for various organs was calculated for a linear, a bell-shaped, a plateau and a mixture between a bell-shaped and plateau dose-response relationship for typical treatment plans of Hodgkin's disease patients. The model parameters (α and R were obtained by a fit of the dose-response relationships to these OED data and to the A-bomb survivors. For

  7. Dose-response relationship of dicentric chromosomes in human lymphocytes obtained for the fission neutron therapy facility MEDAPP at the research reactor FRM II.

    Science.gov (United States)

    Schmid, E; Wagner, F M; Romm, H; Walsh, L; Roos, H

    2009-02-01

    The biological effectiveness of neutrons from the neutron therapy facility MEDAPP (mean neutron energy 1.9 MeV) at the new research reactor FRM II at Garching, Germany, has been analyzed, at different depths in a polyethylene phantom. Whole blood samples were exposed to the MEDAPP beam in special irradiation chambers to total doses of 0.14-3.52 Gy at 2-cm depth, and 0.18-3.04 Gy at 6-cm depth of the phantom. The neutron and gamma-ray absorbed dose rates were measured to be 0.55 Gy min(-1) and 0.27 Gy min(-1) at 2-cm depth, while they were 0.28 and 0.25 Gy min(-1) at 6-cm depth. Although the irradiation conditions at the MEDAPP beam and the RENT beam of the former FRM I research reactor were not identical, neutrons from both facilities gave a similar linear-quadratic dose-response relationship for dicentric chromosomes at a depth of 2 cm. Different dose-response curves for dicentrics were obtained for the MEDAPP beam at 2 and 6 cm depth, suggesting a significantly lower biological effectiveness of the radiation with increasing depth. No obvious differences in the dose-response curves for dicentric chromosomes estimated under interactive or additive prediction between neutrons or gamma-rays and the experimentally obtained dose-response curves could be determined. Relative to (60)Co gamma-rays, the values for the relative biological effectiveness at the MEDAPP beam decrease from 5.9 at 0.14 Gy to 1.6 at 3.52 Gy at 2-cm depth, and from 4.1 at 0.18 Gy to 1.5 at 3.04 Gy at 6-cm depth. Using the best possible conditions of consistency, i.e., using blood samples from the same donor and the same measurement techniques for about two decades, avoiding the inter-individual variations in sensitivity or the differences in methodology usually associated with inter-laboratory comparisons, a linear-quadratic dose-response relationship for the mixed neutron and gamma-ray MEDAPP field as well as for its fission neutron part was obtained. Therefore, the debate on whether the fission

  8. Systems Cancer Biology and the Controlling Mechanisms for the J-Shaped Cancer Dose Response: Towards Relaxing the LNT Hypothesis

    OpenAIRE

    Lou, In Chio; Zhao, Yuchao; Wu, YingJie; Ricci, Paolo F

    2012-01-01

    The hormesis phenomena or J-shaped dose response have been accepted as a common phenomenon regardless of the involved biological model, endpoint measured and chemical class/physical stressor. This paper first introduced a mathematical dose response model based on systems biology approach. It links molecular-level cell cycle checkpoint control information to clonal growth cancer model to predict the possible shapes of the dose response curves of Ionizing Radiation (IR) induced tumor transforma...

  9. Effects and dose-response relationships of resistance training on physical performance in youth athletes: a systematic review and meta-analysis.

    Science.gov (United States)

    Lesinski, Melanie; Prieske, Olaf; Granacher, Urs

    2016-07-01

    To quantify age, sex, sport and training type-specific effects of resistance training on physical performance, and to characterise dose-response relationships of resistance training parameters that could maximise gains in physical performance in youth athletes. Systematic review and meta-analysis of intervention studies. Studies were identified by systematic literature search in the databases PubMed and Web of Science (1985-2015). Weighted mean standardised mean differences (SMDwm) were calculated using random-effects models. Only studies with an active control group were included if these investigated the effects of resistance training in youth athletes (6-18 years) and tested at least one physical performance measure. 43 studies met the inclusion criteria. Our analyses revealed moderate effects of resistance training on muscle strength and vertical jump performance (SMDwm 0.8-1.09), and small effects on linear sprint, agility and sport-specific performance (SMDwm 0.58-0.75). Effects were moderated by sex and resistance training type. Independently computed dose-response relationships for resistance training parameters revealed that a training period of >23 weeks, 5 sets/exercise, 6-8 repetitions/set, a training intensity of 80-89% of 1 repetition maximum (RM), and 3-4 min rest between sets were most effective to improve muscle strength (SMDwm 2.09-3.40). Resistance training is an effective method to enhance muscle strength and jump performance in youth athletes, moderated by sex and resistance training type. Dose-response relationships for key training parameters indicate that youth coaches should primarily implement resistance training programmes with fewer repetitions and higher intensities to improve physical performance measures of youth athletes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  10. Dicentric chromosomes and gamma-H2AX foci formation in lymphocytes of human blood samples exposed to a CT scanner: a direct comparison of dose response relationships.

    Science.gov (United States)

    Golfier, Sven; Jost, Gregor; Pietsch, Hubertus; Lengsfeld, Philipp; Eckardt-Schupp, Friederike; Schmid, Ernst; Voth, Matthias

    2009-02-01

    Experiments using the induction of dicentric chromosomes (dicentrics) as well as the gamma-H2AX foci formation in lymphocytes of blood samples from a healthy donor were performed to directly evaluate the radiation sensitivity of both biological endpoints. For computed tomography scans at dose levels from 0.025 to 1 Gy, a linear-quadratic dose-response relationship for dicentrics and a linear dose-response relationship for gamma-H2AX foci were obtained. The coefficients of the dose-response relationship for dicentrics are alpha = (3.76 +/- 0.29) x 10(-2) Gy(-1) and beta = (5.54 +/- 0.45) x 10(-2) Gy(-2), the linear coefficient for gamma-H2AX foci is (7.38 +/- 0.11) Gy(-1). The findings indicate that scoring of dicentrics as well as microscopic analysis of gamma-H2AX foci are sensitive methods to quantify a radiation-induced biological damage at low doses. However, since gamma-H2AX foci can be partially repaired within a few hours, biological damages present for days or even months, which constitute the clinically relevant endpoints, can only be quantified reliably by scoring of chromosome aberrations. Thus currently the quantification of dicentrics or reciprocal translocations remains the recommended method for estimating the effect of exposures to low dose levels of radiation ('biological dosimetry'). However, owing to the high radiation sensitivity of the gamma-H2AX foci assay observed in the present study, further investigations on the effectiveness of low-linear energy transfer radiation qualities in producing gamma-H2AX foci in lymphocytes from healthy donors should be performed.

  11. The Relationship between Zinc Intake and Serum/Plasma Zinc Concentration in Children: A Systematic Review and Dose-Response Meta-Analysis

    Science.gov (United States)

    Moran, Victoria Hall; Stammers, Anna-Louise; Medina, Marisol Warthon; Patel, Sujata; Dykes, Fiona; Souverein, Olga W.; Dullemeijer, Carla; Pérez-Rodrigo, Carmen; Serra-Majem, Lluis; Nissensohn, Mariela; Lowe, Nicola M.

    2012-01-01

    Recommendations for zinc intake during childhood vary widely across Europe. The EURRECA project attempts to consolidate the basis for the definition of micronutrient requirements, taking into account relationships among intake, status and health outcomes, in order to harmonise these recommendations. Data on zinc intake and biomarkers of zinc status reported in randomised controlled trials (RCTs) can provide estimates of dose-response relationships which may be used for underpinning zinc reference values. This systematic review included all RCTs of apparently healthy children aged 1–17 years published by February 2010 which provided data on zinc intake and biomarkers of zinc status. An intake-status regression coefficient () was calculated for each individual study and calculated the overall pooled and SE () using random effects meta-analysis on a double log scale. The pooled dose-response relationship between zinc intake and zinc status indicated that a doubling of the zinc intake increased the serum/plasma zinc status by 9%. This evidence can be utilised, together with currently used balance studies and repletion/depletion studies, when setting zinc recommendations as a basis for nutrition policies. PMID:23016120

  12. The Relationship between Zinc Intake and Serum/Plasma Zinc Concentration in Children: A Systematic Review and Dose-Response Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Nicola M. Lowe

    2012-07-01

    Full Text Available Recommendations for zinc intake during childhood vary widely across Europe. The EURRECA project attempts to consolidate the basis for the definition of micronutrient requirements, taking into account relationships among intake, status and health outcomes, in order to harmonise these recommendations. Data on zinc intake and biomarkers of zinc status reported in randomised controlled trials (RCTs can provide estimates of dose-response relationships which may be used for underpinning zinc reference values. This systematic review included all RCTs of apparently healthy children aged 1–17 years published by February 2010 which provided data on zinc intake and biomarkers of zinc status. An intake-status regression coefficient ( was calculated for each individual study and calculated the overall pooled  and SE ( using random effects meta-analysis on a double log scale. The pooled dose-response relationship between zinc intake and zinc status indicated that a doubling of the zinc intake increased the serum/plasma zinc status by 9%. This evidence can be utilised, together with currently used balance studies and repletion/depletion studies, when setting zinc recommendations as a basis for nutrition policies.

  13. Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose-volume outcome relationships

    Energy Technology Data Exchange (ETDEWEB)

    Naqa, I El [Washington University, Saint Louis, MO (United States); Suneja, G [Brown Medical School, Providence, RI (United States); Lindsay, P E [Washington University, St. Louis, MO (United States); Hope, A J [Washington University, Saint Louis, MO (United States); Alaly, J R [Washington University, Saint Louis, MO (United States); Vicic, M [Washington University, Saint Louis, MO (United States); Bradley, J D [Washington University, Saint Louis, MO (United States); Apte, A [Washington University, Saint Louis, MO (United States); Deasy, J O [Washington University, Saint Louis, MO (United States)

    2006-11-21

    Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

  14. Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose volume outcome relationships

    Science.gov (United States)

    El Naqa, I.; Suneja, G.; Lindsay, P. E.; Hope, A. J.; Alaly, J. R.; Vicic, M.; Bradley, J. D.; Apte, A.; Deasy, J. O.

    2006-11-01

    Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

  15. Toxicity of TiO2 nanoparticles on soil nitrification at environmentally relevant concentrations: Lack of classical dose-response relationships.

    Science.gov (United States)

    Simonin, Marie; Martins, Jean M F; Le Roux, Xavier; Uzu, Gaëlle; Calas, Aude; Richaume, Agnès

    2017-03-01

    Titanium-dioxide nanoparticles (TiO2-NPs) are increasingly released in agricultural soils through, e.g. biosolids, irrigation or nanoagrochemicals. Soils are submitted to a wide range of concentrations of TiO2-NPs depending on the type of exposure. However, most studies have assessed the effects of unrealistically high concentrations, and the dose-response relationships are not well characterized for soil microbial communities. Here, using soil microcosms, we assessed the impact of TiO2-NPs at concentrations ranging from 0.05 to 500 mg kg(-1 )dry-soil, on the activity and abundance of ammonia-oxidizing archaea (AOA) and bacteria (AOB), and nitrite-oxidizing bacteria (Nitrobacter and Nitrospira). In addition, aggregation and oxidative potential of TiO2-NPs were measured in the spiking suspensions, as they can be important drivers of TiO2-NPs toxicity. After 90 days of exposure, non-classical dose-response relationships were observed for nitrifier abundance or activity, making threshold concentrations impossible to compute. Indeed, AOA abundance was reduced by 40% by TiO2-NPs whatever the concentration, while Nitrospira was never affected. Moreover, AOB and Nitrobacter abundances were decreased mainly at intermediate concentrations nitrification was reduced by 25% at the lowest (0.05 mg kg(-1)) and the highest (100 and 500 mg kg(-1)) TiO2-NPs concentrations. Path analyses indicated that TiO2-NPs affected nitrification through an effect on the specific activity of nitrifiers, in addition to indirect effects on nitrifier abundances. Altogether these results point out the need to include very low concentrations of NPs in soil toxicological studies, and the lack of relevance of classical dose-response tests and ecotoxicological dose metrics (EC50, IC50…) for TiO2-NPs impact on soil microorganisms.

  16. Dose-Response Relationship between Cumulative Occupational Lead Exposure and the Associated Health Damages: A 20-Year Cohort Study of a Smelter in China.

    Science.gov (United States)

    Wu, Yue; Gu, Jun-Ming; Huang, Yun; Duan, Yan-Ying; Huang, Rui-Xue; Hu, Jian-An

    2016-03-16

    Long-term airborne lead exposure, even below official occupational limits, has been found to cause lead poisoning at higher frequencies than expected, which suggests that China's existing occupational exposure limits should be reexamined. A retrospective cohort study was conducted on 1832 smelting workers from 1988 to 2008 in China. These were individuals who entered the plant and came into continuous contact with lead at work for longer than 3 months. The dose-response relationship between occupational cumulative lead exposure and lead poisoning, abnormal blood lead, urinary lead and erythrocyte zinc protoporphyrin (ZPP) were analyzed and the benchmark dose lower bound confidence limits (BMDLs) were calculated. Statistically significant positive correlations were found between cumulative lead dust and lead fumes exposures and workplace seniority, blood lead, urinary lead and ZPP values. A dose-response relationship was observed between cumulative lead dust or lead fumes exposure and lead poisoning (p lead dust and fumes doses were 0.68 mg-year/m³ and 0.30 mg-year/m³ for lead poisoning, respectively. The BMDLs of workplace airborne lead concentrations associated with lead poisoning were 0.02 mg/m³ and 0.01 mg/m³ for occupational exposure lead dust and lead fume, respectively. In conclusion, BMDLs for airborne lead were lower than occupational exposure limits, suggesting that the occupational lead exposure limits need re-examination and adjustment. Occupational cumulative exposure limits (OCELs) should be established to better prevent occupational lead poisoning.

  17. Dose-response relationship of robot-assisted stroke motor rehabilitation: the impact of initial motor status.

    Science.gov (United States)

    Hsieh, Yu-wei; Wu, Ching-yi; Lin, Keh-chung; Yao, Grace; Wu, Kuen-yuh; Chang, Ya-ju

    2012-10-01

    The increasing availability of robot-assisted therapy (RT), which provides quantifiable, reproducible, interactive, and intensive practice, holds promise for stroke rehabilitation, but data on its dose-response relation are scanty. This study used 2 different intensities of RT to examine the treatment effects of RT and the effect on outcomes of the severity of initial motor deficits. Fifty-four patients with stroke were randomized to a 4-week intervention of higher-intensity RT, lower-intensity RT, or control treatment. The primary outcome, the Fugl-Meyer Assessment, was administered at baseline, midterm, and posttreatment. Secondary outcomes included the Medical Research Council scale, the Motor Activity Log, and the physical domains of the Stroke Impact Scale. The higher-intensity RT group showed significantly greater improvements on the Fugl-Meyer Assessment than the lower-intensity RT and control treatment groups at midterm (P=0.003 and P=0.02) and at posttreatment (P=0.04 and P=0.02). Within-group gains on the secondary outcomes were significant, but the differences among the 3 groups did not reach significance. Recovery rates of the higher-intensity RT group were higher than those of the lower-intensity RT group, particularly on the Fugl-Meyer Assessment. Scatterplots with curve fitting showed that patients with moderate motor deficits gained more improvements than those with severe or mild deficits after the higher-intensity RT. This study demonstrated the higher treatment intensity provided by RT was associated with better motor outcome for patients with stroke, which may shape further stroke rehabilitation. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00917605.

  18. Radiation hormesis in plant

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae Sung; Song, Hi Sup; Lee, Young Keun; Lee, Byung Hun; Shin, In Chul; Lim, Young Taek

    2000-04-01

    This research was performed to investigate the effects of low dose {gamma}-ray radiation on the seed germination and the following physiological responses in vegetable crops. Special attention was focused on whether the resistance of vegetables against the unfavorable conditions of environment such as subsequent high doses of radiation or Phytophthora blight of pepper could be enhanced as an aspect of radiation hormesis. Analysis and characterization of antioxidant enzyme from plant culture cells and radiation tolerant of transformed plants from antioxidant (POD) were accomplished in the plant irradiated with different dose of {gamma}-ray. (author)

  19. Radiation hormesis in plant

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae Sung; Song, Hi Sup; Lee, Young Keun; Cun, Ki Jung; Shin, In Chul; Lim, Young Taek

    1999-04-01

    This research was performed to investigate the effects of low dose {gamma}-ray radiation on the seed germination and the following physiological responses in vegetable crops. Special attention was focused on whether the resistance of vegetables against the unfavorable conditions of environment such as acid rain or soil types could be enhanced as an aspect of radiation hormesis. Analysis and characterization of antioxidant enzyme from plant culture cells and radiation tolerant of transformed plants from antioxidant enzyme (POD) were accomplished in the plant irradiated with difference dosage of {gamma}-ray.

  20. Glyphosate-resistant and -susceptible soybean (Glycine max) and canola (Brassica napus) dose response and metabolism relationships with glyphosate.

    Science.gov (United States)

    Nandula, Vijay K; Reddy, Krishna N; Rimando, Agnes M; Duke, Stephen O; Poston, Daniel H

    2007-05-02

    Experiments were conducted to determine (1) dose response of glyphosate-resistant (GR) and -susceptible (non-GR) soybean [Glycine max (L.) Merr.] and canola (Brassica napus L.) to glyphosate, (2) if differential metabolism of glyphosate to aminomethyl phosphonic acid (AMPA) is the underlying mechanism for differential resistance to glyphosate among GR soybean varieties, and (3) the extent of metabolism of glyphosate to AMPA in GR canola and to correlate metabolism to injury from AMPA. GR50 (glyphosate dose required to cause a 50% reduction in plant dry weight) values for GR (Asgrow 4603RR) and non-GR (HBKC 5025) soybean were 22.8 kg ae ha-1 and 0.47 kg ha-1, respectively, with GR soybean exhibiting a 49-fold level of resistance to glyphosate as compared to non-GR soybean. Differential reduction in chlorophyll by glyphosate was observed between GR soybean varieties, but there were no differences in shoot fresh weight reduction. No significant differences were found between GR varieties in metabolism of glyphosate to AMPA, and in shikimate levels. These results indicate that GR soybean varieties were able to outgrow the initial injury from glyphosate, which was previously caused at least in part by AMPA. GR50 values for GR (Hyola 514RR) and non-GR (Hyola 440) canola were 14.1 and 0.30 kg ha-1, respectively, with GR canola exhibiting a 47-fold level of resistance to glyphosate when compared to non-GR canola. Glyphosate did not cause reduction in chlorophyll content and shoot fresh weight in GR canola, unlike GR soybean. Less glyphosate (per unit leaf weight) was recovered in glyphosate-treated GR canola as compared to glyphosate-treated GR soybean. External application of AMPA caused similar injury in both GR and non-GR canola. The presence of a bacterial glyphosate oxidoreductase gene in GR canola contributes to breakdown of glyphosate to AMPA. However, the AMPA from glyphosate breakdown could have been metabolized to nonphytotoxic metabolites before causing injury

  1. Determining the most appropriate dose metrics for evaluating dose-response relationships of metal-based nanoparticles to zebrafish embryos

    NARCIS (Netherlands)

    Hua, Jing

    2015-01-01

    Nanoparticles (NPs) exhibit special physicochemical properties compared to bulk particles. The difference in properties could, in principle, produce different effects on organisms. It is therefore important to determine the relationship between the physicochemical characteristics of NPs and their

  2. The dose-response relationship between the patch test and ROAT and the potential use for regulatory purposes

    DEFF Research Database (Denmark)

    Fischer, Louise Arup; Voelund, Aage; Andersen, Klaus Ejner

    2009-01-01

    BACKGROUND: Allergic contact dermatitis is common and can be prevented. The relationship between thresholds for patch tests and the repeated open application test (ROAT) is unclear. It would be desirable if patch test and ROAT data from already sensitized individuals could be used in prevention. ...

  3. The capacity of short-chain fructo-oligosaccharides to stimulate faecal bifidobacteria: a dose-response relationship study in healthy humans

    Directory of Open Access Journals (Sweden)

    Simoneau Guy

    2006-03-01

    Full Text Available Abstract Background Short-chain fructo-oligosaccharides (scFOS are well-known for their bifidogenicity. In a large study comprising 200 healthy volunteers, we determined the bifidogenic properties of 7 non-digestible carbohydrates administered at a dose of 10 g/d in the diet; we analysed dose-response relationships of the bifidogenic substrates at doses ranging from 2.5 to 10 g/d in comparison with a placebo. The aim of this presentation is to give more details about the dose-response effects of short-chain fructo-oligosaccharides (scFOS. Methods Forty healthy volunteers (18 males, 22 females eating their usual diets were randomly divided into 5 groups of 8 subjects and received scFOS at a dose of 2.5, 5.0, 7.5 and 10 g/d or a placebo for 7 d. Stools were collected before (day (d 8 and at the end (day (d 15 of sugar consumption, and tolerance was evaluated using a daily chart. Results (m ± SEM Bifidobacteria counts increase was higher in scFOS than in placebo group for all doses tested [2.5 g/d (from 9.15 ± 0.59 to 9.39 ± 0.70; P = 0.02; 5 g/d (from 10.21 ± 0.21 to 10.67 ± 0.22; P = 0.03; 7.5 g/d (from 9.28 ± 0.49 to 9.85 ± 0.35;P = 0.01; 10 g/d (from 9.00 ± 0.81 to 10.18 ± 0.60; P = 0.003]. A significant correlation between the ingested dose of scFOS and faecal bifidobacteria counts was observed at d15 (r2 = 0.307, P Conclusion This study showed that scFOS is bifidogenic and well tolerated at doses ranging from 2.5 to 10 g/d, and that there is a dose-response relationship in healthy volunteers.

  4. A dose-response relationship for marketable yield reduction of two lettuce (Lactuca sativa L.) cultivars exposed to tropospheric ozone in Southern Europe.

    Science.gov (United States)

    Marzuoli, Riccardo; Finco, Angelo; Chiesa, Maria; Gerosa, Giacomo

    2016-12-27

    The present study investigated the response to ozone (O3) of two cultivars (cv.'Romana' and cv. 'Canasta') of irrigated lettuce grown in an open-top chamber (OTC) experiment in Mediterranean conditions. Two different levels of O3 were applied, ambient O3 in non-filtered OTCs (NF-OTCs) and -40% of ambient O3 in charcoal-filtered OTCs (CF-OTCs), during four consecutive growing cycles. At the end of each growing cycle, the marketable yield (fresh biomass) was assessed while during the growing periods, measurements of the stomatal conductance at leaf level were performed and used to define a stomatal conductance model for calculation of the phytotoxic ozone dose (POD) absorbed by the plants.Results showed that O3 caused statistically significant yield reductions in the first and in the last growing cycle. In general, the marketable yield of the NF-OTC plants was always lower than the CF-OTC plants for both cultivars, with mean reductions of -18.5 and -14.5% for 'Romana' and 'Canasta', respectively. On the contrary, there was no statistically significant difference in marketable yield due to the cultivar factor or to the interaction between O3 and cultivar in any of the growing cycle performed.Dose-response relationships for the marketable relative yield based on the POD values were calculated according to different flux threshold values (Y). The best regression fit was obtained using an instantaneous flux threshold of 6 nmol O3 m(-2) s(-1) (POD6); the same value was obtained also for other crops. According to the generic lettuce dose-response relationship, an O3 critical level of 1 mmol O3 m(-2) of POD6 for a 15% of marketable yield loss was found.

  5. Dose-response relationship in music therapy for people with serious mental disorders: systematic review and meta-analysis.

    Science.gov (United States)

    Gold, Christian; Solli, Hans Petter; Krüger, Viggo; Lie, Stein Atle

    2009-04-01

    Serious mental disorders have considerable individual and societal impact, and traditional treatments may show limited effects. Music therapy may be beneficial in psychosis and depression, including treatment-resistant cases. The aim of this review was to examine the benefits of music therapy for people with serious mental disorders. All existing prospective studies were combined using mixed-effects meta-analysis models, allowing to examine the influence of study design (RCT vs. CCT vs. pre-post study), type of disorder (psychotic vs. non-psychotic), and number of sessions. Results showed that music therapy, when added to standard care, has strong and significant effects on global state, general symptoms, negative symptoms, depression, anxiety, functioning, and musical engagement. Significant dose-effect relationships were identified for general, negative, and depressive symptoms, as well as functioning, with explained variance ranging from 73% to 78%. Small effect sizes for these outcomes are achieved after 3 to 10, large effects after 16 to 51 sessions. The findings suggest that music therapy is an effective treatment which helps people with psychotic and non-psychotic severe mental disorders to improve global state, symptoms, and functioning. Slight improvements can be seen with a few therapy sessions, but longer courses or more frequent sessions are needed to achieve more substantial benefits.

  6. Radiation hormesis in higher plants

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae Sung [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    1996-03-01

    The most remarkable aspect in the hormesis law is that low dose of harmful agents can produce effect that are diametrically opposite to the effect found with high doses of the same agent. Minute quantities of a harmful agent bring about very small change in the organism and control mechanisms appear to subjugate normal processes to place the organism in a state of alert and repair. The stimulated organism is more responsive to changes in environmental factors than it did before being alerted. Routine functions, including repair and defense, have priority for available energy and material. The alerted organism utilizes nutrients more efficiently, grows faster, shows improved defense reactions, matures faster, reproduces more effectively, has less disease, and lives longer. Accelerated germination, sprouting, growth, development, blooming and ripening, and increased crop yield and resistance to disease are found in plants. Another concept supported by the data is that low doses of ionizing radiation provide increased resistance to subsequent high doses of radiation. The hormesis varies with subject plant, variety, state of seed, environmental and cultural conditions, physiologic function measured, dose rate and total exposure. The results of hormesis are less consistently found, probably due to the great number of uncontrolled variables in the experiments. The general dosage for radiation hormesis in about 100 times ambient or 100 times less than a definitely harmful dose, but these must be modified to the occasion. Although little is known about most mechanisms of hormesis reaction, overcompensation of repair mechanism is offered as on mechanism. Radiation hormesis can provide more efficient use of resources, maximum production of foods, and increased health by the use of ionizing radiation as a useful tool in our technologic society. Efficient utilization of nature`s resources demands support to explore the practical application of radiation hormesis.

  7. Hormesis and the salk polio vaccine.

    Science.gov (United States)

    Calabrese, Edward J

    2012-01-01

    The production of the Salk vaccine polio virus by monkey kidney cells was generated using the synthetic tissue culture medium, Mixture 199. In this paper's retrospective assessment of this process, it was discovered that Mixture 199 was modified by the addition of ethanol to optimize animal cell survival based on experimentation that revealed a hormetic-like biphasic response relationship. This hormesis-based optimization procedure was then applied to all uses of Mixture 199 and modifications of it, including its application to the Salk polio vaccine during preliminary testing and in its subsequent major societal treatment programs.

  8. Interactions of tiagabine with ethosuximide in the mouse pentylenetetrazole-induced seizure model: an isobolographic analysis for non-parallel dose-response relationship curves.

    Science.gov (United States)

    Luszczki, Jarogniew J

    2008-11-01

    The aim of this study was to characterize the interaction between tiagabine (TGB) and ethosuximide (ETS), two antiepileptic drugs, in pentylenetetrazole (PTZ)-induced clonic seizures in mice using isobolographic analysis. The nature of the interaction between the drugs administered in combination was ascertained by estimating plasma and brain concentrations of ETS and TGB using fluorescence polarization immunoassay (FPIA) and high-performance liquid chromatography (HPLC). The results indicated that both drugs produced clear anticonvulsant effects against PTZ-induced clonic seizures in mice, but that their dose-response relationship curves (DRRCs) were not parallel, consequently necessitating the isobolographic analysis for non-parallel DRRCs. The isobolographic analysis revealed that the combination of TGB with ETS at the fixed-ratio of 1:1 exerted an additive interaction against PTZ-induced clonic seizures in mice. FPIA documented that TGB significantly elevated brain ETS concentrations (by 64%), while having no effect on plasma ETS concentrations in experimental animals. In contrast, ETS had no significant impact on plasma and brain concentrations of TGB in mice, as measured by HPLC. It can be concluded that the additive interaction between TGB and ETS at the fixed-ratio of 1:1 in the PTZ test was complicated by a significant pharmacokinetic increase in total brain ETS concentrations. At present, there are no recommendations to use this drug combination in epileptic patients.

  9. Dose-response relationship of baroreflex sensitivity and heart rate variability to individually-tailored exercise training in patients with heart failure.

    Science.gov (United States)

    Iellamo, Ferdinando; Manzi, Vincenzo; Caminiti, Giuseppe; Sposato, Barbara; Massaro, Michele; Cerrito, Anna; Rosano, Giuseppe; Volterrani, Maurizio

    2013-06-20

    Heart Rate Variability (HRV) and Baroreflex Sensitivity (BRS) are impaired in patients with Chronic Heart Failure (CHF) and carry negative prognosis. Exercise training improves these parameters. However, the relationship between exercise training with HRV and BRS has been investigated without regard for individual training loads. We tested the hypothesis that in CHF patients changes in HRV and BRS are dose-response related to individual volume/intensity training load (TL). Twenty patients with stable postinfarction CHF under optimal medical treatment were randomized to either aerobic continuous training (ACT) or aerobic interval training (AIT) for 12weeks. Individualized TL was monitored by the Training Impulses (TRIMPi) method, which was determined using the individual HR and lactate profiling determined during a treadmill test at baseline. HRV (standard deviation of mean R-R interval) and BRS were assessed at rest and 3weeks apart, throughout the study. HRV, BRS and R-R interval increased significantly with training, being very highly correlated to the dose of exercise with a second-order regression model (r(2) ranged from 0.75 to 0.96; Pincrease in functional capacity. No significant differences were detected between ACT and AIT in any variable. These results suggest that improvements in HRV and BRS by exercise training in CHF patients are dose related to TL in a non-linear fashion on an individual basis, with optimal results at moderate doses of exercise. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  10. Assessment of The Dose-Response Relationship of Radiation-Induced Bystander Effect in Two Cell Lines Exposed to High Doses of Ionizing Radiation (6 and 8 Gy).

    Science.gov (United States)

    Bahreyni Toossi, Mohammad Taghi; Khademi, Sara; Azimian, Hosein; Mohebbi, Shokoufeh; Soleymanifard, Shokouhozaman

    2017-10-01

    The dose-response relationship of radiation-induced bystander effect (RIBE) is controversial at high dose levels. The aim of the present study is to assess RIBE at high dose levels by examination of different endpoints. This experimental study used the medium transfer technique to induce RIBE. The cells were divided into two main groups: QU-DB cells which received medium from autologous irradiated cells and MRC5 cells which received medium from irradiated QU-DB cells. Colony, MTT, and micronucleus assays were performed to quantify bystander responses. The medium was diluted and transferred to bystander cells to investigate whether medium dilution could revive the RIBE response that disappeared at a high dose. The RIBE level in QU-DB bystander cells increased in the dose range of 0.5 to 4 Gy, but decreased at 6 and 8 Gy. The Micronucleated cells per 1000 binucleated cells (MNBN) frequency of QU-DB bystander cells which received the most diluted medium from 6 and 8 Gy QU-DB irradiated cells reached the maximum level compared to the MNBN frequency of the cells that received complete medium (Pbystander cells. This finding confirmed that a negative feedback mechanism was responsible for the decrease in RIBE response at high doses. Decrease of RIBE at high doses might be used to predict that in radiosurgery, brachytherapy and grid therapy, in which high dose per fraction is applied, normal tissue damage owing to RIBE may decrease.

  11. Dose-response relationships of oral habits associated with the risk of oral pre-malignant lesions among men who chew betel quid.

    Science.gov (United States)

    Yen, Amy Ming-Fang; Chen, Shao-Ching; Chen, Tony Hsiu-Hsi

    2007-08-01

    Betel quid, cigarettes and alcohol are well-recognized risk factors for oral cancer. However, the combined effect of the frequency and duration of these oral habits on the risk for developing oral pre-malignancies among betel quid users has not been fully addressed. In this study, an oral screening programme for men chewing betel quid was carried out by well-trained dentists for early detection of oral pre-malignancy lesions. Using generalized logit model and proportional odds model, we found that, compared with the occasional user, the adjusted odds ratios of developing leukoplakia for men chewing one to 10 pieces of betel quid, 11-20 pieces, and more than 20 pieces per day were estimated as 2.14 (95% confidence interval [CI] 1.62-2.81), 2.99 (95% CI 2.06-4.27), and 5.37 (95% CI 3.76-7.47), respectively. The corresponding figures for erythroleukoplakia were 3.69 (95% CI 1.55-8.79), 13.78 (95% CI 5.76-32.98), and 36.64 (95% CI 15.94-84.16), respectively. Similar results were found while the duration was considered. The dose-response relationships were not as noteworthy for cigarette and alcohol drinking.

  12. For whom the bell (curve) tolls: cortisol rapidly affects memory retrieval by an inverted U-shaped dose-response relationship.

    Science.gov (United States)

    Schilling, Thomas M; Kölsch, Monika; Larra, Mauro F; Zech, Carina M; Blumenthal, Terry D; Frings, Christian; Schächinger, Hartmut

    2013-09-01

    Stress and cortisol are generally considered to impair declarative memory retrieval, although opposite results have also been reported. Dose-dependent effects and differences between genomic and non-genomic cortisol effects are possible reasons for these discrepancies. The aim of the current experiment was to assess the non-genomic effects of escalating doses of intravenous cortisol on cued recall of socially relevant information in humans. 40 participants (age range 20-30 years; 20 females) learned associations between male faces with a neutral facial expression and descriptions of either positive or negative social behaviors and were tested one week later in a cued recall paradigm. Escalating doses of cortisol (0, 3, 6, 12, 24 mg) were administered 8 min before testing according to a between-subjects design. An inverted U-shaped dose-response relationship between salivary cortisol levels and recall performance was observed, with moderate elevation of salivary cortisol resulting in the best recall performance. This is the first study in humans demonstrating that cortisol rapidly modulates declarative memory retrieval via a dose-dependent, non-genomic mechanism that follows an inverted U-shaped curve. Our result further emphasizes the importance of fast cortisol effects for human cognition.

  13. Antioxidants reveal an inverted U-shaped dose-response relationship between reactive oxygen species levels and the rate of aging in Caenorhabditis elegans.

    Science.gov (United States)

    Desjardins, David; Cacho-Valadez, Briseida; Liu, Ju-Ling; Wang, Ying; Yee, Callista; Bernard, Kristine; Khaki, Arman; Breton, Lionel; Hekimi, Siegfried

    2017-02-01

    Reactive oxygen species (ROS) are potentially toxic, but they are also signaling molecules that modulate aging. Recent observations that ROS can promote longevity have to be reconciled with the numerous claims about the benefits of antioxidants on lifespan. Here, three antioxidants [N-acetylcysteine (NAC), vitamin C, and resveratrol (RSV)] were tested on Caenorhabditis elegans mutants that alter drug uptake, mitochondrial function, and ROS metabolism. We observed that like pro-oxidants, antioxidants can both lengthen and shorten lifespan, dependent on concentration, genotypes, and conditions. The effects of antioxidants thus reveal an inverted U-shaped dose-response relationship between ROS levels and lifespan. In addition, we observed that RSV can act additively to both NAC and paraquat, to dramatically increase lifespan. This suggests that the effect of compounds that modulate ROS levels can be additive when their loci of action or mechanisms of action are sufficiently distinct. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  14. The ligand-receptor-G-protein ternary complex as a GTP-synthase. steady-state proton pumping and dose-response relationships for beta -adrenoceptors.

    Science.gov (United States)

    Broadley, K J; Nederkoorn, P H; Timmerman, H; Timms, D; Davies, R H

    2000-07-21

    Steady-state solutions are developed for the rate of G alpha.GTP production in a synthase model of the ligand-receptor-G-protein ternary complex activated by a ligand-receptor proton pumping mechanism. The effective rate, k(31), defining the proton transfer, phosphorylation and G alpha.GTP release is a controlling rate of the synthase in the presence of a ligand with an efficient mode of signal activation, the ligand-receptor interaction taking place under effectively equilibrium conditions. The composite rate, however, becomes an amplifying factor in any dose-response relationship. The amplification is a triple product of the rate, k(31), the equilibrium constant associated with the activation of the proton signal, K(act)and the fraction of agonist conformer transmitting the signal, f(*). Where the rate of activation of the proton signal becomes critically inefficient, the rate of activation, k(act 1)replaces k(31)K(act). A correlation between beta(1)-adrenergic receptor-stimulated GDP release and adenylate cyclase activation shows that this correlation is not unique to an exchange reaction. Within the initiating Tyr-Arg-Tyr receptor proton shuttle mechanism, the position of Arg(r156) paralleldictates the high-(R(p)) and low-(R(u)) ligand-binding affinities. These states are close to R(*)and R(0)of the equilibrium model (De Lean et al., 1980, J. Biol. Chem.255, 7108-7117). An increased rate of hydrogen ion diffusion into a receptor mutant can give rise to constitutive activity while increased rates of G-protein release and changes in receptor state balance can contribute to the resultant level of action. Constitutive action will arise from a faster rate of G-protein release alone if proton diffusion in the wild-type receptor contributes to a basal level of G-protein activation. Competitive ligand-receptor occupancy for constitutive mutants shows that, where the rate of G-protein activation from the proportion of ligand-occupied receptors is less than the

  15. Tales of two similar hypotheses: the rise and fall of chemical and radiation hormesis.

    Science.gov (United States)

    Calabrese, E J; Baldwin, L A

    2000-01-01

    This paper compares the historical developments of chemical and radiation hormesis from their respective inceptions in the late 1880's for chemical hormesis and early 1900's for radiation hormesis to the mid 1930's to 1940 during which both hypotheses rose to some prominence but then became marginalized within the scientific community. This analysis documents that there were marked differences in their respective temporal developments, and the direction and maturity of research. In general, the formulation of the chemical hormesis hypothesis displayed an earlier, more-extensive and more sophisticated development than the radiation hormesis hypothesis. It was able to attract prestigious researchers with international reputations from leading institutions, to be the subject of numerous dissertations, to have its findings published in leading journals, and to have its concepts incorporated into leading microbiological texts. While both areas became the object of criticism from leading scientists, the intensity of the challenge was greatest for chemical hormesis due to its more visible association with the medical practice of homeopathy. Despite the presence of legitimate and flawed criticism, the most significant limitations of both chemical and radiation hormesis and their respective ultimate undoing were due to their: (1) lack of development of a coherent dose-response theory using data of low dose stimulation from both the chemical and radiation domains; (2) difficulty in replication of low dose stimulatory responses without an adequate study design especially with respect to an appropriate number and properly spaced doses below the toxic threshold; (3) modest degree of stimulation even under optimal conditions which was difficult to distinguish from normal variation; and (4) lack of appreciation of the practical and/or commercial applications of the concepts of low dose stimulation.

  16. The relationship between dietary protein consumption and risk of fracture: a subgroup and dose-response meta-analysis of prospective cohort studies.

    Science.gov (United States)

    Wu, Ai-Min; Sun, Xiao-Lei; Lv, Qing-Bo; Zhou, Yong; Xia, Dong-Dong; Xu, Hua-Zi; Huang, Qi-Shan; Chi, Yong-Long

    2015-03-16

    It is still debate of the relationship between the dietary protein consumption and risk of fracture. We searched Medline and Embase to assess the effects of dietary protein consumption on risk of fracture. Twelve prospective cohort studies with 407,104 participants were included, higher total protein consumption may be decrease 11% risk of hip fractures, with adj. RR of 0.89 (0.82, 0.97), no significant difference was found for total protein and risk of all fractures and limb fracture; for animal protein consumption and risk of all fractures and hip fracture, with adj.RR of 0.79 (032, 1.96) and 1.04 (0.70, 1.54); for vegetable protein consumption and risk of all fractures, hip fracture and limb fractures with adj.RR of 0.77 (0.52, 1.12), 1.00 (0.53, 1.91), and 0.94 (0.40, 2.22), the subgroup of vegetable protein consumption and risk of all fractures of postmenopausal women with adj.RR of 0.78(0.52,1.16). Dose-response meta-analysis the relationship of total/animal/vegetable protein and hip fracture was consistent to the results of forest plot, the line of total protein and hip fracture was below the Y = 1.0 line. This meta-analysis showed that total dietary protein consumption may be decrease the risk of hip fracture, but not for animal or vegetable protein.

  17. Can poisons stimulate bees? Appreciating the potential of hormesis in bee-pesticide research.

    Science.gov (United States)

    Cutler, G Christopher; Rix, Rachel R

    2015-10-01

    Hormesis, a biphasic dose response whereby exposure to low doses of a stressor can stimulate biological processes, has been reported in many organisms, including pest insects when they are exposed to low doses of a pesticide. However, awareness of the hormesis phenomenon seems to be limited among bee researchers, in spite of the increased emphasis of late on pollinator toxicology and risk assessment. In this commentary, we show that there are several examples in the literature of substances that are toxic to bees at high doses but stimulatory at low doses. Appreciation of the hormetic dose response by bee researchers will improve our fundamental understanding of how bees respond to low doses of chemical stressors, and may be useful in pollinator risk assessment.

  18. DOSE-RESPONSE Relationships Between Whole-Body Vibration and Lumbar Disk DISEASE—A Field Study on 388 Drivers of Different Vehicles

    Science.gov (United States)

    Schwarze, S.; Notbohm, G.; Dupuis, H.; Hartung, E.

    1998-08-01

    In a longitudinal study, the dose-response relationships between long term occupational exposure to whole-body vibration and degenerative processes in the lumbar spine caused by the lumbar disks were examined. From 1990 to 1992, 388 vibration-exposed workers from different driving jobs were examined medically and by lumbar X-ray. For each individual, a history of all exposure conditions was recorded, and a cumulative vibration dose was calculated allowing comparisons between groups of low, middle, and high intensity of exposure. 310 subjects were selected for a follow-up four years later, of whom 90·6% (n=281) agreed to participate. In comparing the exposure groups, the results indicate that the limit value ofazw(8h)=0·8 m/s2should be reviewed. The best fit between the lifelong vibration dose and the occurrence of a lumbar syndrome was obtained by applying a daily reference ofazw(8h)=0·6 ms2as a limit value. The results became more distinct still when only those subjects were included in the statistical analysis who had had no lumbar symptoms up to the end of the first year of exposure. The prevalence of lumbar syndrome is 1·55 times higher in the highly exposed group when compared to the reference group with low exposure (CI95%=1·24/1·95). Calculating the cumulative incidence of new cases of lumbar syndrome in the follow-up period yields a relative risk ofRRMH=1·37 (CI95%=0·86/2·17) for the highly exposed group. It is concluded that the limit value for the calculation of an individual lifelong vibration dose should be based on a daily reference exposure ofazw(8h)=0·6 m/s2. With increasing dose it is more and more probable that cases of lumbar syndrome are caused by exposure to vibration.

  19. The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers.

    Science.gov (United States)

    Ekwaru, John Paul; Zwicker, Jennifer D; Holick, Michael F; Giovannucci, Edward; Veugelers, Paul J

    2014-01-01

    Unlike vitamin D recommendations by the Institute of Medicine, the Clinical Practice Guidelines by the Endocrine Society acknowledge body weight differentials and recommend obese subjects be given two to three times more vitamin D to satisfy their body's vitamin D requirement. However, the Endocrine Society also acknowledges that there are no good studies that clearly justify this. In this study we examined the combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OH)D) and serum calcium in healthy volunteers. We analyzed 22,214 recordings of vitamin D supplement use and serum 25(OH)D from 17,614 healthy adult volunteers participating in a preventive health program. This program encourages the use of vitamin D supplementation and monitors its use and serum 25(OH)D and serum calcium levels. Participants reported vitamin D supplementation ranging from 0 to 55,000 IU per day and had serum 25(OH)D levels ranging from 10.1 to 394 nmol/L. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 12.0 nmol/L per 1,000 IU in the supplementation interval of 0 to 1,000 IU per day and by 1.1 nmol/L per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 19.8 nmol/L and 8.0 nmol/L lower, respectively (Pweight subjects. This observational study provides body weight specific recommendations to achieve 25(OH)D targets.

  20. Age-related differences in the dose-response relationship of muscle protein synthesis to resistance exercise in young and old men.

    Science.gov (United States)

    Kumar, Vinod; Selby, Anna; Rankin, Debbie; Patel, Rekha; Atherton, Philip; Hildebrandt, Wulf; Williams, John; Smith, Kenneth; Seynnes, Olivier; Hiscock, Natalie; Rennie, Michael J

    2009-01-15

    We investigated how myofibrillar protein synthesis (MPS) and muscle anabolic signalling were affected by resistance exercise at 20-90% of 1 repetition maximum (1 RM) in two groups (25 each) of post-absorptive, healthy, young (24 +/- 6 years) and old (70 +/- 5 years) men with identical body mass indices (24 +/- 2 kg m(-2)). We hypothesized that, in response to exercise, anabolic signalling molecule phosphorylation and MPS would be modified in a dose-dependant fashion, but to a lesser extent in older men. Vastus lateralis muscle was sampled before, immediately after, and 1, 2 and 4 h post-exercise. MPS was measured by incorporation of [1,2-(13)C] leucine (gas chromatography-combustion-mass spectrometry using plasma [1,2-(13)C]alpha-ketoisocaparoate as surrogate precursor); the phosphorylation of p70 ribosomal S6 kinase (p70s6K) and eukaryotic initiation factor 4E binding protein 1 (4EBP1) was measured using Western analysis with anti-phosphoantibodies. In each group, there was a sigmoidal dose-response relationship between MPS at 1-2 h post-exercise and exercise intensity, which was blunted (P men. At all intensities, MPS fell in both groups to near-basal values by 2-4 h post-exercise. The phosphorylation of p70s6K and 4EBP1 at 60-90% 1 RM was blunted in older men. At 1 h post-exercise at 60-90% 1 RM, p70s6K phosphorylation predicted the rate of MPS at 1-2 h post-exercise in the young but not in the old. The results suggest that in the post-absorptive state: (i) MPS is dose dependant on intensity rising to a plateau at 60-90% 1 RM; (ii) older men show anabolic resistance of signalling and MPS to resistance exercise.

  1. The dose-response relationship between the amount of straw provided on the floor and gastric ulceration of pars oesophagea in growing pigs.

    Science.gov (United States)

    Jensen, Karin H; Jørgensen, Lisbeth; Haugegaard, Svend; Herskin, Mette S; Jensen, Margit B; Pedersen, Lene J; Canibe, Nuria

    2017-01-12

    The aim of the present study was (1) to determine the dose-response relationship between the amount of straw provided on the floor and oesophageal ulceration in pigs kept under typical Danish production conditions (18 pigs/pen, 0.7m(2)/pig, partly slatted floor, ad libitum access to feed), (2) to reveal whether straw ingestion explains the effect of straw provision on the stomach health and (3) to elucidate the effect of straw ingestion on the stomach conditions. Data were collected at slaughter (approximately 100kg body weight) on pigs provided with straw amounts in the range 10g to 500g wheat straw/pig/day from 30kg body weight and fed a wheat-based pelleted feed added 15% non-heated and non-pelleted rolled barley. Aims (1) and (2) included 712 pigs kept in 42 pens, whereas (3) was studied on a subset of 37 pigs with either none or obvious amounts of straw in the stomach. The amount of straw provided affected stomach health in a curvilinear manner. Provision of up to approximately 300gstraw/pig/day progressively decreased the risk of oesophageal ulceration and scarring. At larger amounts of straw the ulceroprotective effect of straw was reduced which requires further investigation. Straw ingestion appeared to be an essential intermediary factor for the improvement of stomach health. The number of pigs without straw in the stomach decreased linearly with the logarithm of the amount of straw provided, which explained the effect of straw provision on stomach health. The structure of the stomach contents increased as revealed by the increased weight and dry matter content and decreased sedimentation of the digesta. Provision of approximately 300gstraw/pig/day on the floor may be a potential strategy to reduce, but not inevitably eliminate, oesophageal ulceration in pigs in commercial pig production.

  2. Model identification for dose response signal detection

    OpenAIRE

    Bretz, Frank; Dette, Holger; Titoff, Stefanie; Volgushev, Stanislav

    2012-01-01

    We consider the problem of detecting a dose response signal if several competing regression models are available to describe the dose response relationship. In particular, we re-analyze the MCP-Mod approach from Bretz et al. (2005), which has become a very popular tool for this problem in recent years. We propose an improvement based on likelihood ratio tests and prove that in linear models this approach is always at least as powerful as the MCP-Mod method. This result remains ...

  3. The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers.

    Directory of Open Access Journals (Sweden)

    John Paul Ekwaru

    Full Text Available Unlike vitamin D recommendations by the Institute of Medicine, the Clinical Practice Guidelines by the Endocrine Society acknowledge body weight differentials and recommend obese subjects be given two to three times more vitamin D to satisfy their body's vitamin D requirement. However, the Endocrine Society also acknowledges that there are no good studies that clearly justify this. In this study we examined the combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OHD and serum calcium in healthy volunteers. We analyzed 22,214 recordings of vitamin D supplement use and serum 25(OHD from 17,614 healthy adult volunteers participating in a preventive health program. This program encourages the use of vitamin D supplementation and monitors its use and serum 25(OHD and serum calcium levels. Participants reported vitamin D supplementation ranging from 0 to 55,000 IU per day and had serum 25(OHD levels ranging from 10.1 to 394 nmol/L. The dose response relationship between vitamin D supplementation and serum 25(OHD followed an exponential curve. On average, serum 25(OHD increased by 12.0 nmol/L per 1,000 IU in the supplementation interval of 0 to 1,000 IU per day and by 1.1 nmol/L per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OHD. Relative to normal weight subjects, obese and overweight participants had serum 25(OHD that were on average 19.8 nmol/L and 8.0 nmol/L lower, respectively (P<0.001. We did not observe any increase in the risk for hypercalcemia with increasing vitamin D supplementation. We recommend vitamin D supplementation be 2 to 3 times higher for obese subjects and 1.5 times higher for overweight subjects relative to normal weight subjects. This observational study provides body weight specific recommendations to achieve 25(OHD targets.

  4. Anoxia-conditioning hormesis alters the relationship between irradiation doses for survival and sterility in the cactus moth, Cactoblastis cactorum (Lepidoptera: Pyralidae)

    Science.gov (United States)

    One of the most important components of a Sterile Insect Technique (SIT) program is appropriate irradiation dose. Knowing the organismal dose-response enables the selection of a dose that induces the highest level of sterility while preserving the sexual competitiveness and quality of the sterile in...

  5. Description of dose response curve

    OpenAIRE

    Al-Samarai, Firas

    2011-01-01

    The book included several methods to estimate LD50, in addition to explain how to use several programs to estimate LD50. Moreover the book illustrate the description of the dose response curves. Firas Al-Samarai

  6. Hormesis and Paradoxical Effects of Drooping Birch (Betula pendula Roth) Parameters Under Motor Traffic Pollution.

    Science.gov (United States)

    Erofeeva, Elena A

    2015-01-01

    Various plant indexes are used or recommended for bioindication. However, the nonmonotonic dose-response dependences (hormesis and paradoxical effects) of these indexes are insufficiently explored upon exposure to pollution. We studied the dependences of these Betula pendula indexes on the intensity of motor traffic pollution. Regression analysis did not reveal any dependence of chlorophyll and carotenoid content on traffic intensity (in 2008 and 2010-2013). Lipid peroxidation rate had different versions of paradoxical effects in 2008 and 2010 to 2012 and increased in comparison with control under an increase in pollution level in 2013. In 2010 to 2012, all dose-response dependences for total protein and thiol group content were biphasic and multiphasic paradoxical effects. In 2013, an increase in traffic intensity induced a linear reduction in protein content and an increase in thiol group level in comparison with the control. In most cases, the studied phenological indexes and seed production decreased monotonically in comparison with the control following an increase in traffic intensity. Only in 2010 and 2013, share of fallen leaves had hormesis and paradoxical effect accordingly. Fluctuating asymmetry had a paradoxical effect and hormesis in 2008 and 2012, accordingly, and increased in comparison with the control under an increase in the level of pollution in 2010 to 2011.

  7. Transgenerational shifts in reproduction hormesis in green peach aphid exposed to low concentrations of imidacloprid.

    Science.gov (United States)

    Ayyanath, Murali-Mohan; Cutler, G Christopher; Scott-Dupree, Cynthia D; Sibley, Paul K

    2013-01-01

    Hormesis is a biphasic phenomenon that in toxicology is characterized by low-dose stimulation and high-dose inhibition. It has been observed in a wide range of organisms in response to many chemical stressors, including insects exposed to pesticides, with potential repercussions for agriculture and pest management. To address questions related to the nature of the dose-response and potential consequences on biological fitness, we examined transgenerational hormesis in the green peach aphid, Myzus persicae, when exposed to sublethal concentrations of the insecticide imidacloprid. A hormetic response in the form of increased reproduction was consistently observed and a model previously developed to test for hormesis adequately fit some of our data. However, the nature of the dose-response differed within and across generations depending upon the duration and mode of exposure. Decreased reproduction in intermediate generations confirmed that fitness tradeoffs were a consequence of the hormetic response. However, recovery to levels of reproduction equal to that of controls in subsequent generations and significantly greater total reproduction after four generations suggested that biological fitness was increased by exposure to low concentrations of the insecticide, even when insects were continuously exposed to the stressor. This was especially evident in a greenhouse experiment where the instantaneous rate of population increase almost doubled and total aphid production more than quadrupled when aphids were exposed to potato plants systemically treated with low amounts of imidacloprid. Our results show that although fitness tradeoffs do occur with hormetic responses, this does not necessarily compromise overall biological fitness.

  8. Topics on study of low dose-effect relationship

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Takeshi [Toho Univ., School of Medicine, Tokyo (Japan); Ohyama, Harumi

    1999-09-01

    It is not exceptional but usually observed that a dose-effect relationship in biosystem is not linear. Sometimes, the low dose-effect relationship appears entirely contrary to the expectation from high dose-effect. This is called a 'hormesis' phenomena. A high dose irradiation inflicts certainly an injury on biosystem. No matter how low the dose may be, an irradiation might inflict some injury on biosystem according to Linear Non-Threshold hypothesis(LNT). On the contrary to the expectation, a low dose irradiation stimulates immune system, and promotes cell proliferation. This is called 'radiation hormesis'. The studies of the radiation hormesis are made on from four points of view as follows: (1) radiation adaptive response, (2) revitalization caused by a low dose stimulation, (3) a low dose response unexpected from the LNT hypothesis, (4) negation of the LNT hypothesis. The various empirical proofs of radiation hormesis are introduced in the report. (M . Suetake)

  9. Dose response problems in carcinogenesis.

    Science.gov (United States)

    Crump, K S

    1979-03-01

    The estimation of risks from exposure to carcinogens is an important problem from the viewpoint of protection of human health. It also poses some very difficult dose-response problems. Two dose-response models may fit experimental data about equally well and yet predict responses that differ by many orders of magnitude at low doses. Mechanisms of carcinogenesis are not sufficiently understood so that the shape of the dose-response curve at low doses can be satisfactorily predicted. Mathematical theories of carcinogenesis and statistical procedures can be of use with dose-reponse problems such as this and, in addition, can lead to a better understanding of the mechanisms of carcinogenesis. In this paper, mathematical dose-response models of carcinogenesis are considered as well as various proposed dose-response procedures for estimating carcinogenic risks at low doses. Areas are suggested in which further work may be useful. These areas include experimental design problems, statistical procedures for use with time-to-occurrence data, and mathematical models that incorporate such biological features as pharmacokinetics of carcinogens, synergistic effects, DNA repair, susceptible subpopulations, and immune reactions.

  10. Dose-response-a challenge for allelopathy?

    Science.gov (United States)

    Belz, Regina G; Hurle, Karl; Duke, Stephen O

    2005-04-01

    The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.

  11. Spatial distribution and dose-response relationship for different operation modes in a reaction-diffusion model of the MAPK cascade

    Science.gov (United States)

    Zhao, Qi; Yi, Ming; Liu, Yan

    2011-10-01

    The mitogen-activated protein kinase (MAPK) cascade plays a critical role in the control of cell growth. Deregulation of this pathway contributes to the development of many cancers. To better understand its signal transduction, we constructed a reaction-diffusion model for the MAPK pathway. We modeled the three layers of phosphorylation-dephosphorylation reactions and diffusion processes from the cell membrane to the nucleus. Based on different types of feedback in the MAPK cascade, four operation modes are introduced. For each of the four modes, spatial distributions and dose-response curves of active kinases (i.e. ppMAPK) are explored by numerical simulation. The effects of propagation length, diffusion coefficient and feedback strength on the pathway dynamics are investigated. We found that intrinsic bistability in the MAPK cascade can generate a traveling wave of ppMAPK with constant amplitude when the propagation length is short. ppMAPK in this mode of intrinsic bistability decays more slowly than it does in all other modes as the propagation length increases. Moreover, we examined the global and local responses to Ras-GTP of these four modes, and demonstrated how the shapes of these dose-response curves change as the propagation length increases. Also, we found that larger diffusion constant gives a higher response level on the zero-order regime and makes the ppMAPK profiles flatter under strong Ras-GTP stimulus. Furthermore, we observed that spatial responses of ppMAPK are more sensitive to negative feedback than to positive feedback in the broader signal range. Finally, we showed how oscillatory signals pass through the kinase cascade, and found that high frequency signals are damped faster than low frequency ones.

  12. Optimal experimental design strategies for detecting hormesis

    OpenAIRE

    2010-01-01

    Hormesis is a widely observed phenomenon in many branches of life sciences ranging from toxicology studies to agronomy with obvious public health and risk assessment implications. We address optimal experimental design strategies for determining the presence of hormesis in a controlled environment using the recently proposed Hunt-Bowman model. We propose alternative models that have an implicit hormetic threshold, discuss their advantages over current models, construct and study properties of...

  13. Dose-response relationship of electromagnetic radiation and its research progress%电磁辐射生物效应的量效关系研究进展

    Institute of Scientific and Technical Information of China (English)

    邹勇; 王丽峰; 胡向军

    2012-01-01

    The growing concern about adverse health effects caused by electromagnetic radiation has been discussed given the widespread use of electromagnetic waves in telecommunications, industry, military and medical fields. It was found that a certain magnitude of electromagnetic radiation may cause varying degrees of damage to organisms. Although dose-response relationship of electromagnetic radiation has not been established,the dose-response relationship is summarized here.%随着电磁波在通信、工业、军事、医疗等各个领域的广泛应用,电磁辐射对健康的影响越来越受重视.研究发现.一定强度的电磁辐射可引起生物体不同程度的损伤,但电磁辐射损伤的剂量效应关系尚不明确,本文就电磁辐射损伤的量效关系研究进行综述.

  14. Systems Cancer Biology and the Controlling Mechanisms for the J-Shaped Cancer Dose Response: Towards Relaxing the LNT Hypothesis.

    Science.gov (United States)

    Lou, In Chio; Zhao, Yuchao; Wu, Yingjie; Ricci, Paolo F

    2012-01-01

    The hormesis phenomena or J-shaped dose response have been accepted as a common phenomenon regardless of the involved biological model, endpoint measured and chemical class/physical stressor. This paper first introduced a mathematical dose response model based on systems biology approach. It links molecular-level cell cycle checkpoint control information to clonal growth cancer model to predict the possible shapes of the dose response curves of Ionizing Radiation (IR) induced tumor transformation frequency. J-shaped dose response curves have been captured with consideration of cell cycle checkpoint control mechanisms. The simulation results indicate the shape of the dose response curve relates to the behavior of the saddle-node points of the model in the bifurcation diagram. A simplified version of the model in previous work of the authors was used mathematically to analyze behaviors relating to the saddle-node points for the J-shaped dose response curve. It indicates that low-linear energy transfer (LET) is more likely to have a J-shaped dose response curve. This result emphasizes the significance of systems biology approach, which encourages collaboration of multidiscipline of biologists, toxicologists and mathematicians, to illustrate complex cancer-related events, and confirm the biphasic dose-response at low doses.

  15. Mitochondrial stress extends lifespan in C. elegans through neuronal hormesis.

    Science.gov (United States)

    Maglioni, Silvia; Schiavi, Alfonso; Runci, Alessandra; Shaik, Anjumara; Ventura, Natascia

    2014-08-01

    Progressive neuronal deterioration accompanied by sensory functions decline is typically observed during aging. On the other hand, structural or functional alterations of specific sensory neurons extend lifespan in the nematode Caenorhabditis elegans. Hormesis is a phenomenon by which the body benefits from moderate stress of various kinds which at high doses are harmful. Several studies indicate that different stressors can hormetically extend lifespan in C. elegans and suggest that hormetic effects could be exploited as a strategy to slow down aging and the development of age-associated (neuronal) diseases in humans. Mitochondria play a central role in the aging process and hormetic-like bimodal dose-response effects on C. elegans lifespan have been observed following different levels of mitochondrial stress. Here we tested the hypothesis that mitochondrial stress may hormetically extend C. elegans lifespan through subtle neuronal alterations. In support of our hypothesis we find that life-lengthening dose of mitochondrial stress reduces the functionality of a subset of ciliated sensory neurons in young animals. Notably, the same pro-longevity mitochondrial treatments rescue the sensory deficits in old animals. We also show that mitochondrial stress extends C. elegans lifespan acting in part through genes required for the functionality of those neurons. To our knowledge this is the first study describing a direct causal connection between sensory neuron dysfunction and extended longevity following mitochondrial stress. Our work supports the potential anti-aging effect of neuronal hormesis and open interesting possibility for the development of therapeutic strategy for age-associated neurodegenerative disorders.

  16. Awareness of hormesis will enhance future research in basic and applied neuroscience.

    Science.gov (United States)

    Mattson, Mark P

    2008-01-01

    Hormesis is defined operationally as responses of cells or organisms to an exogenous or intrinsic factor (chemical, temperature, psychological challenge, etc.) in which the factor induces stimulatory or beneficial effects at low doses and inhibitory or adverse effects at high doses. The compendium of articles by Calabrese entitled "Neuroscience and Hormesis" provides a broad range of examples of neurobiological processes and responses to environmental factors that exhibit biphasic dose responses, the signature of hormesis. Nerve cell networks are the "first responders" to environmental challenges--they perceive the challenge and orchestrate coordinated adaptive responses that typically involve autonomic, neuroendocrine, and behavioral changes. In addition to direct adaptive responses of neurons to environmental stressors, cells subjected to a stressor produce and release molecules such as growth factors, cytokines, and hormones that alert adjacent and even distant cells to impending danger. The discoveries that some molecules (e.g., carbon monoxide and nitric oxide) and elements (e.g., selenium and iron) that are toxic at high doses play fundamental roles in cellular signaling or metabolism suggest that during evolution, organisms (and their nervous systems) co-opted environmental toxins and used them to their advantage. Neurons also respond adaptively to everyday stressors, including physical exercise, cognitive challenges, and dietary energy restriction, each of which activates pathways linked to the production of neurotrophic factors and cellular stress resistance proteins. The development of interventions that activate hormetic signaling pathways in neurons is a promising new approach for the preventation and treatment of a range of neurological disorders.

  17. The relationship between zinc intake and serum/plasma zinc concentration in pregnant and lactating women: A systematic review with dose-response meta-analyses

    NARCIS (Netherlands)

    Hall Moran, V.; Skinner, A.L.; Warthon Medina, M.; Patel, S.; Dykes, F.; Souverein, O.W.; Dullemeijer, C.; Lowe, N.M.M.

    2012-01-01

    Recommendations for zinc intake during pregnancy and lactation vary widely across Europe. Using data on zinc intake and biomarkers of zinc status reported in randomized controlled trials (RCTs) and observational studies can provide estimates of dose–response relationships that may be used for underp

  18. Unequal brothers : are homeopathy and hormesis linked?

    Science.gov (United States)

    Oberbaum, Menachem; Frass, Michael; Gropp, Cornelius

    2015-04-01

    The debate between those who believe homeopathy and hormesis derive from the same root and those who believe the two are different phenomena is as old as hormesis. It is an emotionally loaded discussion, with both sides fielding arguments which are far from scientific. Careful analysis of the basic paradigms of the two systems questions the claim of the homeopaths, who find similarities between them. The authors discuss these paradigms, indicating the differences between the claims of homeopathy and hormesis. It is time for thorough and serious research to lay this question to rest. One possible approach is to compare the activity of a hormetic agent, prepared in the usual way, with that of the same agent in the same concentration prepared homeopathically by serial dilution and succussion.

  19. Optimal experimental design strategies for detecting hormesis.

    Science.gov (United States)

    Dette, Holger; Pepelyshev, Andrey; Wong, Weng Kee

    2011-12-01

    Hormesis is a widely observed phenomenon in many branches of life sciences, ranging from toxicology studies to agronomy, with obvious public health and risk assessment implications. We address optimal experimental design strategies for determining the presence of hormesis in a controlled environment using the recently proposed Hunt-Bowman model. We propose alternative models that have an implicit hormetic threshold, discuss their advantages over current models, and construct and study properties of optimal designs for (i) estimating model parameters, (ii) estimating the threshold dose, and (iii) testing for the presence of hormesis. We also determine maximin optimal designs that maximize the minimum of the design efficiencies when we have multiple design criteria or there is model uncertainty where we have a few plausible models of interest. We apply these optimal design strategies to a teratology study and show that the proposed designs outperform the implemented design by a wide margin for many situations.

  20. Transgenerational shifts in reproduction hormesis in green peach aphid exposed to low concentrations of imidacloprid.

    Directory of Open Access Journals (Sweden)

    Murali-Mohan Ayyanath

    Full Text Available Hormesis is a biphasic phenomenon that in toxicology is characterized by low-dose stimulation and high-dose inhibition. It has been observed in a wide range of organisms in response to many chemical stressors, including insects exposed to pesticides, with potential repercussions for agriculture and pest management. To address questions related to the nature of the dose-response and potential consequences on biological fitness, we examined transgenerational hormesis in the green peach aphid, Myzus persicae, when exposed to sublethal concentrations of the insecticide imidacloprid. A hormetic response in the form of increased reproduction was consistently observed and a model previously developed to test for hormesis adequately fit some of our data. However, the nature of the dose-response differed within and across generations depending upon the duration and mode of exposure. Decreased reproduction in intermediate generations confirmed that fitness tradeoffs were a consequence of the hormetic response. However, recovery to levels of reproduction equal to that of controls in subsequent generations and significantly greater total reproduction after four generations suggested that biological fitness was increased by exposure to low concentrations of the insecticide, even when insects were continuously exposed to the stressor. This was especially evident in a greenhouse experiment where the instantaneous rate of population increase almost doubled and total aphid production more than quadrupled when aphids were exposed to potato plants systemically treated with low amounts of imidacloprid. Our results show that although fitness tradeoffs do occur with hormetic responses, this does not necessarily compromise overall biological fitness.

  1. A dose-response relationship for time to bone pain resolution after stereotactic body radiotherapy (SBRT) for renal cell carcinoma (RCC) bony metastases

    Energy Technology Data Exchange (ETDEWEB)

    Jhaveri, Pavan M. [Dept. of Radiology, Section of Radiation Oncology, Baylor College of Medicine, Houston (United States); Teh, Bin S.; Paulino, Arnold C.; Blanco, Angel I.; Butler, E. Brian [Dept. of Radiation Oncology, The Methodist Hospital/The Methodist Hospital Research Inst., Houston (United States)], email: bteh@tmhs.org; Lo, Simon S. [Dept. of Radiation Oncology, Univ. Hospitals Seidman Cancer Center, Case Western Reserve Univ., Cleveland (United States); Amato, Robert J. [Dept. of Internal Medicine, Div. of Oncology, Univ. of Texas Health Sciences Center, Houston (United States)

    2012-05-15

    Background. To investigate the utility of stereotactic body radiotherapy (SBRT) in the treatment of painful renal cell carcinoma (RCC) bone metastases, and for a possible dose effect on time to symptom relief. Material and methods. Eighteen patients with 24 painful osseous lesions from metastatic RCC were treated with SBRT. The most common treatment regimens were 24 Gy in 3 fractions and 40 Gy in 5 fractions. The times from treatment to first reported pain relief and time to symptom recurrence were evaluated. Median follow-up was 38 weeks (1-156 weeks). Results. Seventy-eight percent of all patients had pain relief. Patients treated with a BED > 85 Gy achieved faster and more durable pain relief compared to those treated with a BED < 85 Gy. There was decrease in time to pain relief after a change in treatment regimen to 8 Gy x 5 fractions (BED = 86). There was only one patient with grade 1 skin toxicity. No neurological or other toxicity was observed. Conclusions. SBRT can safely and effectively treat painful RCC bony metastases. There appears to be a relationship between radiation dose and time to stable pain relief.

  2. Single toxin dose-response models revisited

    Science.gov (United States)

    Glaholt, SP; Kyker-Snowman, E; Shaw, JR; Chen, CY

    2016-01-01

    The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of four models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48 hours) toxicity tests with mortality as a function of NiCl or CuSO4 toxin. PMID:27847315

  3. Do toxic ions induce hormesis in plants?

    Science.gov (United States)

    Poschenrieder, Charlotte; Cabot, Catalina; Martos, Soledad; Gallego, Berta; Barceló, Juan

    2013-11-01

    The concept of hormesis in plants is critically reviewed, taking growth stimulation by low concentrations of toxic trace elements as a reference. The importance of both non-adaptive and adaptive mechanisms underlying ion-induced hormetic growth responses is highlighted. The activation of defense mechanisms by metal ions and pathogenic elicitors and the cross talk between the signals induced by metal ions and biotic stressors are considered. The production of reactive oxygen species and, consequently, the induction of stress-induced antioxidants, are key mechanisms in metal ion-induced hormesis in plants. It is concluded that in the current scientific literature, hormesis is used as an "umbrella" term that includes a wide range of different mechanisms. It is recommended that the term hormesis be used in plant toxicology as a descriptive term for the stimulated phase in growth response curves that is induced by low concentrations of toxic metal ions without evidence of the underlying mechanisms. If the mechanisms underlying the stimulated growth phase have been identified, specific terms, such as amelioration, defense gene activation, priming or acclimation, should be used. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. Dose-Response Calculator for ArcGIS

    Science.gov (United States)

    Hanser, Steven E.; Aldridge, Cameron L.; Leu, Matthias; Nielsen, Scott E.

    2011-01-01

    The Dose-Response Calculator for ArcGIS is a tool that extends the Environmental Systems Research Institute (ESRI) ArcGIS 10 Desktop application to aid with the visualization of relationships between two raster GIS datasets. A dose-response curve is a line graph commonly used in medical research to examine the effects of different dosage rates of a drug or chemical (for example, carcinogen) on an outcome of interest (for example, cell mutations) (Russell and others, 1982). Dose-response curves have recently been used in ecological studies to examine the influence of an explanatory dose variable (for example, percentage of habitat cover, distance to disturbance) on a predicted response (for example, survival, probability of occurrence, abundance) (Aldridge and others, 2008). These dose curves have been created by calculating the predicted response value from a statistical model at different levels of the explanatory dose variable while holding values of other explanatory variables constant. Curves (plots) developed using the Dose-Response Calculator overcome the need to hold variables constant by using values extracted from the predicted response surface of a spatially explicit statistical model fit in a GIS, which include the variation of all explanatory variables, to visualize the univariate response to the dose variable. Application of the Dose-Response Calculator can be extended beyond the assessment of statistical model predictions and may be used to visualize the relationship between any two raster GIS datasets (see example in tool instructions). This tool generates tabular data for use in further exploration of dose-response relationships and a graph of the dose-response curve.

  5. Study on the dose-response relationship of asbestosis prevalence%接触石棉尘量与石棉肺发病的剂量-反应关系研究

    Institute of Scientific and Technical Information of China (English)

    孙统达; 朱胜军

    2001-01-01

    Objective To learn the dose-response relationship of asbestosis prevalence in the workers of small towns chrysotile processing plants.Methods To collect the chrysotile dust concentration records of all workplaces and the prevalence of asbestosis during recent 37 years;the chrysotile fiber concentration could be gotten by calculation from the chrysotile dust concentration;the amount of accumulative exposure amount to chrysotile fibers might be calculated from exposure concentration multiplied with exposure time.The dose-response relationship between chrysotile and fiber concentration and? asbestosis prevalence was established by the method of life table.Results The maximum allowable dust concentration and fiber concentration of asbestos dust were predicted as 2.71mg/m3 and 1.93 f/ml respectively,according to the presumption that the workers would work for 30 years and the prevalence of asbestosis would be controlled under 1%.Conclusion The present hygienic standard of asbestos dust(MAC)of our country is reasonable.%目的探讨乡镇石棉加工人员接触石棉尘量与石棉肺发病的剂量-反应关系。方法记录接尘工人的职业史、体检史,纤维计数浓度由质量浓度通过公式换算得到,累积接尘量由接触浓度与时间相乘所得,以寿命表法建立石棉尘质量浓度与纤维计数浓度的剂量患病概率直线回归方程式。结果按1%石棉肺患病率、工人30年工作年限计算,预测石棉尘质量浓度与纤维计数浓度应低于2.71mg/m3与1.93f/ml。结论现行国家石棉尘卫生标准是合理的。

  6. Is hormesis an underestimated factor in the development of herbicide resistance?

    Directory of Open Access Journals (Sweden)

    Belz, Regina G.

    2014-02-01

    Full Text Available The growing impact of herbicide resistant weeds increasingly affects weed management and the delay of resistance evolution has become a major task of chemical weed control. Hormesis and, thus, the phenomenon that low doses of herbicides can boost weed growth could be of importance in this regard since the recommended field rate may represent a low dose for weeds that have evolved resistance to the applied herbicide and, thus, a potential hormetic dose. Applying the field rate may thus not only directly select resistant biotypes, it may also indirectly promote the success and spread of resistant biotypes via hormesis. Nevertheless, hormetic effects in resistant weeds are hitherto merely randomly observed and, thus, a clear quantitative basis to judge the significance of hormesis for resistance evolution is lacking. Therefore, this study aimed at quantifying the degree and frequency of herbicide hormesis in sensitive and resistant weed species in order to provide a first indication of whether the phenomenon deserves consideration as a potential factor contributing to the development of herbicide resistance. In germination assays complete dose-response experiments were conducted with sensitive and resistant biotypes of Matricaria inodora (ALS-target-site resistant; treated with iodosulfuron-methyl-sodium/mesosulfuron-methyl, Eleusine indica (glyphosateresistant; treated with glyphosate, and Chenopodium album (triazine/triazinone-target-site resistant; treated with terbuthylazine. After 10 days of cultivation under controlled conditions plant growth was analyzed by measuring shoot/root length and mass. Results indicated that herbicide hormesis occurred on average with a total frequency of 29% in sensitive/resistant biotypes with an average growth increase of 53% occurring typically within a dose zone exceeding 350fold. Hormetic effects occurred, however, very variable and only for specific endpoints and not plant growth in general. If such a

  7. Additive interactions of pregabalin with lamotrigine, oxcarbazepine and topiramate in the mouse maximal electroshock-induced seizure model: a type I isobolographic analysis for non-parallel dose-response relationship curves.

    Science.gov (United States)

    Luszczki, Jarogniew J; Filip, Damian; Czuczwar, Stanislaw J

    2010-10-01

    The aim of this study was to characterize the anticonvulsant effects of pregabalin (PGB-a third-generation antiepileptic drug) in combination with three second-generation antiepileptic drugs (i.e., lamotrigine [LTG], oxcarbazepine [OXC] and topiramate [TPM]) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Potential adverse-effect profiles of interactions of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured. In the mouse MES model, PGB administered singly had its DRRC non-parallel to that for LTG, OXC and TPM. With type I isobolography for non-parallel DRRCs, the combinations of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 exerted additive interaction. In all combinations, neither motor coordination, long-term memory nor muscular strength were affected. In conclusion, the additive interactions between PGB and LTG, OXC and TPM are worthy of consideration while extrapolating the results from this study to clinical settings.

  8. The dose-response relationship of chrysotile asbestos exposure and lung cancer in cohort study%温石棉暴露与肺癌剂量反应关系的队列研究

    Institute of Scientific and Technical Information of China (English)

    任晓慧; 周鼎伦; 杜利利; 王绵珍; 兰亚佳

    2013-01-01

    目的 用固定队列研究方法研究温石棉矿工接触石棉粉尘量与肺癌发病的剂量反应关系,探讨不同石棉暴露剂量下的肺癌发病规律.方法 从2009年7月开始,采用回顾性队列研究方法,入选条件为1981年1月1日至1988年12月31日登记在册,工龄满1年,没有明显心肺疾病者,将符合标准的1932例石棉矿工纳入队列,追踪29年(1981至2009年),记录接尘矿工的个人信息、职业史、疾病史、健康资料,收集该矿历年粉尘浓度监测资料.应用寿命表法建立石棉尘质量浓度的剂量反应关系,拟合剂量患病概率回归方程,估算不同工作年限不同粉尘浓度下肺癌超额发病率.结果 工人累积接尘量与肺癌累积发病概率有明显的剂量反应关系,且吸烟组的肺癌累积发病概率明显高于非吸烟组.当每年累积接尘量(cumulative exposure,Ce)小于2000 mg/m3时,肺癌累积发病概率(Px)为6.58/万;当2000 mg/m3≤每年累积接尘量<3000 mg/m3时,肺癌累积发病概率为91.72/万;当每年累积接尘量大于5000 mg/m3时,肺癌累积发病概率高达141.02/万.应用3种模型进行拟合,得出最优回归方程:Px =-0.0004 Ce2 +0.0052Ce-0.0011(r2=0.9387).开展本次研究的石棉矿生产车间2009年的平均粉尘浓度超标85倍,根据方程推测在此暴露环境下工作40年肺癌的超额发病率将达到112.598/万.结论 石棉矿工石棉累积接尘量与肺癌间存在明显的剂量反应关系,肺癌发病风险随暴露量的增加呈现上升趋势.%Objective To clarify the dose-response relationship between asbestos dust exposure and lung cancer incidence in chrysotile asbestos miners by fixed cohort study and to investigate the incidence rates of lung cancer in exposure to different concentrations of asbestos dust.Methods A retrospective cohort study was conducted in 1932 asbestos miners who registered from January 1,1981 to December 31,1988,had worked for at least 1 year,and had

  9. Design methods for some dose-response models

    NARCIS (Netherlands)

    Albers, Willem/Wim; Strijbosch, Leo W.G.; Does, Ronald J.M.M.

    1990-01-01

    A recently described design method for one-parameter biomedical models such as limiting or serial dilution assays is generalized to two-parameter models for which the dose-response relationship can be expressed as a linear regression model with parameters α (intercept) and β (slope). Design formulae

  10. Association between cigarette smoking and hypertension in men: a dose response relationship analysis%男性吸烟与高血压病的剂量-反应关系

    Institute of Scientific and Technical Information of China (English)

    胡文斌; 张婷; 史建国; 秦威; 仝岚; 沈月平

    2014-01-01

    Objective To estimate the dose response relationship between cigarette smoking and hypertension in men based on restricted cubic spline method.Methods Under the proportion to the population size,38 520 subjects were randomly selected from May to August 2012 with cluster sampling method in urban and rural areas of Kunshan,China.Each participant received face-to-face interview with the standardized questionnaire,and physical examination.Restricted cubic spline was employed to estimate the dose response relation of cigarette smoking on the risk of hypertension.Results The overall prevalence of cigarette smoking was 22.6% (8 691/38 520),prevalence of cigarette smoking in men was 46.1% (8 499/18 454).Multiple logistic regression analysis showed that current smoking (OR =1.16,95% CI:1.05-1.28) and previous cigarette smoking (OR =1.32,95% CI:1.07-1.63) were associated with hypertension after adjusted confounding factors (age,sex,body mass index,education,family income per month,urban or rural areas,physical activity and physical exercise) in men.After further adjusting drinking status,only previous cigarette smoking was associated with hypertension (OR =1.28,95 % CI:1.04-1.58).The restricted cubic spline model indicated a linear dose-response relation between hypertension and cigarette smoking per day in men (non-linearity test P =0.604 1).However,a non-linear dose response relation was found between duration of smoking (non-linearity test P < 0.000 1),smoking index (non-linearity test P =0.009 9) and hypertension.Conclusion Long-term and heavy cigarette smoking is associated with hypertension in men.%目的 采用限制性立方样条模型,探讨男性吸烟与高血压病的剂量-反应关系.方法 采用与人口规模成比例的整群抽样方法,于2012年5至8月对江苏省昆山市18岁以上38 520名户籍居民进行问卷调查和体格测量.采用logistic回归模型和限制性立方样条模型,分析男性吸烟数量、年限及吸烟指

  11. Classification, Dose-response Modelling and the Evaluation of Biomarkers in a Micro-array Setting

    OpenAIRE

    Lin, Dan

    2008-01-01

    Dose-response microarray experiments consist of monitoring expression levels of thousands of genes with respect to increasing dose of the treatment under investigation. The primary goal of such an experiment is to establish a dose-response relationship, while the secondary goals are to determine the minimum effective dose level and to identify the shape of the dose-response curve. Recently, Lin et al.[1] discussed several testing procedures to test for monotone trend based on isotonic regress...

  12. Ultraviolet radiation: questions of hazard, homeostasis, or hormesis?

    Energy Technology Data Exchange (ETDEWEB)

    Sliney, D. [USA Center for Health Promotion and Preventive Medicine, Gunpowder, MD (United States)

    2004-07-01

    The general approach taken when dealing with health issues arising from chronic human exposure to solar ultraviolet radiation appear to be quite different from that taken with the safety of human exposure to ionizing radiation. The public climate for accepting scientific risk assessments of human exposure appears to be markedly different for these two types of radiation exposures. Issues relating to setting exposure guidelines, such as dose response, with arguments over ''linear-no-threshold'' or ''hormesis,'' have engendered much debate and have severely challenged the development of a consensus on how to best control the health hazards from low-level ionizing radiation exposure. By contrast, these same questions are rarely raised in the public policy arena with regard to health policies for dealing with ultraviolet, non-ionizing radiation. Ultraviolet radiation exposure is a known carcinogen, but workers and the general public willingly expose themselves routinely to levels of ultraviolet radiation exceeding health exposure guidelines. Occupational health and safety advisors are constantly challenged on how to cope with exposure of the outdoor worker to the ultraviolet radiation in sunlight that can exceed health guidelines. A de facto consensus that permits workers to be exposed far above guidelines appears to exist because of the overwhelming public acceptance of the concept that ultraviolet radiation in sunlight has some benefit, despite the risk. A similar public perception generally does not exist for ionizing radiation, but are there similar risks? From a biophysical standpoint, the generally accepted target molecule is DNA and the single-hit theory would apply to both. Unlike ionizing radiation the target organs are limited to skin and eye. Furthermore, cancer of the eye in humans is virtually unknown; whereas, cancer of the skin is most common. It would be well to examine whether the potential for different outcomes

  13. Simplified Warfarin Dose-response Pharmacodynamic Models

    OpenAIRE

    Kim, Seongho; Gaweda, Adam E.; Wu, Dongfeng; Li, Lang; Shesh N Rai; Brier, Michael E.

    2015-01-01

    Warfarin is a frequently used oral anticoagulant for long-term prevention and treatment of thromboembolic events. Due to its narrow therapeutic range and large inter-individual dose-response variability, it is highly desirable to personalize warfarin dosing. However, the complexity of the conventional kinetic-pharmacodynamic (K-PD) models hampers the development of the personalized dose management. To avert this challenge, we propose simplified PD models for warfarin dose-response relationshi...

  14. The key events dose-response framework: its potential for application to foodborne pathogenic microorganisms.

    NARCIS (Netherlands)

    Buchanan, R.L.; Havelaar, A.H.; Smith, M.A.; Whiting, R.C.; Julien, E.

    2009-01-01

    The Key Events Dose-Response Framework (KEDRF) is an analytical approach that facilitates the use of currently available data to gain insight regarding dose-response relationships. The use of the KEDRF also helps identify critical knowledge gaps that once filled, will reduce reliance on assumptions.

  15. Statistical strategies for averaging EC50 from multiple dose-response experiments.

    Science.gov (United States)

    Jiang, Xiaoqi; Kopp-Schneider, Annette

    2015-11-01

    In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.

  16. Inferring mechanisms from dose-response curves

    OpenAIRE

    Chow, Carson C.; Ong, Karen M.; Dougherty, Edward J.; Simons, S. Stoney

    2011-01-01

    The steady state dose-response curve of ligand-mediated gene induction usually appears to precisely follow a first-order Hill equation (Hill coefficient equal to 1). Additionally, various cofactors/reagents can affect both the potency and the maximum activity of gene induction in a gene-specific manner. Recently, we have developed a general theory for which an unspecified sequence of steps or reactions yields a first-order Hill dose-response curve (FHDC) for plots of the final product vs. ini...

  17. 曲马多抑制瑞芬太尼致术后痛觉过敏的量效关系%Dose-response relationship of tramadol for inhibiting postoperative hyperalgesia after remifentanil-based anesthesia

    Institute of Scientific and Technical Information of China (English)

    张黄丽; 刘保江; 薛朝霞

    2011-01-01

    Objective To investigate the dose-response relationship of tramadol for inhibiting the postoperative hyperalgesia after remifentanil-based anesthesia. Methods Sixty ASA Ⅰ or Ⅱ , 20 - 60 year-old patients receiving laparoscopic cholecystectomy were randomly allocated into six tramadol dose groups( 3.1,2.5,2.0,1.6,1.3,1.0 mg/kg ). All patients received tramadol before the beginning of the surgery. Propofol and remifentanil were used for the general anaesthesia. Remifentanil was infused at 0.25 μg/( kg · min ).Pain was assessed with VAS at 15 min after tracheal extubation( VAS <4 was defined as effective ). A Probit analysis was performed to calculate the efficient doses of tramadol for inhibiting hyperalgesia in 50% and 95% of patients ( ED50 and ED95 ). Results The ED50 of tramadol was 1.66 mg/kg ( 95 % CI 1.41 - 1.94 mg/kg ) and ED95 was 3.10 mg/kg ( 95 % CI 2.47 - 5.59 mg/kg ). Conclusion The ED50 and ED95 of tramadol for inhibiting the postoperative hyperalgesia after remifentanil-based anesthesia with 0.25 μg/( kg · min ) of remifentanil in patients following laparoscopic cholecystectomy are 1.66 mg/kg and 3.10 mg/kg, respectively.%目的 确定曲马多抑制瑞芬太尼致术后痛觉过敏的量效关系.方法 选择60例ASAⅠ或Ⅱ级,20-60岁择期全麻腹腔镜下行胆囊切除术的成年患者,按所用曲马多的剂量(3.1,2.5,2.0,1.6,1.3,1.0 mg/kg)随机分为6组.于手术开始前给予规定剂量的曲马多.以丙泊酚和瑞芬太尼行全静脉麻醉,瑞芬太尼维持剂量为0.25 μg/(kg · min),记录清醒拔管后15 minVAS评分(VAS4分为抑制痛觉过敏有效),用Probit回归分析数据,得出曲马多抑制瑞芬太尼致术后痛觉过敏的ED 50 和ED 95.结果 曲马多抑制瑞芬太尼致术后痛觉过敏的ED 50 为1.66 mg/kg(95%可信区间:1.41-1.94 mg/kg),ED 95 为 3.10 mg/kg(95%可信区间:2.47-5.59 mg/kg).结论 曲马多抑制瑞芬太尼致术后痛觉过敏的ED 50 和ED 95 分别为1.66 mg

  18. Fundamental Flaws of Hormesis for Public Health Decisions

    OpenAIRE

    Thayer, Kristina A.; Melnick, Ronald; Burns, Kathy; DAVIS, Devra; Huff, James

    2005-01-01

    Hormesis (defined operationally as low-dose stimulation, high-dose inhibition) is often used to promote the notion that while high-level exposures to toxic chemicals could be detrimental to human health, low-level exposures would be beneficial. Some proponents claim hormesis is an adaptive, generalizable phenomenon and argue that the default assumption for risk assessments should be that toxic chemicals induce stimulatory (i.e., “beneficial”) effects at low exposures. In many cases, nonmonoto...

  19. Dose-response analysis using R

    DEFF Research Database (Denmark)

    Ritz, Christian; Baty, Florent; Streibig, Jens Carl

    2015-01-01

    Dose-response analysis can be carried out using multi-purpose commercial statistical software, but except for a few special cases the analysis easily becomes cumbersome as relevant, non-standard output requires manual programming. The extension package drc for the statistical environment R provides...

  20. Hormesis in Aging and Neurodegeneration—A Prodigy Awaiting Dissection

    Directory of Open Access Journals (Sweden)

    Lei Mao

    2013-06-01

    Full Text Available Hormesis describes the drug action of low dose stimulation and high dose inhibition. The hormesis phenomenon has been observed in a wide range of biological systems. Although known in its descriptive context, the underlying mode-of-action of hormesis is largely unexplored. Recently, the hormesis concept has been receiving increasing attention in the field of aging research. It has been proposed that within a certain concentration window, reactive oxygen species (ROS or reactive nitrogen species (RNS could act as major mediators of anti-aging and neuroprotective processes. Such hormetic phenomena could have potential therapeutic applications, if properly employed. Here, we review the current theories of hormetic phenomena in regard to aging and neurodegeneration, with the focus on its underlying mechanism. Facilitated by a simple mathematical model, we show for the first time that ROS-mediated hormesis can be explained by the addition of different biomolecular reactions including oxidative damage, MAPK signaling and autophagy stimulation. Due to their divergent scales, the optimal hormetic window is sensitive to each kinetic parameter, which may vary between individuals. Therefore, therapeutic utilization of hormesis requires quantitative characterizations in order to access the optimal hormetic window for each individual. This calls for a personalized medicine approach for a longer human healthspan.

  1. Molecular gerontology: from homeodynamics to hormesis.

    Science.gov (United States)

    Rattan, Suresh I S

    2014-01-01

    The science and study of the biological basis of aging, biogerontology, is now a well-established field with solid scientific base. A paradigm-shift in gerontology has occurred by realising the fact that biological aging occurs in spite of the presence of complex homeodynamic pathways of maintenance, repair and defence, and there is no "enemy within". This viewpoint separates the modulation of aging from the treatment of one or more age-related diseases. A promising strategy in biogerontology is to slow down aging and to extend healthspan by hormetin-mediated hormesis. Physical, nutritional and mental hormetins, which initiate stress responses and strengthen the homeodynamics, are potentially effective aging modulators. As a biomedical issue, the biological process of aging underlies all major diseases, and while the optimal treatment of every disease is a social and moral necessity, preventing the onset of agerelated diseases by intervening in the basic process of aging is the best approach for designing novel pharmaceutical interventions.

  2. Healthy ageing - from molecules to hormesis

    DEFF Research Database (Denmark)

    Rattan, Suresh

    2012-01-01

    Ageing can be understood at various levels, from evolutionary and biological levels to psychological and sociological levels. At the molecular biological level ageing is characterized by the stochastic occurrence and progressive accumulation of molecular damage. Failure of homeodynamics, increased...... molecular heterogeneity, altered cellular functioning and reduced stress tolerance are the determinants of health status, probability of diseases and the duration of survival. The inefficiency and imperfection of the maintenance and repair systems underlie the biological basis of ageing. Two major issues...... life style alterations are examples of ageing interventions. A promising healthy-ageing approach is that of hormesis by strengthening the homeodynamic ability of self-maintenance through transient and repetitive mild stress-inducing hormetins. Achieving the goal of extended health-span will depend...

  3. Molecular gerontology: from homeodynamics to hormesis

    DEFF Research Database (Denmark)

    Rattan, Suresh

    2014-01-01

    The science and study of the biological basis of aging, biogerontology, is now a well-established field with solid scientific base. A paradigm-shift in gerontology has occurred by realising the fact that biological aging occurs in spite of the presence of complex homeodynamic pathways of maintena......The science and study of the biological basis of aging, biogerontology, is now a well-established field with solid scientific base. A paradigm-shift in gerontology has occurred by realising the fact that biological aging occurs in spite of the presence of complex homeodynamic pathways...... of maintenance, repair and defence, and there is no “enemy within”. This viewpoint separates the modulation of aging from the treatment of one or more age-related diseases. A promising strategy in biogerontology is to slow down aging and to extend healthspan by hormetin-mediated hormesis. Physical, nutritional...

  4. A strategy to model nonmonotonic dose-response curve and estimate IC50.

    Science.gov (United States)

    Zhang, Hui; Holden-Wiltse, Jeanne; Wang, Jiong; Liang, Hua

    2013-01-01

    The half-maximal inhibitory concentration IC[Formula: see text] is an important pharmacodynamic index of drug effectiveness. To estimate this value, the dose response relationship needs to be established, which is generally achieved by fitting monotonic sigmoidal models. However, recent studies on Human Immunodeficiency Virus (HIV) mutants developing resistance to antiviral drugs show that the dose response curve may not be monotonic. Traditional models can fail for nonmonotonic data and ignore observations that may be of biologic significance. Therefore, we propose a nonparametric model to describe the dose response relationship and fit the curve using local polynomial regression. The nonparametric approach is shown to be promising especially for estimating the IC[Formula: see text] of some HIV inhibitory drugs, in which there is a dose-dependent stimulation of response for mutant strains. This model strategy may be applicable to general pharmacologic, toxicologic, or other biomedical data that exhibits a nonmonotonic dose response relationship for which traditional parametric models fail.

  5. Analytical modelling of regional radiotherapy dose response of lung

    Science.gov (United States)

    Lee, Sangkyu; Stroian, Gabriela; Kopek, Neil; AlBahhar, Mahmood; Seuntjens, Jan; El Naqa, Issam

    2012-06-01

    Knowledge of the dose-response of radiation-induced lung disease (RILD) is necessary for optimization of radiotherapy (RT) treatment plans involving thoracic cavity irradiation. This study models the time-dependent relationship between local radiation dose and post-treatment lung tissue damage measured by computed tomography (CT) imaging. Fifty-eight follow-up diagnostic CT scans from 21 non-small-cell lung cancer patients were examined. The extent of RILD was segmented on the follow-up CT images based on the increase of physical density relative to the pre-treatment CT image. The segmented RILD was locally correlated with dose distribution calculated by analytical anisotropic algorithm and the Monte Carlo method to generate the corresponding dose-response curves. The Lyman-Kutcher-Burman (LKB) model was fit to the dose-response curves at six post-RT time periods, and temporal change in the LKB parameters was recorded. In this study, we observed significant correlation between the probability of lung tissue damage and the local dose for 96% of the follow-up studies. Dose-injury correlation at the first three months after RT was significantly different from later follow-up periods in terms of steepness and threshold dose as estimated from the LKB model. Dependence of dose response on superior-inferior tumour position was also observed. The time-dependent analytical modelling of RILD might provide better understanding of the long-term behaviour of the disease and could potentially be applied to improve inverse treatment planning optimization.

  6. Hormesis and adaptive cellular control systems

    Science.gov (United States)

    Hormetic dose response occurs for many endpoints associated with exposures of biological organisms to environmental stressors. Cell-based U- or inverted U-shaped responses may derive from common processes involved in activation of adaptive responses required to protect cells from...

  7. Hormesis and adaptive cellular control systems

    Science.gov (United States)

    Hormetic dose response occurs for many endpoints associated with exposures of biological organisms to environmental stressors. Cell-based U- or inverted U-shaped responses may derive from common processes involved in activation of adaptive responses required to protect cells from...

  8. The Dose-Response Relationship of the Compound Based on Phosphaphenanthrene and Triazine Groups in Epoxy Resin%磷杂菲三嗪双基化合物阻燃环氧树脂的量效关系*

    Institute of Scientific and Technical Information of China (English)

    钱立军; 邱勇

    2013-01-01

    Trif-DOPO has been used to prepare non-halogen flame retardant epoxy resin composites in diglycidyl ether of bisphenol-A with 4, 4’-diamino-diphenyl sulfone as curing agent. The properties of the epoxy resin composites including thermal properties, flame retardancy and water absorbency were detected by DSC, TGA, LOI measurement, UL94 vertical burning test, cone calorimetry and water absorption experiment. According to the results, we investigate the dose-response relationship between Trif-DOPO and the properties of epoxy resin composites. The results indicate that Trif-DOPO and the epoxy resin matrix constitute the intumescent flame-retardant system. With the increase of phosphorus fraction from 1.0%to 2.0%in the composites, compared with control sample, the flame retardant samples’time to ignition (TTI), total heat release (THR), average effective heat of combustion (av-EHC) and glass transition temperature (Tg) are all in negative correlation with the amount of Trif-DOPO while the expansion ratio of cone calorimetry residue is in positive correlation. Although the flame retardant samples’peak heat release rate (pk-HRR) and average heat release rate (av-HRR) both decrease dramatically, within the range of investigation, the loadings of flame retardant have little influence on them. Besides, the limiting oxygen index (LOI) of epoxy resin composites first increases, and then decreases with more Trif-DOPO added. The sample can obtain a LOI value of 36.0%and reach UL94 V-0 rating when the phosphorus fraction reaches 1.2%in the composite. Trif-DOPO can reduce the water-absorption rate of the epoxy resin composites to some extent as well.%  将三-(DOPO-羟甲基苯氧基)-三嗪(Trif-DOPO)添加到双酚A缩水甘油醚/4,4′-二氨基二苯砜环氧树脂(EP)体系中,制备了一种无卤阻燃EP,利用差示扫描量热仪、热失重分析仪、根限氧指数(LOI)测定仪、垂直燃烧测试仪、锥形量热仪及吸水性试验测试

  9. Comments on Ortwin Renn's article 'Hormesis and risk communication': considerations about uncertainity, ignorance and governance.

    Science.gov (United States)

    De Marchi, Bruna

    2003-01-01

    After acknowledging Renn's careful investigation and valuable insights, this paper expands on some issues that have been somewhat neglected in his account. It addresses the relationship between risk, uncertainity and ignorance in risk assessment, focusing in particular on the need to recognize that framing assumptions condition all subsequent steps. Subsequently, it discusses the implications for risk communication in the case of hormesis. The author maintains that problems of risk are strictly and irremediably intertwined with problems of governance. Therefore, she is doubtful that regulatory agencies would promote, and the public would welcome, modifications in current regimes on the basis of still limited and debated evidence of good.

  10. Hormesis: Decoding Two Sides of the Same Coin

    Directory of Open Access Journals (Sweden)

    Dipita Bhakta-Guha

    2015-12-01

    Full Text Available In the paradigm of drug administration, determining the correct dosage of a therapeutic is often a challenge. Several drugs have been noted to demonstrate contradictory effects per se at high and low doses. This duality in function of a drug at different concentrations is known as hormesis. Therefore, it becomes necessary to study these biphasic functions in order to understand the mechanistic basis of their effects. In this article, we focus on different molecules and pathways associated with diseases that possess a duality in their function and thus prove to be the seat of hormesis. In particular, we have highlighted the pathways and factors involved in the progression of cancer and how the biphasic behavior of the molecules involved can alter the manifestations of cancer. Because of the pragmatic role that it exhibits, the imminent need is to draw attention to the concept of hormesis. Herein, we also discuss different stressors that trigger hormesis and how stress-mediated responses increase the overall adaptive response of an individual to stress stimulus. We talk about common pathways through which cancer progresses (such as nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1, sirtuin-forkhead box O (SIRT-FOXO and others, analyzing how diverse molecules associated with these pathways conform to hormesis.

  11. Dose-response relationship of induction kinetics of In vivo DNA damage and repair in mouse leukocytes exposed to gamma radiation; Relacion dosis-respuesta de la cinetica de induccion de dano y reparacion del ADN In vivo en leucocitos de raton expuestos a radiacion gamma

    Energy Technology Data Exchange (ETDEWEB)

    Mendiola C, M.T.; Morales, R.P. [Instituto Nacional de Investigaciones Nucleares, Gerencia de Investigacion Basica, Departamento de Biologia, A.P. 18-1027, 11801 Mexico D.F. (Mexico)

    2000-07-01

    The Unicellular electrophoresis in gel technique is a useful tool in the determination of simple ruptures and labile sites to the alkali in DNA of eucariontes cells. The determination of the induction kinetics of damage and repair of DNA can give more information. The objective of this work was to determine whether the analysis of the area under the damage/repair induction kinetics curve in comets percent or the comets frequency in the two peaks of maximum induction is adequate for determining the dose-response relationship. The mice were exposed at the doses of 0.5, 1.0, 2.0 Gy. (Author)

  12. A Strategy to Model Nonmonotonic Dose-Response Curve and Estimate IC50

    OpenAIRE

    Hui Zhang; Jeanne Holden-Wiltse; Jiong Wang; Hua Liang

    2013-01-01

    The half-maximal inhibitory concentration IC[Formula: see text] is an important pharmacodynamic index of drug effectiveness. To estimate this value, the dose response relationship needs to be established, which is generally achieved by fitting monotonic sigmoidal models. However, recent studies on Human Immunodeficiency Virus (HIV) mutants developing resistance to antiviral drugs show that the dose response curve may not be monotonic. Traditional models can fail for nonmonotonic data and igno...

  13. Biphasic toxicodynamic features of some antimicrobial agents on microbial growth: a dynamic mathematical model and its implications on hormesis

    Directory of Open Access Journals (Sweden)

    Murado Miguel A

    2010-08-01

    Full Text Available Abstract Background In the present work, we describe a group of anomalous dose-response (DR profiles and develop a dynamic model that is able to explain them. Responses were obtained from conventional assays of three antimicrobial agents (nisin, pediocin and phenol against two microorganisms (Carnobacterium piscicola and Leuconostoc mesenteroides. Results Some of these anomalous profiles show biphasic trends which are usually attributed to hormetic responses. But they can also be explained as the result of the time-course of the response from a microbial population with a bimodal distribution of sensitivity to an effector, and there is evidence suggesting this last origin. In light of interest in the hormetic phenomenology and the possibility of confusing it with other phenomena, especially in the bioassay of complex materials we try to define some criteria which allow us to distinguish between sensu stricto hormesis and biphasic responses due to other causes. Finally, we discuss some problems concerning the metric of the dose in connection with the exposure time, and we make a cautionary suggestion about the use of bacteriocins as antimicrobial agents. Conclusions The mathematical model proposed, which combines the basis of DR theory with microbial growth kinetics, can generate and explain all types of anomalous experimental profiles. These profiles could also be described in a simpler way by means of bisigmoidal equations. Such equations could be successfully used in a microbiology and toxicology context to discriminate between hormesis and other biphasic phenomena.

  14. Patient factors that influence warfarin dose response.

    Science.gov (United States)

    White, Pamela J

    2010-06-01

    Warfarin has long been the mainstay of oral anticoagulation therapy for the treatment and prevention of venous and arterial thrombosis. The narrow therapeutic index of warfarin, and the complex number of factors that influence international normalized ratio (INR) response, makes optimization of warfarin therapy challenging. Determination of the appropriate warfarin dose during initiation and maintenance therapy requires an understanding of patient factors that influence dose response: age, body weight, nutritional status, acute and chronic disease states, and changes in concomitant drug therapy and diet. This review will examine specific clinical factors that can affect the pharmacokinetics and pharmacodynamics of warfarin, as well as the role of pharmacogenetics in optimizing warfarin therapy.

  15. Herbicide phosphinothricin causes direct stimulation hormesis.

    Science.gov (United States)

    Dragićević, Milan; Platiša, Jelena; Nikolić, Radomirka; Todorović, Slađana; Bogdanović, Milica; Mitić, Nevena; Simonović, Ana

    2012-01-01

    Herbicide phosphinothricin (PPT) inhibits glutamine synthetase (GS), a key enzyme in nitrogen assimilation, thus causing ammonia accumulation, glutamine depletion and eventually plant death. However, the growth response of Lotus corniculatus L. plants immersed in solutions with a broad range of PPT concentrations is biphasic, with pronounced stimulating effect on biomass production at concentrations ≤ 50 μM and growth inhibition at higher concentrations. The growth stimulation at low PPT concentrations is a result of activation of chloroplastic isoform GS2, while the growth suppression is caused by inhibition of both cytosolic GS1 and GS2 at higher PPT concentrations. Since the results are obtained in cell-free system (e.g. protein extracts), to which the principles of homeostasis are not applicable, this PPT effect is an unambiguous example of direct stimulation hormesis. A detailed molecular mechanism of concentration-dependent interaction of both PPT and a related GS inhibitor, methionine sulfoximine, with GS holoenzymes is proposed. The mechanism is in concurrence with all experimental and literature data.

  16. Radiation hormesis and the linear-no-threshold assumption

    CERN Document Server

    Sanders, Charles L

    2009-01-01

    Current radiation protection standards are based upon the application of the linear no-threshold (LNT) assumption, which considers that even very low doses of ionizing radiation can cause cancer. The radiation hormesis hypothesis, by contrast, proposes that low-dose ionizing radiation is beneficial. In this book, the author examines all facets of radiation hormesis in detail, including the history of the concept and mechanisms, and presents comprehensive, up-to-date reviews for major cancer types. It is explained how low-dose radiation can in fact decrease all-cause and all-cancer mortality an

  17. Development of a dose-response model for SARS coronavirus.

    Science.gov (United States)

    Watanabe, Toru; Bartrand, Timothy A; Weir, Mark H; Omura, Tatsuo; Haas, Charles N

    2010-07-01

    In order to develop a dose-response model for SARS coronavirus (SARS-CoV), the pooled data sets for infection of transgenic mice susceptible to SARS-CoV and infection of mice with murine hepatitis virus strain 1, which may be a clinically relevant model of SARS, were fit to beta-Poisson and exponential models with the maximum likelihood method. The exponential model (k= 4.1 x l0(2)) could describe the dose-response relationship of the pooled data sets. The beta-Poisson model did not provide a statistically significant improvement in fit. With the exponential model, the infectivity of SARS-CoV was calculated and compared with those of other coronaviruses. The does of SARS-CoV corresponding to 10% and 50% responses (illness) were estimated at 43 and 280 PFU, respectively. Its estimated infectivity was comparable to that of HCoV-229E, known as an agent of human common cold, and also similar to those of some animal coronaviruses belonging to the same genetic group. Moreover, the exponential model was applied to the analysis of the epidemiological data of SARS outbreak that occurred at an apartment complex in Hong Kong in 2003. The estimated dose of SARS-CoV for apartment residents during the outbreak, which was back-calculated from the reported number of cases, ranged from 16 to 160 PFU/person, depending on the floor. The exponential model developed here is the sole dose-response model for SARS-CoV at the present and would enable us to understand the possibility for reemergence of SARS.

  18. Dose-response behavior of the bacterium Vibrio fischeri exposed to pharmaceuticals and personal care products.

    Science.gov (United States)

    Ortiz de García, Sheyla; García-Encina, Pedro A; Irusta-Mata, Rubén

    2016-01-01

    The presence of pharmaceuticals and personal care products (PPCPs) in the environment has become a real and widespread concern in recent years. Therefore, the primary goal of this study was to investigate 20 common and widely used PPCPs to assess their individual and combined effect on an important species in one trophic level, i.e., bacteria. The ecotoxicological effects of PPCPs at two different concentration ranges were determined in the bacterium Vibrio fischeri using Microtox(®) and were statistically analyzed using three models in the GraphPad Prism 6 program for Windows, v.6.03. A four-parameter model best fit the majority of the compounds. The half maximal effective concentration (EC50) of each PPCP was estimated using the best-fitting model and was compared with the results from a recent study. Comparative analysis indicated that most compounds showed the same level of toxicity. Moreover, the stimulatory effects of PPCPs at environmental concentrations (low doses) were assessed. These results indicated that certain compounds have traditional inverted U- or J-shaped dose-response curves, and 55% of them presented a stimulatory effect below the zero effect-concentration point. Effective concentrations of 0 (EC0), 5 (EC5) and 50% (EC50) were calculated for each PPCP as the ecotoxicological points. All compounds that presented narcosis as a mode of toxic action at high doses also exhibited stimulation at low concentrations. The maximum stimulatory effect of a mixture was higher than the highest stimulatory effect of each individually tested compound. Moreover, when the exposure time was increased, the hormetic effect decreased. Hormesis is being increasingly included in dose-response studies because this may have a harmful, beneficial or indifferent effect in an environment. Despite the results obtained in this research, further investigations need to be conducted to elucidate the behavior of PPCPs in aquatic environments.

  19. Cellular bystander effects and radiation hormesis

    Directory of Open Access Journals (Sweden)

    Loredana MARCU

    2009-05-01

    Full Text Available Bystander effects describe the effects of extracellular mediators from irradiated cells on neighbouring non-irradiated cells resulting in radiation-induced effects in unirradiated cells. Although the underlying mechanisms are largely unknown, it is widely recognised that two types of cellular communication (i.e. via gap junctions and/or release of molecular messengers into the extracellular environment play an essential role. Additionally, the effects can be significantly modulated by parameters such as cell type, cell-cycle stage and cell density. Some of the common bystander effects or biological end points which are evidenced after low-dose irradiation are: chromosomal instability, cell killing and delayed cell death, mutagenesis, micronucleus formation, gene and protein expression changes. Through these end points it is likely that bystander effects can be both detrimental and beneficial. By increasing mutation levels of cells bystander effects increase the likelihood of genetic defects and in turn cancer. On the other hand by removing damaged cells from the population and preventing the growth of cancer cells, bystander effects are beneficial.Radiation hormesis is a term used to relate the beneficial effects of small doses of radiation on living cells, whether plant, animal or human. Experiments on bacteria, plants and animals have demonstrated that several biological mechanisms are stimulated by low dose radiation, such as: protein synthesis, gene activation, detoxication of free radicals and stimulation of the immune system. These mechanisms were also observed in humans.The present review paper is a compilation of the most recent data on bystander effects and the possible implications of cellular response to radiation on cell growth and development.

  20. Dose-response relationship between steady noise and hearing loss in exposed workers%稳态噪声作业工人听力损失与噪声接触的剂量-反应关系

    Institute of Scientific and Technical Information of China (English)

    张旭慧; 朱益民; 夏予勇

    2001-01-01

    Objective To understand the incidence of hearing loss in the workers exposed to steady noise and its risk factors.Methods A cross-sectional study was conducted in 481 employees exposed to steady noise for one year or more without any ear disorder.Their age,sex and hearing were investigated and noise level in the workplace were monitored.Results Incidence of hearing loss was 11.9% in the workers exposed to noise.There was significant difference in noise level between the workplaces where those with and without hearing loss worked and in length of exposure to noise and index of exposure to noise between workers with and without hearing loss(P<0.05),in a dose-response pattern.Conclusions Noise level,length of exposure to noise and index of noise exposure are major factors causing hearing loss in the workers exposed to noise,and especially the index of noise exposure can be used to reflect the level of their exposure in a more perfect way.%目的研究稳态噪声作业工人的听力损失发生状况以及影响因素。方法采用横断面研究方法,以参加稳态噪声作业一年或一年以上的无耳病史的481名工人为研究对象,调查年龄、性别、噪声作业的工龄、听力损失情况和作业场所噪声强度。结果作业工人听力损失的发生率为11.9%(按人数计)。听力损失者与非听力损失者噪声强度、接噪工龄和接噪指数的分布差别有显著意义(P均小于0.05)。而且与听力损失的危险性存在剂量-反应关系。结论噪声强度、接噪工龄和接噪指数是影响作业工人听力的主要因素,特别是接噪指数能较全面反映作业工人噪声接触水平。

  1. The Occurrence of Hormesis in Plants and Algae

    DEFF Research Database (Denmark)

    Cedergreen, Nina; Streibig, Jens C; Kudsk, Per

    2007-01-01

    This paper evaluated the frequency, magnitude and dose/concentration range of hormesis in four species: The aquatic plant Lemna minor, the micro-alga Pseudokirchneriella subcapitata and the two terrestrial plants Tripleurospermum inodorum and Stellaria media exposed to nine herbicides and one...

  2. Ozone as u-shaped dose responses molecules (hormetins).

    Science.gov (United States)

    Martínez-Sánchez, G; Pérez-Davison, G; Re, L; Giuliani, A

    2010-05-10

    Redox environment involves a broad network of pro-oxidant and antioxidant components. Health benefit or damage can be induced as a consequence of an adaptive cellular stress response. A consequence of hormetic amplification is an increase in the homeodynamic space of a living system in terms of an increased defense capacity and a reduced load of damaged macromolecules. Ozone, when used at appropriate doses, promotes the formation of reactive oxygen species and lipid peroxides allows them to become late and long-lasting messengers. Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The paradoxical concept that ozone eventually induces an antioxidant response capable of reversing a chronic oxidative stress is common in the animal and vegetal kingdom; it is already supported by findings of an increased level of antioxidant enzymes during ozone therapy. Those facts can include ozone as a hormetin. The established scientific foundations of hormesis are ready to pave the way for new and effective approaches in redox-related disease research and intervention; ozone therapy can be a good candidate.

  3. Selective toxin effects on faster and slower growing individuals in the formation of hormesis at the population level - A case study with Lactuca sativa and PCIB.

    Science.gov (United States)

    Belz, Regina G; Sinkkonen, Aki

    2016-10-01

    Natural plant populations have large phenotypic plasticity that enhances acclimation to local stress factors such as toxin exposures. While consequences of high toxin exposures are well addressed, effects of low-dose toxin exposures on plant populations are seldom investigated. In particular, the importance of 'selective low-dose toxicity' and hormesis, i.e. stimulatory effects, has not been studied simultaneously. Since selective toxicity can change the size distribution of populations, we assumed that hormesis alters the size distribution at the population level, and investigated whether and how these two low-dose phenomena coexist. The study was conducted with Lactuca sativa L. exposed to the auxin-inhibitor 2-(p-chlorophenoxy)-2-methylpropionic acid (PCIB) in vitro. In two separate experiments, L. sativa was exposed to 12 PCIB doses in 24 replicates (50 plants/replicate). Shoot/root growth responses at the population level were compared to the fast-growing (≥90% percentile) and the slow-growing subpopulations (≤10% percentile) by Mann-Whitney U testing and dose-response modelling. In the formation of pronounced PCIB hormesis at the population level, low-dose effects proved selective, but widely stimulatory which seems to counteract low-dose selective toxicity. The selectivity of hormesis was dose- and growth rate-dependent. Stimulation occurred at lower concentrations and stimulation percentage was higher among slow-growing individuals, but partly or entirely masked at the population level by moderate or negligible stimulation among the faster growing individuals. We conclude that the hormetic effect up to the maximum stimulation may be primarily facilitated by an increase in size of the most slow-growing individuals, while thereafter it seems that mainly the fast-growing individuals contributed to the observed hormesis at the population level. As size distribution within a population is related to survival, our study hints that selective effects on slow

  4. Influences of mechanical exposure biographies on physical capabilities of workers from automotive industry - a study on possible dose-response relationships and consequences for short and long term job rotation.

    Science.gov (United States)

    Rademacher, Holger; Bruder, Ralph; Sinn-Behrendt, Andrea; Landau, Kurt

    2012-01-01

    This paper describes a field study in production areas of a vehicle manufacturing plant, where 106 male workers (aged from 20 to 63 years) were examined and interviewed by the authors. Aim of study was to identify relationships between specific physical worker capabilities and doses of mechanical exposures using self-developed standardized questionnaires as well as a battery of work-specific tests. The dependent variables are different "physical capabilities", classified using a five-point rating scale with regard to the grade of limitation of the respective capability. Independent variables are "age" and specific "mechanical exposures". Several exposures were combined and multiplied with their respective durations in order to determine doses on three different body regions - back, shoulder-neck and upper limbs. There are significant positive correlations between "age" and "dose of mechanical exposure on back/shoulder-neck/upper limbs region". The analysis of the relationship between dose of exposure and different capabilities to lift or reposition loads (with variable weight) shows weak significant correlations for all three body regions. Data analysis shows no significant correlations between any dose of mechanical exposure and capabilities to work in awkward body postures.These results should be considered in age management programs when scheduling future employee assignments to workplaces, especially for production systems where manual handling tasks are dominant.

  5. Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Torekov, Signe Sørensen; Kipnes, M S; Harley, R E;

    2011-01-01

    To evaluate the dose-response relationship of the recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes, with respect to reductions in fasting, postprandial and 11-h serum glucose profiles....

  6. Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis.

    Science.gov (United States)

    Singh, François; Charles, Anne-Laure; Schlagowski, Anna-Isabel; Bouitbir, Jamal; Bonifacio, Annalisa; Piquard, François; Krähenbühl, Stephan; Geny, Bernard; Zoll, Joffrey

    2015-07-01

    Even though oxidative stress damage from excessive production of ROS is a well known phenomenon, the impact of reductive stress remains poorly understood. This study tested the hypothesis that cellular reductive stress could lead to mitochondrial malfunction, triggering a mitochondrial hormesis (mitohormesis) phenomenon able to protect mitochondria from the deleterious effects of statins. We performed several in vitro experiments on L6 myoblasts and studied the effects of N-acetylcysteine (NAC) at different exposure times. Direct NAC exposure (1mM) led to reductive stress, impairing mitochondrial function by decreasing maximal mitochondrial respiration and increasing H₂O₂production. After 24h of incubation, the reactive oxygen species (ROS) production was increased. The resulting mitochondrial oxidation activated mitochondrial biogenesis pathways at the mRNA level. After one week of exposure, mitochondria were well-adapted as shown by the decrease of cellular ROS, the increase of mitochondrial content, as well as of the antioxidant capacities. Atorvastatin (ATO) exposure (100μM) for 24h increased ROS levels, reduced the percentage of live cells, and increased the total percentage of apoptotic cells. NAC exposure during 3days failed to protect cells from the deleterious effects of statins. On the other hand, NAC pretreatment during one week triggered mitochondrial hormesis and reduced the deleterious effect of statins. These results contribute to a better understanding of the redox-dependant pathways linked to mitochondria, showing that reductive stress could trigger mitochondrial hormesis phenomenon.

  7. Review of dose-response curves for acute antimigraine drugs

    DEFF Research Database (Denmark)

    Hougaard, Anders; Tfelt-Hansen, Peer

    2015-01-01

    INTRODUCTION: Dose-response curves for efficacy and tolerability are the important determinants for the choice of doses of acute migraine drugs. Areas covered: Dose-response curves for the efficacy of seven triptans (5-HT1B/1D receptor agonists), a 5-HT1F receptor agonist (lasmiditan) and four oral...... calcitonin-gene related peptide receptor antagonists (telcagepant, MK-3207, BI 44370 TA and BMS-927711) in placebo-controlled trials were reviewed. In addition, dose-response curves for adverse events (AEs) were reviewed. Expert opinion: For most triptans, the dose-response curve for efficacy is flat......, whereas AEs often increase with increasing doses. The two other groups of drugs also have flat dose-response curves for efficacy. Overall, the triptans still have the most favorable efficacy-tolerability profile. Current acute antimigraine drugs do not fulfill the expectations of the patients, and thus...

  8. Health effects of low doses at low dose rates: dose-response relationship modeling in a cohort of workers of the nuclear industry; Effets sanitaires des faibles doses a faibles debits de dose: modelisation de la relation dose-reponse dans une cohorte de travailleurs du nucleaire

    Energy Technology Data Exchange (ETDEWEB)

    Metz-Flamant, Camille

    2011-09-19

    The aim of this thesis is to contribute to a better understanding of the health effects of chronic external low doses of ionising radiation. This work is based on the French cohort of CEA-AREVA NC nuclear workers. The mains stages of this thesis were (1) conducting a review of epidemiological studies on nuclear workers, (2) completing the database and performing a descriptive analysis of the cohort, (3) quantifying risk by different statistical methods and (4) modelling the exposure-time-risk relationship. The cohort includes monitored workers employed more than one year between 1950 and 1994 at CEA or AREVA NC companies. Individual annual external exposure, history of work, vital status and causes of death were reconstructed for each worker. Standardized mortality ratios using French national mortality rates as external reference were computed. Exposure-risk analysis was conducted in the cohort using the linear excess relative risk model, based on both Poisson regression and Cox model. Time dependent modifying factors were investigated by adding an interaction term in the model or by using exposure time windows. The cohort includes 36, 769 workers, followed-up until age 60 in average. During the 1968- 2004 period, 5, 443 deaths, 2, 213 cancers, 62 leukemia and 1, 314 cardiovascular diseases were recorded. Among the 57% exposed workers, the mean cumulative dose was 21.5 milli-sieverts (mSv). A strong Healthy Worker Effect is observed in the cohort. Significant elevated risks of pleura cancer and melanoma deaths were observed in the cohort but not associated with dose. No significant association was observed with solid cancers, lung cancer and cardiovascular diseases. A significant dose-response relationship was observed for leukemia excluding chronic lymphatic leukemia, mainly for doses received less than 15 years before and for yearly dose rates higher than 10 mSv. This PhD work contributes to the evaluation of risks associated to chronic external radiation

  9. Dose response relationship in anti-stress gene regulatory networks.

    OpenAIRE

    Qiang Zhang; Andersen, Melvin E.

    2007-01-01

    To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misf...

  10. Dose-Response Relationship of Phototherapy for Hyperbilirubinemia

    DEFF Research Database (Denmark)

    Vandborg, Pernille Kure; Hansen, Bo Moelholm; Greisen, Gorm

    2012-01-01

    Using light-emitting diodes during conventional phototherapy, it is possible to reduce the distance from light source to infant, thus increasing light irradiance. The objective of this study was to search for a "saturation point" (ie, an irradiation level above which there is no further decrease ...

  11. Dose-response features of neuroprotective agents: an integrative summary.

    Science.gov (United States)

    Calabrese, Edward J

    2008-01-01

    This article provides an integrative summary of the effects of neuroprotective agents on neuronal survival and neurite outgrowth using primary cell cultures, multiple neuronal cell lines, and astroglial cells. These findings are dealt with in considerable detail in the following three articles (Calabrese, 2008a, 2008b, 2008c) of this series of issues of Critical Reviews in Toxicology. The principal finding is that the overwhelming majority of neuroprotective agents display biphasic dose responses, characterized by modest low-dose enhancement/stimulation and high-dose inhibitory responses. The quantitative features of these dose responses are consistent with the hormetic dose-response model. Mechanisms that account for numerous hormetic dose responses of neuroprotective agents are summarized, as well as the clinical implications of specific experimental findings.

  12. Assembled cross-species perchlorate dose-response data

    Data.gov (United States)

    U.S. Environmental Protection Agency — This data set contains dose-response data for perchlorate exposure in multiple species. These data were assembled from peer-reviewed studies. Species included in...

  13. Nonparallel nephrotoxicity dose-response curves of aminoglycosides.

    OpenAIRE

    1981-01-01

    Nephrotoxicity comparisons of aminoglycosides in rats, utilizing large multiples of human doses, have indicated an advantage for netilmicin. However, no nephrotoxicity advantage of netilmicin has been demonstrated at the lower doses used in clinics. Some high-dose studies in rats have also suggested that the slope of the nephrotoxicity dose-response curve of netilmicin was less steep than the slopes of other aminoglycosides. Therefore, the slopes of the nephrotoxicity dose-response curves of ...

  14. Nonlinearity of dose-response functions for carcinogenicity.

    OpenAIRE

    Hoel, D G; Portier, C J

    1994-01-01

    Carcinogenesis data for 315 chemicals were obtained from the National Cancer Institute-National Toxicology Program (NCI-NTP) bioassay programs and were analyzed to examine the shape of carcinogenesis dose-response curves. Tumor site data were more often consistent with a quadratic response than with a linear response, suggesting that the routine use of linear dose-response models will often overestimate risk. Information from in vivo short-term mutagenicity and genotoxicity assays was also ob...

  15. Patients who do not respond to the "usual" dose: why Terry fell off the dose-response curve.

    Science.gov (United States)

    Preskorn, Sheldon H

    2009-11-01

    Clinical trials are aimed at determining what happens in the "usual" patient; however, clinicians are interested in what happens in their patients even if they are not usual. The usual dose-response relationship is determined as part of the drug development process required for approval of a new drug. However, clinicians are likely to encounter patients who "fall off" the usual dose-response curve because they are either sensitive or resistant to the beneficial (efficacy) or adverse effects of a drug. This column is the first in a series that will examine why specific patients fall off the usual dose-response curve and how clinicians can manage such patients when they encounter them. This column discusses what a dose-response curve is, how it is determined, and why it is clinically important.

  16. Coffee and tea consumption and risk of lung cancer: a dose-response analysis of observational studies.

    Science.gov (United States)

    Wang, Yaopeng; Yu, Xuyi; Wu, Yili; Zhang, Dongfeng

    2012-11-01

    Results from the recent meta-analysis suggested a favorable effect of green tea consumption and risk of lung cancer, while no significant association was found between black tea consumption and risk of lung cancer. Besides, a significantly positive association was found between coffee consumption and risk of lung cancer. However, the relationship of green tea and coffee consumption is unclear. Thus the dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression. Results suggested that a linear dose-response relationship exists between coffee consumption and risk of lung cancer, while the dose-response relationship is nonlinear between green tea consumption and risk of lung cancer.

  17. Physical activity and cancer risk: dose-response and cancer, all sites and site-specific.

    Science.gov (United States)

    Thune, I; Furberg, A S

    2001-06-01

    The association between physical activity and overall and site-specific cancer risk is elaborated in relation to whether any observed dose-response association between physical activity and cancer can be interpreted in terms of how much physical activity (type, intensity, duration, frequency) is needed to influence site- and gender-specific cancer risk. Observational studies were reviewed that have examined the independent effect of the volume of occupational physical activity (OPA) and/or leisure time physical activity (LPA) on overall and site-specific cancer risk. The evidence of cohort and case-control studies suggests that both leisure time and occupational physical activity protect against overall cancer risk, with a graded dose-response association suggested in both sexes. Confounding effects such as diet, body weight, and parity are often included as a covariate in the analyses, with little influence on the observed associations. A crude graded inverse dose-response association was observed between physical activity and colon cancer in 48 studies including 40,674 colon/colorectal cancer cases for both sexes. A dose-response effect of physical activity on colon cancer risk was especially observed, when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed as MET-hours per week. An observed inverse association with a dose-response relationship between physical activity and breast cancer was also identified in the majority of the 41 studies including 108,031 breast cancer cases. The dose-response relationship was in particular observed in case-control studies and supported by observations in cohort studies when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed by MET-hours per week. This association between physical activity and breast cancer risk is possibly dependent on age at exposure, age at diagnosis, menopausal status and other effect

  18. Stress and fish reproduction: the roles of allostasis and hormesis.

    Science.gov (United States)

    Schreck, Carl B

    2010-02-01

    This paper is a review of the effects of stress on reproduction in fishes. I hope to further the development of the concepts of allostasis and hormesis as relevant to understanding reproduction in general and in fish in particular. The main contentions I derive in this review are the following: Stressors affect fish reproduction in a variety of ways depending on the nature and severity of the stressor. The effects are transduced through a hormonal cascade initiated by perception of the stressor and involving the hypothalamus-pituitary-interrenal axis, the catecholamines, and also cytokines. Mounting a stress response and resisting a stressor is an energetically costly process, including costs associated with allostasis, attempting to reset homeostatic norms. Responses in emergency situations (e.g., being chased by a predator or a net) can be different from those where fish can cope (e.g., being in a more crowded environment) with a stressor, but both situations involve energy re-budgeting. Emergency responses happen in concert with the onset of energy limitations (e.g., the fish may not eat), while coping with allostatic overload can happen in a more energy-rich environment (e.g., the fish can continue to eat). Low levels of stress may have a positive effect on reproductive processes while greater stress has negative effects on fish reproduction. The concept of hormesis is a useful way to think about the effect of stressors on fish reproduction since responses can be nonmonotonal, often biphasic.

  19. The myth and reality of reversal of aging by hormesis.

    Science.gov (United States)

    Sonneborn, Joan Smith

    2005-12-01

    Hormesis is an adaptive response to low doses of otherwise harmful agents by triggering a cascade of stress-specific resistance pathways. Evidence from protozoa, nematodes, flies, rodents, and primates indicate that stress-induced tolerance modulates survival and longevity. "Reality" is that hormesis can prolong the healthy life span. Genetic background provides the potential for longevity duration induced by stress. Senesence, or aging, is generally thought to be due to a different impact of selection for alleles positive for reproduction during early life but harmful in later life, a process called antagonistic pleiotropy (multiple phenotypic changes by a single gene). After reproduction, life span is "invisible" to selection. I propose the revision that mutations selected for survival until reproduction in early life may also extend later life (protagonistic pleiotropy). The protagonist candidate genes for extended life span are hormetic response genes, which activate the protective effect in both early and later life. My revision of the earlier evolutionary theory implies that natural selection of genes critical for early survival (life span until reproduction) can also be beneficial for extended longevity in old age, tipping the evolutionary balance in favor of a latent inducible life span extension unless excess stressor challenge exceeds the protection capacity. Mimetic triggers of the stress response promise the option of tricking the induction of metabolic pathways that confer resistance to environmental challenges, increased healthy life span, rejuvenation, and disease intervention without the danger of overwhelming damage by the stressor. Public policy should anticipate an increase in healthy life span.

  20. 有毒物质Hormesis效应的识别与评价%Ways to identify and evaluate the Hormesis induced by toxic substances

    Institute of Scientific and Technical Information of China (English)

    朱鸿林; 张燕; 赏国锋; 沈国清

    2011-01-01

    , let the function be expressed as Y = 0.3994 - 1.4472 X2 + 1.707X, which can be reflected in an inverted U- shape curve. The area under the hormetic zone and the magnitude of the stimulatory response could be obtained. The adoption of the direct integral method may help us to work out the hormetic area with AUCH and AUCZEP while the ratio of AUCH and AUCZEP is 45.34% . When we conduct a dose-response experiment and enhance responses at some low concentrations, statistical analyses should be done to determine if the enhanced responses result in chance occurrence. Therefore, we have pointed out in this paper that the incidence of hormesis can be statistically evaluated by using the ratio of AUCH and AUCZEP, which implies that the stated method proposed in this paper is mainly applicable to the continuous data.

  1. Dose-Response Relation Between Work Hours and Cardiovascular Disease Risk: Findings From the Panel Study of Income Dynamics.

    Science.gov (United States)

    Conway, Sadie H; Pompeii, Lisa A; Roberts, Robert E; Follis, Jack L; Gimeno, David

    2016-03-01

    The aim of this study was to examine the presence of a dose-response relationship between work hours and incident cardiovascular disease (CVD) in a representative sample of U.S. workers. A retrospective cohort study of 1926 individuals from the Panel Study of Income Dynamics (1986 to 2011) employed for at least 10 years. Restricted cubic spline regression was used to estimate the dose-response relationship of work hours with CVD. A dose-response relationship was observed in which an average workweek of 46 hours or more for at least 10 years was associated with an increased risk of CVD. Compared with working 45 hours per week, working an additional 10 hours per week or more for at least 10 years increased CVD risk by at least 16%. Working more than 45 work hours per week for at least 10 years may be an independent risk factor for CVD.

  2. Steepness of the radiation dose-response curve for dose-per-fraction escalation keeping the number of fractions fixed.

    Science.gov (United States)

    Bentzen, Søren M

    2005-01-01

    Clinically, there is growing interest in strategies for intensifying radiation therapy by escalating the dose per fraction. This paper considers the steepness of the dose-response curve in this case. The steepness of a radiation dose-response curve is most conveniently quantified by the normalized dose-response gradient, gamma. Under the assumption of a linear-quadratic dose-effect model, a simple analytical relationship is derived between the gamma-value for a dose-response curve generated by varying the total dose while keeping the number of fractions constant, i.e. escalating the dose per fraction, and the gamma-value for a dose-response curve generated by varying the total dose while keeping the dose per fraction constant. This formulation is compared with clinical dose-response data from the literature and shown to be in good agreement with the observations. Some implications of this formulation for non-uniform dose distributions delivered using 3D conformal radiotherapy or intensity modulated radiotherapy (IMRT) are briefly discussed.

  3. Pseudomonas aeruginosa dose response and bathing water infection.

    Science.gov (United States)

    Roser, D J; van den Akker, B; Boase, S; Haas, C N; Ashbolt, N J; Rice, S A

    2014-03-01

    Pseudomonas aeruginosa is the opportunistic pathogen mostly implicated in folliculitis and acute otitis externa in pools and hot tubs. Nevertheless, infection risks remain poorly quantified. This paper reviews disease aetiologies and bacterial skin colonization science to advance dose-response theory development. Three model forms are identified for predicting disease likelihood from pathogen density. Two are based on Furumoto & Mickey's exponential 'single-hit' model and predict infection likelihood and severity (lesions/m2), respectively. 'Third-generation', mechanistic, dose-response algorithm development is additionally scoped. The proposed formulation integrates dispersion, epidermal interaction, and follicle invasion. The review also details uncertainties needing consideration which pertain to water quality, outbreaks, exposure time, infection sites, biofilms, cerumen, environmental factors (e.g. skin saturation, hydrodynamics), and whether P. aeruginosa is endogenous or exogenous. The review's findings are used to propose a conceptual infection model and identify research priorities including pool dose-response modelling, epidermis ecology and infection likelihood-based hygiene management.

  4. Stress to the Rescue: Is Hormesis a ‘Cure’ For Aging?

    DEFF Research Database (Denmark)

    Kahn, Arnold; Olsen, Anders

    2009-01-01

    Despite the fact that the phenomenon of hormesis has been known for many years it is still very much an area of controversy just how useful hormetic treatments are in preventing age-related human diseases and increasing life expectancy. Since there are no data in humans demonstrating hormesis as ...... as an effective anti-ageing strategy we turn to a simple model organism for insight. In this review we explore what can be predicted about the usefulness of hormetic treatments in humans based upon studies conducted in the soil nematode Caenorhabditis elegans.......Despite the fact that the phenomenon of hormesis has been known for many years it is still very much an area of controversy just how useful hormetic treatments are in preventing age-related human diseases and increasing life expectancy. Since there are no data in humans demonstrating hormesis...

  5. A Theoretical Model for the Hormetic Dose-response Curve for Anticancer Agents.

    Science.gov (United States)

    Yoshimasu, Tatsuya; Ohashi, Takuya; Oura, Shoji; Kokawa, Yozo; Kawago, Mitsumasa; Hirai, Yoshimitsu; Miyasaka, Miwako; Nishiguchi, Haruka; Kawashima, Sayoko; Yata, Yumi; Honda, Mariko; Fujimoto, Takahiro; Okamura, Yoshitaka

    2015-11-01

    In the present article, we quantitatively evaluated the dose-response relationship of hormetic reactions of anticancer agents in vitro. Serial dilutions of gemcitabine, cisplatin, 5-fluorouracil, vinorelbine, and paclitaxel were administered to the A549 non-small-cell lung cancer cell line. The bi-phasic sigmoidal curve with hormetic and cytotoxic effects is given by the formula y=(a-b/(1+exp(c(*)log(x)-d)))/(1+exp(e(*)log(x)-f)), that was used to perform a non-linear least square regression. The dose-responses of the five anticancer agents were fitted to this equation. Gemcitabine and 5-fluorouracil, which had the lowest ED50 for their hormetic reaction, had the most pronounced promotive effects out of the five anticancer agents tested. The hormetic reaction progressed exponentially with culturing time. Our theoretical model will be useful in predicting how hormetic reactions affect patients with malignant tumors.

  6. The hormesis concept and risk assessment: are there unique ethical and policy considerations?

    Science.gov (United States)

    Hoffmann, Gr; Stempsey, We

    2008-08-01

    The hormesis concept holds that low doses of toxic substances and radiation elicit modest biological responses opposite to those caused by higher doses of the same agents. This concept stands in contrast to the prevailing views that a threshold model predicts most responses to toxicants at low doses and that linear extrapolation best predicts mutagenic and carcinogenic responses. Beyond the scientific considerations, there has been concern that inclusion of the hormesis model in risk assessment would raise complex ethical questions, pose serious challenges for policy makers, and threaten public safety. This article briefly reviews the growing evidence for hormesis and offers a perspective on the related ethical and societal issues. Complexities stem from the nature of biphasic curves, in which biological responses fall both above and below background levels. The monotonic responses of the threshold and linear models lend themselves to a single policy objective--avoiding harm associated with exposures. The biphasic responses of the hormesis model, however, suggest the possibility of accruing benefit as well as avoiding harm. The prospect of applying the hormesis model to public health policy is impeded by insufficient ability to identify the hormetic and toxic zones with precision. Moreover, heterogeneity among individuals in susceptibility to toxicants suggests that benefit and risk may be distributed unequally in the population. The potential shift in policy objectives associated with hormesis is considered relative to the difficulty of balancing the ethical principles of nonmaleficence and beneficence while maintaining a higher priority on the former.

  7. Dose-response aligned circuits in signaling systems.

    Science.gov (United States)

    Yan, Long; Ouyang, Qi; Wang, Hongli

    2012-01-01

    Cells use biological signal transduction pathways to respond to environmental stimuli and the behavior of many cell types depends on precise sensing and transmission of external information. A notable property of signal transduction that was characterized in the Saccharomyces cerevisiae yeast cell and many mammalian cells is the alignment of dose-response curves. It was found that the dose response of the receptor matches closely the dose responses of the downstream. This dose-response alignment (DoRA) renders equal sensitivities and concordant responses in different parts of signaling system and guarantees a faithful information transmission. The experimental observations raise interesting questions about the nature of the information transmission through DoRA signaling networks and design principles of signaling systems with this function. Here, we performed an exhaustive computational analysis on network architectures that underlie the DoRA function in simple regulatory networks composed of two and three enzymes. The minimal circuits capable of DoRA were examined with Michaelis-Menten kinetics. Several motifs that are essential for the dynamical function of DoRA were identified. Systematic analysis of the topology space of robust DoRA circuits revealed that, rather than fine-tuning the network's parameters, the function is primarily realized by enzymatic regulations on the controlled node that are constrained in limiting regions of saturation or linearity.

  8. Dose-response meta-analysis of differences in means

    Directory of Open Access Journals (Sweden)

    Alessio Crippa

    2016-08-01

    Full Text Available Abstract Background Meta-analytical methods are frequently used to combine dose-response findings expressed in terms of relative risks. However, no methodology has been established when results are summarized in terms of differences in means of quantitative outcomes. Methods We proposed a two-stage approach. A flexible dose-response model is estimated within each study (first stage taking into account the covariance of the data points (mean differences, standardized mean differences. Parameters describing the study-specific curves are then combined using a multivariate random-effects model (second stage to address heterogeneity across studies. Results The method is fairly general and can accommodate a variety of parametric functions. Compared to traditional non-linear models (e.g. E max, logistic, spline models do not assume any pre-specified dose-response curve. Spline models allow inclusion of studies with a small number of dose levels, and almost any shape, even non monotonic ones, can be estimated using only two parameters. We illustrated the method using dose-response data arising from five clinical trials on an antipsychotic drug, aripiprazole, and improvement in symptoms in shizoaffective patients. Using the Positive and Negative Syndrome Scale (PANSS, pooled results indicated a non-linear association with the maximum change in mean PANSS score equal to 10.40 (95 % confidence interval 7.48, 13.30 observed for 19.32 mg/day of aripiprazole. No substantial change in PANSS score was observed above this value. An estimated dose of 10.43 mg/day was found to produce 80 % of the maximum predicted response. Conclusion The described approach should be adopted to combine correlated differences in means of quantitative outcomes arising from multiple studies. Sensitivity analysis can be a useful tool to assess the robustness of the overall dose-response curve to different modelling strategies. A user-friendly R package has been developed to facilitate

  9. Methods for meta-analysis of pharmacodynamic dose-response data with application to multi-arm studies of alogliptin

    NARCIS (Netherlands)

    Langford, Oliver; Aronson, Jeffrey K; van Valkenhoef, Gert; Stevens, Richard J

    2016-01-01

    Standard methods for meta-analysis of dose-response data in epidemiology assume a model with a single scalar parameter, such as log-linear relationships between exposure and outcome; such models are implicitly unbounded. In contrast, in pharmacology, multi-parameter models, such as the widely used E

  10. Bayesian multimodel inference for dose-response studies

    Science.gov (United States)

    Link, W.A.; Albers, P.H.

    2007-01-01

    Statistical inference in dose?response studies is model-based: The analyst posits a mathematical model of the relation between exposure and response, estimates parameters of the model, and reports conclusions conditional on the model. Such analyses rarely include any accounting for the uncertainties associated with model selection. The Bayesian inferential system provides a convenient framework for model selection and multimodel inference. In this paper we briefly describe the Bayesian paradigm and Bayesian multimodel inference. We then present a family of models for multinomial dose?response data and apply Bayesian multimodel inferential methods to the analysis of data on the reproductive success of American kestrels (Falco sparveriuss) exposed to various sublethal dietary concentrations of methylmercury.

  11. Model Averaging Software for Dichotomous Dose Response Risk Estimation

    Directory of Open Access Journals (Sweden)

    Matthew W. Wheeler

    2008-02-01

    Full Text Available Model averaging has been shown to be a useful method for incorporating model uncertainty in quantitative risk estimation. In certain circumstances this technique is computationally complex, requiring sophisticated software to carry out the computation. We introduce software that implements model averaging for risk assessment based upon dichotomous dose-response data. This software, which we call Model Averaging for Dichotomous Response Benchmark Dose (MADr-BMD, fits the quantal response models, which are also used in the US Environmental Protection Agency benchmark dose software suite, and generates a model-averaged dose response model to generate benchmark dose and benchmark dose lower bound estimates. The software fulfills a need for risk assessors, allowing them to go beyond one single model in their risk assessments based on quantal data by focusing on a set of models that describes the experimental data.

  12. Optimal designs for dose response curves with common parameters

    OpenAIRE

    Feller, Chrystel; Schorning, Kirsten; Dette, Holger; Bermann, Georgina; Bornkamp, Björn

    2016-01-01

    A common problem in Phase II clinical trials is the comparison of dose response curves corresponding to different treatment groups. If the effect of the dose level is described by parametric regression models and the treatments differ in the administration frequency (but not in the sort of drug) a reasonable assumption is that the regression models for the different treatments share common parameters. This paper develops optimal design theory for the comparison of different regression models ...

  13. Characterization of a developmental toxicity dose-response model.

    OpenAIRE

    Faustman, E M; Wellington, D G; Smith, W P; Kimmel, C A

    1989-01-01

    The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included ...

  14. Interpretation of the margin of exposure for genotoxic carcinogens - elicitation of expert knowledge about the form of the dose response curve at human relevant exposures.

    Science.gov (United States)

    Boobis, Alan; Flari, Villie; Gosling, John Paul; Hart, Andy; Craig, Peter; Rushton, Lesley; Idahosa-Taylor, Ehi

    2013-07-01

    The general approach to risk assessment of genotoxic carcinogens has been to advise reduction of exposure to "as low as reasonably achievable/practicable" (ALARA/P). However, whilst this remains the preferred risk management option, it does not provide guidance on the urgency or extent of risk management actions necessary. To address this, the "Margin of Exposure" (MOE) approach has been proposed. The MOE is the ratio between the point of departure for carcinogenesis and estimated human exposure. However, interpretation of the MOE requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures. In a structured elicitation exercise, we captured expert opinion on available scientific evidence for low dose-response relationships for genotoxic carcinogens. This allowed assessment of: available evidence for the nature of dose-response relationships at human relevant exposures; the generality of judgments about such dose-response relationships; uncertainties affecting judgments on the nature of such dose-response relationships; and whether this last should differ for different classes of genotoxic carcinogens. Elicitation results reflected the variability in experts' views on the form of the dose-response curve for low dose exposure and major sources of uncertainty affecting the assumption of a linear relationship.

  15. Biphasic dose response in low level light therapy - an update.

    Science.gov (United States)

    Huang, Ying-Ying; Sharma, Sulbha K; Carroll, James; Hamblin, Michael R

    2011-01-01

    Low-level laser (light) therapy (LLLT) has been known since 1967 but still remains controversial due to incomplete understanding of the basic mechanisms and the selection of inappropriate dosimetric parameters that led to negative studies. The biphasic dose-response or Arndt-Schulz curve in LLLT has been shown both in vitro studies and in animal experiments. This review will provide an update to our previous (Huang et al. 2009) coverage of this topic. In vitro mediators of LLLT such as adenosine triphosphate (ATP) and mitochondrial membrane potential show biphasic patterns, while others such as mitochondrial reactive oxygen species show a triphasic dose-response with two distinct peaks. The Janus nature of reactive oxygen species (ROS) that may act as a beneficial signaling molecule at low concentrations and a harmful cytotoxic agent at high concentrations, may partly explain the observed responses in vivo. Transcranial LLLT for traumatic brain injury (TBI) in mice shows a distinct biphasic pattern with peaks in beneficial neurological effects observed when the number of treatments is varied, and when the energy density of an individual treatment is varied. Further understanding of the extent to which biphasic dose responses apply in LLLT will be necessary to optimize clinical treatments.

  16. Cell mechanics and stress: from molecular details to the 'universal cell reaction' and hormesis.

    Science.gov (United States)

    Agutter, Paul S

    2007-04-01

    The 'universal cell reaction' (UCR), a coordinated biphasic response to external (noxious and other) stimuli observed in all living cells, was described by Nasonov and his colleagues in the mid-20th century. This work has received no attention from cell biologists in the West, but the UCR merits serious consideration. Although it is non-specific, it is likely to be underpinned by precise mechanisms and, if these mechanisms were characterized and their relationship to the UCR elucidated, then our understanding of the integration of cellular function could be improved. As a step towards identifying such mechanisms, I review some recent advances in understanding cell mechanics and the stress response and I suggest potentially testable hypotheses. There is a particular need for time-course studies of cellular responses to different stimulus doses or intensities. I also suggest a correspondence with hormesis; re-investigation of the UCR using modern biophysical and molecular-biological techniques might throw light on this much-discussed phenomenon.

  17. Hormesis does not make sense except in the light of TOR-driven aging.

    Science.gov (United States)

    Blagosklonny, Mikhail V

    2011-11-01

    Weak stresses (including weak oxidative stress, cytostatic agents, heat shock, hypoxia, calorie restriction) may extend lifespan. Known as hormesis, this is the most controversial notion in gerontology. For one, it is believed that aging is caused by accumulation of molecular damage. If so, hormetic stresses (by causing damage) must shorten lifespan. To solve the paradox, it was suggested that, by activating repair, hormetic stresses eventually decrease damage. Similarly, Baron Munchausen escaped from a swamp by pulling himself up by his own hair. Instead, I discuss that aging is not caused by accumulation of molecular damage. Although molecular damage accumulates, organisms do not live long enough to age from this accumulation. Instead, aging is driven by overactivated signal-transduction pathways including the TOR (Target of Rapamycin) pathway. A diverse group of hormetic conditions can be divided into two groups. "Hormesis A" inhibits the TOR pathway. "Hormesis B" increases aging-tolerance, defined as the ability to survive catastrophic complications of aging. Hormesis A includes calorie restriction, resveratrol, rapamycin, p53-inducing agents and, in part, physical exercise, heat shock and hypoxia. Hormesis B includes ischemic preconditioning and, in part, physical exercise, heat shock, hypoxia and medical interventions.

  18. 非稳态噪声与作业工人高频听力损失的剂量-反应关系研究%A study on dose -response relationship between human hearing loss and non -stationary noise among workers

    Institute of Scientific and Technical Information of China (English)

    张旭慧; 张磊; 夏予勇; 王强; 许玉洋; 陈建春; 舒丽萍; 朱益民

    2015-01-01

    目的:研究非稳态噪声作业工人的听力损失发生状况以及影响因素。方法采用横断面研究方法,以接触非稳态噪声≥1年的无耳病史的571名男性工人为研究对象,采用问卷调查噪声接触史、吸烟与饮酒等情况。对噪声接触者测定500、1000、2000、3000、4000和6000 Hz 6个频段的听阈,并进行作业环境8 h 等效声级检测,分析影响听力损失的因素。结果非稳态噪声作业工人双耳高频听力损失的患病率为52.54%,单耳高频听力损失患病率为71.98%(按人数计)。不同的现场噪声8 h 等效声级、接噪工龄和累积噪声暴露量者之间听力损失的患病率差异均有统计学意义(P 均<0.01)。8 h 等效声级、接噪工龄和累积噪声暴露量与高频听力损失的危险性存在剂量-反应关系(P 均<0.01)。结论非稳态噪声接触对作业工人高频听力造成损害,具有剂量-反应关系。%Objective To investigate the incidence and risk factors of hearing loss among the workers exposed to non -stationary noise.Methods A cross -sectional study was conducted among the participants.571 male workers without any history of ear disorder were enrolled in this study.They had been exposed to non -stationary noise for one year or more. The history of noise exposure,smoking and drinking behavior were interviewed by using a questionnaire.The noise exposure in the workplace was measured at eight -hour equivalent noise level (LEX.8h )and the thresholds of hearing at 500,1 000,2 000,3 000,4 000 and 6 000 Hz were detected.Results The prevalence of high -frequency hearing loss of two ears was 52.54%,while the prevalence of hearing loss of one ear was 71.98%.There were significant differences of prevalence among different groups of workers in LEX.8h ,duration of noise exposure and the cumulative noise exposure (CNE)(P <0.01).There was a dose response relationship between noise exposure and the

  19. Modeling and regression analysis of semiochemical dose-response curves of insect antennal reception and behavior.

    Science.gov (United States)

    Byers, John A

    2013-08-01

    Dose-response curves of the effects of semiochemicals on neurophysiology and behavior are reported in many articles in insect chemical ecology. Most curves are shown in figures representing points connected by straight lines, in which the x-axis has order of magnitude increases in dosage vs. responses on the y-axis. The lack of regression curves indicates that the nature of the dose-response relationship is not well understood. Thus, a computer model was developed to simulate a flux of various numbers of pheromone molecules (10(3) to 5 × 10(6)) passing by 10(4) receptors distributed among 10(6) positions along an insect antenna. Each receptor was depolarized by at least one strike by a molecule, and subsequent strikes had no additional effect. The simulations showed that with an increase in pheromone release rate, the antennal response would increase in a convex fashion and not in a logarithmic relation as suggested previously. Non-linear regression showed that a family of kinetic formation functions fit the simulated data nearly perfectly (R(2) >0.999). This is reasonable because olfactory receptors have proteins that bind to the pheromone molecule and are expected to exhibit enzyme kinetics. Over 90 dose-response relationships reported in the literature of electroantennographic and behavioral bioassays in the laboratory and field were analyzed by the logarithmic and kinetic formation functions. This analysis showed that in 95% of the cases, the kinetic functions explained the relationships better than the logarithmic (mean of about 20% better). The kinetic curves become sigmoid when graphed on a log scale on the x-axis. Dose-catch relationships in the field are similar to dose-EAR (effective attraction radius, in which a spherical radius indicates the trapping effect of a lure) and the circular EARc in two dimensions used in mass trapping models. The use of kinetic formation functions for dose-response curves of attractants, and kinetic decay curves for

  20. Dose-response of strengthening exercise for treatment of severe neck pain in women

    DEFF Research Database (Denmark)

    Andersen, Christoffer H; Andersen, Lars Louis; Pedersen, Mogens T

    2013-01-01

    Specific strength training is shown relieves neck pain in office workers. The purpose of this study is to evaluate the effectiveness of specific strength training in women with severe neck pain and to analyze the dose-response relationship between training adherence and pain reduction. 118...... untrained women with severe neck pain (>30 mm VAS pain) were included from a larger study, in which the subjects were randomized to 20-weeks specific strength training for the neck/shoulders or to a control group. In the intention-to-treat analysis, the training group experienced greater pain relief than...

  1. Dose-response model of murine typhus (Rickettsia typhi: time post inoculation and host age dependency analysis

    Directory of Open Access Journals (Sweden)

    Tamrakar Sushil B

    2012-03-01

    Full Text Available Abstract Background Rickettsia typhi (R. mooseri is the causative agent of murine typhus. It is one of the most widely distributed flea-borne diseases with a relatively mild febrile initial illness with six to 14 days of incubation period. The bacterium is gram negative and an obligate intracellular pathogen. The disease is transmitted to humans and vertebrate host through fleabites or via contact with infected feces. This paper develops dose-response models of different routes of exposure for typhus in rodents. Methods Data from published articles were analyzed using parametric dose-response relationship models. Dose-response relationships were fit to data using the method of maximum likelihood estimation (MLE. Results Dose-response models quantifying the effects of different ages of rats and time post inoculation in BALB/c mice were analyzed in the study. Both the adult rats (inoculated intradermally and newborn rats (inoculated subcutaneously were best fit by exponential models and both distributions could be described by a single dose-response relationship. The BALB/C mice inoculated subcutaneously were best fit by Beta-Poisson models. The time post inoculation analysis showed that there was a definite time and response relationship existed in this case. Conclusions Intradermally or subcutaneously inoculated rats (adult and newborn models suggest that less than 1 plaque-forming unit (PFU (1.33 to 0.38 in 95% confidence limits of the pathogen is enough to seroconvert 50% of the exposed population on average. For the BALB/c mouse time post inoculation model, an average dose of 0.28 plaque-forming units (PFU (0.75 to 0.11 in 95% confidence limits will seroconvert 50% of the exposed mice.

  2. Quantitative Dose-Response Curves from Subcellular Lipid Multilayer Microarrays

    Science.gov (United States)

    Kusi-Appiah, A. E.; Lowry, T. W.; Darrow, E. M.; Wilson, K.; Chadwick, B. P.; Davidson, M. W.; Lenhert, S.

    2015-01-01

    The dose-dependent bioactivity of small molecules on cells is a crucial factor in drug discovery and personalized medicine. Although small-molecule microarrays are a promising platform for miniaturized screening, it has been a challenge to use them to obtain quantitative dose-response curves in vitro, especially for lipophilic compounds. Here we establish a small-molecule microarray assay capable of controlling the dosage of small lipophilic molecules delivered to cells by varying the sub-cellular volumes of surface supported lipid micro- and nanostructure arrays fabricated with nanointaglio. Features with sub-cellular lateral dimensions were found necessary to obtain normal cell adhesion with HeLa cells. The volumes of the lipophilic drug-containing nanostructures were determined using a fluorescence microscope calibrated by atomic-force microscopy. We used the surface supported lipid volume information to obtain EC-50 values for the response of HeLa cells to three FDA-approved lipophilic anticancer drugs, docetaxel, imiquimod and triethylenemelamine, which were found to be significantly different from neat lipid controls. No significant toxicity was observed on the control cells surrounding the drug/lipid patterns, indicating lack of interference or leakage from the arrays. Comparison of the microarray data to dose-response curves for the same drugs delivered liposomally from solution revealed quantitative differences in the efficacy values, which we explain in terms of cell-adhesion playing a more important role in the surface-based assay. The assay should be scalable to a density of at least 10,000 dose response curves on the area of a standard microtiter plate. PMID:26167949

  3. Environmental standards for ionizing radiation: theoretical basis for dose-response curves.

    Science.gov (United States)

    Upton, A C

    1983-10-01

    The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells. For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about dose-response relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell.

  4. Maximum likelihood estimation for cytogenetic dose-response curves

    Energy Technology Data Exchange (ETDEWEB)

    Frome, E.L; DuFrain, R.J.

    1983-10-01

    In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa(..gamma..d + g(t, tau)d/sup 2/), where t is the time and d is dose. The coefficient of the d/sup 2/ term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.

  5. Heavy particle irradiation, neurochemistry and behavior: thresholds, dose-response curves and recovery of function

    Science.gov (United States)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

    2004-01-01

    Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity.

  6. Bayesian penalized log-likelihood ratio approach for dose response clinical trial studies.

    Science.gov (United States)

    Tang, Yuanyuan; Cai, Chunyan; Sun, Liangrui; He, Jianghua

    2017-02-13

    In literature, there are a few unified approaches to test proof of concept and estimate a target dose, including the multiple comparison procedure using modeling approach, and the permutation approach proposed by Klingenberg. We discuss and compare the operating characteristics of these unified approaches and further develop an alternative approach in a Bayesian framework based on the posterior distribution of a penalized log-likelihood ratio test statistic. Our Bayesian approach is much more flexible to handle linear or nonlinear dose-response relationships and is more efficient than the permutation approach. The operating characteristics of our Bayesian approach are comparable to and sometimes better than both approaches in a wide range of dose-response relationships. It yields credible intervals as well as predictive distribution for the response rate at a specific dose level for the target dose estimation. Our Bayesian approach can be easily extended to continuous, categorical, and time-to-event responses. We illustrate the performance of our proposed method with extensive simulations and Phase II clinical trial data examples.

  7. Heavy particle irradiation, neurochemistry and behavior: thresholds, dose-response curves and recovery of function

    Science.gov (United States)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

    2004-01-01

    Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.

  8. Dose Response Association between Physical Activity and Biological, Demographic, and Perceptions of Health Variables

    Directory of Open Access Journals (Sweden)

    Paul D. Loprinzi

    2013-08-01

    Full Text Available Background: Few population-based studies have examined the association between physical activity (PA and cardiovascular disease risk factors, demographic variables, and perceptions of health status, and we do not have a clear understanding of the dose-response relationship among these variables. Methods: Data from the 2003-2006 National Health and Nutrition Examination Survey was used to examine the dose-response relationship between objectively measured PA and metabolic syndrome (and its individual cardiovascular disease risk factors, demographic variables, and perceptions of health. After exclusions, 5,538 participants 18 years or older were included in the present study, with 2,538 participants providing fasting glucose and 2,527 providing fasting triglyceride data. PA was categorized into deciles. Results: Overall, the health benefits showed a general pattern of increase with each increasing levels of PA. Of the ten PA classifications examined, participants in the highest moderate-to-vigorous physical activity (MVPA category (at least 71 min/day had the lowest odds of developing metabolic syndrome. Conclusion: At a minimum, sedentary adults should strive to meet current PA guidelines (i.e., 150 min/week of MVPA, with additional positive benefits associated with engaging in three times this level of PA.

  9. Low blood lead level effects on intelligence: can a dose-response curve be determined from the epidemiological data?

    Science.gov (United States)

    Banner, W; Kahn, C M

    2014-02-01

    CONTEXT. Recent publications have graphically demonstrated a curvilinear relationship between measures of intelligence and blood lead levels at low concentrations (dose-response curves. METHODS. Random data based on varied distributions were constructed to simulate a previous study using a single, randomly generated covariate income (Inc) to demonstrate the impact of normally versus exponentially distributed data on the shape of the graph of intelligence quotient (IQ) versus blood lead. We also used an existing database of US blood lead levels and constructed a similar model of income and IQ using both assumptions of distribution for the intermediate variable income. RESULTS. When both lead and income are exponentially distributed, the graph of lead and IQ will be a curve. CONCLUSION. The apparent shape of a dose-response relationship from simulated epidemiological data is nonlinear when one variable and a covariate are exponentially distributed. A non-linear biological relationship should not be assumed and in fact may be the least likely explanation. The use of observational epidemiological data to discern a dose-response relationship between two variables may be misleading.

  10. Alcohol and cirrhosis: dose--response or threshold effect?

    DEFF Research Database (Denmark)

    Kamper-Jørgensen, Mads; Grønbaek, Morten; Tolstrup, Janne;

    2004-01-01

    BACKGROUND/AIMS: General population studies have shown a strong association between alcohol intake and death from alcoholic cirrhosis, but whether this is a dose-response or a threshold effect remains unknown, and the relation among alcohol misusers has not been studied. METHODS: A cohort of 6152...... alcohol misusing men and women aged 15-83 were interviewed about drinking pattern and social issues and followed for 84,257 person-years. Outcome was alcoholic cirrhosis mortality. Data was analyzed by means of Cox-regression models. RESULTS: In this large prospective cohort study of alcohol misusers...... there was a 27 fold increased mortality from alcoholic cirrhosis in men and a 35 fold increased mortality from alcoholic cirrhosis in women compared to the Danish population. Number of drinks per day was not significantly associated with death from alcoholic cirrhosis, since there was no additional risk of death...

  11. Dose Response of Alanine Detectors Irradiated with Carbon Ion Beams

    DEFF Research Database (Denmark)

    Herrmann, Rochus; Jäkel, Oliver; Palmans, Hugo

    2011-01-01

    Purpose: The dose response of the alanine detector shows a dependence on particle energy and type, when irradiated with ion beams. The purpose of this study is to investigate the response behaviour of the alanine detector in clinical carbon ion beams and compare the results with model predictions....... Methods: Alanine detectors have been irradiated with carbon ions with an energy range of 89-400 MeV/u. The relative effectiveness of alanine has been measured in this regime. Pristine and spread out Bragg peak depth-dose curves have been measured with alanine dosimeters. The track-structure based alanine......-dose curves deviate from predictions in the peak region, most pronounced at the distal edge of the peak. Conclusions: The used model and its implementation show a good overall agreement for quasi mono energetic measurements. Deviations in depth-dose measurements are mainly attributed to uncertainties...

  12. Dose-response curve estimation: a semiparametric mixture approach.

    Science.gov (United States)

    Yuan, Ying; Yin, Guosheng

    2011-12-01

    In the estimation of a dose-response curve, parametric models are straightforward and efficient but subject to model misspecifications; nonparametric methods are robust but less efficient. As a compromise, we propose a semiparametric approach that combines the advantages of parametric and nonparametric curve estimates. In a mixture form, our estimator takes a weighted average of the parametric and nonparametric curve estimates, in which a higher weight is assigned to the estimate with a better model fit. When the parametric model assumption holds, the semiparametric curve estimate converges to the parametric estimate and thus achieves high efficiency; when the parametric model is misspecified, the semiparametric estimate converges to the nonparametric estimate and remains consistent. We also consider an adaptive weighting scheme to allow the weight to vary according to the local fit of the models. We conduct extensive simulation studies to investigate the performance of the proposed methods and illustrate them with two real examples.

  13. Insulin dose response analysis of free fatty acid kinetics.

    Science.gov (United States)

    Jensen, Michael D; Nielsen, Søren

    2007-01-01

    Insulin regulation of free fatty acid (FFA) release is an important aspect of metabolic function; however, FFA release is exquisitely sensitive to insulin, which complicates the design and analysis of dose response experiments. We measured FFA ([(3)H]palmitate) and glucose ([(3)H]glucose) kinetics in 7 nonobese men, 7 nonobese women, 7 obese men, and 7 obese women by using a two-step insulin clamp (0.25 and 2.5 mU/kg fat-free mass per minute). Obese men and women were characterized as having a BMI of 28 or greater and body fat of 28% and 40% or greater for men and for women, respectively. Nonobese men and women had 22% and 35% or less body fat, respectively. All volunteers were Caucasian. Glucose disposal increased in a linear fashion with plasma insulin concentrations. The nonlinear suppression of plasma palmitate flux and concentrations could be linearized by logarithmically transforming both the insulin concentration and palmitate axes, except in nonobese men. We repeated the studies in 7 nonobese and 7 obese men, using 1.0 mU/kg fat-free mass per minute as the second insulin dose, which linearized the log-transformed lipolysis measures. The indices of insulin regulation of lipolysis predicted using 2 points (basal and second insulin dose) vs 3 points (basal, low, and high dose) were not different provided the proper second dose was selected. The EC(50) for insulin suppression of lipolysis correlated linearly with plasma triglycerides (r = 0.52, P < .001) and exponentially with insulin sensitivity(glucose) (r = 0.70, P < .001). We conclude that log transformation of insulin dose response data for FFA permits straightforward data analysis and simplifies the estimation of metabolically relevant parameters.

  14. Time course and dose response of alpha tocopherol on oxidative stress in haemodialysis patients

    Directory of Open Access Journals (Sweden)

    Coombes Jeff S

    2009-10-01

    Full Text Available Abstract Background Oxidative stress is associated with increased cardiovascular morbidity and mortality particularly in patients with end stage kidney disease. Although observational data from the general population has shown dietary antioxidant intake is associated with reduced cardiovascular morbidity and mortality, most clinical intervention trials have failed to support this relationship. This may be a consequence of not using an effective antioxidant dose and/or not investigating patients with elevated oxidative stress. The SPACE study, conducted in haemodialysis patients, reported that 800 IU/day of alpha tocopherol significantly reduced cardiovascular disease endpoints. A recent time course and dose response study conducted in hypercholesterolaemic patients that found 1600 IU/day of alpha tocopherol was an optimal dose. There is no such dose response data available for haemodialysis patients. Therefore the aim of this study is to investigate the effect of different doses of oral alpha tocopherol on oxidative stress in haemodialysis patients with elevated oxidative stress and the time taken to achieve this effect. Methods The study will consist of a time-course followed by a dose response study. In the time course study 20 haemodialysis patients with elevated oxidative stress will take either 1600 IU/day natural (RRR alpha tocopherol for 20 weeks or placebo. Blood will be collected every two weeks and analysed for a marker of oxidative stress (plasma F2-isoprostanes and alpha tocopherol. The optimum time period to significantly decrease plasma F2-isoprostanes will be determined from this study. In the dose response study 60 patients will be randomised to receive either placebo, 100, 200, 400, 800 or 1600 IU/day of natural (RRR alpha tocopherol for a time period determined from the time course study. Blood will be collected at baseline and every two weeks and analysed for plasma F2-isoprostanes and alpha tocopherol. It is hypothesised that

  15. Hormesis-based anti-aging products: a case study of a novel cosmetic

    DEFF Research Database (Denmark)

    Rattan, Suresh; Kryzch, Valerie; Schnebert, Sylvianne

    2013-01-01

    and cosmeceuticals. Here we present the example of a skin care cosmetic as one of the first successful product developments incorporating the ideas of hormesis. This was based on the studies to analyse the molecular effects of active ingredients extracted from the roots of the Chinese herb Sanchi (Panax notoginseng......, nutritional and mental hormetins...

  16. Model Uncertainty via the Integration of Hormesis and LNT as the Default in Cancer Risk Assessment

    Directory of Open Access Journals (Sweden)

    Edward J. Calabrese

    2015-12-01

    Full Text Available On June 23, 2015, the US Nuclear Regulatory Commission (NRC issued a formal notice in the Federal Register that it would consider whether “it should amend its ‘Standards for Protection Against Radiation’ regulations from the linear non-threshold (LNT model of radiation protection to the hormesis model.” The present commentary supports this recommendation based on the (1 flawed and deceptive history of the adoption of LNT by the US National Academy of Sciences (NAS in 1956; (2 the documented capacity of hormesis to make more accurate predictions of biological responses for diverse biological end points in the low-dose zone; (3 the occurrence of extensive hormetic data from the peer-reviewed biomedical literature that revealed hormetic responses are highly generalizable, being independent of biological model, end point measured, inducing agent, level of biological organization, and mechanism; and (4 the integration of hormesis and LNT models via a model uncertainty methodology that optimizes public health responses at 10−4. Thus, both LNT and hormesis can be integratively used for risk assessment purposes, and this integration defines the so-called “regulatory sweet spot.”

  17. Radiation hormesis. Stimulatory effects of low level ionizing radiation on plant

    Energy Technology Data Exchange (ETDEWEB)

    Kinoshita, Shigenobu; Masui, Hisashi; Yoshida, Shigeo; Murata, Isao [Osaka Univ., Suita (Japan). Faculty of Engineering

    1999-04-01

    Recently, the study for radiation hormesis has been executed against animals and plants; subharmful doses of radiation may evoke a stimulatory response in any organism. We executed irradiating experiments of dry seeds with fusion (D-T) neutron, fission neutron, cobalt-60 gamma-ray and investigated existence of the radiation hormesis effects by measuring germination, the length of a stalk and the total weight of a seed leaf on the 7th day after starting cultivation. And we estimated radiation hormesis effects by relative effectiveness, the ratio of the mean value of measurement subjects for the irradiated group to that of non-irradiated group. In relation to Raphanus sativus, the hormesis effects on seed leaf growth from irradiated seeds have only turned up in seed groups irradiated by the fusion (D-T) neutron. We have confirmed that absorbed dose range which revealed the effects is from 1 cGy to 10 Gy and the increasing rate is from 5 percent to 25 percent against a control group. (author)

  18. Non-linear uptake and hormesis effects of selenium in red-winged blackbirds (Agelaius phoeniceus).

    Science.gov (United States)

    Harding, Lee E

    2008-01-25

    Effects of selenium on reproductive success were assessed in red-winged blackbirds (Agelaius phoeniceus). Mean egg selenium (MES) ranged from 2.96 to 21.7 mg/kg dry weight with individual eggs up to 40 mg/kg. Uptake was non-linear: increments in MES declined as aqueous selenium increased; the asymptote was approximately 23 mg/kg. Eggs were heavier and more were laid in 2004 compared to 2005, a year of record rainfall and below-normal temperatures. Mortality of embryos that were incubated to full term was low (2.6% in 2004 and 3.2% in 2005), as was the prevalence of embryonic defects (2.7% in 2004 and 5.1% in 2005). Abnormalities in nestlings were also rare. Egg mortality was caused by predation, weather, and parental abandonment. Nestlings died from predation, starvation, and hypothermia associated with rain and cold, drowning, and bacterial infections. Nestling liver concentrations reached 81 mg/kg dry wt. selenium and were highest at the most highly selenium-exposed sites. Blood glutathione peroxidase (a selenium-dependent enzyme indicative of selenium exposure) was unrelated to liver selenium concentrations, egg selenium, or ambient selenium exposure. The selenium concentration in prey that parents fed to nestlings was higher at the selenium-exposed sites (up to 37 mg/kg dry wt. Se) compared to reference sites. Aqueous selenate:selenite ratios were related to redox differences and were much higher at the site with the highest MES, liver selenium, and prey item selenium concentrations. Hatchability showed U-shaped, or hormesis, relationships with MES: productivity increased with selenium concentrations at low exposures and decreased at high exposures. The effects threshold was approximately 22 mg/kg dry wt. MES.

  19. 糖尿病因素对患者米库氯铵肌松效应的影响:量效和时效关系%Effect of diabetes mellitus factor on mivacurium-induced muscle relaxation: dose-response relationship and time-course

    Institute of Scientific and Technical Information of China (English)

    张瑞英; 胡继军; 窦峰诠; 李超; 刘斌; 刘冬; 黄松浦; 高国雷; 程庆春

    2016-01-01

    Objective To evaluate the effect of diabetes mellitus factor on the dose-response relationship and time-course of muscle relaxation induced by mivacurium.Methods The patients of either sex,aged 40-64 yr,with body mass index of 20-25 kg/m2,of American Society of Anesthesiologists physical status Ⅰ or Ⅱ,with normal neuromuscular function,scheduled for elective surgery under general anesthesia,were enrolled in the study.The patients were divided into 2 groups depending on whether or not the patients suffered from the type 2 diabetes mellitus:diabetes mellitus group (group D,n =80) and non-diabetes mellitus group (group ND,n=80).The patients in either group were further divided into 4 subgroups (n=20 each) using a random number table:D1,D2,D3 and D4 subgroups or ND1,ND2,ND3 and ND4 subgroups in which mivacurium 20,40,60 and 80 μg/kg were intravenously injected,respectively.Anesthesia was induced with intravenous midazolam,fentanyl and etomidate in sequence.After loss of consciousness,the function of neuromuscular junction was monitored using the CLMRIS-1 closed loop system.The corresponding doses of mivacurium were injected intravenously over 5 s.When the maximum muscle relaxation was achieved,laryngeal mask airway was inserted,and the patients were mechanically ventilated.Anesthesia was maintained with target-controlled infusion of propofol and remifentanil,and bispectral index values were maintained at 40-60.The maximum muscle relaxation,onset time (time from the end of mivacurium injection to the maximum muscle relaxation),duration of action (time for maintenance of maximum muscle relaxation) and recovery time (from the end of action duration to T1 returned to 90%) were recorded.Results Compared with group ND,the ED50,ED75 and ED95 of mivacurium were significantly decreased by 8.8%,9.2% and 9.2% respectively in group D (P<0.05).Compared with the corresponding ND subgroups,the onset time was significantly prolonged by 35%,36%,39% and 40

  20. Body Mass Index and Risk of Parkinson’s Disease: A Dose-Response Meta-Analysis of Prospective Studies

    OpenAIRE

    Yun-Liang Wang; Yu-Tong Wang; Jin-Feng Li; Yu-Zheng Zhang; Hong-Lei Yin; Bing Han

    2015-01-01

    Background A number of epidemiologic studies examining the relationship between body mass index (BMI) and the future occurrence of Parkinson’s disease (PD) reported largely inconsistent findings. We conducted a dose-response meta-analysis of prospective studies to clarify this association. Methods Eligible prospective studies were identified by a search of PubMed and by checking the references of related publications. The generalized least squares trend estimation was employed to compute stud...

  1. Developing guidelines for economic evaluation of environmental impacts in EIAs. Part II: Case studies and dose-response literature

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2005-07-01

    This Part II of the report contains full versions of the case studies for air, water and land (Chapters 2-4), which were only summarised in Part I. In addition, during the work the research team has collected a large amount of literature and information on dose response relationships for air and water pollution relevant to China. This information is included as Chapters 5 and 6.

  2. Household physical activity and cancer risk: a systematic review and dose-response meta-analysis of epidemiological studies

    OpenAIRE

    Yun Shi; Tingting Li; Ying Wang; Lingling Zhou; Qin Qin; Jieyun Yin; Sheng Wei; Li Liu; Shaofa Nie

    2015-01-01

    Controversial results of the association between household physical activity and cancer risk were reported among previous epidemiological studies. We conducted a meta-analysis to investigate the relationship of household physical activity and cancer risk quantitatively, especially in dose-response manner. PubMed, Embase, Web of science and the Cochrane Library were searched for cohort or case-control studies that examined the association between household physical activity and cancer risks. R...

  3. Dose response for TCDD promotion of hepatocarcinogenesis in rats initiated with DEN: histologic, biochemical, and cell proliferation endpoints.

    Science.gov (United States)

    Maronpot, R R; Foley, J F; Takahashi, K; Goldsworthy, T; Clark, G; Tritscher, A; Portier, C; Lucier, G

    1993-12-01

    The present study examines the dose-response relationship for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) promotion of histologic and biochemical parameters by using a two-stage model for hepatocarcinogenesis in female Sprague-Dawley rats initiated with a single intraperitoneal dose of 175 mg of diethylnitrosamine (DEN)/kg body weight at 70 days of age. Starting 2 weeks after initiation, treatment groups of 8-10 rats were given TCDD by gavage in corn oil once every 2 weeks for 30 weeks. Doses were 3.5, 10.7, 35.7, and 125 ng TCDD/kg body weight/day. A significant body weight reduction was present in the noninitiated group that received 125 ng TCDD. Relative liver weight was statistically increased in initiated rats treated with > or = 10.7 ng TCDD and in noninitiated rats treated with > or = 35.7 ng TCDD. Histopathologic evidence of cytotoxicity was dose-related in all TCDD-treated groups. There was a statistically significant dose response in the bromodeoxyuridine (BrdU) S-phase labeling index (LI) in the DEN-initiated rats (p < 0.01) and a marginally significant trend in the saline-treated rats (p = 0.10), but proliferating cell nuclear antigen S-phase LI and growth fraction within altered hepatic foci showed no increase. Among the DEN-initiated groups there was a significant increase in glutathione S-transferase altered hepatic foci stereological parameters in the 125 ng TCDD group. This study demonstrates that dose-response relationships for TCDD's effects on cell proliferation growth of altered hepatic foci are different from previously reported effects on P450 gene expression, indicating that different biological or biochemical responses may exhibit different dose-response relationships.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Hormesis depends upon the life-stage and duration of exposure: examples for a pesticide and a nanomaterial

    OpenAIRE

    Tyne, William; Little, Simon; Spurgeon, David J.; Svendsen, Claus

    2015-01-01

    Tests to assess toxic effects on the reproduction of adult C. elegans after 72 h exposure for two chemicals, (3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU)), also known as diuron, and silver nanoparticles (Ag NPs) indicated potential, although not significant hormesis. Follow up toxicity tests comparing the potential hormesis concentrations with controls at high replication confirmed that the stimulatory effect was repeatable and also statistically significant within the test. To...

  5. CALUX measurements: statistical inferences for the dose-response curve.

    Science.gov (United States)

    Elskens, M; Baston, D S; Stumpf, C; Haedrich, J; Keupers, I; Croes, K; Denison, M S; Baeyens, W; Goeyens, L

    2011-09-30

    Chemical Activated LUciferase gene eXpression [CALUX] is a reporter gene mammalian cell bioassay used for detection and semi-quantitative analyses of dioxin-like compounds. CALUX dose-response curves for 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] are typically smooth and sigmoidal when the dose is portrayed on a logarithmic scale. Non-linear regression models are used to calibrate the CALUX response versus TCDD standards and to convert the sample response into Bioanalytical EQuivalents (BEQs). Several complications may arise in terms of statistical inference, specifically and most important is the uncertainty assessment of the predicted BEQ. This paper presents the use of linear calibration functions based on Box-Cox transformations to overcome the issue of uncertainty assessment. Main issues being addressed are (i) confidence and prediction intervals for the CALUX response, (ii) confidence and prediction intervals for the predicted BEQ-value, and (iii) detection/estimation capabilities for the sigmoid and linearized models. Statistical comparisons between different calculation methods involving inverse prediction, effective concentration ratios (ECR(20-50-80)) and slope ratio were achieved with example datasets in order to provide guidance for optimizing BEQ determinations and expand assay performance with the recombinant mouse hepatoma CALUX cell line H1L6.1c3.

  6. Dose-response effect of the lercanidipine/enalapril combination: a pooled analysis.

    Science.gov (United States)

    Rizzoni, Damiano

    2016-10-01

    The dose-effect relationship of fixed-dose combinations of anti-hypertensive drugs has been only poorly explored. This pooled analysis investigates the dose-response relationship of fixed-dose lercanidipine + enalapril in patients with mild-to-moderate hypertension. This was an individual patient data analysis of four randomized studies (n = 2340). The primary efficacy variable was the change from baseline in sitting diastolic blood pressure (SDBP). Secondary variables were change from baseline in sitting systolic BP (SSBP), proportion of responder patients, and safety. All fixed-dose combinations were superior to placebo in the reduction of SDBP. The greatest effect was observed with the market-available combination lercanidipine 20 mg/enalapril 20 mg (-15.3 mmHg vs. baseline; p < 0.05). The reduction in SDBP associated with the other two marketed fixed combinations of lercanidipine/enalapril were -10.7 mmHg for the 10 mg/20 mg combination and -9.8 mmHg for the 10 mg/10 mg combination (p < .05 for both comparisons). Similar findings were reported for SSBP reduction: the greatest effect was observed with lercanidipine 20 mg/enalapril 20 mg (-19.2 mmHg). The reduction in SSBP was -12.5 mmHg for the 10 mg/20 mg combination and -11.1 mmHg for the 10 mg/10 mg combination (p < .05 for all comparisons). The highest responder rate was reported with lercanidipine 20 mg/enalapril 20 mg (75.0%); this figure was 56.1% with the 10 mg/20 mg and 53.0% with the 10/10 mg combination. No safety concerns were reported. This pooled analysis of four randomized studies shows evidence of a dose-response effect in BP reduction with different fixed combinations of lercanidipine + enalapril. To our knowledge, this is the first analysis investigating the dose-response effect of a specific fixed-dose combination of anti-hypertensive agents. Further studies on this intriguing topic are however necessary.

  7. Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

    DEFF Research Database (Denmark)

    Appelt, A. L.; Ploen, J.; Vogelius, I. R.

    2013-01-01

    of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from the histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect......Purpose: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we...... estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination...

  8. Body mass index and risk of renal cell cancer: a dose-response meta-analysis of published cohort studies.

    Science.gov (United States)

    Wang, Furan; Xu, Yinghua

    2014-10-01

    Obesity is accepted as one of the major risk factors for renal cell cancer (RCC). However, conflicting results persist for the pooled risks based on the results from case-control and cohort studies combined, and the exact shape of the dose-response relationship has not been clearly defined yet. To help elucidate the role of obesity, PubMed and Embase databases were searched for published cohort studies on associations between body mass index (BMI) and risk of RCC. Random-effects models and dose-response meta-analyses were used to pool study results. Subgroup analyses were conducted by the available characteristics of studies and participants. Cohort studies (21) with 15,144 cases and 9,080,052 participants were identified. Compared to normal weight, the pooled relative risks and the corresponding 95% confidence intervals of RCC were 1.28(1.24-1.33) for preobesity and 1.77(1.68-1.87) for obesity, respectively. A nonlinear dose-response relationship was also found for RCC risk with BMI (p = 0.000), and the risk increased by 4% for each 1 kg/m(2) increment in BMI. There was no significant between-study heterogeneity among studies (I(2) = 35.6% for preobesity and I(2) = 44.2% for obesity, respectively). Subgroup analysis showed a basically consistent result with the overall analysis. These results suggest that increased BMI are associated with increased risk of RCC both for men and women. © 2014 UICC.

  9. A Grid Algorithm for High Throughput Fitting of Dose-Response Curve Data

    OpenAIRE

    Wang, Yuhong; Jadhav, Ajit; Southal, Noel; Huang, Ruili; Nguyen, Dac-Trung

    2010-01-01

    We describe a novel algorithm, Grid algorithm, and the corresponding computer program for high throughput fitting of dose-response curves that are described by the four-parameter symmetric logistic dose-response model. The Grid algorithm searches through all points in a grid of four dimensions (parameters) and finds the optimum one that corresponds to the best fit. Using simulated dose-response curves, we examined the Grid program’s performance in reproducing the actual values that were used ...

  10. Targeting the age-related occurrence, removal, and accumulation of molecular damage by hormesis.

    Science.gov (United States)

    Rattan, Suresh I S

    2010-06-01

    Strategies for testing and developing effective means of intervention, prevention, and modulation of aging incorporate means to minimize the occurrence and accumulation of molecular damage, to reduce molecular heterogeneity, and to evaluate the relevance of the type and extent of damage with respect to its role in aging and age-related diseases. One such approach is that of mild stress-induced hormesis, which stimulates maintenance and repair systems and strengthens the homeodynamic space of cells and organisms. Hormesis through mild heat shock, natural and synthetic hormetins, and other stressors brings about several antiaging effects in human fibroblasts, keratinocytes, and telomerase-immortalized bone marrow stem cells. Depending on the cell type, these antiaging hormetic effects include extension of replicative life span, enhanced proteasomal activities, increased chaperone levels, and improved wound healing, angiogenesis, and differentiation. The main molecular pathways for achieving such hormetic effects are through targeting the processes for the repair and removal of molecular damage, which can slow aging.

  11. Hormesis, allostatic buffering capacity and physiological mechanism of physical activity: a new theoretic framework.

    Science.gov (United States)

    Li, Guolin; He, Hong

    2009-05-01

    Despite great progress made in sports medicine, the physiological mechanism of moderate physical activity-induced physical fitness remains only partly understood. Combined with the hormetic characteristic of physical activity and property of allostasis, we first propose the hormesis induced allostatic buffering capacity enhancement as a physiological mechanism to explain the moderate physical activity-induced physical fitness. As stressful stimulus, physical activity can induce several stresses in the host, including eustress ('good stress') and distress ('bad stress'), which may have both positive and negative effects. Too little or too much physical activities will introduce too weak eustress or too strong distress and result in allostasis load through weakening allostatic buffering capacity or damaging allostatic buffering capacity respectively. However, moderate physical activities will introduce eustress and contribute to the hormesis induced allostatic buffering capacity enhancement, which benefits organism.

  12. Sex specific effects of heat induced hormesis in Hsf-deficient Drosophila melanogaster

    DEFF Research Database (Denmark)

    Sørensen, J G; Kristensen, Torsten Nygård; Kristensen, K V;

    2007-01-01

    In insects mild heat stress early in life has been reported to increase life span and heat resistance later in life, a phenomenon termed hormesis. Here, we test if the induction of the heat shock response by mild heat stress is mediating hormesis in longevity and heat resistance at older age....... To test this hypothesis we used two heat shock transcription factor (Hsf) mutant stocks. One stock harbours a mutation giving rise to a heat sensitive Hsf which inactivates the heat shock response at high temperature and the other is a rescued mutant giving rise to a wild-type phenotype. We measured...... longevity, heat resistance and expression level of a heat shock protein, Hsp70, in controls and mildly heat treated flies. We found a marked difference between males and females with males showing a beneficial effect of the early heat treatment on longevity and heat resistance later in life in the rescued...

  13. Hormesis-Based Anti-Aging Products: A Case Study of a Novel Cosmetic

    OpenAIRE

    Rattan, Suresh I.S.; Kryzch, Valérie; Schnebert, Sylvianne; Perrier, Eric; Nizard, Carine

    2012-01-01

    Application of hormesis in aging research and interventions is becoming increasingly attractive and successful. The reason for this is the realization that mild stress-induced activation of one or more stress response (SR) pathways, and its consequent stimulation of repair mechanisms, is effective in reducing the age-related accumulation of molecular damage. For example, repeated heat stress-induced synthesis of heat shock proteins has been shown to have a variety of anti-aging effects on gro...

  14. Nutrient removal by Chlorella vulgaris F1068 under cetyltrimethyl ammonium bromide induced hormesis.

    Science.gov (United States)

    Zhou, Qiongzhi; Li, Feng; Ge, Fei; Liu, Na; Kuang, Yangduo

    2016-10-01

    Toxicants are generally harmful to biotechnology in wastewater treatment. However, trace toxicant can induce microbial hormesis, but to date, it is still unknown how this phenomenon affects nutrient removal during municipal wastewater treatment process. Therefore, this study focused on the effects of hormesis induced by cetyltrimethyl ammonium bromide (CTAB), a representative quaternary ammonium cationic surfactant, on nutrient removal by Chlorella vulgaris F1068. Results showed that when the concentration of CTAB was less than 10 ng/L, the cellular components chlorophyll a, proteins, polysaccharides, and total lipids increased by 10.11, 58.17, 38.78, and 11.87 %, respectively, and some enzymes in nutrient metabolism of algal cells, such as glutamine synthetase (GS), acid phosphatase (ACP), H(+)-ATPase, and esterase, were also enhanced. As a result, the removal efficiencies of ammonia nitrogen (NH4 (+)) and total phosphorus (TP) increased by 14.66 and 8.51 %, respectively, compared to the control during a 7-day test period. The underlying mechanism was mainly due to an enhanced photosynthetic activity of C. vulgaris F1068 indicated by the increase in chlorophyll fluorescence parameters (the value of Fv/Fm, ΦII, Fv/Fo, and rETR increased by 12.99, 7.56, 25.59, and 8.11 %, respectively) and adenylate energy charge (AEC) (from 0.68 to 0.72). These results suggest that hormesis induced by trace toxicants could enhance the nutrient removal, which would be further considered in the design of municipal wastewater treatment processes. Graphical abstract The schematic mechanism of C. vulgaris F1068 under CTAB induced hormesis. Green arrows ( ) represent the increase and the red arrow ( ) represents the decrease.

  15. Bayesian dose-response analysis for epidemiological studies with complex uncertainty in dose estimation.

    Science.gov (United States)

    Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian E; Simon, Steven L

    2016-02-10

    Most conventional risk analysis methods rely on a single best estimate of exposure per person, which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the relationship between radiation dose and disease outcomes by accounting for shared and unshared uncertainty in estimated dose. Our Bayesian risk analysis method utilizes multiple realizations of sets (vectors) of doses generated by a two-dimensional Monte Carlo simulation method that properly separates shared and unshared errors in dose estimation. The exposure model used in this work is taken from a study of the risk of thyroid nodules among a cohort of 2376 subjects who were exposed to fallout from nuclear testing in Kazakhstan. We assessed the performance of our method through an extensive series of simulations and comparisons against conventional regression risk analysis methods. When the estimated doses contain relatively small amounts of uncertainty, the Bayesian method using multiple a priori plausible draws of dose vectors gave similar results to the conventional regression-based methods of dose-response analysis. However, when large and complex mixtures of shared and unshared uncertainties are present, the Bayesian method using multiple dose vectors had significantly lower relative bias than conventional regression-based risk analysis methods and better coverage, that is, a markedly increased capability to include the true risk coefficient within the 95% credible interval of the Bayesian-based risk estimate. An evaluation of the dose-response using our method is presented for an epidemiological study of thyroid disease following radiation exposure.

  16. QSAR study on the non-monotonic dose-response curve of PCBs in chicken embryo hepatocyte bioassay

    Institute of Scientific and Technical Information of China (English)

    MU YunSong; ZHANG AiQian; GAO ChangAn; PENG SuFen; WANG LianSheng

    2009-01-01

    Endocrine disrupting chemicals (EDCs) in the natural environment exhibit a unique non-monotonic dose-response curve and it is impossible to select one simple index to characterize the bilogogical activity of these compounds. Quantitative structure-activity relationship (QSAR) study on non-monotonic dose-response curve has become a real challenge presently. In order to explore the possible mechanism for the non-monotonic dose-response curve of polychlorinated biphenyls con-geners (PCBs) in chicken embryo hepatocyte bioassay, AM1 method of ChemOffice was adopted to calculate necessary structure descriptors for PCBs, while the interactions between PCBs and simulated AhR ligand binding domain (LBD) were analyzed by using FlexX in SYBYL7.0. Different binding modes for PCBs have been distinguished not only from aligned conformation but also from free binding energy. Some QSAR models were established separately for both low and high doses ranges, revealing that receptor binding may predominate in the interference of the physiological function of cytochrome P4501A-P4501A in the low doses range. But with the higher doses range, the EROD suppression might he related to acute toxicity owing to molecular polarity or distribution of charges and consequently damage structure and function of chicken embryo hepatocyte.

  17. In situ protocol for the determination of dose-response effect of low-fluoride dentifrices on enamel remineralization

    Directory of Open Access Journals (Sweden)

    Rebeca Lima AFONSO

    2013-12-01

    Full Text Available No in situ protocol has assessed the dose-response effects of fluoride dentifrices involving low-fluoride formulations. Objective: To assess the ability of an in situ remineralization model in determining dose-response effects of dentifrices containing low fluoride concentrations ([F] on bovine enamel. Material and Methods: Volunteers wore palatal appliances containing demineralized enamel blocks and brushed their teeth and devices with the dentifrices supplied (double-blind, crossover protocol separately for 3 and 7 days. Surface hardness (SH, integrated subsurface hardness (ΔKHN and [F] in enamel were determined. Data were analyzed by ANOVA, Tukey's test and Pearson's correlation (p<0.05. Results: Dose-response relationships were verified between [F] in dentifrices and SH, ΔKHN and enamel [F]. Higher correlation coefficients between enamel [F] and SH and ΔKHN were obtained for the 3-day period. Significant differences in SH and ΔKHN were observed among all groups for the 3-day period, but not between 0-275, 275-550, and 550-1,100 µg F/g dentifrices for the 7-day period, nor between 3- and 7-day periods for the 1,100 µg F/g groups. Conclusions: Considering that the peak remineralization capacity of the conventional dentifrice (1,100 µg F/g was achieved in 3 days, this experimental period could be used in future studies assessing new dentifrice formulations, especially at low-fluoride concentrations.

  18. QSAR study on the non-monotonic dose-response curve of PCBs in chicken embryo hepatocyte bioassay

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Endocrine disrupting chemicals (EDCs) in the natural environment exhibit a unique non-monotonic dose-response curve and it is impossible to select one simple index to characterize the bilogogical activity of these compounds. Quantitative structure-activity relationship (QSAR) study on non-monotonic dose-response curve has become a real challenge presently. In order to explore the possible mechanism for the non-monotonic dose-response curve of polychlorinated biphenyls congeners (PCBs) in chicken embryo hepatocyte bioassay, AM1 method of ChemOffice was adopted to calculate necessary structure descriptors for PCBs, while the interactions between PCBs and simulated AhR ligand binding domain (LBD) were analyzed by using FlexX in SYBYL7.0. Different binding modes for PCBs have been distinguished not only from aligned conformation but also from free binding energy. Some QSAR models were established separately for both low and high doses ranges, revealing that receptor binding may predominate in the interference of the physiological function of cytochrome P4501A-P4501A in the low doses range. But with the higher doses range, the EROD suppression might be related to acute toxicity owing to molecular polarity or distribution of charges and consequently damage structure and function of chicken embryo hepatocyte.

  19. Hormesis and Paradoxical Effects of Drooping Birch (Betula pendula Roth Parameters Under Motor Traffic Pollution

    Directory of Open Access Journals (Sweden)

    Elena A. Erofeeva

    2015-06-01

    Full Text Available Various plant indexes are used or recommended for bioindication. However, the nonmonotonic dose–response dependences (hormesis and paradoxical effects of these indexes are insufficiently explored upon exposure to pollution. We studied the dependences of these Betula pendula indexes on the intensity of motor traffic pollution. Regression analysis did not reveal any dependence of chlorophyll and carotenoid content on traffic intensity (in 2008 and 2010-2013. Lipid peroxidation rate had different versions of paradoxical effects in 2008 and 2010 to 2012 and increased in comparison with control under an increase in pollution level in 2013. In 2010 to 2012, all dose–response dependences for total protein and thiol group content were biphasic and multiphasic paradoxical effects. In 2013, an increase in traffic intensity induced a linear reduction in protein content and an increase in thiol group level in comparison with the control. In most cases, the studied phenological indexes and seed production decreased monotonically in comparison with the control following an increase in traffic intensity. Only in 2010 and 2013, share of fallen leaves had hormesis and paradoxical effect accordingly. Fluctuating asymmetry had a paradoxical effect and hormesis in 2008 and 2012, accordingly, and increased in comparison with the control under an increase in the level of pollution in 2010 to 2011.

  20. A randomized, dose-response study of sugammadex given for the reversal of deep rocuronium- or vecuronium-induced neuromuscular blockade under sevoflurane anesthesia

    DEFF Research Database (Denmark)

    Duvaldestin, Philippe; Kuizenga, Karel; Saldien, Vera;

    2010-01-01

    Sugammadex is the first of a new class of selective muscle relaxant binding drugs developed for the rapid and complete reversal of neuromuscular blockade induced by rocuronium and vecuronium. Many studies have demonstrated a dose-response relationship with sugammadex for reversal of neuromuscular...

  1. Characterizing dose-responses of catalase to nitrofurazone exposure in model ciliated protozoan Euplotes vannus for ecotoxicity assessment: enzyme activity and mRNA expression.

    Science.gov (United States)

    Li, Jiqiu; Zhou, Liang; Lin, Xiaofeng; Yi, Zhenzhen; Al-Rasheid, Khaled A S

    2014-02-01

    In environmental studies, some biological responses, known as biomarkers, have been used as a powerful bioassay tool for more than four decades. Disparity between enzyme activity and mRNA abundance leads to correlation equivocality, which makes the application of biomarkers for environmental risk assessment more complicated. This study investigates this disparity in the case of catalase when used as a biomarker for detecting ecotoxicity induced by antibiotics in aquatic ecosystems. In particular, dose-responses for catalase activity and mRNA expression abundance were investigated in Euplotes vannus which were exposed to graded doses of nitrofurazone for several discrete durations, and dose-response models were developed to characterize the dose-response dynamics. Significant differences were found in both catalase activity and mRNA expression abundance among the E. vannus treated with nitrofurazone. Catalase activity showed a hormetic-like effect in terms of dose-response, characterized by a biphasic relationship which was more clearly evident after a longer exposure period, while mRNA expression abundance increased linearly with the exposure duration. Additionally, the correlation between catalase activity and mRNA expression abundance reversed along with the duration of exposure to nitrofurazone. Taken together, our results demonstrate that catalase mRNA expression offers a more straightforward dose-response model than enzyme activity. Our findings suggest that both catalase enzyme activity and mRNA expression abundance can be used jointly as bioassay tools for detecting ecotoxicity induced by nitrofurazone in aquatic ecosystems.

  2. The analysis of dose-response curve from bioassays with quantal response: Deterministic or statistical approaches?

    Science.gov (United States)

    Mougabure-Cueto, G; Sfara, V

    2016-04-25

    Dose-response relations can be obtained from systems at any structural level of biological matter, from the molecular to the organismic level. There are two types of approaches for analyzing dose-response curves: a deterministic approach, based on the law of mass action, and a statistical approach, based on the assumed probabilities distribution of phenotypic characters. Models based on the law of mass action have been proposed to analyze dose-response relations across the entire range of biological systems. The purpose of this paper is to discuss the principles that determine the dose-response relations. Dose-response curves of simple systems are the result of chemical interactions between reacting molecules, and therefore are supported by the law of mass action. In consequence, the shape of these curves is perfectly sustained by physicochemical features. However, dose-response curves of bioassays with quantal response are not explained by the simple collision of molecules but by phenotypic variations among individuals and can be interpreted as individual tolerances. The expression of tolerance is the result of many genetic and environmental factors and thus can be considered a random variable. In consequence, the shape of its associated dose-response curve has no physicochemical bearings; instead, they are originated from random biological variations. Due to the randomness of tolerance there is no reason to use deterministic equations for its analysis; on the contrary, statistical models are the appropriate tools for analyzing these dose-response relations.

  3. Hormesis-based anti-aging products: a case study of a novel cosmetic.

    Science.gov (United States)

    Rattan, Suresh I S; Kryzch, Valérie; Schnebert, Sylvianne; Perrier, Eric; Nizard, Carine

    2013-01-01

    Application of hormesis in aging research and interventions is becoming increasingly attractive and successful. The reason for this is the realization that mild stress-induced activation of one or more stress response (SR) pathways, and its consequent stimulation of repair mechanisms, is effective in reducing the age-related accumulation of molecular damage. For example, repeated heat stress-induced synthesis of heat shock proteins has been shown to have a variety of anti-aging effects on growth and other cellular and biochemical characteristics of normal human skin fibroblasts, keratinocytes and endothelial cells undergoing aging in vitro. Therefore, searching for potential hormetins - conditions and compounds eliciting SR-mediated hormesis - is drawing attention of not only the researchers but also the industry involved in developing healthcare products, including nutriceuticals, functional foods and cosmeceuticals. Here we present the example of a skin care cosmetic as one of the first successful product developments incorporating the ideas of hormesis. This was based on the studies to analyse the molecular effects of active ingredients extracted from the roots of the Chinese herb Sanchi (Panax notoginseng) on gene expression at the level of mRNAs and proteins in human skin cells. The results showed that the ginsenosides extracted from Sanchi induced the transcription of stress genes and increased the synthesis of stress proteins, especially the heat shock protein HSP1A1 or Hsp70, in normal human keratinocytes and dermal fibroblasts. Furthermore, this extract also has significant positive effects against facial wrinkles and other symptoms of facial skin aging as tested clinically, which may be due to its hormetic mode of action by stress-induced synthesis of chaperones involved in protein repair and removal of abnormal proteins. Acceptance of such a hormesis-based product by the wider public could be instrumental in the social recognition of the concept of

  4. Pulmonary inflammation and crystalline silica in respirable coal mine dust: dose-response

    Indian Academy of Sciences (India)

    E D Kuempel; M D Attfield; V Vallyathan; N L Lapp; J M Hale; R J Smith; V Castranova

    2003-02-01

    This study describes the quantitative relationships between early pulmonary responses and the estimated lungburden or cumulative exposure of respirable-quartz or coal mine dust. Data from a previous bronchoalveolar lavage (BAL) study in coal miners ( = 20) and nonminers ( = 16) were used including cell counts of alveolar macrophages (AMs) and polymorphonuclear leukocytes (PMNs), and the antioxidant superoxide dismutase (SOD) levels. Miners’ individual working lifetime particulate exposures were estimated from work histories and mine air sampling data, and quartz lung-burdens were estimated using a lung dosimetry model. Results show that quartz, as either cumulative exposure or estimated lung-burden, was a highly statistically significant predictor of PMN response ( < 0.0001); however cumulative coal dust exposure did not significantly add to the prediction of PMNs ( = 0.2) above that predicted by cumulative quartz exposure ( < 0.0001). Despite the small study size, radiographic category was also significantly related to increasing levels of both PMNs and quartz lung burden (-values < 0.04). SOD in BAL fluid rose linearly with quartz lung burden ( < 0.01), but AM count in BAL fluid did not ( > 0.4). This study demonstrates dose-response relationships between respirable crystalline silica in coal mine dust and pulmonary inflammation, antioxidant production, and radiographic small opacities.

  5. Dose response for TCDD promotion of hepatocarcinogenesis in rats initiated with DEN: histologic, biochemical, and cell proliferation endpoints.

    OpenAIRE

    Maronpot, R R; Foley, J F; Takahashi, K; Goldsworthy, T; Clark, G; Tritscher, A; Portier, C; Lucier, G

    1993-01-01

    The present study examines the dose-response relationship for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) promotion of histologic and biochemical parameters by using a two-stage model for hepatocarcinogenesis in female Sprague-Dawley rats initiated with a single intraperitoneal dose of 175 mg of diethylnitrosamine (DEN)/kg body weight at 70 days of age. Starting 2 weeks after initiation, treatment groups of 8-10 rats were given TCDD by gavage in corn oil once every 2 weeks for 30 weeks. Doses ...

  6. Slope of the dose-response curve: usefulness in assessing bronchial responses to inhaled histamine.

    OpenAIRE

    Cockcroft, D. W.; Berscheid, B A

    1983-01-01

    The value of determining the slope of the histamine dose-response curve, in addition to the histamine provocation concentration producing a 20% reduction in FEV1 (PC20-FEV1), was assessed by analysis of histamine dose-response curves in 40 patients selected as having a wide range of increased non-specific bronchial responsiveness to inhaled histamine. The histamine dose-response curves were found to be fit the linear curve (dose v response, mean r2 = 0.97) better than the logarithmic curve (l...

  7. Methods for meta-analysis of pharmacodynamic dose-response data with application to multi-arm studies of alogliptin.

    Science.gov (United States)

    Langford, Oliver; Aronson, Jeffrey K; van Valkenhoef, Gert; Stevens, Richard J

    2016-03-17

    Standard methods for meta-analysis of dose-response data in epidemiology assume a model with a single scalar parameter, such as log-linear relationships between exposure and outcome; such models are implicitly unbounded. In contrast, in pharmacology, multi-parameter models, such as the widely used Emax model, are used to describe relationships that are bounded above and below. We propose methods for estimating the parameters of a dose-response model by meta-analysis of summary data from the results of randomized controlled trials of a drug, in which each trial uses multiple doses of the drug of interest (possibly including dose 0 or placebo). We assume that, for each randomized arm of each trial, the mean and standard error of a continuous response measure and the corresponding allocated dose are available. We consider weighted least squares fitting of the model to the mean and dose pairs from all arms of all studies, and a two-stage procedure in which scalar inverse-variance meta-analysis is performed at each dose, and the dose-response model is fitted to the results by weighted least squares. We then compare these with two further methods inspired by network meta-analysis that fit the model to the contrasts between doses. We illustrate the methods by estimating the parameters of the Emax model to a collection of multi-arm, multiple-dose, randomized controlled trials of alogliptin, a drug for the management of diabetes mellitus, and further examine the properties of the four methods with sensitivity analyses and a simulation study. We find that all four methods produce broadly comparable point estimates for the parameters of most interest, but a single-stage method based on contrasts between doses produces the most appropriate confidence intervals. Although simpler methods may have pragmatic advantages, such as the use of standard software for scalar meta-analysis, more sophisticated methods are nevertheless preferable for their advantages in estimation.

  8. Dose response studies and longterm evaluation of auranofin in rheumatoid arthritis.

    Science.gov (United States)

    Champion, G D; Cairns, D R; Bieri, D; Adena, M A; Browne, C D; Cohen, M L; Day, R O; Edmonds, J P; Graham, G G; de Jager, J

    1988-01-01

    Fifty-eight patients with rheumatoid arthritis (RA) entered a double blind trial of auranofin (AF) designed to assess dose response relationships and longterm outcome. Multivariate analysis of repeated measures with trend analysis and discriminant function analysis of standard measures of RA activity were applied to a randomized double blind trial of AF at daily doses of 4, 6 and 8 mg over 6 months. Improvement occurred in each group. There was a highly significant (p less than 0.001) linear trend in the 6 mg group, 73% of whom showed linear improvement. A significant correlation (p less than 0.05) was found between response of individual patients and AF dose (mg/kg/day), but there was no significant correlation between dosage and mean steady state serum gold concentration. No significant correlation was seen between outcome and pretreatment demographic and disease variables. In a subsequent 6 month phase of dosage adjustment, aiming for optimal dosage, no advantage resulted from increasing the dose above 6 mg/day. Patients apparently benefiting from treatment continued an open long-term trial of AF. By 45 months, 33.5% had stopped treatment due to lack of efficacy and 14.5% due to toxicity, mainly rash and diarrhea.

  9. Dose-response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies.

    Science.gov (United States)

    Webb, Nicholas E; Montefiori, David C; Lee, Benhur

    2015-09-29

    A new generation of HIV broadly neutralizing antibodies (bnAbs) with remarkable potency, breadth and epitope diversity has rejuvenated interest in immunotherapeutic strategies. Potencies defined by in vitro IC50 and IC80 values (50 and 80% inhibitory concentrations) figure prominently into the selection of clinical candidates; however, much higher therapeutic levels will be required to reduce multiple logs of virus and impede escape. Here we predict bnAb potency at therapeutic levels by analysing dose-response curve slopes, and show that slope is independent of IC50/IC80 and specifically relates to bnAb epitope class. With few exceptions, CD4-binding site and V3-glycan bnAbs exhibit slopes >1, indicative of higher expected therapeutic effectiveness, whereas V2-glycan, gp41 membrane-proximal external region (MPER) and gp120-gp41 bnAbs exhibit less favourable slopes <1. Our results indicate that slope is one major predictor of both potency and breadth for bnAbs at clinically relevant concentrations, and may better coordinate the relationship between bnAb epitope structure and therapeutic expectations.

  10. Toward a unified approach to dose-response modeling in ecotoxicology.

    Science.gov (United States)

    Ritz, Christian

    2010-01-01

    This study reviews dose-response models that are used in ecotoxicology. The focus lies on clarification of differences and similarities between models, and as a side effect, their different guises in ecotoxicology are unravelled. A look at frequently used dose-response models reveals major discrepancies, among other things in naming conventions. Therefore, there is a need for a unified view on dose-response modeling in order to improve the understanding of it and to facilitate communication and comparison of findings across studies, thus realizing its full potential. This study attempts to establish a general framework that encompasses most dose-response models that are of interest to ecotoxicologists in practice. The framework includes commonly used models such as the log-logistic and Weibull models, but also features entire suites of models as found in various guidance documents. An outline on how the proposed framework can be implemented in statistical software systems is also provided.

  11. Dose-response regressions for algal growth and similar continuous endpoints: Calculation of effective concentrations

    DEFF Research Database (Denmark)

    Christensen, Erik R.; Kusk, Kresten Ole; Nyholm, Niels

    2009-01-01

    % inhibition). For illustration, data from closed, freshwater algal assays are analyzed using the green alga Pseudokirchneriella subcapitata with growth rate as the response parameter. Dose-response regressions for four test chemicals (tetraethylammonium bromide, musculamine, benzonitrile, and 4...

  12. Preconditioning is hormesis part II: How the conditioning dose mediates protection: Dose optimization within temporal and mechanistic frameworks.

    Science.gov (United States)

    Calabrese, Edward J

    2016-08-01

    In Part I, hormetic doses of a variety of agents stimulated adaptive responses that conditioned and protected cells against the subsequent toxicity resulting from a second, higher dose (called a challenging dose) of the same or different agents. Herein (Part II), the optimal conditioning (hormetic) doses of many agents are documented, cellular mechanisms and temporal profiles are examined from which the conditioning (hormetic) responses are elicited, and the optimal conditioning doses are compared to the levels at which optimal protection occurs in response to the toxic challenge dose. Entry criteria for study evaluation required a conditioning mechanism-induced endpoint response, an hormetic/biphasic dose response for the protective response following the challenging dose, and a mechanistic assessment of how the conditioning dose afforded protection against a toxic challenging dose. The conditioning dose that demonstrated the largest increase in a mechanism-related conditioning (hormetic) response (i.e., prior to administration of the challenging dose) was the same dose that was optimally protective following the challenging dose. Specific receptor antagonists and/or inhibitors of cell signaling pathways which blocked the induction of conditioning (hormetic) effects during the conditioning period abolished the protective effects following the application of a challenge dose, thus identifying a specific and essential component of the hormetic mechanism. Conditioning responses often had sufficient doses to assess the nature of the dose response. In each of the cases these mechanism-based endpoints displayed an hormetic dose response. The present analysis reveals that hormetic biphasic dose responses were associated with both the conditioning process and the protective effects elicited following the challenging dose. Furthermore, based on optimal dosage, temporal relationships and the known mediating actions of receptor-based and/or cell signaling-based mechanisms

  13. Is the integration of hormesis and essentiality into ecotoxicology now opening Pandora's Box?

    Science.gov (United States)

    Kefford, Ben J; Zalizniak, Liliana; Warne, Michael St J; Nugegoda, Dayanthi

    2008-02-01

    Hormesis and essentiality are likely real and common effects at the level of the individual. However, the widespread incorporation of stimulatory effects into applications of ecotoxicology requires the acceptance of assumptions, value judgements and possibly lowering of water/sediment quality standards. There is also currently little data appropriate for considering hormetic effects in the ecotoxicological context. Except perhaps in the case of fitting concentration-response curves, it is not clear that incorporation of hormetic and essentiality type responses into ecotoxicology is necessary. Furthermore, its incorporation presents considerable intellectual and practical changes for ecotoxicology and could have unanticipated consequences.

  14. Dietary magnesium intake and metabolic syndrome in the adult population: dose-response meta-analysis and meta-regression.

    Science.gov (United States)

    Ju, Sang-Yhun; Choi, Whan-Seok; Ock, Sun-Myeong; Kim, Chul-Min; Kim, Do-Hoon

    2014-12-22

    ncreasing evidence has suggested an association between dietary magnesium intake and metabolic syndrome. However, previous research examining dietary magnesium intake and metabolic syndrome has produced mixed results. Our objective was to determine the relationship between dietary magnesium intake and metabolic syndrome in the adult population using a dose-response meta-analysis. We searched the PubMed, Embase and the Cochrane Library databases from August, 1965, to May, 2014. Observational studies reporting risk ratios with 95% confidence intervals (CIs) for metabolic syndrome in ≥ 3 categories of dietary magnesium intake levels were selected. The data extraction was performed independently by two authors, and the quality of the studies was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). Based on eight cross-sectional studies and two prospective cohort studies, the pooled relative risks of metabolic syndrome per 150 mg/day increment in magnesium intake was 0.88 (95% CI, 0.84-0.93; I(2) = 36.3%). The meta-regression model showed a generally linear, inverse relationship between magnesium intake (mg/day) and metabolic syndrome. This dose-response meta-analysis indicates that dietary magnesium intake is significantly and inversely associated with the risk of metabolic syndrome. However, randomized clinical trials will be necessary to address the issue of causality and to determine whether magnesium supplementation is effective for the prevention of metabolic syndrome.

  15. A sex-specific dose-response curve for testosterone: could excessive testosterone limit sexual interaction in women?

    Science.gov (United States)

    Krapf, Jill M; Simon, James A

    2017-04-01

    Testosterone treatment increases sexual desire and well-being in women with hypoactive sexual desire disorder; however, many studies have shown only modest benefits limited to moderate doses. Unlike men, available data indicate women show a bell-shaped dose-response curve for testosterone, wherein a threshold dosage of testosterone leads to desirable sexual function effects, but exceeding this threshold results in a lack of further positive sexual effects or may have a negative impact. Emotional and physical side-effects of excess testosterone, including aggression and virilization, may counteract the modest benefits on sexual interaction, providing a possible explanation for a threshold dose of testosterone in women. In this commentary, we will review and critically analyze data supporting a curvilinear dose-response relationship between testosterone treatment and sexual activity in women with low libido, and also explore possible explanations for this observed relationship. Understanding optimal dosing of testosterone unique to women may bring us one step closer to overcoming regulatory barriers in treating female sexual dysfunction.

  16. A grid algorithm for high throughput fitting of dose-response curve data.

    Science.gov (United States)

    Wang, Yuhong; Jadhav, Ajit; Southal, Noel; Huang, Ruili; Nguyen, Dac-Trung

    2010-10-21

    We describe a novel algorithm, Grid algorithm, and the corresponding computer program for high throughput fitting of dose-response curves that are described by the four-parameter symmetric logistic dose-response model. The Grid algorithm searches through all points in a grid of four dimensions (parameters) and finds the optimum one that corresponds to the best fit. Using simulated dose-response curves, we examined the Grid program's performance in reproducing the actual values that were used to generate the simulated data and compared it with the DRC package for the language and environment R and the XLfit add-in for Microsoft Excel. The Grid program was robust and consistently recovered the actual values for both complete and partial curves with or without noise. Both DRC and XLfit performed well on data without noise, but they were sensitive to and their performance degraded rapidly with increasing noise. The Grid program is automated and scalable to millions of dose-response curves, and it is able to process 100,000 dose-response curves from high throughput screening experiment per CPU hour. The Grid program has the potential of greatly increasing the productivity of large-scale dose-response data analysis and early drug discovery processes, and it is also applicable to many other curve fitting problems in chemical, biological, and medical sciences.

  17. Hormesis associated with a low dose of methylmercury injected into mallard eggs

    Science.gov (United States)

    Heinz, Gary H.; Hoffman, David J.; Klimstra, Jon D.; Stebbins, Katherine R.; Kondrad, Shannon L.; Erwin, Carol A.

    2012-01-01

    We injected mallard (Anas platyrhynchos) eggs with methylmercury chloride at doses of 0, 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 μg mercury/g egg contents on a wet-weight basis. A case of hormesis seemed to occur because hatching success of eggs injected with 0.05 μg mercury (the lowest dose) was significantly greater (93.3%) than that of controls (72.6%), whereas hatching success decreased at progressively greater doses of mercury. Our finding of hormesis when a low dose of methylmercury was injected into eggs agrees with a similar observation in a study in which a group of female mallards was fed a low dietary concentration of methylmercury and hatching of their eggs was significantly better than that of controls. If methylmercury has a hormetic effect at low concentrations in avian eggs, these low concentrations may be important in a regulatory sense in that they may represent a no-observed adverse effect level (NOAEL).

  18. Evidence supporting radiation hormesis in atomic bomb survivor cancer mortality data.

    Science.gov (United States)

    Doss, Mohan

    2012-12-01

    A recent update on the atomic bomb survivor cancer mortality data has concluded that excess relative risk (ERR) for solid cancers increases linearly with dose and that zero dose is the best estimate for the threshold, apparently validating the present use of the linear no threshold (LNT) model for estimating the cancer risk from low dose radiation. A major flaw in the standard ERR formalism for estimating cancer risk from radiation (and other carcinogens) is that it ignores the potential for a large systematic bias in the measured baseline cancer mortality rate, which can have a major effect on the ERR values. Cancer rates are highly variable from year to year and between adjacent regions and so the likelihood of such a bias is high. Calculations show that a correction for such a bias can lower the ERRs in the atomic bomb survivor data to negative values for intermediate doses. This is consistent with the phenomenon of radiation hormesis, providing a rational explanation for the decreased risk of cancer observed at intermediate doses for which there is no explanation based on the LNT model. The recent atomic bomb survivor data provides additional evidence for radiation hormesis in humans.

  19. Mitochondrial Hormesis in Pancreatic β Cells: Does Uncoupling Protein 2 Play a Role?

    Directory of Open Access Journals (Sweden)

    Ning Li

    2012-01-01

    Full Text Available In pancreatic β cells, mitochondrial metabolism translates glucose sensing into signals regulating insulin secretion. Chronic exposure of β cells to excessive nutrients, namely, glucolipotoxicity, impairs β-cell function. This is associated with elevated ROS production from overstimulated mitochondria. Mitochondria are not only the major source of cellular ROS, they are also the primary target of ROS attacks. The mitochondrial uncoupling protein UCP2, even though its uncoupling properties are debated, has been associated with protective functions against ROS toxicity. Hormesis, an adaptive response to cellular stresses, might contribute to the protection against β-cell death, possibly limiting the development of type 2 diabetes. Mitochondrial hormesis, or mitohormesis, is a defense mechanism observed in ROS-induced stress-responses by mitochondria. In β cells, mitochondrial damages induced by sublethal exogenous H2O2 can induce secondary repair and defense mechanisms. In this context, UCP2 is a marker of mitohormesis, being upregulated following stress conditions. When overexpressed in nonstressed naïve cells, UCP2 confers resistance to oxidative stress. Whether treatment with mitohormetic inducers is sufficient to restore or ameliorate secretory function of β cells remains to be determined.

  20. Transcript expression patterns illuminate the mechanistic background of hormesis in caenorhabditis elegans maupas.

    Science.gov (United States)

    Steinberg, Christian E W; Pietsch, Kerstin; Saul, Nadine; Menzel, Stefanie; Swain, Suresh C; Stürzenbaum, Stephen R; Menzel, Ralph

    2013-01-01

    The animal model Caenorhabditis elegans was employed to study polyphenol- and humic substances-induced hormetic changes in lifespan. A detailed insight into the underlying mechanism of hormesis was uncovered by applying whole genome DNA microarray experimentation over a range of quercetin (Q), tannic acid (TA), and humic substances (HuminFeed(®), HF) concentrations. The transcriptional response to all exposures followed a non-linear mode which highlighted differential signaling and metabolic pathways. While low Q concentrations regulated processes improving the health of the nematodes, higher concentrations extended lifespan and modulated substantially the global transcriptional response. Over-represented transcripts were notably part of the biotransformation process: enhanced catabolism of toxic intermediates possibly contributes to the lifespan extension. The regulation of transcription, Dauer entry, and nucleosome suggests the presence of distinct exposure dependent differences in transcription and signaling pathways. TA- and HF-mediated transcript expression patterns were overall similar to each other, but changed across the concentration range indicating that their transcriptional dynamics are complex and cannot be attributed to a simple adaptive response. In contrast, Q-mediated hormesis was well aligned to fit the definition of an adaptive response. Simple molecules are more likely to induce an adaptive response than more complex molecules.

  1. Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson's disease.

    Science.gov (United States)

    Qi, Hui; Li, Shixue

    2014-04-01

    A dose-response meta-analysis was carried out between Parkinson's disease (PD) risk, and coffee, tea and caffeine consumption. A comprehensive search was carried out to identify eligible studies. The fixed or random effect model was used based on heterogeneity test. The dose-response relationship was assessed by restricted cubic spline. A total of 13 articles involving 901 764 participants for coffee, eight articles involving 344 895 participants for tea and seven articles involving 492 724 participants for caffeine were included. A non-linear relationship was found between coffee consumption and PD risk overall, and the strength of protection reached the maximum at approximately 3 cups/day (smoking-adjusted relative risk: 0.72, 95% confidence interval 0.65-0.81). A linear relationship was found between tea and caffeine consumption, and PD risk overall, and the smoking-adjusted risk of PD decreased by 26% and 17% for every two cups/day and 200 mg/day increments, respectively. The association of coffee and tea consumption with PD risk was stronger for men than that for women, and the association of caffeine consumption with PD risk was stronger for ever users of hormones than that for never users of hormones among postmenopausal women. The aforementioned associations were weaker for USA relative to Europe or Asia. A linear dose-relationship for decreased PD risk with tea and caffeine consumption was found, whereas the strength of protection reached a maximum at approximately 3 cups/day for coffee consumption overall. Further studies are required to confirm the findings. © 2013 Japan Geriatrics Society.

  2. Study on the dose response characteristics of a scanning liquid ion-chamber electronic portal imaging device

    CERN Document Server

    Ma Shao Gang; Song Yi Xin

    2002-01-01

    Objective: To study the dose response characteristics and the influence factors such as gantry angle, field size and acquisition mode on the dosimetric response curves, when using a scanning liquid ion-chamber electronic portal imaging device (EPID) for dose verification. Methods: All experiments were carried out on a Varian 600 C/D accelerator (6 MV X-ray) equipped with a Varian PortalVision sup T sup M MK2 type EPID. To obtain the dose response curve, the relationship between the incident radiation intensity to the detector and the pixel value output from the EPID were established. Firstly, the different dose rates of 6 MV X-rays were obtained by varying SSD. Secondly, three digital portal images were acquired for each dose rate using the EPID and averaged to avoid the influence of the dose rate fluctuations of the accelerator. The pixel values of all images were read using self-designed image analysis software, and and average for a region consisting of 11 x 11 pixels around the center was taken as the res...

  3. Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis.

    Science.gov (United States)

    Crippa, Alessio; Discacciati, Andrea; Larsson, Susanna C; Wolk, Alicja; Orsini, Nicola

    2014-10-15

    Several studies have analyzed the relationship between coffee consumption and mortality, but the shape of the association remains unclear. We conducted a dose-response meta-analysis of prospective studies to examine the dose-response associations between coffee consumption and mortality from all causes, cardiovascular disease (CVD), and all cancers. Pertinent studies, published between 1966 and 2013, were identified by searching PubMed and by reviewing the reference lists of the selected articles. Prospective studies in which investigators reported relative risks of mortality from all causes, CVD, and all cancers for 3 or more categories of coffee consumption were eligible. Results from individual studies were pooled using a random-effects model. Twenty-one prospective studies, with 121,915 deaths and 997,464 participants, met the inclusion criteria. There was strong evidence of nonlinear associations between coffee consumption and mortality for all causes and CVD (P for nonlinearity Coffee consumption was not associated with cancer mortality. Findings from this meta-analysis indicate that coffee consumption is inversely associated with all-cause and CVD mortality.

  4. Association between dietary vitamin C intake and risk of esophageal cancer: A dose-response meta-analysis.

    Science.gov (United States)

    Bo, Yacong; Lu, Yan; Zhao, Yan; Zhao, Erjiang; Yuan, Ling; Lu, Weiquan; Cui, Lingling; Lu, Quanjun

    2016-04-15

    While several epidemiological studies have investigated the association between vitamin C and risk of esophageal cancer, the results remain inconsistent. In the present study, a meta-analysis was conducted to assess the impact of dietary vitamin C intake on esophageal cancer risk. Online databases were searched up to March 29, 2015, for studies on the association between dietary vitamin C intake and esophageal cancer risk. Pooled risk ratios (RRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Dose-response analyses were performed using the method of restricted cubic splines with four knots at percentiles of 5, 35, 65 and 95% of the distribution. Publication bias was estimated using Egger's tests and funnel plots. In all, 15 articles were included in this meta-analysis, including 20 studies, containing 7063 controls and 3955 cases of esophageal cancer. By comparing the highest vs. the lowest categories of vitamin C intake, we found that vitamin C was inversely associated with the risk of esophageal cancer [overall OR = 0.58, 95% CI = 0.49-0.68, I(2) = 56%]. A linear dose-response relationship was found. With an increase in dietary vitamin C intake of 50 mg/day, the risk of esophageal cancer statistically decreased by 13% (OR = 0.87, 95% CI = 0.80-0.93, p(linearity) = 0.0002). In conclusion, our analysis suggested that the higher intake of dietary vitamin C might have a protective effect against esophageal cancer.

  5. Modeling Dose-response at Low Dose: A Systems Biology Approach for Ionization Radiation.

    Science.gov (United States)

    Zhao, Yuchao; Ricci, Paolo F

    2010-03-18

    For ionization radiation (IR) induced cancer, a linear non-threshold (LNT) model at very low doses is the default used by a number of national and international organizations and in regulatory law. This default denies any positive benefit from any level of exposure. However, experimental observations and theoretical biology have found that both linear and J-shaped IR dose-response curves can exist at those very low doses. We develop low dose J-shaped dose-response, based on systems biology, and thus justify its use regarding exposure to IR. This approach incorporates detailed, molecular and cellular descriptions of biological/toxicological mechanisms to develop a dose-response model through a set of nonlinear, differential equations describing the signaling pathways and biochemical mechanisms of cell cycle checkpoint, apoptosis, and tumor incidence due to IR. This approach yields a J-shaped dose response curve while showing where LNT behaviors are likely to occur. The results confirm the hypothesis of the J-shaped dose response curve: the main reason is that, at low-doses of IR, cells stimulate protective systems through a longer cell arrest time per unit of IR dose. We suggest that the policy implications of this approach are an increasingly correct way to deal with precautionary measures in public health.

  6. Digitoxin medication and cancer; case control and internal dose-response studies

    Directory of Open Access Journals (Sweden)

    Spigset Olav

    2001-08-01

    Full Text Available Abstract Background Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population. Methods Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases. Results The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. Conclusion Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease.These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents.

  7. Dose response of retinol and isotretinoin in the prevention of nonmelanoma skin cancer recurrence.

    Science.gov (United States)

    Clouser, Mary C; Roe, Denise J; Foote, Janet A; Harris, Robin B; Alberts, David S

    2010-01-01

    Using data from a randomized, double blind, study of the efficacy of retinol or isotretinoin vs. placebo on recurrence of nonmelanoma skin cancer in high-risk subjects, a reanalysis of the original intent to treat analysis was performed in a dose-response format. Cox proportional hazards models describe the relationship between dose quartiles of isotretinoin and retinol use and time to first occurrence of squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) in crude and adjusted models. Neither the isotretinoin nor retinol models showed any significance at any quartile for reduction in first BCC or SCC occurrence. Crude and adjusted retinol models show a statistically significant increase in risk of developing an SCC in the first quartile, whereas only the crude model shows a statistically significant increase in risk in the first quartile of the isotretinoin model. For retinol and SCC, hazard ratios (HRs) for the first quartile were as follows: HR = 2.92, 95% confidence interval (CI) = 1.67-5.10 crude; HR = 1.95, 95% CI = 1.00-3.80 adjusted. For isotretinoin and SCC, HRs for the first quartile were as follows: HR = 2.38, 95% CI = 1.35-4.19 crude; HR = 1.69, 95% CI = 0.87-3.31 adjusted. Test for trend was not significant in any of the models. These analyses confirm the results of the original intent to treat analyses and raise an interesting question related to the potential for increased risk for patients in the first quartile of retinol dose.

  8. Influence of Exercise Intensity for Improving Depressed Mood in Depression: A Dose-Response Study.

    Science.gov (United States)

    Meyer, Jacob D; Koltyn, Kelli F; Stegner, Aaron J; Kim, Jee-Seon; Cook, Dane B

    2016-07-01

    Exercise effectively improves mood in major depressive disorder (MDD), but the optimal exercise stimulus to improve depressed mood is unknown. To determine the dose-response relationship of acute exercise intensity with depressed mood responses to exercise in MDD. We hypothesized that the acute response to exercise would differ between light, moderate, and hard intensity exercise with higher intensities yielding more beneficial responses. Once weekly, 24 women (age: 38.6±14.0) diagnosed with MDD underwent a 30-minute session at one of three steady-state exercise intensities (light, moderate, hard; rating of perceived exertion 11, 13 or 15) or quiet rest on a stationary bicycle. Depressed mood was evaluated with the Profile of Mood States before, 10 and 30 minutes post-exercise. Exercise reduced depressed mood 10 and 30 minutes following exercise, but this effect was not influenced by exercise intensity. Participants not currently taking antidepressants (n=10) had higher baseline depression scores, but did not demonstrate a different antidepressant response to exercise compared to those taking antidepressants. To acutely improve depressed mood, exercise of any intensity significantly improved feelings of depression with no differential effect following light, moderate, or hard exercise. Pharmacological antidepressant usage did not limit the mood-enhancing effect of acute exercise. Acute exercise should be used as a symptom management tool to improve mood in depression, with even light exercise an effective recommendation. These results need to be replicated and extended to other components of exercise prescription (e.g., duration, frequency, mode) to optimize exercise guidelines for improving depression. Copyright © 2016. Published by Elsevier Ltd.

  9. [Dose response curve of paclitaxel measured by histoculture drug response assay].

    Science.gov (United States)

    Yoshimasu, Tatsuya; Oura, Shoji; Hirai, Issei; Kokawa, Yozo; Okamura, Yoshitaka; Furukawa, Tomoko

    2005-04-01

    Dose response curves of paclitaxel were measured by histoculture drug response assay (HDRA) in 11 lung cancer patients. Inhibition rates of paclitaxel at several concentrations were measured and fitted to the sigmoid dose response curve, using non-linear least square analysis, with fitting equation y=A (1-1/(1+exp (b (x-log (ED50)). Parameters A, b, and ED50 were 88.3+/-6.0 (80.0-100.0) %, 9.57+/-4.32 (2.25-15.0), and 26.8+/-8.1 (15.0-41.0) microg/ml, respectively. The parameter b was lower in well-differentiated tumors compared with moderately and poorly-differentiated tumors. Dose response curves of paclitaxel could be measured by HDRA in lung cancer. This method provides us more information for drug sensitivity than the usual HDRA method. This may lead to the improved accuracy of HDRA.

  10. Lack-of-fit tests for assessing mean structures for continuous dose-response data

    DEFF Research Database (Denmark)

    Martinussen, Torben

    2011-01-01

    We review a range of lack-of-fit tests suitable for assessing the appropriateness of the mean function in dose-response models. The review encompasses both well-known tests and new tests based on recent developments in statistics, which we have extended to the dose-response case. We argue...... that the classical methods are inadequate in certain situations, where the new tests may be applied. Power comparisons are carried out by means of extensive simulation studies, covering both designs with and without replicates at small and large sample sizes. Three datasets from dose-response applications illustrate...... differences and similarities between the tests. The results suggest that the new tests perform better and exhibit a wider applicability....

  11. The hypnotic and analgesic effects of oral clonidine during sevoflurane anesthesia in children: a dose-response study.

    Science.gov (United States)

    Inomata, Shinichi; Kihara, Shin-Ichi; Miyabe, Masayuki; Sumiya, Kenji; Baba, Yasuyuki; Kohda, Yukinao; Toyooka, Hidenori

    2002-06-01

    Although clonidine has both hypnotic and analgesic actions, the dose relationship for each actions is still unknown in a clinical setting when clonidine is used as a premedication in children. We studied 80 ASA physical status I children (age range, 3-8 yr). Subjects were randomly divided into two groups (minimum alveolar anesthetic concentration [MAC]-Awake group, n = 40; MAC-Tetanus group, n = 40). Each patient received one dose of clonidine from 1 to 5 microg/kg orally, 100 min before arrival at the operating room. Anesthesia was induced and maintained with sevoflurane in oxygen and air. Before tracheal intubation, end-tidal sevoflurane was decreased stepwise by 0.2% at the start of 1.2%, a verbal command was given to the patients, and MAC-awake was determined in each patient. We also investigated MAC-tetanus, determined with transcutaneous electric tetanic stimulations, after tracheal intubation in each patient by observing the motor response to a transcutaneous electric tetanic stimulus to the ulnar nerve at a sevoflurane concentration decreased stepwise by 0.25% at the start of 2.75%. The initial reduction in MAC-tetanus was not as steep as that in MAC-awake. Clonidine reduced MAC-tetanus by 40% at the maximal dose of 5 microg/kg, whereas MAC-awake was already reduced by 50% at 2 microg/kg. We conclude that separate dose-response relationships for oral clonidine are present regarding the hypnotic and analgesic effects in children undergoing sevoflurane anesthesia. Separate dose-response relationships for oral clonidine were found regarding the hypnotic and analgesic effects in children undergoing sevoflurane anesthesia.

  12. Escitalopram dose-response revisited: an alternative psychometric approach to evaluate clinical effects of escitalopram compared to citalopram and placebo in patients with major depression.

    Science.gov (United States)

    Bech, Per; Tanghøj, Per; Cialdella, Philippe; Andersen, Henning Friis; Pedersen, Anders Gersel

    2004-09-01

    In continuation of a previous psychometric analysis of dose-response data for citalopram in depression, the corresponding study data for escitalopram is of interest, since escitalopram is the active enantiomer of citalopram and because citalopram was used as the active control. Revisiting those corresponding data, the psychometric properties of the Montgomery-Asberg Depression Scale (MADRS) and the Hamilton Depression Scale (HAMD) were investigated by focusing on the unidimensional HAMD6 and MADRS6. Effect sizes were calculated and compared for two dosages of escitalopram (10 mg and 20 mg daily) and between each of these two dosages and 40 mg citalopram daily. The results showed that the three depression scales MADRS6, MADRS10 and HAMD6 were psychometrically acceptable (coefficient of homogeneity of 0.40 or higher). In the severely depressed patients (MADRS10> or =30) a rather clear dose-response relationship for escitalopram was seen on all three scales after 6 and 8 wk of therapy. Thus, the effect size for 10 mg escitalopram ranged from 0.28 to 0.38 while the effect sizes for 20 mg escitalopram ranged from 0.57 to 0.77. This difference was statistically significant (pescitalopram and 40 mg citalopram was seen after 8 wk of therapy for MADRS10 (effect size 0.71 vs. 0.37). An item analysis identified 'suicidal thoughts' to be the most discriminating item in this respect. These results for the severely depressed patients were confirmed by the patients self-reported quality of life evaluation. When all included patients were analysed, however, no clear dose-response relationship was seen. In conclusion, a dose-response relationship for escitalopram was seen in the severely depressed patients on all outcome scales after 6 and 8 wk of treatment. After 8 wk of treatment 20 mg escitalopram was superior to 40 mg citalopram, but not after 2 wk of treatment.

  13. Dose-response relationship of sertindole and haloperidol using the pharmacopsychometric triangle

    DEFF Research Database (Denmark)

    Bech, P; Tanghøj, P; Andreasson, K;

    2011-01-01

    Renewed insight into dose-related effects of sertindole and haloperidol was sought by re-analysing published data for antipsychotic effect, extrapyramidal effect, and patient wellbeing - i.e., the important pharmacopsychometric triangle domains.......Renewed insight into dose-related effects of sertindole and haloperidol was sought by re-analysing published data for antipsychotic effect, extrapyramidal effect, and patient wellbeing - i.e., the important pharmacopsychometric triangle domains....

  14. Epidemiological methods for assessing dose-response and dose-effect relationships

    DEFF Research Database (Denmark)

    Kjellström, Tord; Grandjean, Philippe

    2007-01-01

    and their compounds. An entirely new structure and illustrations represent the vast array of advancements made since the last edition. Special emphasis has been placed on the toxic effects in humans with chapters on the diagnosis, treatment and prevention of metal poisoning. This up-to-date reference provides easy...... and Toxicity Carcinogenicity of Metal Compounds Immunotoxicology of Metals Reproductive and Developmental Toxicity of Metals Ecotoxicology of Metals - Sources, Transport, and Effects in the Ecosystem Risk Assessment Diagnosis and Treatment of Metal Poisoning - General Aspects Principles for Prevention...... of the Toxic Effects of Metals Aluminum Antimony Arsenic Barium Beryllium Bismuth Cadmium Chromium Cobalt Copper Gallium and Semiconductor Compounds Germanium Indium Iron Lead Manganese Mercury Molybdenum Nickel Palladium Platinum Selenium Silver Tellurium Thallium Tin Titanium Tungsten Uranium Vanadium Zinc...

  15. Fertility of Tall Girls Treated with High-Dose Estrogen, a Dose-Response Relationship

    NARCIS (Netherlands)

    Hendriks, A. E. J.; Drop, S. L. S.; Laven, J. S. E.; Boot, A. M.

    2012-01-01

    Context: High-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life. Objective: The aim was to study the effect of estrogen dose on fertility outcome of these women. Design/Setting: We conducted a retrospective cohort study of university hosp

  16. The effect of nitrous oxide on the dose-response relationship of rocuronium.

    Science.gov (United States)

    Kopman, Aaron F; Chin, Wanda A; Moe, Jimmy; Malik, Rawshan

    2005-05-01

    It has been generally assumed that nitrous oxide (N(2)O) enhances the effects of nondepolarizing muscle relaxants only weakly if at all. More recent evidence suggests that drug potency may be more intense under N(2)O anesthesia compared with total IV anesthesia (TIVA). However, the magnitude of this effect has not been well defined. We measured the 50% effective dose of rocuronium in 35 patients receiving N(2)O-propofol-opioid anesthesia and a comparable group receiving TIVA. A single dose of rocuronium was given to each patient and drug potency was calculated for each individual from the Hill equation assuming a log-dose/logit slope of 4.5. In both groups, the relaxant was administered 15 min after induction of anesthesia. Neuromuscular function was measured using electromyography with single stimuli at 0.10 Hz. We measured a 50% effective dose of 0.209 +/- 0.051 mg/kg during TIVA and of 0.166 +/- 0.041 mg/kg during N(2)O anesthesia, a decrease of 20% (P < 0.001). The clinical importance of this effect must be considered modest; however, estimates of potency that are usually obtained during N(2)O anesthesia may underestimate drug requirements at the time of induction of anesthesia.

  17. In vitro study of dose-response relationship of fluoride with dental enamel

    Directory of Open Access Journals (Sweden)

    Arthur, Rodrigo Alex et al.

    2007-01-01

    Full Text Available Modelos in vitro para avaliação da reatividade do fluoreto (F devem apresentar resposta dose-efeito. Dessa forma, o objetivo desse estudo foi avaliar a relação dose-resposta do fluoreto presente em solução aquosa com o esmalte dental bovino. Cento e vinte blocos de esmalte bovino (5 × 5 × 2 mm, 60 hígidos e 60 com lesão artificial de cárie, foram submetidos durante 10 minutos à água destilada e deionizada (controle negativo e soluções aquosas contendo 50, 100, 200 ou 400 µg F/mL. Cada grupo experimental recebeu 12 blocos hígidos e 12 blocos com lesão artificial de cárie. Duas camadas consecutivas de esmalte dental foram removidas de todos os blocos dentais por meio de ataque ácido e o fluoreto extraído foi determinado com eletrodo específico. Os resultados de fluoreto incorporado foram expressos em µg por g de esmalte removido, considerando a quantidade total das duas camadas. A incorporação de fluoreto pelo esmalte hígido mostrou uma relação dose-resposta linear (p = 0,0001, enquanto que os blocos com lesão de cárie mostraram relação polinomial quadrática (p < 0,0001. Os resultados sugerem que o modelo in vitro de reatividade empregado no presente estudo é apropriado para avaliar a relação doseresposta entre o fluoreto em solução aquosa e aquele incorporado pelo esmalte dental bovino hígido ou com lesão artificial de cárie.

  18. Dose-response relationships between four pesticides and phosphorus uptake by hyphae of arbuscular mycorrhizas

    DEFF Research Database (Denmark)

    Schweiger, P.F.; Jakobsen, I.

    1998-01-01

    The effect of the fungicides carbendazim, fenpropimorph and propiconazole and of the insecticide dimethoate on plant P uptake via external hyphae of arbuscular mycorrhizal (AM) fungi was examined. Mycorrhizal plants were grown in a two-compartment system where a root-free hyphal compartment...

  19. Dose-response relationships of clothianidin, imidacloprid, and thiamethoxam to Blissus occiduus (Hemiptera: Blissidae).

    Science.gov (United States)

    Stamm, M D; Baxendale, F P; Heng-Moss, T M; Siegfried, B D; Blankenship, E E; Gaussoin, R E

    2011-02-01

    The western chinch bug, Blissus occiduus Barber (Hemiptera: Blissidae), has emerged as a serious pest of buffalograss, Buchlod dactyloides (Nuttall) Engelmann. In general, neonicotinoid insecticides effectively control a variety of turfgrass insects, particularly phloem-feeding pests. However, because of well documented inconsistencies in control, these compounds are generally not recommended for chinch bugs. This study was designed to document the contact and systemic toxicity of three neonicotinoid insecticides (clothianidin, imidacloprid, and thiamethoxam) to B. occiduus. In contact bioassays, thiamethoxam was approximately 20-fold less toxic than clothianidin or imidacloprid to B. occiduus nymphs and three-fold more toxic to adults. In adult systemic bioassays, thiamethoxam was up to five-fold more toxic than clothianidin or imidacloprid. Interestingly, thiamethoxam was significantly more toxic to adults than to nymphs in both contact and systemic bioassays. This was not observed with clothianidin or imidacloprid. Bifenthrin, used for comparative purposes, exhibited 1844-fold and 122-fold increase in toxicity to nymphs and adults, respectively. These results provide the first documentation of the relative toxicity of these neonicotinoid insecticides to B. occiduus.

  20. Non-Linear Dose-Response Relationships in Biology, Toxicology and Medicine - An International Conference

    Energy Technology Data Exchange (ETDEWEB)

    Calabrese, Edward J.; Kostecki, Paul T.

    2002-05-28

    Conference abstract book contains seven sections: Plenary-4 abstracts; Chemical-9 abstracts; Radiation-7 abstracts; Ultra Low Doses and Medicine-6 abstracts; Biomedical-11 abstracts; Risk Assessment-5 abstracts and Poster Sessions-25 abstracts. Each abstract was provided by the author/presenter participating in the conference.

  1. Ozone dose-response relationships for spring oilseed rape and broccoli

    Science.gov (United States)

    De Bock, Maarten; Op de Beeck, Maarten; De Temmerman, Ludwig; Guisez, Yves; Ceulemans, Reinhart; Vandermeiren, Karine

    2011-03-01

    Tropospheric ozone is an important air pollutant with known detrimental effects for several crops. Ozone effects on seed yield, oil percentage, oil yield and 1000 seed weight were examined for spring oilseed rape ( Brassica napus cv. Ability). For broccoli ( Brassica oleracea L. cv. Italica cv. Monaco) the effects on fresh marketable weight and total dry weight were studied. Current ozone levels were compared with an increase of 20 and 40 ppb during 8 h per day, over the entire growing season. Oilseed rape seed yield was negatively correlated with ozone dose indices calculated from emergence until harvest. This resulted in an R2 of 0.24 and 0.26 ( p crops (UNECE, Mills, 2004), can indeed be applied for spring oilseed rape. The reduction of oilseed rape yield showed the highest correlation with the ozone uptake during the vegetative growth stage: when only the first 47 days after emergence were used to calculate POD 6, R2 values increased up to 0.476 or even 0.545 when the first 23 days were excluded. The highest ozone treatments, corresponding to the future ambient level by 2100 (IPCC, Meehl et al., 2007), led to a reduction of approximately 30% in oilseed rape seed yield in comparison to the current ozone concentrations. Oil percentage was also significantly reduced in response to ozone ( p oil yield was even more severely affected by elevated ozone exposure compared to seed yield: critical levels for oil yield dropped to 3.2 ppm h and 3.9 mmol m -2. For broccoli the applied ozone doses had no effect on yield.

  2. The time-dose-response relationship for elicitation of contact dermatitis in isoeugenol allergic individuals

    DEFF Research Database (Denmark)

    Andersen, Klaus Ejner; Johansen, Jeanne Duus; Bruze, M

    2001-01-01

    and was 15 days for the 0.05% solution. There was a highly significant correlation between the patients' patch test threshold and the number of days until a positive ROAT. In conclusion, the time until an isoeugenol allergic individual reacts in a ROAT depends on the individual sensitivity as well...

  3. Dose-response relationship of cadmium or radiation-induced embryotoxicity in mouse whole embryo culture

    Energy Technology Data Exchange (ETDEWEB)

    Nakashima, Kiyohito; Kawamata, Akitoshi; Matsuoka, Masato; Wakisaka, Takashi; Fujiki, Yoshishige (Asahi University School of Dentistry, Gifu (Japan))

    1988-12-01

    Mouse embryos of B6C3F/sub 1/ strain were exposed in vitro to 1.2 to 2.2 {mu}M cadmium chloride (Cd) or to 100 to 320 R x-rays, and the effects of the exposure on development were examined after 39 h of culture. Development of embryos was assessed from lethality, formation of the neural tube defect, diameter and protein of yolk sac, crown-rump and head lengths, embryonic protein, and number of somites. Incidence of the neural tube defect increased from 3.4 to 100% by 1.2 to 2.0 {mu}M Cd, while embryo deaths increased from 13.8 to 93.3% by 2.0 to 2.2 {mu}M Cd. Embryonic protein was significantly reduced at the teratogenic range, but the number of somites was only affected by 1.6 to 2.0 {mu}M Cd. X-irradiation at 100 to 320 R induced the neural tube defect in 2.9 to 72.7% of the embryos. An embryolethal effect was observed only at the 320 R dose. Crown-rump and head lengths and embryonic protein were significantly affected at the teratogenic range, but the diameter and protein of yolk sac and number of somites were hardly affected. Cadmium- or radiation-induced response data of both teratogenicity and endpoints indicating inhibition of embryonic development were acceptably fitted to a linear log-probit regression. These regressions suggest that as an estimation of interference in development of embryos, embryonic protein and head length are sensitive endpoints while the number of somites is an insensitive criterion. (author).

  4. Pregabalin versus gabapentin in partial epilepsy: a meta-analysis of dose-response relationships

    Directory of Open Access Journals (Sweden)

    Thompson Sally

    2010-11-01

    Full Text Available Abstract Background To compare the efficacy of pregabalin and gabapentin at comparable effective dose levels in patients with refractory partial epilepsy. Methods Eight randomized placebo controlled trials investigating the efficacy of pregabalin (4 studies and gabapentin (4 studies over 12 weeks were identified with a systematic literature search. The endpoints of interest were "responder rate" (where response was defined as at least a 50% reduction from baseline in the number of seizures and "change from baseline in seizure-free days over the last 28 days (SFD". Results of all trials were analyzed using an indirect comparison approach with placebo as the common comparator. The base-case analysis used the intention-to-treat last observation carried forward method. Two sensitivity analyses were conducted among completer and responder populations. Results The base-case analysis revealed statistically significant differences in response rate in favor of pregabalin 300 mg versus gabapentin 1200 mg (odds ratio, 1.82; 95% confidence interval, 1.02, 3.25 and pregabalin 600 mg versus gabapentin 1800 mg (odds ratio, 2.52; 95% confidence interval, 1.21, 5.27. Both sensitivity analyses supported the findings of the base-case analysis, although statistical significance was not demonstrated. All dose levels of pregabalin (150 mg to 600 mg were more efficacious than corresponding dosages of gabapentin (900 mg to 2400 mg in terms of SFD over the last 28 days. Conclusion In patients with refractory partial epilepsy, pregabalin is likely to be more effective than gabapentin at comparable effective doses, based on clinical response and the number of SFD.

  5. Pancreatic beta cell function increases in a linear dose-response manner following exercise training in adults with prediabetes

    DEFF Research Database (Denmark)

    Malin, Steven K; Solomon, Thomas; Blaszczak, Alecia

    2013-01-01

    composition (dual-energy x-ray absorptiometry and computed tomography) were also measured before and after the intervention. Exercise dose was computed using VO2-heart rate derived linear-regression equations. Subjects expended 474.5±8.8 kcal/session (2372.5±44.1 kcal/week) during the intervention, and lost...... ~8% body weight. Exercise increased first and second phase DI (P2000 kcal/week) are necessary to enhance beta-cell function in adults with poor insulin secretion capacity.......While some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic beta-cell function is unknown. Thirty-five older, obese adults with prediabetes underwent a progressive 12-week supervised exercise...

  6. Hormesis of Glyceollin I, an Induced Phytoalexin from Soybean, on Budding Yeast Chronological Lifespan Extension

    Directory of Open Access Journals (Sweden)

    Yuancai Liu

    2014-01-01

    Full Text Available Glyceollin I, an induced phytoalexin isolated from soybean, has been reported to have various bioactivities, including anti-bacterial, anti-nematode, anti-fungal, anti-estrogenic and anti-cancer, anti-oxidant, anti-inflammatory, insulin sensitivity enhancing, and attenuation of vascular contractions. Here we show that glyceollin I has hormesis and extends yeast life span at low (nM doses in a calorie restriction (CR-dependent manner, while it reduces life span and inhibits yeast cell proliferation at higher (μM doses. In contrast, the other two isomers (glyceollin II and III cannot extend yeast life span and only show life span reduction and antiproliferation at higher doses. Our results in anti-aging activity indicate that glyceollin I might be a promising calorie restriction mimetic candidate, and the high content of glyceollins could improve the bioactivity of soybean as functional food ingredients.

  7. Establishing cellular stress response profiles as biomarkers of homeodynamics, health, and hormesis

    DEFF Research Database (Denmark)

    Demirovic, Dino; Rattan, Suresh

    2013-01-01

    strategy, which makes use of SRP for achieving healthy aging and extending the healthspan, is that of strengthening the homeodynamics through repeated mild stress-induced hormesis by physical, biological and nutritional hormetins. Furthermore, SRP can also be the basis for defining health as a state...... of having adequate physical and mental independence of activities of daily living, by identifying a set of measurable parameters at the most fundamental level of biological organization.......Aging is the progressive shrinkage of the homeodynamic space. A crucial component of the homeodynamic space is the stress response (SR), by virtue of which a living system senses disturbance and initiates a series of events for maintenance, repair, adaptation, remodeling and survival. Here we...

  8. Follicular and endocrine dose responses according to anti-Müllerian hormone levels in IVF patients treated with a novel human recombinant FSH (FE 999049)

    DEFF Research Database (Denmark)

    Bosch, Ernesto; Nyboe Andersen, Anders; Barri, Pedro

    2015-01-01

    responses were observed for the number of follicles ≥ 12 mm, and serum levels of oestradiol, inhibin B, inhibin A and progesterone at end of stimulation. In comparison with the higher AMH stratum, patients in the lower AMH stratum had significantly different slopes of the dose-response curves...... for these hormones, and no clear dose-related increase was observed for the number of follicles in these patients. CONCLUSIONS: Dose-response relationships between rhFSH and follicular development and endocrine parameters are significantly different for IVF/ICSI patients with lower and higher serum AMH levels......: Follicular development and endocrine parameters during controlled ovarian stimulation (COS) with rhFSH. RESULTS: Serum FSH levels increased with increasing rhFSH doses and steady-state levels for each dose were similar in both AMH strata. In the whole study population, significant (P dose...

  9. The ecological stress theory of aging and hormesis: an energetic evolutionary model.

    Science.gov (United States)

    Parsons, Peter A

    2007-06-01

    Free-living organisms normally struggle to exist in harsh environments that are nutritionally and energetically inadequate, where evolutionary adaptation is challenged by internal stresses within organisms and external stresses from the environment. The incorporation of environmental variables into aging theories such as the free-radical and metabolic rate/oxidative stress theories, is the basis of the ecological stress theory of aging and hormesis. Environmental variation from optimum to lethal extremes gives a fitness-stress continuum, where energetic efficiency, or fitness, is inversely related to stress level; in the evolutionary context survival is a more direct measure of fitness for assessing aging than is lifespan. On this continuum, the hormetic zone is in the optimum region, while aging emphasizes survival towards lethal extremes. At the limits of survival, a convergence of physiological and genetical processes is expected under accumulating stress from Reactive Oxygen Species, ROS. Limited ecologically-oriented studies imply that major genes are important towards limits of survival compared with the hormetic zone. Future investigations could usefully explore outlier populations physiologically and genetically, since there is the likelihood that genetic variability may be lower in those cohorts managing to survive to extremely advanced ages as found in highly stressed ecological outlier populations. If so, an evolutionary explanation of the mortality-rate decline typical of cohorts of the extremely old emerges. In summary, an energetic evolutionary approach produces a general aging theory which automatically incorporates hormesis, since the theory is based on a fitness-stress continuum covering the whole range of possible abiotic environments of natural populations.

  10. Signaling and Damaging Functions of Free Radicals in Aging-Free Radical Theory, Hormesis, and TOR.

    Science.gov (United States)

    Afanas'ev, Igor

    2010-10-01

    Harman's Free Radical Theory of Aging has been considered as a major theory of aging for more than 50 years. In 1956 Dr. Harman proposed that the accumulation of free radicals with the age causes the damage of biomolecules by these reactive species and the development of pathological disorders resulting in cell senescence and organismal aging. His hypothesis was supported by numerous experimental studies demonstrated an increase in free radical levels in cells and living organisms with aging. In subsequent years important discoveries of new physiological free radicals superoxide and nitric oxide have been made that led to understanding of other important functions of free radicals. It has been shown that superoxide and nitric oxide together with their diamagnetic reaction products hydrogen peroxide and peroxynitrite (all are now named reactive oxygen and nitrogen species, ROS and RNS) function as signaling species in many physiological enzymatic/gene processes. Furthermore, the disturbance of ROS and RNS physiological signaling can be an origin of various pathologies and aging. These discoveries demanded to widen original free radical theory of aging and to consider the damaging ROS signaling as an important, maybe major route to cell senescence and organismal aging. However, some experimental findings such as the extension of lifespan by calorie restriction of yeast, flies, worms, and mice, and favorable effects of physical exercises stimulated criticism of free radical theory because the expansion of lifespan accompanied in some cases by increasing oxidative stress. On these grounds such theories as Hormesis and Target of rapamycin (mTOR) theories refute the role of ROS and oxidative stress in aging. Accordingly, a major purpose of this review to show that ROS signaling is probably the most important enzyme/gene pathway responsible for the development of cell senescence and organismal aging and that ROS signaling might be considered as further development of free

  11. Dose Response Effects of Lisdexamfetamine Dimesylate Treatment in Adults with ADHD: An Exploratory Study

    Science.gov (United States)

    Faraone, Stephen V.; Spencer, Thomas J.; Kollins, Scott H.; Glatt, Stephen J.; Goodman, David

    2012-01-01

    Objective: To explore dose-response effects of lisdexamfetamine dimesylate (LDX) treatment for ADHD. Method: This was a 4-week, randomized, double-blinded, placebo-controlled, parallel-group, forced-dose titration study in adult participants, aged 18 to 55 years, meeting "Diagnostic and Statistical Manual of Mental Disorders" (4th ed., text rev.)…

  12. Empirical Evaluation of Meta-Analytic Approaches for Nutrient and Health Outcome Dose-Response Data

    Science.gov (United States)

    Yu, Winifred W.; Schmid, Christopher H.; Lichtenstein, Alice H.; Lau, Joseph; Trikalinos, Thomas A.

    2013-01-01

    The objective of this study is to empirically compare alternative meta-analytic methods for combining dose-response data from epidemiological studies. We identified meta-analyses of epidemiological studies that analyzed the association between a single nutrient and a dichotomous outcome. For each topic, we performed meta-analyses of odds ratios…

  13. Dose response association of pregnancy cigarette smoke exposure, childhood stature, overweight and obesity

    NARCIS (Netherlands)

    G. Koshy; A. Delpisheh; B.J. Brabin

    2011-01-01

    The combined dose response effects of pregnancy cigarette smoke exposure on childhood overweight, obesity and short stature have not been reported. A community based cross-sectional survey of 3038 children aged 5-11 years from 15 primary schools in Merseyside, UK. Self-completed parental questionnai

  14. Dose-Response Curve of Chromosome Aberrations in Human Lymphocytes Induced by Gamma-Rays

    Directory of Open Access Journals (Sweden)

    Y. Lusiyanti

    2013-12-01

    Full Text Available Chromosome aberration is a biomarker to predict the level of cell damage caused by exposure to ionizing radiation on human body. Dicentric chromosome is a specific chromosome aberration caused by ionizing radiation and is used as a gold standard biodosimetry of individuals over exposed to ionizing radiation. In radiation accident the dicentric assays has been applied as biological dosimetry to estimate radiation absorbed dose and also to confirm the radiation dose received to radiation workers.The purpose of this study was to generate a dose response curve of chromosome aberration (dicentric in human lymphocyte induced by gamma radiation. Peripheral blood samples from three non smoking healthy volunteers aged between 25-48 years old with informed consent were irradiated with dose between 0.1-4.0 Gy and a control using gamma teletherapy source. The culture procedure was conducted following the IAEA standard procedures with slight modifications. Analysis of dose-response curves used was LQ model Y = a + αD + βD2. The result showed that α and β values of the curve obtained were 0.018 ± 0.006 and 0.013 ± 0.002, respectively. Dose response calibration curve for dicentric chromosome aberrations in human lymphocytes induced by gamma-radiation fitted to linear quadratic model. In order to apply the dose response curve of chromosome aberration disentric for biodosimetry, this standar curve still need to be validated.

  15. Dose-response characteristics of ketamine effect on locomotion, cognitive function and central neuronal activity

    NARCIS (Netherlands)

    Imre, G; Fokkema, DS; Den Boer, JA; Ter Horst, GJ

    2006-01-01

    The present dose-response study sought to determine the effects of subanesthetic dosages (4-16 mg/kg) of ketamine on locomotion, sensorimotor gating (PP1), working memory, as well as c-fos expression in various limbic regions implicated in the pathogenesis of schizophrenia. In addition, we examined

  16. Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

    Science.gov (United States)

    Froehlich, Tanya E.; Epstein, Jeffery N.; Nick, Todd G.; Melguizo Castro, Maria S.; Stein, Mark A.; Brinkman, William B.; Graham, Amanda J.; Langberg, Joshua M.; Kahn, Robert S.

    2011-01-01

    Objective: Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response. Method:…

  17. Dose response of a new phytse on dry matter, calcium, and phosphorus digestibility in weaned piglets

    NARCIS (Netherlands)

    Bento, M.H.L.; Pedersen, C.; Plumstead, P.W.; Salmon, L.; Nyachoti, C.M.; Bikker, P.

    2012-01-01

    The present study evaluated the dose response of Buttiauxella phytase on apparent total tract digestibility (ATTD) of DM, Ca, and P in weaned pigs at 2 locations. Experimental diets fed to weaned pigs were a positive control (PC), a negative control (NC), and NC supplemented with increasing levels o

  18. Guidelines for Use of the Approximate Beta-Poisson Dose-Response Model.

    Science.gov (United States)

    Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

    2016-10-05

    For dose-response analysis in quantitative microbial risk assessment (QMRA), the exact beta-Poisson model is a two-parameter mechanistic dose-response model with parameters α>0 and β>0, which involves the Kummer confluent hypergeometric function. Evaluation of a hypergeometric function is a computational challenge. Denoting PI(d) as the probability of infection at a given mean dose d, the widely used dose-response model PI(d)=1-(1+dβ)-α is an approximate formula for the exact beta-Poisson model. Notwithstanding the required conditions α1, issues related to the validity and approximation accuracy of this approximate formula have remained largely ignored in practice, partly because these conditions are too general to provide clear guidance. Consequently, this study proposes a probability measure Pr(0 (22α̂)0.50 for 0.020.99) . This validity measure and rule of thumb were validated by application to all the completed beta-Poisson models (related to 85 data sets) from the QMRA community portal (QMRA Wiki). The results showed that the higher the probability Pr(0 dose-response curve.

  19. Eosinophils in the bronchial mucosa in relation to methacholine dose-response curves in atopic asthma

    NARCIS (Netherlands)

    G.M. Moller (Trude); S.E. Overbeek (Shelley); C.G. van Helden-Meeuwsen; H.C. Hoogsteden (Henk); J.M. Bogaard (Jan)

    1999-01-01

    textabstractAsthma is characterized by both local infiltration of eosinophils in the bronchial mucosa and bronchial hyperreactivity (BHR). A detailed characterization of BHR implies analysis of a histamine or methacholine dose-response curve yielding not only the dose a

  20. Modeling and regression analysis of semiochemical dose-response curves of insect antennal reception and behavior

    Science.gov (United States)

    Dose-response curves with semiochemicals are reported in many articles in insect chemical ecology regarding neurophysiology and behavioral bioassays. Most such curves are shown in figures where the x-axis has order of magnitude increases in dosages versus responses on the y-axis represented by point...

  1. Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

    Science.gov (United States)

    Froehlich, Tanya E.; Epstein, Jeffery N.; Nick, Todd G.; Melguizo Castro, Maria S.; Stein, Mark A.; Brinkman, William B.; Graham, Amanda J.; Langberg, Joshua M.; Kahn, Robert S.

    2011-01-01

    Objective: Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response. Method:…

  2. Estimating the predictive quality of dose-response after model selection.

    Science.gov (United States)

    Hu, Chuanpu; Dong, Yingwen

    2007-07-20

    Prediction of dose-response is important in dose selection in drug development. As the true dose-response shape is generally unknown, model selection is frequently used, and predictions based on the final selected model. Correctly assessing the quality of the predictions requires accounting for the uncertainties caused by the model selection process, which has been difficult. Recently, a new approach called data perturbation has emerged. It allows important predictive characteristics be computed while taking model selection into consideration. We study, through simulation, the performance of data perturbation in estimating standard error of parameter estimates and prediction errors. Data perturbation was found to give excellent prediction error estimates, although at times large Monte Carlo sizes were needed to obtain good standard error estimates. Overall, it is a useful tool to characterize uncertainties in dose-response predictions, with the potential of allowing more accurate dose selection in drug development. We also look at the influence of model selection on estimation bias. This leads to insights into candidate model choices that enable good dose-response prediction.

  3. Effects of measurement strategy and statistical analysis on dose-response relations between physical workload and low back pain

    OpenAIRE

    Jansen, Justin; Burdorf, Alex

    2003-01-01

    textabstractBACKGROUND: In epidemiological studies on physical workloads and back complaints, among the important features in modelling dose-response relations are the measurement strategy of the exposure and the nature of the dose-response relation that is assumed. AIM: To evaluate the effect of these two features on the strength of the dose-response relation between physical load and severe low back pain. METHODS: The study population consisted of 769 workers in nursing homes and homes for ...

  4. Dose-Response of High-Intensity Training (HIT on Atheroprotective miRNA-126 Levels

    Directory of Open Access Journals (Sweden)

    Boris Schmitz

    2017-05-01

    Full Text Available Aim: MicroRNA-126 (miR-126 exerts beneficial effects on vascular integrity, angiogenesis, and atherosclerotic plaque stability. The purpose of this investigation was to analyze the dose-response relationship of high-intensity interval training (HIIT on miR-126-3p and -5p levels.Methods: Sixty-one moderately trained individuals (females = 31 [50.8%]; 22.0 ± 1.84 years were consecutively recruited and allocated into three matched groups using exercise capacity. During a 4-week intervention a HIIT group performed three exercise sessions/week of 4 × 30 s at maximum speed (all-out, a progressive HIIT (proHIIT group performed three exercise sessions/week of 4 × 30 s at maximum speed (all-out with one extra session every week (up to 7 × 30 s and a low-intensity training (LIT control group performed three exercise sessions/week for 25 min <75% of maximum heart rate. Exercise miR-126-3p/-5p plasma levels were determined using capillary blood from earlobes.Results: No exercise-induced increase in miR-126 levels was detected at baseline, neither in the LIT (after 25 min low-intensity running nor the HIIT groups (after 4 min of high-intensity running. After the intervention, the LIT group presented an increase in miR-126-3p, while in the HIIT group, miR-126-3p levels were still reduced (all p < 0.05. An increase for both, miR-126-3p and -5p levels (all p < 0.05, pre- vs. during and post-exercise was detected in the proHIIT group. Between group analysis revealed that miR-126-3p levels after LIT and proHIIT increased by 2.12 ± 2.55 and 1.24 ± 2.46 units (all p < 0.01, respectively, compared to HIIT (−1.05 ± 2.6 units.Conclusions: LIT and proHIIT may be performed to increase individual miR-126 levels. HIIT without progression was less effective in increasing miR-126.

  5. Dose-response of serum 25-hydroxyvitamin D in association with risk of colorectal cancer: A meta-analysis.

    Science.gov (United States)

    Garland, Cedric F; Gorham, Edward D

    2017-04-01

    Fifteen nested case-control or cohort studies in 14 countries have examined the association between serum 25-hydroxyvitamin D [25(OH)D] and risk of colorectal cancer. A meta-analysis of these studies would provide a useful dose-response gradient curve based on pooling of the results of known studies to date. An up-to-date dose-response curve that combines the findings of these studies has not been reported, to our knowledge. This curve would help in designing interventions for future studies. A new meta-analysis would be more precise than any previous analysis due to its larger sample size. Therefore a search of PubMed and other resources was performed in May 2016 for all cohort or nested case-control observational studies that reported risk of colon or colorectal cancer by quantiles of 25(OH)D. All but two of the 15 studies found a trend toward lower risk of colorectal cancer associated with higher serum 25(OH)D. There was a linear reduction in the odds ratio (OR) with each 10ng/ml-increment in 25(OH)D concentration. The lowest quantile of the serum 25(OH)D concentration was generallyD concentrations was statistically significant in 3 studies. The pooled OR from all studies comparing highest with lowest quantile of 25(OH)D was 0.67 (95% confidence interval [CI], 0.59-0.76), meaning there was a 33% lower risk associated with the highest compared with the lowest quantile of serum 25(OH)D. A dose-response analysis revealed that a serum 25(OH)D of 50ng/ml was associated with an OR of 0.4 (95% CI, 0.2-1.0) compared with a concentration of 5ng/ml. The formula for the linear relationship was OR=0.008x. For example, individuals with a 25(OH)D concentration of 50ng/ml had an approximately 60% lower risk of colorectal cancer than those with a concentration of 5ng/ml. Those with a 25(OH)D concentration of 30ng/ml had a 33% lower risk than those with a concentration of 5ng/ml. The inverse association between serum 25(OH)D and risk of colorectal cancer overall was strong and

  6. Association between physical activity and all cancer mortality: Dose-response meta-analysis of cohort studies.

    Science.gov (United States)

    Li, Yingjun; Gu, Mengjia; Jing, Fangyuan; Cai, Shaofang; Bao, Chengzhen; Wang, Jianbing; Jin, Mingjuan; Chen, Kun

    2016-02-15

    The relationship between physical activity (PA) before cancer diagnosis and all cancer mortality among the general population is not well defined because of inconsistent results from published studies. Thus, the lack of a meta-analysis that addresses that issue prompted the current report. We conducted a literature search of PubMed and Web of Science to identify all relevant epidemiological studies published before February 28, 2015. We performed categorical and dose-response meta-analyses to evaluate and quantify the association between pre-diagnosis PA and all cancer mortality. A total of 32 prospective cohort studies involving 59,362 cancer deaths were included in this meta-analysis. The pooled relative risks (RRs) of all cancer mortality were 0.80 [95% confidence interval (CI) = 0.76-0.85)] for highest versus lowest PA group and 0.85 (95% CI = 0.82-0.88) for PA versus non/occasional PA group. Dose-response analysis showed that the increment in pre-diagnosis PA level was associated with a decreased risk of cancer death continuously. Moreover, an increment of 10 MET-h/week was related to a 7% lower risk for all cancer mortality (RR = 0.93, 95% CI = 0.91-0.95). In conclusion, the present meta-analysis provides evidence of an inverse association between pre-diagnosis PA and all cancer mortality among the general population. High-quality epidemiological studies that employ standardized PA assessments and unified definitions of PA levels should be developed in future.

  7. Molecular mechanisms of low dose ionizing radiation-induced hormesis, adaptive responses, radioresistance, bystander effects, and genomic instability.

    Science.gov (United States)

    Tang, Feng Ru; Loke, Weng Keong

    2015-01-01

    To review research progress on the molecular mechanisms of low dose ionizing radiation (LDIR)-induced hormesis, adaptive responses, radioresistance, bystander effects, and genomic instability in order to provide clues for therapeutic approaches to enhance biopositive effects (defined as radiation-induced beneficial effects to the organism), and control bionegative effects (defined as radiation-induced harmful effects to the organism) and related human diseases. Experimental studies have indicated that Ataxia telangiectasia-mutated (ATM), extracellular signal-related kinase (ERK), mitogen-activated protein kinase (MAPK), phospho-c-Jun NH(2)-terminal kinase (JNK) and protein 53 (P53)-related signal transduction pathways may be involved in LDIR-induced hormesis; MAPK, P53 may be important for adaptive response; ATM, cyclooxygenase-2 (COX-2), ERK, JNK, reactive oxygen species (ROS), P53 for radioresistance; COX-2, ERK, MAPK, ROS, tumor necrosis factor receptor alpha (TNFα) for LDIR-induced bystander effect; whereas ATM, ERK, MAPK, P53, ROS, TNFα-related signal transduction pathways are involved in LDIR-induced genomic instability. These results suggest that different manifestations of LDIR-induced cellular responses may have different signal transduction pathways. On the other hand, LDIR-induced different responses may also share the same signal transduction pathways. For instance, P53 has been involved in LDIR-induced hormesis, adaptive response, radioresistance and genomic instability. Current data therefore suggest that caution should be taken when designing therapeutic approaches using LDIR to induce beneficial effects in humans.

  8. Dose-response curve to salbutamol during acute and chronic treatment with formoterol in COPD

    Directory of Open Access Journals (Sweden)

    La Piana GE

    2011-07-01

    Full Text Available Giuseppe Emanuele La Piana¹, Luciano Corda², Enrica Bertella¹, Luigi Taranto Montemurro¹, Laura Pini¹, Claudio Tantucci¹¹Cattedra di Malattie dell'Apparato Respiratorio, Università di Brescia, ²Prima Divisione di Medicina Interna, Spedali Civili, Brescia, ItalyBackground: Use of short-acting ß2-agonists in chronic obstructive pulmonary disease (COPD during treatment with long-acting ß2-agonists is recommended as needed, but its effectiveness is unclear. The purpose of this study was to assess the additional bronchodilating effect of increasing doses of salbutamol during acute and chronic treatment with formoterol in patients with COPD.Methods: Ten patients with COPD underwent a dose-response curve to salbutamol (until 800 µg of cumulative dose after a 1-week washout (baseline, 8 hours after the first administration of formoterol 12 µg (day 1, and after a 12-week and 24-week period of treatment with formoterol (12 µg twice daily by dry powder inhaler. Peak expiratory flow, forced expiratory volume in one second (FEV1, forced vital capacity, and inspiratory capacity were measured at the different periods of treatment and at different steps of the dose-response curve.Results: Despite acute or chronic administration of formoterol, maximal values of peak expiratory flow, FEV1, and forced vital capacity after 800 µg of salbutamol were unchanged compared with baseline. The baseline FEV1 dose-response curve was steeper than that at day 1, week 12, or week 24 (P < 0.0001. Within each dose-response curve, FEV1 was different only at baseline and at day 1 (P < 0.001, when FEV1 was still greater at 800 µg than at 0 µg (P < 0.02. In contrast, the forced vital capacity dose-response curves were similar at the different periods, while within each dose-response curve, forced vital capacity was different in all instances (P < 0.001, always being higher at 800 µg than at 0 µg (P < 0.05.Conclusion: In patients with stable COPD, the maximal effect

  9. Red and processed meat consumption and the risk of lung cancer: a dose-response meta-analysis of 33 published studies.

    Science.gov (United States)

    Xue, Xiu-Juan; Gao, Qing; Qiao, Jian-Hong; Zhang, Jie; Xu, Cui-Ping; Liu, Ju

    2014-01-01

    This meta-analysis was to summarize the published studies about the association between red/processed meat consumption and the risk of lung cancer. 5 databases were systematically reviewed, and random-effect model was used to pool the study results and to assess dose-response relationships. Results shown that six cohort studies and twenty eight case-control studies were included in this meat-analysis. The pooled Risk Radios (RR) for total red meat and processed meat were 1.44 (95% CI, 1.29-1.61) and 1.23 (95% CI, 1.10-1.37), respectively. Dose-response analysis revealed that for every increment of 120 grams red meat per day the risk of lung cancer increases 35% and for every increment of 50 grams red meat per day the risk of lung cancer increases 20%. The present dose-response meta-analysis suggested that both red and processed meat consumption showed a positive effect on lung cancer risk.

  10. Construction of a cytogenetic dose-response curve for low-dose range gamma-irradiation in human peripheral blood lymphocytes using three-color FISH.

    Science.gov (United States)

    Suto, Yumiko; Akiyama, Miho; Noda, Takashi; Hirai, Momoki

    2015-12-01

    In order to estimate biological doses after low-dose ionizing radiation exposure, fluorescence in situ hybridization (FISH) using three differentially colored chromosome painting probes was employed to detect exchange-type chromosome aberrations. A reference dose response curve was constructed using blood samples from a female donor whose lymphocytes consistently exhibited a low frequency of cells at the second mitosis under routine culture conditions. Aberration yields were studied for a total of about 155 thousand metaphases obtained from seven dose-points of gamma irradiations (0, 50, 100, 150, 200, 250 and 300mGy). In situ hybridization was performed using commercially available painting probes for chromosomes 1, 2 and 4. With the aid of an automated image-capturing method, exchange-type aberrations involving painted chromosomes were detected with considerable accuracy and speed. The results on the exchange-type aberrations (dicentrics plus translocations) at the seven dose-points showed a good fit to the linear-quadratic model (y=0.0023+0.0015x+0.0819x(2), P=0.83). A blind test proved the reproducibility of the reference dose-response relationship. In the control experiments using blood samples from another donor, the estimated doses calculated on the basis of the present reference curve were proved to be in good agreement with the actual physical doses applied. The present dose-response curve may serve as a means to assess the individual differences in cytogenetical radio-sensitivities.

  11. Does beer, wine or liquor consumption correlate with the risk of renal cell carcinoma? A dose-response meta-analysis of prospective cohort studies

    Science.gov (United States)

    Xu, Xin; Zhu, Yi; Zheng, Xiangyi; Xie, Liping

    2015-01-01

    Despite plenty of evidence supports an inverse association between alcohol drinking and risk of renal cell carcinoma (RCC), sex-specific and beverage-specific dose-response relationships have not been well established. We examined this association by performing a systematic review and meta-analysis of prospective studies. Studies were identified by comprehensively searching PubMed and EMBASE databases through February 21, 2015. Categorical and dose-response meta-analyses were conducted to identify the effects of alcohol on RCC. A total of eight publications (including seven cohort studies and one pooled analysis of 12 cohort studies) were eligible for this meta-analysis. Dose-response analysis showed that each 5 g/day increment of alcohol intake corresponded to a 5% decrease in risk of RCC for males and 9% for females. Alcohol intakes from wine, beer, and liquor were each associated with a reduced risk of RCC. When these associations were examined separately by gender, statistically significant inverse associations were restricted to alcohol from wine among females (RR = 0.82, 95% CI 0.73–0.91) and to alcohol from beer and from liquor among males (RR = 0.87, 95% CI 0.83–0.91 and RR = 0.95, 95% CI 0.92–0.99, respectively). In conclusion, there exist gender-specific and beverage-specific differences in the association between alcohol intake and RCC risk. PMID:25965820

  12. Aspartame tablets-gamma dose response and usability for routine radiation processing dosimetry using spectrophotometry

    Energy Technology Data Exchange (ETDEWEB)

    Shinde, S.H. [Radiation Safety Systems Division, Bhabha Atomic Research Centre, Mumbai 400 085 (India)]. E-mail: shs_barc@yahoo.com; Mukherjee, T. [Radiation Safety Systems Division, Chemistry Group, Bhabha Atomic Research Centre, Mumbai 400 085 (India)

    2007-02-15

    Aspartame tablets were studied for gamma dose response, using spectrophotometric read-out method. The optimum concentration for ferrous ions was 2x10{sup -4}moldm{sup -3} and xylenol orange with 2.5x10{sup -1}moldm{sup -3} of sulphuric acid for the optimum acidity in FX solution. Wavelength of maximum absorbance is 548nm. Post-irradiation stability is appreciable i.e. for not less than one month. Dose response is non-linear with third order polynomial fit, in the dose range of 1000-10000Gy. This system of aspartame was further used for carrying out relative percentage dose profile measurement in Gamma Cell-220. Results obtained were inter-compared with that of a glutamine dosimeter, which showed that maximum difference between the values of aspartame and glutamine systems is within +/-10%.

  13. Mixed-effects Gaussian process functional regression models with application to dose-response curve prediction.

    Science.gov (United States)

    Shi, J Q; Wang, B; Will, E J; West, R M

    2012-11-20

    We propose a new semiparametric model for functional regression analysis, combining a parametric mixed-effects model with a nonparametric Gaussian process regression model, namely a mixed-effects Gaussian process functional regression model. The parametric component can provide explanatory information between the response and the covariates, whereas the nonparametric component can add nonlinearity. We can model the mean and covariance structures simultaneously, combining the information borrowed from other subjects with the information collected from each individual subject. We apply the model to dose-response curves that describe changes in the responses of subjects for differing levels of the dose of a drug or agent and have a wide application in many areas. We illustrate the method for the management of renal anaemia. An individual dose-response curve is improved when more information is included by this mechanism from the subject/patient over time, enabling a patient-specific treatment regime.

  14. Dose Effects of Ion Beam Exposure on Deinococcus Radiodurans: Survival and Dose Response

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    To explore the survival and dose response of organism for different radiation sources is of great importance in the research of radiobiology. In this study, the survival-dose response of Deinococcus radiodurans (E.coli, as the control) for ultra-violet (UV), γ-rays radiation and ion beam exposure was investigated. The shoulder type of survival curves were found for both UV and γ-ray ionizing radiation, but the saddle type of survival curves were shown for H+ 、 N+( 20keV and 30keV) and Ar+ beam exposure. This dose effect of the survival initially decreased withthe increase in dose and then increased in the high dose range and finally decreased again in thehigher dose range. Our experimental results suggest that D. radiodurans, which is considerablyradio-resistant to UV and x-ray and γ-ray ionizing radiation, do not resist ion beam exposure.

  15. Effects of measurement strategy and statistical analysis on dose-response relations between physical workload and low back pain

    NARCIS (Netherlands)

    J.J.P. Jansen (Justin); A. Burdorf (Alex)

    2003-01-01

    textabstractBACKGROUND: In epidemiological studies on physical workloads and back complaints, among the important features in modelling dose-response relations are the measurement strategy of the exposure and the nature of the dose-response relation that is assumed. AIM: To evaluat

  16. A new method for synthesizing radiation dose-response data from multiple trials applied to prostate cancer

    DEFF Research Database (Denmark)

    Diez, Patricia; Vogelius, Ivan S; Bentzen, Søren M

    2010-01-01

    A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high).......A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high)....

  17. DOSE RESPONSE CURVE OF 60Co FOR PREMATURE CONDENSED CHROMOSOME FRAGMENTS OF HUMAN LYMPHOCYTES

    Institute of Scientific and Technical Information of China (English)

    高锦声; 郑斯英; 等

    1995-01-01

    The dose-response curves obtained by premature condensed chromosome(PCC) and conventional cellular genetic methods can be represented by two linear equations.The ratio of the slopes,KPCC/KM1,is about 28,In compartison to the conventional method.The PCC method has many advantages;e.g.it is faster,simopler,more sensitive and accurate.Its significance in the study of radiation damage is also discussed.

  18. Analysis of Dose Response for Circulatory Disease After Radiotherapy for Benign Disease

    Energy Technology Data Exchange (ETDEWEB)

    Little, Mark P., E-mail: mark.little@nih.gov [Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza South, Rockville, Maryland (United States); Kleinerman, Ruth A. [Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza South, Rockville, Maryland (United States); Stovall, Marilyn; Smith, Susan A. [Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mabuchi, Kiyohiko [Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza South, Rockville, Maryland (United States)

    2012-12-01

    Purpose: To assess the shape of the dose-response for various circulatory disease endpoints, and modifiers by age and time since exposure. Methods and Materials: This was an analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease). Results: There were significant excess risks for all circulatory disease, with an excess relative risk Gy{sup -1} of 0.082 (95% CI 0.031-0.140), and ischemic heart disease, with an excess relative risk Gy{sup -1} of 0.102 (95% CI 0.039-0.174) (both p = 0.01), and indications of excess risk for stroke. There were no statistically significant (p > 0.2) differences between risks by endpoint, and few indications of curvature in the dose-response. There were significant (p < 0.001) modifications of relative risk by time since exposure, the magnitude of which did not vary between endpoints (p > 0.2). Risk modifications were similar if analysis was restricted to patients receiving radiation, although the relative risks were slightly larger and the risk of stroke failed to be significant. The slopes of the dose-response were generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups. Conclusions: There were excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically treated groups at much higher dose, as well as in lower dose-exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers, implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.

  19. Diethylene glycol-induced toxicities show marked threshold dose response in rats

    Energy Technology Data Exchange (ETDEWEB)

    Landry, Greg M., E-mail: Landry.Greg@mayo.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Dunning, Cody L., E-mail: cdunni@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu [Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Latimer, Brian, E-mail: blatim@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Orchard, Elysse, E-mail: eorcha@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Division of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA (United States); McMartin, Kenneth E., E-mail: kmcmar@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States)

    2015-02-01

    Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

  20. Dose response of hydrazine - Deproteinated tooth enamel under blue light stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Yuece, Ulkue Rabia, E-mail: ulkuyuce@hotmail.co [Ankara University, Faculty of Engineering, Department of Engineering Physics, 06100, Tandogan - Ankara (Turkey); Meric, Niyazi, E-mail: meric@ankara.edu.t [Ankara University, Faculty of Engineering, Department of Engineering Physics, 06100, Tandogan - Ankara (Turkey); Atakol, Orhan, E-mail: atakol@science.ankara.edu.t [Ankara University, Science Faculty, Department of Chemistry, 06100, Tandogan - Ankara (Turkey); Yasar, Fusun, E-mail: ab121310@adalet.gov.t [Council of Forensic Medicine, Ankara Branch, Ankara (Turkey)

    2010-08-15

    The beta dose response and Optically Stimulated Luminescence (OSL) signal stability characteristics of human tooth enamel deproteinated by hydrazine reagent under blue photon stimulation are reported. Removal of the protein organic component of tooth enamel resulted in a higher OSL sensitivity and slower fading of OSL signals. The effect of chemical sample preparation on the enamel sample sensitivity is discussed and further steps to make this deproteinization treatment suitable for in vitro dose reconstruction studies are suggested.

  1. Testing the Capacity of the National Biological Dose Response Plan (NBDRP) EX40801

    Science.gov (United States)

    2009-11-01

    providing radiation biological dose estimates using the dicentric chromosome assay (DCA). As indicated in the CRTI-06-0146RD charter, the existing...laboratories of the National Biological Dose Response Plan plus two US laboratories. Samples were scored for the dicentric chromosome assay and the CBMN...Wilkins, R.C. QuickScan dicentric chromosome analysis for radiation biodosimetry , Health Physics Journal, In Press (2009). 2. McNamee, J.P., Flegal

  2. Bayesian fitting of a logistic dose-response curve with numerically derived priors.

    Science.gov (United States)

    Huson, L W; Kinnersley, N

    2009-01-01

    In this report we describe the Bayesian analysis of a logistic dose-response curve in a Phase I study, and we present two simple and intuitive numerical approaches to construction of prior probability distributions for the model parameters. We combine these priors with the expert prior opinion and compare the results of the analyses with those obtained from the use of alternative prior formulations.

  3. Childhood adversity specificity and dose-response effect in non-affective first-episode psychosis

    DEFF Research Database (Denmark)

    Trauelsen, Anne Marie; Bendall, Sarah; Jansen, Jens Einar

    2015-01-01

    BACKGROUND: Reviews conclude that childhood and adolescence sexual, physical, emotional abuse and emotional and physical neglect are all risk factors for psychosis. However, studies suggest only some adversities are associated with psychosis. Dose-response effects of several adversities on risk......% of the control group. Childhood and adolescent sexual, physical, emotional abuse, and physical and emotional neglect, separation and institutionalization were about four to 17 times higher for the FEP group (all p

  4. Mathematical Modeling of Allelopathy. III. A Model for Curve-Fitting Allelochemical Dose Responses

    OpenAIRE

    Liu, Li; An, Min; Johnson, Ian R.; Lovett, John V.

    2003-01-01

    Bioassay techniques are often used to study the effects of allelochemicals on plant processes, and it is generally observed that the processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. A simple empirical model is presented to analyze this type of response. The stimulation-inhibition properties of allelochemical-dose responses can be described by the parameters in the model. The indices, p% reductions, are calculated to assess the alleloc...

  5. Development of Dose-Response Models of Creutzfeldt-Jakob Disease Infection in Nonhuman Primates for Assessing the Risk of Transfusion-Transmitted Variant Creutzfeldt-Jakob Disease

    Science.gov (United States)

    Gregori, Luisa; Anderson, Steven A.; Asher, David M.

    2014-01-01

    ABSTRACT Estimates for the risk of transmitting variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion have relied largely on data from rodent experiments, but the relationship between dose (amount of infected blood) and response (vCJD infection) has never been well quantified. The goal of this study was to develop a dose-response model based on nonhuman primate data to better estimate the likelihood of transfusion-transmitted vCJD (TTvCJD) in humans. Our model used dose-response data from nonhuman primates inoculated intracerebrally (i.c.) with brain tissues of patients with sporadic and familial CJD. We analyzed the data statistically by using a beta-Poisson dose-response model. We further adjusted model parameters to account for the differences in infectivity between blood and brain tissue and in transmission efficiency between intravenous (i.v.) and i.c. routes to estimate dose-dependent TTvCJD infection. The model estimates a mean infection rate of 76% among recipients who receive one unit of whole blood collected from an infected donor near the end of the incubation period. The nonhuman primate model provides estimates that are more consistent with those derived from a risk analysis of transfused nonleukoreduced red blood cells in the United Kingdom than prior estimates based on rodent models. IMPORTANCE TTvCJD was recently identified as one of three emerging infectious diseases posing the greatest immediate threat to the safety of the blood supply. Cases of TTvCJD were reported in recipients of nonleukoreduced red blood cells and coagulation factor VIII manufactured from blood of United Kingdom donors. As the quantity of abnormal prions (the causative agent of TTvCJD) varies significantly in different blood components and products, it is necessary to quantify the dose-response relationship for a wide range of doses for the vCJD agent in transfused blood and plasma derivatives. In this paper, we suggest the first mechanistic dose-response model for

  6. Dose-response investigation into glucose facilitation of memory performance and mood in healthy young adults.

    Science.gov (United States)

    Sünram-Lea, Sandra I; Owen, Lauren; Finnegan, Yvonne; Hu, Henglong

    2011-08-01

    It has been suggested that the memory enhancing effect of glucose follows an inverted U-shaped curve, with 25 g resulting in optimal facilitation in healthy young adults. The aim of this study was to further investigate the dose dependency of the glucose facilitation effect in this population across different memory domains and to assess moderation by interindividual differences in glucose regulation and weight. Following a double-blind, repeated measures design, 30 participants were administered drinks containing five different doses of glucose (0 g, 15 g, 25 g, 50 g, and 60 g) and were tested across a range of memory tasks. Glycaemic response and changes in mood state were assessed following drink administration. Analysis of the data showed that glucose administration did not affect mood, but significant glucose facilitation of several memory tasks was observed. However, dose-response curves differed depending on the memory task with only performance on the long-term memory tasks adhering largely to the previously observed inverted U-shaped dose-response curve. Moderation of the response profiles by interindividual differences in glucose regulation and weight was observed. The current data suggest that dose-response function and optimal dose might depend on cognitive domain and are moderated by interindividual differences in glucose regulation and weight.

  7. Arsenite Effects on Mitochondrial Bioenergetics in Human and Mouse Primary Hepatocytes Follow a Nonlinear Dose Response

    Directory of Open Access Journals (Sweden)

    Hemantkumar Chavan

    2017-01-01

    Full Text Available Arsenite is a known carcinogen and its exposure has been implicated in a variety of noncarcinogenic health concerns. Increased oxidative stress is thought to be the primary cause of arsenite toxicity and the toxic effect is thought to be linear with detrimental effects reported at all concentrations of arsenite. But the paradigm of linear dose response in arsenite toxicity is shifting. In the present study we demonstrate that arsenite effects on mitochondrial respiration in primary hepatocytes follow a nonlinear dose response. In vitro exposure of primary hepatocytes to an environmentally relevant, moderate level of arsenite results in increased oxidant production that appears to arise from changes in the expression and activity of respiratory Complex I of the mitochondrial proton circuit. In primary hepatocytes the excess oxidant production appears to elicit adaptive responses that promote resistance to oxidative stress and a propensity to increased proliferation. Taken together, these results suggest a nonlinear dose-response characteristic of arsenite with low-dose arsenite promoting adaptive responses in a process known as mitohormesis, with transient increase in ROS levels acting as transducers of arsenite-induced mitohormesis.

  8. Quality control procedures for dose-response curve generation using nanoliter dispense technologies.

    Science.gov (United States)

    Quintero, Catherine; Rosenstein, Craig; Hughes, Bethany; Middleton, Richard; Kariv, Ilona

    2007-09-01

    With the advancement of high-throughput biomolecular screening techniques to the lead optimization stage, there is a critical need to quality control (QC) dose-response curves generated by robotic liquid handlers to ensure accurate affinity determinations. One challenge in evaluating the performance of liquid handlers is identifying and validating a robust method for testing dispense volumes across different instruments. Although traditional automated liquid handlers are still considered the standard platform in many laboratories, nanoliter dispensers are becoming more common and pose new challenges for routine quality control procedures. For example, standard gravimetric measurements are unreliable for testing the accuracy of nanoliter liquid dispenses. However, nanoliter dispensing technology allows for the conservation of compound, reduces compound carryover from well to well through discrete dispenses, and eliminates the need for intermediate compound dilution steps to achieve a low final DMSO assay concentration. Moreover, an intermediate dilution step in aqueous solution might result in compound precipitation at high concentrations. This study compared representative automation procedures done on a variety of liquid dispensers, including manual, traditional, and nanodispense volumes. The data confirmed the importance of establishing robust QC procedures for dose-response generation in addition to accuracy and precision determinations for each instrument, and they validated the use of nanoliter pipettors for dose-response testing. The results of this study also support the requirement for thorough mixing during serial compound dilutions prepared for high-throughput lead optimization strategies using traditional liquid handlers.

  9. Dose responses for Colletotrichum lindemuthianum elicitor-mediated enzyme induction in French bean cell suspension cultures.

    Science.gov (United States)

    Dixon, R A; Dey, P M; Murphy, D L; Whitehead, I M

    1981-03-01

    The induction of L-phenylalanine ammonialyase (PAL, EC 4.3.1.5) and flavanone synthase in French bean cell suspension cultures in response to heat-released elicitor from cell walls of the phytopathogenic fungus Colletotrichum lindemuthianum is highly dependent upon elicitor concentration. The elicitor dose-response curve for PAL induction shows two maxima at around 17.5 and 50 μg elicitor carbohydrate per ml culture, whereas the flavanone synthase response shows one maximum at around 100 μg ml(-1). The PAL response is independent of the elicitor concentration present during the lag phase of enzyme induction; if the initial elicitor concentration is increased after 2 h by addition of extra elicitor, or decreased by dilution of the cultures, the dose response curves obtained reflect the concentration of elicitor present at the time of harvest. PAL induction is not prevented by addition of methyl sugar derivatives to the cultures; α-methyl-D-glucoside, itself a weak elicitor of PAL activity, elicits a multiphasic PAL response when increasing concentrations are added in the presence of Colletotrichum elicitor. Eight fractions with different monosaccharide compositions, obtained from the crude elicitor by gel-filtration, each elicit different dose-responses for PAL induction; the response to unfractionated elicitor is not the sum of the response to the isolated fractions. There is no correlation between the ability of the fractions to induce PAL in the cultures and their ability to act as elicitors of isoflavonoid phytoalexin accumulation in bean hypocotyls.

  10. Photon hormesis deactivates alpha-particle induced bystander effects between zebrafish embryos

    Science.gov (United States)

    Ng, C. Y. P.; Cheng, S. H.; Yu, K. N.

    2017-04-01

    In the present work, we studied the effects of low-dose X-ray photons on the alpha-particle induced bystander effects between embryos of the zebrafish, Danio rerio. The effects on the naive whole embryos were studied through quantification of apoptotic signals (amounts of cells undergoing apoptosis) at 24 h post fertilization (hpf) using vital dye acridine orange staining, followed by counting the stained cells under a fluorescent microscope. We report data showing that embryos at 5 hpf subjected to a 4.4 mGy alpha-particle irradiation could release a stress signal into the medium, which could induce bystander effect in partnered naive embryos sharing the same medium. We also report that the bystander effect was deactivated when the irradiated embryos were subjected to a concomitant irradiation of 10 or 14 mGy of X-rays, but no such deactivation was achieved if the concomitant X-ray dose dropped to 2.5 or 5 mGy. In the present study, the significant drop in the amount of apoptotic signals on the embryos having received 4.4 mGy alpha particles together X-rays irradiation from 2.5 or 5 mGy to 10 or 14 mGy, together with the deactivation of RIBE with concomitant irradiation of 10 or 14 mGy of X-rays supported the participation of photon hormesis with an onset dose between 5 and 10 mGy, which might lead to removal of aberrant cells through early apoptosis or induction of high-fidelity DNA repair. As we found that photons and alpha particles could have opposite biological effects when these were simultaneously irradiated onto living organisms, these ionizing radiations could be viewed as two different environmental stressors, and the resultant effects could be regarded as multiple stressor effects. The present work presented the first study on a multiple stressor effect which occurred on bystander organisms. In other words, this was a non-targeted multiple stressor effect. The photon hormesis could also explain some failed attempts to observe neutron-induced bystander

  11. Hormesis and its application in medicinal plant growing%Hormesis及其在药用植物生产中的应用

    Institute of Scientific and Technical Information of China (English)

    郭兰萍; 张小波; 杨光; 黄璐琦; 马炯

    2011-01-01

    Hormesis describes the low-dose stimulation and high-dose inhibition phenomena for all kind lives under toxicity environment.This paper generalized hormesis of medicinal plant on grow and metabolite after introducing the concept and study state of hormesis and analyzing hormesis mechanism and its significance.It points out that hormesis can be well used for medicinal plants growth, including increasing the metabolise, giving a dereaction for cultivated field chosen, guiding the agriculture management during the cultivation and improving the anti-stres.%"Honnesis"是指生物体在不同剂量化学物质刺激下产生的,以双相剂量--反应曲线为特征的一种适应性反应.作者在分析了Hormesis概念、机制、研究现状及生物学意义的基础上,总结了药用植物生长发育及次生代谢产物积累的Hortnesis现象,指出了Hormesis在药用植物生产中的应用,包括提高次生代谢产物,指导中药材适生地的选择,指导中药材生产管理,提高植物整体抗逆性.

  12. Establishing cellular stress response profiles as biomarkers of homeodynamics, health and hormesis.

    Science.gov (United States)

    Demirovic, Dino; Rattan, Suresh I S

    2013-01-01

    Aging is the progressive shrinkage of the homeodynamic space. A crucial component of the homeodynamic space is the stress response (SR), by virtue of which a living system senses disturbance and initiates a series of events for maintenance, repair, adaptation, remodeling and survival. Here we discuss the main intracellular SR pathways in human cells, and argue for the need to define and establish the immediate and delayed stress response profiles (SRP) during aging. Such SRP are required to be established at several age-points, which can be the molecular biomarkers of homeodynamic space and the health status of cells and organisms. SRP can also be useful for testing potential protectors and stimulators of homeodynamics, and can be a standard for monitoring the efficacy of potential pro-survival, health-promoting and aging-modulating conditions, food components and other compounds. An effective strategy, which makes use of SRP for achieving healthy aging and extending the healthspan, is that of strengthening the homeodynamics through repeated mild stress-induced hormesis by physical, biological and nutritional hormetins. Furthermore, SRP can also be the basis for defining health as a state of having adequate physical and mental independence of activities of daily living, by identifying a set of measurable parameters at the most fundamental level of biological organization.

  13. The hormesis effect of plasma-elevated intracellular ROS on HaCaT cells

    Science.gov (United States)

    Szili, Endre J.; Harding, Frances J.; Hong, Sung-Ha; Herrmann, Franziska; Voelcker, Nicolas H.; Short, Robert D.

    2015-12-01

    We have examined the link between ionized-gas plasma delivery of reactive oxygen species (ROS) to immortalized keratinocyte (HaCaT) cells and cell fate, defined in terms of cell viability versus death. Phospholipid vesicles were used as cell mimics to measure the possible intracellular ROS concentration, [ROSi], delivered by various plasma treatments. Cells were exposed to a helium cold atmospheric plasma (CAP) jet for different plasma exposure times (5-60 s) and gas flow rates (50-1000 ml min-1). Based upon the [ROSi] data we argue that plasma-generated ROS in the cell culture medium can readily diffuse into real cells. Plasma exposure that equated to an [ROSi] in the range of 3.81  ×  10-10-9.47  ×  10-8 M, measured at 1 h after the plasma exposure, resulted in increased cell viability at 72 h; whereas a higher [ROSi] at 1 h decreased cell viability after 72 h of culture. This may be because of the manner in which the ROS are delivered by the plasma: HaCaT cells better tolerate a low ROS flux over an extended plasma exposure period of 1 min, compared to a high flux delivered in a few seconds, although the final [ROSi] may be the same. Our results suggest that plasma stimulation of HaCaT cells follows the principle of hormesis.

  14. Commentary on resveratrol and hormesis: resveratrol--a hormetic marvel in waiting?

    Science.gov (United States)

    Marques, Francine Z; Morris, Brian J

    2010-12-01

    Hormesis is a phenomenon in which adaptive responses to low doses of otherwise-harmful factors (also called mild stressors) make cells and organisms more robust. In their review, Calabrese et al. provide evidence for resveratrol acting hormetically in different types of human cell lines. The effects of resveratrol represent a 'two-edged sword' in that it has contrasting effects at low and high doses in healthy and cancerogenous cells. What demarcates a low and a high dose needs to be clarified. Concentrations tested in cell cultures, moreover, may not be relevant to whole organisms. And data from animal models need not apply to humans. Co-morbidities should also be considered. More research is needed to understand the action of resveratrol on all cell types and conditions, and the optimum therapeutic concentration that applies to each of these. Future research needs to determine the dynamics of the effects of resveratrol in different subcellular compartments and the interactions of these. In addition, the interactions between resveratrol, environmental factors, other compounds and medications, diseases and the genetic background of the individual will need to be appreciated in order to gain a complete understanding of the hormetic response of resveratrol.

  15. Pest insect olfaction in an insecticide-contaminated environment : info-disruption or hormesis effect

    Directory of Open Access Journals (Sweden)

    Hélène eTricoire-Leignel

    2012-03-01

    Full Text Available Most animals, including pest insects, live in an odour world and depend strongly on chemical stimuli to get information on their biotic and abiotic environment. Although integrated pest management strategies including the use of insect growth regulators (IGRs are increasingly developed, most insect pest treatments rely on neurotoxic chemicals. These molecules are known to disrupt synaptic transmission, affecting therefore sensory systems. The wide-spread use of neurotoxic insecticides and the growing use of IGRs result in residual accumulation of low concentrations in the environment. These insecticide residues could act as an info-disruptor by modifying the chemical communication system, and therefore decrease chances of reproduction in target insects. However, residues can also induce a non-expected hormesis effect by enhancing reproduction abilities. Low insecticide doses might thus induce adaptive processes in the olfactory pathway of target insects, favouring the development of resistance. The effect of sublethal doses of insecticides has mainly been studied in beneficial insects such as honeybees. We review here what is known on the effects of sublethal doses of insecticides on the olfactory system of insect pests.

  16. Inflammatory modulation of exercise salience: using hormesis to return to a healthy lifestyle

    Directory of Open Access Journals (Sweden)

    Bell Jimmy D

    2010-12-01

    Full Text Available Abstract Most of the human population in the western world has access to unlimited calories and leads an increasingly sedentary lifestyle. The propensity to undertake voluntary exercise or indulge in spontaneous physical exercise, which might be termed "exercise salience", is drawing increased scientific attention. Despite its genetic aspects, this complex behaviour is clearly modulated by the environment and influenced by physiological states. Inflammation is often overlooked as one of these conditions even though it is known to induce a state of reduced mobility. Chronic subclinical inflammation is associated with the metabolic syndrome; a largely lifestyle-induced disease which can lead to decreased exercise salience. The result is a vicious cycle that increases oxidative stress and reduces metabolic flexibility and perpetuates the disease state. In contrast, hormetic stimuli can induce an anti-inflammatory phenotype, thereby enhancing exercise salience, leading to greater biological fitness and improved functional longevity. One general consequence of hormesis is upregulation of mitochondrial function and resistance to oxidative stress. Examples of hormetic factors include calorie restriction, extreme environmental temperatures, physical activity and polyphenols. The hormetic modulation of inflammation, and thus, exercise salience, may help to explain the highly heterogeneous expression of voluntary exercise behaviour and therefore body composition phenotypes of humans living in similar obesogenic environments.

  17. Nuclear energy and health: and the benefits of low-dose radiation hormesis.

    Science.gov (United States)

    Cuttler, Jerry M; Pollycove, Myron

    2009-01-01

    Energy needs worldwide are expected to increase for the foreseeable future, but fuel supplies are limited. Nuclear reactors could supply much of the energy demand in a safe, sustainable manner were it not for fear of potential releases of radioactivity. Such releases would likely deliver a low dose or dose rate of radiation, within the range of naturally occurring radiation, to which life is already accustomed. The key areas of concern are discussed. Studies of actual health effects, especially thyroid cancers, following exposures are assessed. Radiation hormesis is explained, pointing out that beneficial effects are expected following a low dose or dose rate because protective responses against stresses are stimulated. The notions that no amount of radiation is small enough to be harmless and that a nuclear accident could kill hundreds of thousands are challenged in light of experience: more than a century with radiation and six decades with reactors. If nuclear energy is to play a significant role in meeting future needs, regulatory authorities must examine the scientific evidence and communicate the real health effects of nuclear radiation. Negative images and implications of health risks derived by unscientific extrapolations of harmful effects of high doses must be dispelled.

  18. Exercise, oxidants, and antioxidants change the shape of the bell-shaped hormesis curve.

    Science.gov (United States)

    Radak, Zsolt; Ishihara, Kazunari; Tekus, Eva; Varga, Csaba; Posa, Aniko; Balogh, Laszlo; Boldogh, Istvan; Koltai, Erika

    2017-03-03

    It is debated whether exercise-induced ROS production is obligatory to cause adaptive response. It is also claimed that antioxidant treatment could eliminate the adaptive response, which appears to be systemic and reportedly reduces the incidence of a wide range of diseases. Here we suggest that if the antioxidant treatment occurs before the physiological function-ROS dose-response curve reaches peak level, the antioxidants can attenuate function. On the other hand, if the antioxidant treatment takes place after the summit of the bell-shaped dose response curve, antioxidant treatment would have beneficial effects on function. We suggest that the effects of antioxidant treatment are dependent on the intensity of exercise, since the adaptive response, which is multi pathway dependent, is strongly influenced by exercise intensity. It is further suggested that levels of ROS concentration are associated with peak physiological function and can be extended by physical fitness level and this could be the basis for exercise pre-conditioning. Physical inactivity, aging or pathological disorders increase the sensitivity to oxidative stress by altering the bell-shaped dose response curve.

  19. Effect of Enamel Caries Lesion Baseline Severity on Fluoride Dose-Response

    Directory of Open Access Journals (Sweden)

    Frank Lippert

    2017-01-01

    Full Text Available This study aimed to investigate the effect of enamel caries lesion baseline severity on fluoride dose-response under pH cycling conditions. Early caries lesions were created in human enamel specimens at four different severities (8, 16, 24, and 36 h. Lesions were allocated to treatment groups (0, 83, and 367 ppm fluoride as sodium fluoride based on Vickers surface microhardness (VHN and pH cycled for 5 d. The cycling model comprised 3 × 1 min fluoride treatments sandwiched between 2 × 60 min demineralization challenges with specimens stored in artificial saliva in between. VHN was measured again and changes versus lesion baseline were calculated (ΔVHN. Data were analyzed using two-way ANOVA (p<0.05. Increased demineralization times led to increased surface softening. The lesion severity×fluoride concentration interaction was significant (p<0.001. Fluoride dose-response was observed in all groups. Lesions initially demineralized for 16 and 8 h showed similar overall rehardening (ΔVHN and more than 24 and 36 h lesions, which were similar. The 8 h lesions showed the greatest fluoride response differential (367 versus 0 ppm F which diminished with increasing lesion baseline severity. The extent of rehardening as a result of the 0 ppm F treatment increased with increasing lesion baseline severity, whereas it decreased for the fluoride treatments. In conclusion, lesion baseline severity impacts the extent of the fluoride dose-response.

  20. Breastfeeding Mode and Risk of Breast Cancer: A Dose-Response Meta-Analysis.

    Science.gov (United States)

    Unar-Munguía, Mishel; Torres-Mejía, Gabriela; Colchero, M Arantxa; González de Cosío, Teresita

    2017-05-01

    Breastfeeding reduces women's risk of breast cancer. Since exclusive breastfeeding has a stronger hormonal effect, it could theoretically result in a greater reduction in breast cancer risk than any breastfeeding mode. No meta-analysis has examined breast cancer risk by breastfeeding mode. Research aim: The authors conducted a meta-analysis for breast cancer risk in parous women who breastfed exclusively or in any mode versus parous women who formula fed their infants, and they estimated the summary dose-response association by the accumulated duration of any breastfeeding mode. A systematic review of studies published between 2005 and 2015 analyzing breastfeeding and breast cancer risk in women was conducted in PubMed and EBSCOhost. A meta-analysis ( n = 65 studies) with fixed effects (or random effects, if heterogeneity existed) was carried out stratified by breastfeeding mode and menopausal and parity status. A summary dose-response association was estimated using the generalized least-squares method. The summary relative risk (SRR) for breast cancer in parous women who breastfed exclusively was 0.72, 95% confidence interval (CI) [0.58, 0.90], versus parous women who had never breastfed. For parous women who breastfed in any mode, the SRR was lower in both premenopausal women (0.86, 95% CI [0.80, 0.93]) and postmenopausal women (0.89, 95% CI [0.83, 0.95]). There was no heterogeneity or publication bias. There is weak evidence of a difference between exclusive and any breastfeeding mode ( p = .08). The summary dose-response curve was nonlinear ( p < .001). Exclusive breastfeeding among parous women reduces the risk of breast cancer compared with parous women who do not breastfeed exclusively.

  1. Dose-response curve of a microfluidic magnetic bead-based surface coverage sandwich assay.

    Science.gov (United States)

    Cornaglia, Matteo; Trouillon, Raphaël; Tekin, H Cumhur; Lehnert, Thomas; Gijs, Martin A M

    2015-09-25

    Magnetic micro- and nanoparticles ('magnetic beads') have been used to advantage in many microfluidic devices for sensitive antigen (Ag) detection. Today, assays that use as read-out of the signal the number count of immobilized beads on a surface for quantification of a sample's analyte concentration have been among the most sensitive and have allowed protein detection lower than the fgmL(-1) concentration range. Recently, we have proposed in this category a magnetic bead surface coverage assay (Tekin et al., 2013 [1]), in which 'large' (2.8μm) antibody (Ab)-functionalized magnetic beads captured their Ag from a serum and these Ag-carrying beads were subsequently exposed to a surface pattern of fixed 'small' (1.0μm) Ab-coated magnetic beads. When the system was exposed to a magnetic induction field, the magnet dipole attractive interactions between the two bead types were used as a handle to approach both bead surfaces and assist with Ag-Ab immunocomplex formation, while unspecific binding (in absence of an Ag) of a large bead was reduced by exploiting viscous drag flow. The dose-response curve of this type of assay had two remarkable features: (i) its ability to detect an output signal (i.e. bead number count) for very low Ag concentrations, and (ii) an output signal of the assay that was non-linear with respect to Ag concentration. We explain here the observed dose-response curves and show that the type of interactions and the concept of our assay are in favour of detecting the lowest analyte concentrations (where typically either zero or one Ag is carried per large bead), while higher concentrations are less efficiently detected. We propose a random walk process for the Ag-carrying bead over the magnetic landscape of small beads and this model description explains the enhanced overall capture probability of this assay and its particular non-linear dose response curves.

  2. Investigating quartz optically stimulated luminescence dose-response curves at high doses

    Energy Technology Data Exchange (ETDEWEB)

    Lowick, Sally E., E-mail: lowick@geo.unibe.c [Institut fuer Geologie, Universitaet Bern, Baltzerstrasse 1-3, 3012 Bern (Switzerland); Preusser, Frank [Institut fuer Geologie, Universitaet Bern, Baltzerstrasse 1-3, 3012 Bern (Switzerland); Wintle, Ann G. [Institute of Geography and Earth Sciences, Aberystwyth University, AberystwythSY23 3DB (United Kingdom)

    2010-10-15

    Despite the general expectation that optically stimulated luminescence (OSL) growth should be described by a simple saturating exponential function, an additional high dose component is often reported in the dose response of quartz. Although often reported as linear, it appears that this response is the early expression of a second saturating exponential. While some studies using equivalent doses that fall in this high dose region have produced ages that correlate well with independent dating, others report that it results in unreliable age determinations. Two fine grain sedimentary quartz samples that display such a response were used to investigate the origin of this additional high dose component: three experiments were conducted to examine their dose-response up to >1000 Gy. The high dose rates provided by laboratory irradiation were found not to induce a sensitivity change in the response to a subsequent test dose, with the latter not being significantly different from those generated following naturally acquired doses. The relative percentage contributions of the fast and medium OSL components remained fixed throughout the dose-response curve, suggesting that the electron traps that give rise to the initial OSL do not change with dose. An attempt was made to investigate a change in luminescence centre recombination probability by monitoring the depletion of the '325 {sup o}C' thermoluminescence (TL) during the optical stimulation that would result in depletion of the OSL signal. The emissions measured through both the conventional ultraviolet (UV), and a longer wavelength violet/blue (VB) window, displayed similar relative growth with dose, although it was not possible to resolve the origin of the VB emissions. No evidence was found to indicate whether the additional component at high doses occurs naturally or is a product of laboratory treatment. However, it appears that these samples display an increased sensitivity of quartz OSL to high doses

  3. IncucyteDRC: An R package for the dose response analysis of live cell imaging data

    OpenAIRE

    Philip J. Chapman; Dominic I. James; Amanda J. Watson; Hopkins, Gemma V.; Waddell, Ian D.; Ogilvie, Donald J.

    2016-01-01

    We present IncucyteDRC, an R package for the analysis of data from live cell imaging cell proliferation experiments carried out on the Essen Biosciences IncuCyte ZOOM instrument. The package provides a simple workflow for summarising data into a form that can be used to calculate dose response curves and EC50 values for small molecule inhibitors. Data from different cell lines, or cell lines grown under different conditions, can be normalised as to their doubling time. A simple graphical web ...

  4. The Synthetic Elicitor 2-(5-Bromo-2-Hydroxy-Phenyl)-Thiazolidine-4-Carboxylic Acid Links Plant Immunity to Hormesis.

    Science.gov (United States)

    Rodriguez-Salus, Melinda; Bektas, Yasemin; Schroeder, Mercedes; Knoth, Colleen; Vu, Trang; Roberts, Philip; Kaloshian, Isgouhi; Eulgem, Thomas

    2016-01-01

    Synthetic elicitors are drug-like compounds that induce plant immune responses but are structurally distinct from natural defense elicitors. Using high-throughput screening, we previously identified 114 synthetic elicitors that activate the expression of a pathogen-responsive reporter gene in Arabidopsis (Arabidopsis thaliana). Here, we report on the characterization of one of these compounds, 2-(5-bromo-2-hydroxy-phenyl)-thiazolidine-4-carboxylic acid (BHTC). BHTC induces disease resistance of plants against bacterial, oomycete, and fungal pathogens and has a unique mode of action and structure. Surprisingly, we found that low doses of BHTC enhanced root growth in Arabidopsis, while high doses of this compound inhibited root growth, besides inducing defense. These effects are reminiscent of the hormetic response, which is characterized by low-dose stimulatory effects of a wide range of agents that are toxic or inhibitory at higher doses. Like its effects on defense, BHTC-induced hormesis in Arabidopsis roots is partially dependent on the WRKY70 transcription factor. Interestingly, BHTC-induced root hormesis is also affected in the auxin-response mutants axr1-3 and slr-1. By messenger RNA sequencing, we uncovered a dramatic difference between transcriptional profiles triggered by low and high doses of BHTC. Only high levels of BHTC induce typical defense-related transcriptional changes. Instead, low BHTC levels trigger a coordinated intercompartmental transcriptional response manifested in the suppression of photosynthesis- and respiration-related genes in the nucleus, chloroplasts, and mitochondria as well as the induction of development-related nuclear genes. Taken together, our functional characterization of BHTC links defense regulation to hormesis and provides a hypothetical transcriptional scenario for the induction of hormetic root growth.

  5. Deriving ozone dose-response of photosynthesis in adult forest trees from branch-level cuvette gas exchange assessment

    Energy Technology Data Exchange (ETDEWEB)

    Then, C. [Unit of Alpine Timberline Ecophysiology, Federal Office and Research Centre for Forests, Rennweg 1, A-6020 Innsbruck (Austria); Ecophysiology of Plants, Department of Ecology, Technische Universitaet Muenchen, Life Science Center Weihenstephan, Am Hochanger 13, D-85354 Freising (Germany)], E-mail: christiane.then@uibk.ac.at; Loew, M.; Matyssek, R. [Ecophysiology of Plants, Department of Ecology, Technische Universitaet Muenchen, Life Science Center Weihenstephan, Am Hochanger 13, D-85354 Freising (Germany); Wieser, G. [Unit of Alpine Timberline Ecophysiology, Federal Office and Research Centre for Forests, Rennweg 1, A-6020 Innsbruck (Austria)

    2008-06-15

    Branch-level gas exchange provided the basis for assessing ozone flux in order to derive the dose-response relationship between cumulative O{sub 3} uptake (COU) and carbon gain in the upper sun crown of adult Fagus sylvatica. Fluxes of ozone, CO{sub 2} and water vapour were monitored simultaneously by climatized branch cuvettes. The cuvettes allowed branch exposure to an ambient or twice-ambient O{sub 3} regime, while tree crowns were exposed to the same O{sub 3} regimes (twice-ambient generated by a free-air canopy O{sub 3} exposure system). COU levels higher than 20 mmol m{sup -2} led to a pronounced decline in carbon gain under elevated O{sub 3}. The limiting COU range is consistent with findings on neighbouring branches exposed to twice-ambient O{sub 3} through free-air fumigation. The cuvette approach allows to estimate O{sub 3} flux at peripheral crown positions, where boundary layers are low, yielding a meso-scale within-crown resolution of photosynthetic foliage sensitivity under whole-tree free-air O{sub 3} fumigation. - Branch-level O{sub 3} dose dependence of photosynthesis derived from cuvette assessment yields sun-crown foliage sensitivity under whole-tree free-air O{sub 3} fumigation.

  6. Dietary fiber intake and risk of type 2 diabetes: a dose-response analysis of prospective studies.

    Science.gov (United States)

    Yao, Baodong; Fang, Hong; Xu, Wanghong; Yan, Yujie; Xu, Huilin; Liu, Yinan; Mo, Miao; Zhang, Hua; Zhao, Yanping

    2014-02-01

    Observational studies suggest an association between dietary fiber intake and risk of type 2 diabetes, but the results are inconclusive. We conducted a meta-analysis of prospective studies evaluating the associations of dietary fiber intake and risk of type 2 diabetes. Relevant studies were identified by searching EMBASE (from 1974 to April 2013) and PubMed (from 1966 to April 2013). The fixed or random-effect model was selected based on the homogeneity test among studies. In addition, a 2-stage random-effects dose-response meta-analysis was performed. We identified 17 prospective cohort studies of dietary fiber intake and risk of type 2 diabetes involving 19,033 cases and 488,293 participants. The combined RR (95 % CI) of type 2 diabetes for intake of total dietary fiber, cereal fiber, fruit fiber and insoluble fiber was 0.81 (0.73-0.90), 0.77 (0.69-0.85), 0.94 (0.88-0.99) and 0.75 (0.63-0.89), respectively. A nonlinear relationship was found of total dietary fiber intake with risk of type 2 diabetes (P for nonlinearity fiber intake. Findings from this meta-analysis indicate that the intakes of dietary fiber may be inversely associated with risk of type 2 diabetes.

  7. Coffee consumption and risk of endometrial cancer: a dose-response meta-analysis of prospective cohort studies.

    Science.gov (United States)

    Zhou, Quan; Luo, Mei-Ling; Li, Hui; Li, Min; Zhou, Jian-Guo

    2015-08-25

    This is a dose-response (DR) meta-analysis to evaluate the association of coffee consumption on endometrial cancer (EC) risk. A total 1,534,039 participants from 13 published articles were added in this meta-analysis. The RR of total coffee consumption and EC were 0.80 (95% CI: 0.74-0.86). A stronger association between coffee intake and EC incidence was found in patients who were never treated with hormones, 0.60 (95% CI: 0.50-0.72), and subjects with a BMI ≥25 kg/m(2), 0.57 (95% CI: 0.46-0.71). The overall RRs for caffeinated and decaffeinated coffee were 0.66 (95% CI: 0.52-0.84) and 0.77 (95% CI: 0.63-0.94), respectively. A linear DR relationship was seen in coffee, caffeinated coffee, decaffeinated coffee and caffeine intake. The EC risk decreased by 5% for every 1 cup per day of coffee intake, 7% for every 1 cup per day of caffeinated coffee intake, 4% for every 1 cup per day of decaffeinated intake of coffee, and 4% for every 100 mg of caffeine intake per day. In conclusion, coffee and intake of caffeine might significantly reduce the incidence of EC, and these effects may be modified by BMI and history of hormone therapy.

  8. Can exposure limitations for well-known contact allergens be simplified? An analysis of dose-response patch test data.

    Science.gov (United States)

    Fischer, Louise Arup; Menné, Torkil; Voelund, Aage; Johansen, Jeanne Duus

    2011-06-01

    Allergic contact dermatitis is triggered by chemicals in the environment. Primary prevention is aimed at minimizing the risk of induction, whereas secondary and tertiary prevention are aimed at reducing elicitation. To identify the elicitation doses that will elicit an allergic reaction in 10% of allergic individuals under patch test conditions (ED(10) patch test) for different allergens, and to compare the results with those for different allergens and with animal data indicating sensitizing potency from the literature. The literature was searched for patch test elicitation studies that fulfilled six selected criteria. The elicitation doses were calculated, and fitted dose-response curves were drawn. Sixteen studies with eight different allergens-methylchloroisothiazolinone/ methylisothiazolinone, formaldehyde, nickel, cobalt, chromium, isoeugenol, hydroxyiso hexyl 3-cyclohexene carboxaldehyde, and methyldibromo glutaronitrile-were selected. The median ED(10) value was 0.835 µg/cm(2). The ED(10) patch test values were all within a factor of 7 from the lowest to the highest value, leaving out three outliers. No obvious patterns between the sensitization and elicitation doses for the allergens were found. We found a rather small variation in the ED(10) patch test between the allergens, and no clear relationship between induction potency and elicitation threshold of a range of allergens. This knowledge may stimulate thoughts on introducing a generic approach for limitations in exposure to well-known allergens. © 2011 John Wiley & Sons A/S.

  9. Acute Effects of Classroom Exercise Breaks on Executive Function and Math Performance: A Dose-Response Study.

    Science.gov (United States)

    Howie, Erin K; Schatz, Jeffrey; Pate, Russell R

    2015-01-01

    The purpose of this study was to determine the acute dose-response relationship of classroom exercise breaks with executive function and math performance in 9- to 12-year-old children by comparing 5-min, 10-min, or 20-min classroom exercise breaks to 10 min of sedentary classroom activity. This study used a within-subjects experimental design conducted in the spring of 2012. Ninety-six 4th- and 5th-grade students in 5 classrooms in South Carolina were randomized to receive each of 4 treatments: 5-min, 10-min, or 20-min exercise breaks or 10 min of a sedentary lesson led by research staff. Students completed the Trail-Making Test, an Operational Digit Recall test, and a math fluency test immediately before and after each condition. Planned linear contrasts were used to compare posttest scores between conditions using a repeated-measures mixed model, adjusted for gender, classroom, and the time-varying pretest scores. Potential effect modifiers were added as interaction terms. Math scores were higher after the 10-min and 20-min exercise breaks compared with the sedentary condition (d = 0.24, p = .04, and d = 0.27, p = .02, respectively), and an interaction was observed with gender, IQ, aerobic fitness, and lower engagement in some of the conditions. There were no improvements in executive function tasks. A 10-min and 20-min classroom exercise break moderately improved math performance in students compared with a seated classroom lesson.

  10. EMS in Viracept--initial ('traditional') assessment of risk to patients based on linear dose response relations.

    Science.gov (United States)

    Gocke, Elmar; Müller, Lutz; Pfister, Thomas

    2009-11-12

    Prior to having performed in depth toxicological, genotoxicological and DMPK studies on ethyl methanesulfonate (EMS) providing solid evidence for a thresholded dose response relationship, we had prepared and shared with regulatory authorities a preliminary risk estimate based on standard linear dose-effect projections. We estimated that maximal lifetime cancer risk was in the order of 10(-3) (for lifetime ingestion of the maximally contaminated tablets) or 10(-4) for the exposure lasting for 3 months. This estimate was based on a lifetime cancer study with methyl methanesulfonate (MMS; as insufficient data were available for EMS) in rodents and default linear back extrapolation. Analogous estimates were made specifically for breast cancer based on short term tumorigenicity studies with EMS in rats, for the induction of heritable mutations based on specific locus and dominant lethal tests in mice and for the induction of birth defects based on teratogenicity studies in mice. We concluded that even under worst case assumptions of linear dose relations the chance of experiencing these adverse effects would be very small, comprising at most a minute additional burden among the background incidence of the patients.

  11. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts after Exposure to Very Low Doses of High LET Radiation

    Science.gov (United States)

    Hada, M.; George, Kerry; Cucinotta, Francis A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivors with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (1-20 cGy) of 170 MeV/u Si-28- ions or 600 MeV/u Fe-56-ions. Chromosomes were analyzed using the whole chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving greater than 2 breaks in 2 or more chromosomes). The curves for doses above 10 cGy were fitted with linear or linear-quadratic functions. For Si-28- ions no dose response was observed in the 2-10 cGy dose range, suggesting a non-target effect in this range.

  12. Influence of lung parenchymal destruction on the different indexes of the methacholine dose-response curve in COPD patients

    NARCIS (Netherlands)

    G.T. Verhoeven; A.F.M. Verbraak (Anton); S. Boere-van der Straat; H.C. Hoogsteden (Henk); J.M. Bogaard (Jan)

    2000-01-01

    textabstractSTUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose-response curves in COPD is still a matter of debate. Bronchial hyperresponsiveness (BHR) in patients with COPD could be influenced by the destruction of the parenchyma and the

  13. Hazard identification and characterisation, and dose response assessment of spore forming pathogens in cooked chilled food containing vegetables

    NARCIS (Netherlands)

    Leusden FM van; MGB

    2001-01-01

    A hazard identification and characterisation, including a preliminary dose response assessment, of sporeforming pathogens in cooked chilled food containing vegetables was performed according to the structure and principles for a quantitative microbiological risk assessment as described by the Codex

  14. Measures of Abdominal Adiposity and Risk of Stroke:A Dose-Response Meta-analysis of Prospective Studies

    Institute of Scientific and Technical Information of China (English)

    ZHONG Chong Ke; ZHONG Xiao Yan; XU Tan; ZHANG Yong Hong

    2016-01-01

    ObjectiveWaist circumference, waist-to-hip ratio and waist-to-height ratio, which are the indicators or measures of abdominal adiposity, have long been hypothesized to increase therisk of stroke; yet evidence accumulated till date is not conclusive. Here, we conducted a dose-response meta-analysis to summarize evidences of the association between these measures of abdominal adiposity and the risk of stroke. MethodsPubMed and Web of Science databases were searched from inception to May 2015. Two investigators independently conducted the study selection and data extraction. Dose-response relationships were assessed by the generalized least squares trend estimation, while the summaryeffect estimates were evaluated by the use of fixed- or random-effect models. Subgroup and sensitivity analyses were performed to assess the potential sources of heterogeneity and the robustness of the pooled estimation. Publication biasof the literaturewas evaluated usingBegg’s and Egger’s test. ResultsAltogether 15 prospective cohort studies were identified in this study. The summary of relative risks (95% confidence intervals) of stroke for the highest versus the lowest categories was 1.28 (1.18-1.40) for waist circumference, 1.32 (1.21-1.44) for waist-to-hip ratio, and 1.49 (1.24-1.78) for waist-to-height ratio. For a 10-cm increase in waist circumference, the relative risk of stroke increased by 10%; for a 0.1-unit increase in waist-to-hip ratio, the relative risk increased by 16%; and for a 0.05-unit increase in waist-to-height ratio, the relative risk increased by 13%. There was evidence of a nonlinear association between waist-to-hip ratio and stroke risk,Pnonlinearity=0.028. ConclusionFindings from our meta-analysis indicated that waist circumference, waist-to-hip ratio, and waist-to-height ratio were positively associated with the risk of stroke, particularly ischemic stroke.

  15. Accelerometer-measured dose-response for physical activity, sedentary time, and mortality in US adults

    DEFF Research Database (Denmark)

    Matthews, Charles E; Keadle, S. K.; Troiano, Richard P

    2016-01-01

    Background: Moderate-to-vigorous-intensity physical activity is recommended to maintain and improve health, but the mortality benefits of light activity and risk for sedentary time remain uncertain. Objectives: Using accelerometer-based measures, we 1) described the mortality dose-response for se......Background: Moderate-to-vigorous-intensity physical activity is recommended to maintain and improve health, but the mortality benefits of light activity and risk for sedentary time remain uncertain. Objectives: Using accelerometer-based measures, we 1) described the mortality dose......-response for sedentary time and light-and moderateto-vigorous-intensity activity using restricted cubic splines, and 2) estimated the mortality benefits associated with replacing sedentary time with physical activity, accounting for total activity. Design: US adults (n = 4840) from NHANES (2003-2006) wore...... an accelerometer for #7 d and were followed prospectively for mortality. Proportional hazards models were used to estimate adjusted HRs and 95% CIs for mortality associations with time spent sedentary and in light-and moderate-to-vigorous-intensity physical activity. Splines were used to graphically present...

  16. Cancer risk assessment: Optimizing human health through linear dose-response models.

    Science.gov (United States)

    Calabrese, Edward J; Shamoun, Dima Yazji; Hanekamp, Jaap C

    2015-07-01

    This paper proposes that generic cancer risk assessments be based on the integration of the Linear Non-Threshold (LNT) and hormetic dose-responses since optimal hormetic beneficial responses are estimated to occur at the dose associated with a 10(-4) risk level based on the use of a LNT model as applied to animal cancer studies. The adoption of the 10(-4) risk estimate provides a theoretical and practical integration of two competing risk assessment models whose predictions cannot be validated in human population studies or with standard chronic animal bioassay data. This model-integration reveals both substantial protection of the population from cancer effects (i.e. functional utility of the LNT model) while offering the possibility of significant reductions in cancer incidence should the hormetic dose-response model predictions be correct. The dose yielding the 10(-4) cancer risk therefore yields the optimized toxicologically based "regulatory sweet spot". Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Mathematical Modeling of Allelopathy. III. A Model for Curve-Fitting Allelochemical Dose Responses

    Science.gov (United States)

    Liu, De Li; An, Min; Johnson, Ian R.; Lovett, John V.

    2003-01-01

    Bioassay techniques are often used to study the effects of allelochemicals on plant processes, and it is generally observed that the processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. A simple empirical model is presented to analyze this type of response. The stimulation-inhibition properties of allelochemical-dose responses can be described by the parameters in the model. The indices, p% reductions, are calculated to assess the allelochemical effects. The model is compared with experimental data for the response of lettuce seedling growth to Centaurepensin, the olfactory response of weevil larvae to α-terpineol, and the responses of annual ryegrass (Lolium multiflorum Lam.), creeping red fescue (Festuca rubra L., cv. Ensylva), Kentucky bluegrass (Poa pratensis L., cv. Kenblue), perennial ryegrass (L. perenne L., cv. Manhattan), and Rebel tall fescue (F. arundinacea Schreb) seedling growth to leachates of Rebel and Kentucky 31 tall fescue. The results show that the model gives a good description to observations and can be used to fit a wide range of dose responses. Assessments of the effects of leachates of Rebel and Kentucky 31 tall fescue clearly differentiate the properties of the allelopathic sources and the relative sensitivities of indicators such as the length of root and leaf. PMID:19330111

  18. Hierarchical dose-response modeling for high-throughput toxicity screening of environmental chemicals.

    Science.gov (United States)

    Wilson, Ander; Reif, David M; Reich, Brian J

    2014-03-01

    High-throughput screening (HTS) of environmental chemicals is used to identify chemicals with high potential for adverse human health and environmental effects from among the thousands of untested chemicals. Predicting physiologically relevant activity with HTS data requires estimating the response of a large number of chemicals across a battery of screening assays based on sparse dose-response data for each chemical-assay combination. Many standard dose-response methods are inadequate because they treat each curve separately and under-perform when there are as few as 6-10 observations per curve. We propose a semiparametric Bayesian model that borrows strength across chemicals and assays. Our method directly parametrizes the efficacy and potency of the chemicals as well as the probability of response. We use the ToxCast data from the U.S. Environmental Protection Agency (EPA) as motivation. We demonstrate that our hierarchical method provides more accurate estimates of the probability of response, efficacy, and potency than separate curve estimation in a simulation study. We use our semiparametric method to compare the efficacy of chemicals in the ToxCast data to well-characterized reference chemicals on estrogen receptor α (ERα) and peroxisome proliferator-activated receptor γ (PPARγ) assays, then estimate the probability that other chemicals are active at lower concentrations than the reference chemicals.

  19. Transcriptional profiling of the dose response: a more powerful approach for characterizing drug activities.

    Directory of Open Access Journals (Sweden)

    Rui-Ru Ji

    2009-09-01

    Full Text Available The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacological parameters such as the EC50, and enable an in-depth analysis of coordinated dose-dependent treatment effects. The approach was applied to a transcriptional profiling study that evaluated four kinase inhibitors (imatinib, nilotinib, dasatinib and PD0325901 across a six-logarithm dose range, using 12 arrays per compound. The transcript responses proved a powerful means to characterize and compare the compounds: the distribution of EC50 values for the transcriptome was linked to specific targets, dose-dependent effects on cellular processes were identified using automated pathway analysis, and a connection was seen between EC50s in standard cellular assays and transcriptional EC50s. Our approach greatly enriches the information that can be obtained from standard transcriptional profiling technology. Moreover, these methods are automated, robust to non-optimized assays, and could be applied to other sources of quantitative data.

  20. Dose-response plasma appearance of coffee chlorogenic and phenolic acids in adults.

    Science.gov (United States)

    Renouf, Mathieu; Marmet, Cynthia; Giuffrida, Francesca; Lepage, Mélissa; Barron, Denis; Beaumont, Maurice; Williamson, Gary; Dionisi, Fabiola

    2014-02-01

    Coffee contains phenolic compounds, mainly chlorogenic acids (CGAs). Even though coffee intake has been associated with some health benefits in epidemiological studies, the bioavailability of coffee phenolics is not fully understood. We performed a dose-response study measuring plasma bioavailability of phenolics after drinking three increasing, but still nutritionally relevant doses of instant pure soluble coffee. The study design was a one treatment (coffee) three-dose randomized cross-over design, with a washout period of 2 wks between visits. CGAs, phenolic acids, and late-appearing metabolites all increased with increasing ingested dose. Hence, the sum of area under the curve was significantly higher for the medium to low dose, and high to medium dose, by 2.23- and 2.38-fold, respectively. CGAs were not well absorbed in their intact form, regardless of the dose. CGA and phenolic acids appeared rapidly in plasma, indicating an early absorption in the gastrointestinal tract. Late-appearing metabolites were the most abundant, regardless of the dose. This study confirmed previous findings about coffee bioavailability but also showed that coffee phenolics appear in a positive dose-response manner in plasma when drank at nutritionally relevant doses. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Mathematical Modeling of Allelopathy. III. A Model for Curve-Fitting Allelochemical Dose Responses.

    Science.gov (United States)

    Liu, De Li; An, Min; Johnson, Ian R; Lovett, John V

    2003-01-01

    Bioassay techniques are often used to study the effects of allelochemicals on plant processes, and it is generally observed that the processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. A simple empirical model is presented to analyze this type of response. The stimulation-inhibition properties of allelochemical-dose responses can be described by the parameters in the model. The indices, p% reductions, are calculated to assess the allelochemical effects. The model is compared with experimental data for the response of lettuce seedling growth to Centaurepensin, the olfactory response of weevil larvae to alpha-terpineol, and the responses of annual ryegrass (Lolium multiflorum Lam.), creeping red fescue (Festuca rubra L., cv. Ensylva), Kentucky bluegrass (Poa pratensis L., cv. Kenblue), perennial ryegrass (L. perenne L., cv. Manhattan), and Rebel tall fescue (F. arundinacea Schreb) seedling growth to leachates of Rebel and Kentucky 31 tall fescue. The results show that the model gives a good description to observations and can be used to fit a wide range of dose responses. Assessments of the effects of leachates of Rebel and Kentucky 31 tall fescue clearly differentiate the properties of the allelopathic sources and the relative sensitivities of indicators such as the length of root and leaf.

  2. Dose-response effects of aerobic exercise on estrogen among women at high risk for breast cancer: a randomized controlled trial.

    Science.gov (United States)

    Schmitz, Kathryn H; Williams, Nancy I; Kontos, Despina; Domchek, Susan; Morales, Knashawn H; Hwang, Wei-Ting; Grant, Lorita L; DiGiovanni, Laura; Salvatore, Domenick; Fenderson, Desire'; Schnall, Mitchell; Galantino, Mary Lou; Stopfer, Jill; Kurzer, Mindy S; Wu, Shandong; Adelman, Jessica; Brown, Justin C; Good, Jerene

    2015-11-01

    Medical and surgical interventions for elevated breast cancer risk (e.g., BRCA1/2 mutation, family history) focus on reducing estrogen exposure. Women at elevated risk may be interested in less aggressive approaches to risk reduction. For example, exercise might reduce estrogen, yet has fewer serious side effects and less negative impact than surgery or hormonal medications. Randomized controlled trial. Increased risk defined by risk prediction models or BRCA mutation status. Eligibility: Age 18-50, eumenorrheic, non-smokers, and body mass index (BMI) between 21 and 50 kg/m(2). 139 were randomized. Treadmill exercise: 150 or 300 min/week, five menstrual cycles. Control group maintained exercise estrogen. Secondary measures: urinary progesterone, quantitative digitized breast dynamic contrast-enhanced magnetic resonance imaging background parenchymal enhancement. Mean age 34 years, mean BMI 26.8 kg/m(2). A linear dose-response relationship was observed such that every 100 min of exercise is associated with 3.6 % lower follicular phase estrogen AUC (linear trend test, p = 0.03). No changes in luteal phase estrogen or progesterone levels. There was also a dose-response effect noted: for every 100 min of exercise, there was a 9.7 % decrease in background parenchymal enhancement as measured by imaging (linear trend test, p = 0.009). Linear dose-response effect observed to reduce follicular phase estrogen exposure measured via urine and hormone sensitive breast tissue as measured by imaging. Future research should explore maintenance of effects and extent to which findings are repeatable in lower risk women. Given the high benefit to risk ratio, clinicians can inform young women at increased risk that exercise may blunt estrogen exposure while considering whether to try other preventive therapies.

  3. Intake of fruit and vegetables and risk of bladder cancer: a dose-response meta-analysis of observational studies.

    Science.gov (United States)

    Yao, Baodong; Yan, Yujie; Ye, Xianwu; Fang, Hong; Xu, Huilin; Liu, Yinan; Li, Sheran; Zhao, Yanping

    2014-12-01

    Observational studies suggest an association between fruit and vegetables intake and risk of bladder cancer, but the results are controversial. We therefore summarized the evidence from observational studies in categorical, linear, and nonlinear, dose-response meta-analysis. Pertinent studies were identified by searching EMBASE and PubMed from their inception to August 2013. Thirty-one observational studies involving 12,610 cases and 1,121,649 participants were included. The combined rate ratio (RR, 95 % CI) of bladder cancer for the highest versus lowest intake was 0.83 (0.69-0.99) for total fruit and vegetables, 0.81 (0.70-0.93) for total vegetables, 0.77 (0.69-0.87) for total fruit, 0.84 (0.77-0.91) for cruciferous vegetables, 0.79 (0.68-0.91) for citrus fruits, and 0.74 (0.66-0.84) for yellow-orange vegetables. Subgroup analysis showed study design and gender as possible sources of heterogeneity. A nonlinear relationship was found of citrus fruits intake with risk of bladder cancer (P for nonlinearity = 0.018), and the RRs (95 % CI) of bladder cancer were 0.87 (0.78-0.96), 0.80 (0.67-0.94), 0.79 (0.66-0.94), 0.79 (0.65-0.96), and 0.79 (0.64-0.99) for 30, 60, 90, 120, and 150 g/day. A nonlinear relationship was also found of yellow-orange vegetable intake with risk of bladder cancer risk (P for nonlinearity = 0.033). Some evidence of publication bias was observed for fruit, citrus fruits, and yellow-orange vegetables. This meta-analysis supports the hypothesis that intakes of fruit and vegetables may reduce the risk of bladder cancer. Future well-designed studies are required to confirm this finding.

  4. Hormesis method for increasing oat straw with a view to viability of direct-seeding systems1

    Directory of Open Access Journals (Sweden)

    Leandro Augusto Felix Tavares

    Full Text Available In conservation agriculture, mainly under direct seeding, maintaining the vegetation ground cover is essential, since this serves as a reservoir of nutrients which are slowly released to plants by microorganisms. Some authors have sought to study increases in the amount of straw in the soil, in addition to slowing down the process of decomposition, with hormesis being one of the techniques used. This technique states that all chemical substances are both poisonous and nonpoisonous, with only the dosage determining whether they are lethal or not. This study aimed to evaluate the dry weight and agronomic characteristics of a crop of black oat subjected to hormesis. The experimental design was of randomised blocks, with 12 treatments and 4 replications, giving a total of 48 experimental lots. The treatments were: Haloxyfop-R Methyl Ester at dosages of 0.625, 1.25 and 2.50 g ha-1; Glyphosate at dosages of 12.50, 25.00 and 50.00 g ha-1; 2,4-D dimethylamine salt at dosages of 100.00, 200.00 and 300.00 g ha-1; Alterbane at a dosage of 500.00 g ha-1; Salicylic acid at a dose of 100 g ha-1; and a control. It was concluded that for the subdosages under test, the herbicides 2,4-D at medium dosage and Verdict at low dosage were shown to be the best treatments for conserving straw as ground cover under direct seeding.

  5. Mobile phone signal exposure triggers a hormesis-like effect in Atm(+/+) and Atm(-/-) mouse embryonic fibroblasts.

    Science.gov (United States)

    Sun, Chuan; Wei, Xiaoxia; Fei, Yue; Su, Liling; Zhao, Xinyuan; Chen, Guangdi; Xu, Zhengping

    2016-11-18

    Radiofrequency electromagnetic fields (RF-EMFs) have been classified by the International Agency for Research on Cancer as possible carcinogens to humans; however, this conclusion is based on limited epidemiological findings and lacks solid support from experimental studies. In particular, there are no consistent data regarding the genotoxicity of RF-EMFs. Ataxia telangiectasia mutated (ATM) is recognised as a chief guardian of genomic stability. To address the debate on whether RF-EMFs are genotoxic, we compared the effects of 1,800 MHz RF-EMF exposure on genomic DNA in mouse embryonic fibroblasts (MEFs) with proficient (Atm(+/+)) or deficient (Atm(-/-)) ATM. In Atm(+/+) MEFs, RF-EMF exposure for 1 h at an average special absorption rate of 4.0 W/kg induced significant DNA single-strand breaks (SSBs) and activated the SSB repair mechanism. This effect reduced the DNA damage to less than that of the background level after 36 hours of exposure. In the Atm(-/-) MEFs, the same RF-EMF exposure for 12 h induced both SSBs and double-strand breaks and activated the two repair processes, which also reduced the DNA damage to less than the control level after prolonged exposure. The observed phenomenon is similar to the hormesis of a toxic substance at a low dose. To the best of our knowledge, this study is the first to report a hormesis-like effect of an RF-EMF.

  6. Adaptation to acrolein through upregulating the protection by glutathione in human bronchial epithelial cells: the materialization of the hormesis concept.

    Science.gov (United States)

    Sthijns, Mireille M J P E; Randall, Matthew J; Bast, Aalt; Haenen, Guido R M M

    2014-04-18

    Acrolein is a thiol reactive compound present in cigarette smoke and plays a pivotal role in the deleterious effects of smoking. Acrolein causes toxicity in human bronchial epithelial cells in a dose dependent manner. GSH forms the first line of defense against acrolein-induced toxicity. At high doses of acrolein (⩾10 μM) the capacity of the cellular protection by GSH is overwhelmed and GSH is not able to quench all the acrolein, resulting in cytotoxicity. At a relatively low dose of acrolein (3 μM), no cytotoxicity is observed due to protection by GSH. Moreover we found that exposure to a low dose of acrolein protects cells against the toxic effect of a second higher dose of acrolein. The adaptation to acrolein is induced via Nrf2 mediated gene expression of γ-glutamylcysteine synthetase leading to elevated GSH levels. This upregulation of the protection by GSH demonstrates a hormetic response to acrolein. Hormesis is an adaptive or compensatory response induced by a relatively subtle challenge of homeostasis by a toxic compound. Insight into the mechanism of hormesis is mandatory for a more accurate societal regulation of toxic compounds.

  7. SO/sub 2/ dose-response sensitivity classification data for crops and natural vegetation species

    Energy Technology Data Exchange (ETDEWEB)

    Irving, P.M.; Ballou, S.W.

    1980-09-01

    Over the past several years studies have been made on the interaction of sulfur dioxide (SO/sub 2/) and vegetation by performing field research and by developing analytical procedures for applying field observation data to energy impact assessments. As a result of this work, numerous reports have been prepared on crop-pollutant interactions, such as dose-response data; on the applications of such data to screening approaches for identifying crops at risk; and on models that predict crop yield reductions from point source emissions of SO/sub 2/. Data that were used for these studies, such as the crop-at-risk screening procedure, are presented in this report. Maps are also presented that show the national distribution of SO/sub 2/-sensitive crops and natural vegetation.

  8. Dose response of xylitol and sorbitol for EPR retrospective dosimetry with applications to chewing gum.

    Science.gov (United States)

    Israelsson, A; Gustafsson, H; Lund, E

    2013-04-01

    The purpose of this investigation was to study the radiation-induced electron paramagnetic resonance signal in sweeteners xylitol and sorbitol for use in retrospective dosimetry. For both sweeteners and chewing gum, the signal changed at an interval of 1-84 d after irradiation with minimal changes after 4-8 d. A dependence on storage conditions was noticed and the exposure of the samples to light and humidity was therefore minimised. Both the xylitol and sorbitol signals showed linearity with dose in the measured dose interval, 0-20 Gy. The dose-response measurements for the chewing gum resulted in a decision threshold of 0.38 Gy and a detection limit of 0.78 Gy. A blind test illustrated the possibility of using chewing gums as a retrospective dosemeter with an uncertainty in the dose determination of 0.17 Gy (1 SD).

  9. Quantitative aspects of informed consent: considering the dose response curve when estimating quantity of information.

    Science.gov (United States)

    Lynöe, N; Hoeyer, K

    2005-12-01

    Information is usually supposed to be a prerequisite for people making decisions on whether or not to participate in a clinical trial. Previously conducted studies and research ethics scandals indicate that participants have sometimes lacked important pieces of information. Over the past few decades the quantity of information believed to be adequate has increased significantly, and in some instances a new maxim seems to be in place: the more information, the better the ethics in terms of respecting a participant's autonomy. The authors hypothesise that the dose-response curve from pharmacology or toxicology serves as a model to illustrate that a large amount of written information does not equal optimality. Using the curve as a pedagogical analogy when teaching ethics to students in clinical sciences, and also in engaging in dialogue with research institutions, may promote reflection on how to adjust information in relation to the preferences of individual participants, thereby transgressing the maxim that more information means better ethics.

  10. SynergyFinder: a web application for analyzing drug combination dose-response matrix data.

    Science.gov (United States)

    Ianevski, Aleksandr; He, Liye; Aittokallio, Tero; Tang, Jing

    2017-08-01

    Rational design of drug combinations has become a promising strategy to tackle the drug sensitivity and resistance problem in cancer treatment. To systematically evaluate the pre-clinical significance of pairwise drug combinations, functional screening assays that probe combination effects in a dose-response matrix assay are commonly used. To facilitate the analysis of such drug combination experiments, we implemented a web application that uses key functions of R-package SynergyFinder, and provides not only the flexibility of using multiple synergy scoring models, but also a user-friendly interface for visualizing the drug combination landscapes in an interactive manner. The SynergyFinder web application is freely accessible at https://synergyfinder.fimm.fi ; The R-package and its source-code are freely available at http://bioconductor.org/packages/release/bioc/html/synergyfinder.html . jing.tang@helsinki.fi.

  11. Extended application of dose-response models of infection on injectable insulin products in vials

    Directory of Open Access Journals (Sweden)

    Mostafa Essam Eissa

    2016-09-01

    Full Text Available Microbial contamination from in-use application of multidose pharmaceutical products constitutes health hazard to the consumer especially when considering injectable medicines. In the present study, an attempt has been made to integrate dose-response models of infections with pharmacopeial preservative efficacy test (PET in a single simulation study that supposed accidental reuse of hypodermic syringe. Probability risk ratio of infection from assumed equal doses of two types of microbes by two routes of infection was greater than 1300 at most equivalent administration doses when considering the same reduction factor for both bacteria in the antimicrobial efficacy test (AET. The probability of infection would diminish much more rapidly for Staphylococcus aureus rather than Pseudomonas aeruginosa. The short interval of product administration increased the risk of infection with regular-type of Insulin vials. The current quantitative study provided extension and made the best use of the standard AET but also highlighted its limitations.

  12. Muller's Nobel lecture on dose-response for ionizing radiation: ideology or science?

    Science.gov (United States)

    Calabrese, Edward J

    2011-12-01

    In his Nobel Prize Lecture of December 12, 1946, Hermann J. Muller argued that the dose-response for radiation-induced germ cell mutations was linear and that there was "no escape from the conclusion that there is no threshold". However, assessment of correspondence between Muller and Curt Stern 1 month prior to his Nobel Prize Lecture reveals that Muller knew the results and implications of a recently completed study at the University of Rochester under the direction of Stern, which directly contradicted his Nobel Prize Lecture. This finding is of historical importance since Muller's Nobel Lecture gained considerable international attention and is a turning point in the acceptance of the linearity model in risk assessment for germ cell mutations and carcinogens.

  13. Clinical application of Chamomilla recutita in phlebitis: dose response curve study.

    Science.gov (United States)

    Reis, Paula Elaine Diniz Dos; Carvalho, Emilia Campos de; Bueno, Paula Carolina Pires; Bastos, Jairo Kenupp

    2011-01-01

    This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5% concentration (mean=29.2h, standard deviation = 8.98) and 5% concentration (mean = 38.8h, standard deviation = 17.47). Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs.

  14. Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve.

    Science.gov (United States)

    Celik, Ilhan; Sürücü, Oguzkan; Dietz, Carsten; Heymach, John V; Force, Jeremy; Höschele, Iris; Becker, Christian M; Folkman, Judah; Kisker, Oliver

    2005-12-01

    We show here that recombinant endostatin protein has a biphasic effect on the inhibition of endothelial cell migration in vitro. In tumor-bearing animals, there is a similar biphasic effect on the inhibition of tumor growth and on circulating endothelial cells after once-daily s.c. injections. This biphasic effect is revealed as a U-shaped curve in which efficacy is optimal between very low and very high doses depending on the tumor type. This result may be applicable to other inhibitors of endothelial growth and to angiogenesis. Furthermore, these results have important implications for clinicians who administer angiogenesis inhibitors for cancer or other angiogenesis-dependent diseases. When these results are taken together with two previous reports of angiogenesis inhibitors with a U-shaped dose-response, they suggest that other regulators of endothelial growth may display a similar pattern.

  15. Dose Response of MARV/Angola Infection in Cynomolgus Macaques following IM or Aerosol Exposure.

    Directory of Open Access Journals (Sweden)

    Sara C Johnston

    Full Text Available Marburg virus infection in humans causes a hemorrhagic disease with a high case fatality rate. Countermeasure development requires the use of well-characterized animal models that mimic human disease. To further characterize the cynomolgus macaque model of MARV/Angola, two independent dose response studies were performed using the intramuscular or aerosol routes of exposure. All animals succumbed at the lowest target dose; therefore, a dose effect could not be determined. For intramuscular-exposed animals, 100 PFU was the first target dose that was not significantly different than higher target doses in terms of time to disposition, clinical pathology, and histopathology. Although a significant difference was not observed between aerosol-exposed animals in the 10 PFU and 100 PFU target dose groups, 100 PFU was determined to be the lowest target dose that could be consistently obtained and accurately titrated in aerosol studies.

  16. Dose-response modeling for the environmental risk assessment in cases of technogenic soil contamination

    Directory of Open Access Journals (Sweden)

    Shitikov Vladimir Kirilloviсh

    2015-09-01

    Full Text Available The review of regression models for the approximation of dependences "dose- response" was performed based on ecotoxicological results. The advantages and deficiencies of different models as well as the problems arising both in modeling and subsequent interpreting results are discussed for the purpose of ecological rationing and estimation of negative influence risk. Search procedures of best dependences based on statistical criteria and the methods of uncertainty estimation of calculated parameters are shown. Construction of models is illustrated in detail using the analysis of toxicity results of soil samples received from uranium mines tailings in Kadzhi-Say province (Kyrgyzstan. Threshold values of activity for U-238 and Ra-226 radionuclides providing the minimum probability of ecological risk were determined.

  17. Parity and risk of colorectal cancer: a dose-response meta-analysis of prospective studies.

    Directory of Open Access Journals (Sweden)

    Hong-Bo Guan

    Full Text Available BACKGROUND: Association between parity and colorectal cancer (CRC risk has been investigated by several epidemiological studies but results are controversial, yet a comprehensive and quantitative assessment of this association has not been reported so far. METHODS: Relevant published studies of parity and CRC were identified using MEDLINE, EMBASE and Web of Science databases through end of April 2013. Two authors independently assessed eligibility and extracted data. Eleven prospective studies reported relative risk (RR estimates and 95% confidence intervals (CIs of CRC risk associated with parity. We pooled the RR from individual studies using fixed- or random-effects models and carried out heterogeneity and publication bias analyses. RESULTS: The summary RR for the ever parity vs. nulliparous was 0.95 (95% CI: 0.88-1.02, with no heterogeneity (Q = 9.04, P = 0.443, I (2 = 0.5%. Likewise, no significant association was yielded for the highest vs. lowest parity number (RR = 1.02, 95% CI: 0.89-1.17, with moderate heterogeneity (Q = 17.48, P = 0.094, I (2 = 37.1%. Dose-response analysis still indicated no effect of parity on CRC risk and the summary RR of per one livebirth was 0.99 (95% CI: 0.96-1.02, with moderate of heterogeneity (Q = 16.50, P<0.021, I (2 = 57.6%. Similar results were observed among all the subgroup analyses. No evidence of publication bias and significant heterogeneity between subgroups were detected by meta-regression analyses. CONCLUSION: Results of this dose-response meta-analysis of prospective studies found that there was little evidence of an association between parity and CRC risk.

  18. KINETIC SIMULATIONS OF THERMOLUMINESCENCE DOSE RESPONSE: LONG OVERDUE CONFRONTATION WITH THE EFFECTS OF IONISATION DENSITY.

    Science.gov (United States)

    Horowitz, Y S; Eliyahu, I; Oster, L

    2016-12-01

    The reader will time-travel through almost seven decades of kinetic models and mathematical simulations of thermoluminescence (TL) characteristics based on the band-gap theory of the solid state. From post-World-War II, ideas concerning electron trapping mechanisms to the highly idealised one trap-one recombination (OTOR) model first elaborated in 1956 but still in 'high gear' today. The review caresses but purposely avoids in-depth discussion of the endless stream of papers discussing the intricacies of glow peak shapes arising from first-order, second-order, mixed-order and general-order kinetics predominantly based on non-interacting systems, and then on to the more physically realistic scenarios that have attempted to analyse complex systems involving ever greater numbers of interacting trapping centres, luminescent centres and non-luminescent centres. The review emphasises the difficulty the band-gap models have in the simulation of dose response linear/supralinear behaviour and especially the dependence of the supralinearity on ionisation density. The significance of the non-observation of filling-rate supralinearity in the absorption stage is emphasised since it removes from consideration the possibility of TL supralinearity arising from irradiation stage supralinearity. The importance of the simultaneous action of both localised and delocalised transitions has gradually penetrated the mindset of the community of kinetic researchers, but most simulations have concentrated on the shape of glow peaks and the extraction of the glow peak parameters, E (the thermal activation energy) and s (the attempt-to-escape frequency). The simulation of linear/supralinear dose response and its dependence on ionisation density have been largely avoided until recently due to the fundamental schism between the effects of ionisation density and some basic assumptions of the band-gap model. The review finishes with an in-depth presentation and discussion of the most recent

  19. Coffee consumption and risk of fractures: a systematic review and dose-response meta-analysis.

    Science.gov (United States)

    Lee, Dong Ryul; Lee, Jungun; Rota, Matteo; Lee, Juneyoung; Ahn, Hyeong Sik; Park, Sang Min; Shin, Doosup

    2014-06-01

    The data on the association between coffee consumption and the risk of fractures are inconclusive. We performed a comprehensive literature review and meta-analysis to better quantify this association. We identified all potentially relevant articles by searching MEDLINE, EMBASE, Cochrane Library, Web of Science, SCOPUS, and CINAHL (until February 2013). The keywords "coffee," "caffeine," "drink," and "beverage" were used as the exposure factors, and the keyword "fracture" was used as the outcome factor. We determined the overall relative risk (RR) and confidence interval (CI) for the highest and lowest levels of coffee consumption. A dose-response analysis was performed to assess the risk of fractures based on the level of coffee consumption. We included 253,514 participants with 12,939 fracture cases from 9 cohort and 6 case-control studies. The estimated RR of fractures at the highest level of coffee consumption was 1.14 (95% CI: 1.05-1.24; I(2)=0.0%) in women and 0.76 (95% CI: 0.62-0.94; I(2)=7.3%) in men. In the dose-response analysis, the pooled RRs of fractures in women who consumed 2 and 8 cups of coffee per day were 1.02 (95% CI: 1.01-1.04) and 1.54 (95% CI: 1.19-1.99), respectively. Our meta-analysis suggests that daily consumption of coffee is associated with an increased risk of fractures in women and a contrasting decreased risk in men. However, future well-designed studies should be performed to confirm these findings. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Dose-response study of spinal hyperbaric ropivacaine for cesarean section

    Institute of Scientific and Technical Information of China (English)

    CHEN Xin-zhong; CHEN Hong; LOU Ai-fei; L(U) Chang-cheng

    2006-01-01

    Background: Spinal hyperbaric ropivacaine may produce more predictable and reliable anesthesia than plain ropivacaine for cesarean section. The dose-response relation for spinal hyperbaric ropivacaine is undetermined. This double-blind,randomized, dose-response study determined the ED50 (50% effective dose) and ED95 (95% effective dose) of spinal hyperbaric ropivacaine for cesarean section anesthesia. Methods: Sixty parturients undergoing elective cesarean section delivery with use of combined spinal-epidural anesthesia were enrolled in this study. An epidural catheter was placed at the L1~L2 vertebral interspace,then lumbar puncture was performed at the L3~L4 vertebral interspace, and parturients were randomized to receive spinal hyperbaric ropivacaine in doses of 10.5 mg, 12 mg, 13.5 mg, or 15 mg in equal volumes of 3 ml. Sensory levels (pinprick) were assessed every 2.5 min until a T7 level was achieved and motor changes were assessed by modified Bromage Score. A dose was considered effective ifan upper sensory level to pin prick ofT7 or above was achieved and no intraoperative epidural supplement was required. ED50 and ED95 were determined with use of a logistic regression model. Results: ED50 (95% confidence interval)of spinal hyperbaric ropivacaine was determined to be 10.37 (5.23~11.59) mg and ED95 (95% confidence interval) to be 15.39(13.81~23.59) mg. The maximum sensory block levels and the duration of motor block and the rate ofhypotension, but not onset of anesthesia, were significantly related to the ropivacaine dose. Conclusion: The ED50 and ED95 of spinal hyperbaric ropivacaine for cesarean delivery under the conditions of this study were 10.37 mg and 15.39 mg, respectively. Ropivacaine is suitable for spinal anesthesia in cesarean delivery.

  1. A method for inverse bifurcation of biochemical switches: inferring parameters from dose response curves.

    Science.gov (United States)

    Otero-Muras, Irene; Yordanov, Pencho; Stelling, Joerg

    2014-11-20

    Within cells, stimuli are transduced into cell responses by complex networks of biochemical reactions. In many cell decision processes the underlying networks behave as bistable switches, converting graded stimuli or inputs into all or none cell responses. Observing how systems respond to different perturbations, insight can be gained into the underlying molecular mechanisms by developing mathematical models. Emergent properties of systems, like bistability, can be exploited to this purpose. One of the main challenges in modeling intracellular processes, from signaling pathways to gene regulatory networks, is to deal with high structural and parametric uncertainty, due to the complexity of the systems and the difficulty to obtain experimental measurements. Formal methods that exploit structural properties of networks for parameter estimation can help to overcome these problems. We here propose a novel method to infer the kinetic parameters of bistable biochemical network models. Bistable systems typically show hysteretic dose response curves, in which the so called bifurcation points can be located experimentally. We exploit the fact that, at the bifurcation points, a condition for multistationarity derived in the context of the Chemical Reaction Network Theory must be fulfilled. Chemical Reaction Network Theory has attracted attention from the (systems) biology community since it connects the structure of biochemical reaction networks to qualitative properties of the corresponding model of ordinary differential equations. The inverse bifurcation method developed here allows determining the parameters that produce the expected behavior of the dose response curves and, in particular, the observed location of the bifurcation points given by experimental data. Our inverse bifurcation method exploits inherent structural properties of bistable switches in order to estimate kinetic parameters of bistable biochemical networks, opening a promising route for developments in

  2. Mathematical modeling improves EC50 estimations from classical dose-response curves.

    Science.gov (United States)

    Nyman, Elin; Lindgren, Isa; Lövfors, William; Lundengård, Karin; Cervin, Ida; Sjöström, Theresia Arbring; Altimiras, Jordi; Cedersund, Gunnar

    2015-03-01

    The β-adrenergic response is impaired in failing hearts. When studying β-adrenergic function in vitro, the half-maximal effective concentration (EC50 ) is an important measure of ligand response. We previously measured the in vitro contraction force response of chicken heart tissue to increasing concentrations of adrenaline, and observed a decreasing response at high concentrations. The classical interpretation of such data is to assume a maximal response before the decrease, and to fit a sigmoid curve to the remaining data to determine EC50 . Instead, we have applied a mathematical modeling approach to interpret the full dose-response curve in a new way. The developed model predicts a non-steady-state caused by a short resting time between increased concentrations of agonist, which affect the dose-response characterization. Therefore, an improved estimate of EC50 may be calculated using steady-state simulations of the model. The model-based estimation of EC50 is further refined using additional time-resolved data to decrease the uncertainty of the prediction. The resulting model-based EC50 (180-525 nm) is higher than the classically interpreted EC50 (46-191 nm). Mathematical modeling thus makes it possible to re-interpret previously obtained datasets, and to make accurate estimates of EC50 even when steady-state measurements are not experimentally feasible. The mathematical models described here have been submitted to the JWS Online Cellular Systems Modelling Database, and may be accessed at http://jjj.bio.vu.nl/database/nyman. © 2015 FEBS.

  3. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats.

    Directory of Open Access Journals (Sweden)

    Jan B W J Cornelissen

    Full Text Available High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10, and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application.

  4. Probiotics reduce symptoms of antibiotic use in a hospital setting: a randomized dose response study.

    Science.gov (United States)

    Ouwehand, Arthur C; DongLian, Cai; Weijian, Xu; Stewart, Morgan; Ni, Jiayi; Stewart, Tad; Miller, Larry E

    2014-01-16

    Probiotics are known to reduce antibiotic associated diarrhea (AAD) and Clostridium difficile associated diarrhea (CDAD) risk in a strain-specific manner. The aim of this study was to determine the dose-response effect of a four strain probiotic combination (HOWARU(®) Restore) on the incidence of AAD and CDAD and severity of gastrointestinal symptoms in adult in-patients requiring antibiotic therapy. Patients (n=503) were randomized among three study groups: HOWARU(®) Restore probiotic 1.70×10(10) CFU (high-dose, n=168), HOWARU(®) Restore probiotic 4.17×10(9) CFU (low-dose, n=168), or placebo (n=167). Subjects were stratified by gender, age, and duration of antibiotic treatment. Study products were administered daily up to 7 days after the final antibiotic dose. The primary endpoint of the study was the incidence of AAD. Secondary endpoints included incidence of CDAD, diarrhea duration, stools per day, bloody stools, fever, abdominal cramping, and bloating. A significant dose-response effect on AAD was observed with incidences of 12.5, 19.6, and 24.6% with high-dose, low-dose, and placebo, respectively (p=0.02). CDAD was the same in both probiotic groups (1.8%) but different from the placebo group (4.8%; p=0.04). Incidences of fever, abdominal pain, and bloating were lower with increasing probiotic dose. The number of daily liquid stools and average duration of diarrhea decreased with higher probiotic dosage. The tested four strain probiotic combination appears to lower the risk of AAD, CDAD, and gastrointestinal symptoms in a dose-dependent manner in adult in-patients.

  5. An Experimental Toxoplasma gondii Dose Response Challenge Model to Study Therapeutic or Vaccine Efficacy in Cats

    Science.gov (United States)

    Cornelissen, Jan B. W. J.; van der Giessen, Joke W. B.; Takumi, Katsuhisa; Teunis, Peter F. M.; Wisselink, Henk J.

    2014-01-01

    High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10), and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application. PMID:25184619

  6. Aged garlic extract reduces blood pressure in hypertensives: a dose-response trial.

    Science.gov (United States)

    Ried, K; Frank, O R; Stocks, N P

    2013-01-01

    Hypertension affects about 30% of adults worldwide. Garlic has blood pressure-lowering properties and the mechanism of action is biologically plausible. Our trial assessed the effect, dose-response, tolerability and acceptability of different doses of aged garlic extract as an adjunct treatment to existing antihypertensive medication in patients with uncontrolled hypertension. A total of 79 general practice patients with uncontrolled systolic hypertension participated in a double-blind randomised placebo-controlled dose-response trial of 12 weeks. Participants were allocated to one of three garlic groups with either of one, two or four capsules daily of aged garlic extract (240/480/960 mg containing 0.6/1.2/2.4 mg of S-allylcysteine) or placebo. Blood pressure was assessed at 4, 8 and 12 weeks and compared with baseline using a mixed-model approach. Tolerability was monitored throughout the trial and acceptability was assessed at 12 weeks by questionnaire. Mean systolic blood pressure was significantly reduced by 11.8±5.4 mm Hg in the garlic-2-capsule group over 12 weeks compared with placebo (P=0.006), and reached borderline significant reduction in the garlic-4-capsule group at 8 weeks (-7.4±4.1 mm Hg, P=0.07). Changes in systolic blood pressure in the garlic-1-capsule group and diastolic blood pressure were not significantly different to placebo. Tolerability, compliance and acceptability were high in all garlic groups (93%) and highest in the groups taking one or two capsules daily. Our trial suggests aged garlic extract to be an effective and tolerable treatment in uncontrolled hypertension, and may be considered as a safe adjunct treatment to conventional antihypertensive therapy.

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

    Science.gov (United States)

    Schmid, E; Selbach, H-J; Voth, M; Pinkert, J; Gildehaus, F J; Klett, R; Haney, M

    2006-07-01

    The production of dicentric chromosomes in human lymphocytes by beta-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 beta-particles of Y-90 is important for the assessment of radiation risk to the patients. A linear dose-response relationship (alpha = 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 alpha 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.

  8. The energy dependence of the lateral dose response functions of detectors with various densities in photon-beam dosimetry

    Science.gov (United States)

    Khee Looe, Hui; Harder, Dietrich; Poppe, Björn

    2017-02-01

    The lateral dose response function is a general characteristic of the volume effect of a detector used for photon dosimetry in a water phantom. It serves as the convolution kernel transforming the true absorbed dose to water profile, which would be produced within the undisturbed water phantom, into the detector-measured signal profile. The shape of the lateral dose response function characterizes (i) the volume averaging attributable to the detector’s size and (ii) the disturbance of the secondary electron field associated with the deviation of the electron density of the detector material from the surrounding water. In previous work, the characteristic dependence of the shape of the lateral dose response function upon the electron density of the detector material was studied for 6 MV photons by Monte Carlo simulation of a wall-less voxel-sized detector (Looe et al 2015 Phys. Med. Biol. 60 6585-07). This study is here continued for 60Co gamma rays and 15 MV photons in comparison with 6 MV photons. It is found (1) that throughout these photon spectra the shapes of the lateral dose response functions are retaining their characteristic dependence on the detector’s electron density, and (2) that their energy-dependent changes are only moderate. This appears as a practical advantage because the lateral dose response function can then be treated as practically invariant across a clinical photon beam in spite of the known changes of the photon spectrum with increasing distance from the beam axis.

  9. Body Mass Index and Risk of Parkinson's Disease: A Dose-Response Meta-Analysis of Prospective Studies.

    Directory of Open Access Journals (Sweden)

    Yun-Liang Wang

    Full Text Available A number of epidemiologic studies examining the relationship between body mass index (BMI and the future occurrence of Parkinson's disease (PD reported largely inconsistent findings. We conducted a dose-response meta-analysis of prospective studies to clarify this association.Eligible prospective studies were identified by a search of PubMed and by checking the references of related publications. The generalized least squares trend estimation was employed to compute study-specific relative risks (RR and 95% confidence intervals (CI for an increase in BMI of 5 kg/m2, and the random-effects model was used to compute summary RR and 95% CI.A total of 10 prospective studies were included in the final analysis. An increase in BMI of 5 kg/m2 was not associated with PD risk, with a summary RR of 1.00 (95% CI = 0.89-1.12. Results of subgroup analysis found similar results except for a week positive association in studies that adjusted for alcohol consumption (RR = 1.13, 95% CI = 0.99-1.29, and a week inverse association in studies that did not (RR = 0.90, 95% CI = 0.78-1.04. In a separate meta-analysis, no significant association between overweight (25 kg/m2 ≤ BMI ≤29.9 kg/m2, obesity (BMI≥30 kg/m2 or excess weight (BMI≥25 kg/m2 and PD risk was observed.This meta-analysis does not support the notion that higher BMI materially increases PD risk. However, a week positive BMI-PD association that may be masked by confounders still cannot be excluded, and future prospective studies with a good control for potential confounding factors are needed.

  10. Dose-response effect of exercise frequency on bone mineral density in post-menopausal, osteopenic women.

    Science.gov (United States)

    Kemmler, W; von Stengel, S

    2014-06-01

    The purpose of this study was to determine the long-term dose-response relationship of exercise frequency on areal bone mineral density (aBMD) in early post-menopausal women with osteopenia. Based on the 12-year results of the consequently supervised exercise group (EG) of the Erlangen Fitness and Osteoporosis Prevention Study, we retrospectively structured two exercise groups according to the overall exercise frequency. Changes in aBMD at lumbar spine and proximal femur as assessed by dual-energy x-ray absorptiometry technique were compared between a low-frequency exercise group (LEF-EG, n = 16) with 1.5-exercise group (HEF-EG, n = 25) with ≥ 2-3.5 sessions/week. Changes in aBMD at the lumbar spine and proximal femur were significantly more favorable in the HEF-EG compared with the LEF-EG; lumbar spine: (mean value ± standard deviation) 1.1 ± 4.7% vs -4.1 ± 3.0%; P = 0.001, ES: d' = 1.26; total hip: -4.4 ± 3.9% vs -6.7 ± 3.5%, P = 0.045, ES: d' = 0.70). BMD results of the LEF-EG did not significantly differ from the data of the non-training control group (lumbar spine: -4.4 ± 5.2%, total hip: -6.9 ± 5.0%). Although this result might not be generalizable across all exercise types and cohorts, it indicates that to impact bone, an overall exercise frequency of at least 2 sessions/week may be crucial, even if exercise is applied with high intensity/impact.

  11. Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies.

    Science.gov (United States)

    Fedirko, V; Tramacere, I; Bagnardi, V; Rota, M; Scotti, L; Islami, F; Negri, E; Straif, K; Romieu, I; La Vecchia, C; Boffetta, P; Jenab, M

    2011-09-01

    The International Agency for Research on Cancer (IARC) concluded that alcohol consumption is related to colorectal cancer (CRC). However, several issues remain unresolved, including quantification of the association for light (≤1 drink/day) and moderate (2-3 drinks/day) alcohol drinking, investigation of the dose-response relationship, and potential heterogeneity of effects by sex, colorectal site, and geographical region. Twenty-seven cohort and 34 case-control studies presenting results for at least three categories of alcohol intake were identified from a PubMed search of articles published before May 2010. The summary relative risks (RRs) were estimated by the random effects model. Second-order fractional polynomials and random effects meta-regression models were used for modeling the dose-risk relation. The RRs were 1.21 [95% confidence interval (CI) 1.13-1.28] for moderate and 1.52 (95% CI 1.27-1.81) for heavy (≥4 drinks/day) alcohol drinking. The RR for moderate drinkers, compared with non-/occasional drinkers, was stronger for men (RR = 1.24, 95% CI 1.13-1.37) than for women (RR = 1.08, 95% CI 1.03-1.13; P(heterogeneity) = 0.02). For heavy drinkers, the association was stronger in Asian studies (RR = 1.81, 95% CI 1.33-2.46; P(heterogeneity) = 0.04). The dose-risk analysis estimated RRs of 1.07 (95% CI 1.04-1.10), 1.38 (95% CI 1.28-1.50), and 1.82 (95% CI 1.41-2.35) for 10, 50, and 100 g/day of alcohol, respectively. This meta-analysis provides strong evidence for an association between alcohol drinking of >1 drink/day and colorectal cancer risk.

  12. Steroid therapy and the risk of osteonecrosis in SARS patients: a dose-response meta-analysis.

    Science.gov (United States)

    Zhao, R; Wang, H; Wang, X; Feng, F

    2017-03-01

    This meta-analysis synthesized current evidence from 10 trials to evaluate the association between steroid therapy and osteonecrosis incidence in patients with severe acute respiratory syndrome (SARS). Our results suggest that higher cumulative doses and longer treatment durations of steroids are more likely to lead to the development of osteonecrosis in SARS patients. The link between steroid treatment and the risk of osteonecrosis in SARS patients remains unknown. The present meta-analysis aimed to examine the dose-response association between steroid therapy and osteonecrosis incidence in SARS patients. The sex differences in the development of steroid-induced osteonecrosis were also examined. We searched PubMed, Web of Science, CNKI, and WANFANG for studies that involved steroid therapy and reported osteonecrosis data in SARS patients. Two authors independently extracted the data from the individual studies, and the rate ratio (RR) of osteonecrosis was calculated using random-effect models. Ten studies with 1137 recovered SARS patients met the inclusion criteria. Close relationships between osteonecrosis incidence and both the cumulative dose and treatment duration of steroids were observed. The summary RR of osteonecrosis was 1.57 (95% confidence interval (CI) 1.30-1.89, p SARS patients who received higher cumulative doses and longer treatment durations of steroids were more likely to develop osteonecrosis, and there were no sex differences in this dose-dependent side effect. Our findings suggest that it is important to reduce osteonecrosis risk by modifying the cumulative dose and the treatment duration of steroids in SARS patients.

  13. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Dose of High Let Radiation

    Science.gov (United States)

    Hada, M.; George, K.; Chappell, L.; Cucinotta, F. A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (0.01 - 0.20 Gy) of 170 MeV/u Si-28 ions or 600 MeV/u Fe-56 ions, including doses where on average less than one direct ion traversal per cell nucleus occurs. Chromosomes were analyzed using the whole-chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The responses for doses above 0.1 Gy (more than one ion traverses a cell) showed linear dose responses. However, for doses less than 0.1 Gy, both Si-28 ions and Fe-56 ions showed a dose independent response above background chromosome aberrations frequencies. Possible explanations for our results are non-targeted effects due to aberrant cell signaling [1], or delta-ray dose fluctuations [2] where a fraction of cells receive significant delta-ray doses due to the contributions of multiple ion tracks that do not directly traverse cell nuclei where chromosome aberrations are scored.

  14. SU-E-J-51: Dose Response of Common Solid State Detectors in Homogeneous Transverse and Longitudinal Magnetic Fields

    Energy Technology Data Exchange (ETDEWEB)

    Reynolds, M; Fallone, B; Rathee, S [Cross Cancer Institute, Edmonton, AB (Canada)

    2014-06-01

    Purpose: Solid state radiation detectors are often used for dose profiles and percent depth dose measurements. The dose response of selected solid state detectors is evaluated in varying transverse and longitudinal magnetic fields for eventual use in MR-Linac devices. Methods: A PTW 60003 and IBA PFD detector were modeled in the Monte Carlo code PENELOPE, incorporating a magnetic field which was varied in strength and oriented both transversely and longitudinally with respect to the incident photon beam. The detectors' long axis was in turn oriented either parallel or perpendicular to the photon beam. Dose to the active volume of each detector was scored, and its ratio to dose with zero magnetic field strength (dose response) was determined. Accuracy of the simulations was evaluated by measurements using both chambers taken at low field with a small electromagnet. Simulations were also performed in a water phantom to compare to the in air results. Results: Significant dose response was found in transverse field geometries, nearing 20% at 1.5T. The response is highly dependent on relative orientations to the magnetic field and photon beam, and on detector composition. Low field measurements confirm these results. In the presence of longitudinal magnetic fields, the detectors exhibit little dose response, reaching 0.5–1% at 1.5T regardless of detector orientation. Water tank simulations compared well to the in air simulations when not at the beam periphery, where in transverse magnetic fields only, the water tank simulations differed from the in air results. Conclusion: Transverse magnetic fields can cause large deviations in dose response, and are highly position orientation dependent. Comparatively, longitudinal magnetic fields exhibit little to no dose response in each detector as a function of magnetic field strength. Water tank simulations show longitudinal fields are generally easier to work with, but each detector must be evaluated separately.

  15. Dose-responses from multi-model inference for the non-cancer disease mortality of atomic bomb survivors.

    Science.gov (United States)

    Schöllnberger, H; Kaiser, J C; Jacob, P; Walsh, L

    2012-05-01

    The non-cancer mortality data for cerebrovascular disease (CVD) and cardiovascular diseases from Report 13 on the atomic bomb survivors published by the Radiation Effects Research Foundation were analysed to investigate the dose-response for the influence of radiation on these detrimental health effects. Various parametric and categorical models (such as linear-no-threshold (LNT) and a number of threshold and step models) were analysed with a statistical selection protocol that rated the model description of the data. Instead of applying the usual approach of identifying one preferred model for each data set, a set of plausible models was applied, and a sub-set of non-nested models was identified that all fitted the data about equally well. Subsequently, this sub-set of non-nested models was used to perform multi-model inference (MMI), an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. This procedure thereby produces more reliable risk estimates based on a more comprehensive appraisal of model uncertainties. For CVD, MMI yielded a weak dose-response (with a risk estimate of about one-third of the LNT model) below a step at 0.6 Gy and a stronger dose-response at higher doses. The calculated risk estimates are consistent with zero risk below this threshold-dose. For mortalities related to cardiovascular diseases, an LNT-type dose-response was found with risk estimates consistent with zero risk below 2.2 Gy based on 90% confidence intervals. The MMI approach described here resolves a dilemma in practical radiation protection when one is forced to select between models with profoundly different dose-responses for risk estimates.

  16. Dose-responses from multi-model inference for the non-cancer disease mortality of atomic bomb survivors

    Energy Technology Data Exchange (ETDEWEB)

    Schoellnberger, H.; Kaiser, J.C.; Jacob, P. [Institute of Radiation Protection, Helmholtz Zentrum Muenchen, Department of Radiation Sciences, Neuherberg (Germany); Walsh, L. [BfS-Federal Office for Radiation Protection, Neuherberg (Germany)

    2012-05-15

    The non-cancer mortality data for cerebrovascular disease (CVD) and cardiovascular diseases from Report 13 on the atomic bomb survivors published by the Radiation Effects Research Foundation were analysed to investigate the dose-response for the influence of radiation on these detrimental health effects. Various parametric and categorical models (such as linear-no-threshold (LNT) and a number of threshold and step models) were analysed with a statistical selection protocol that rated the model description of the data. Instead of applying the usual approach of identifying one preferred model for each data set, a set of plausible models was applied, and a sub-set of non-nested models was identified that all fitted the data about equally well. Subsequently, this sub-set of non-nested models was used to perform multi-model inference (MMI), an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. This procedure thereby produces more reliable risk estimates based on a more comprehensive appraisal of model uncertainties. For CVD, MMI yielded a weak dose-response (with a risk estimate of about one-third of the LNT model) below a step at 0.6 Gy and a stronger dose-response at higher doses. The calculated risk estimates are consistent with zero risk below this threshold-dose. For mortalities related to cardiovascular diseases, an LNT-type dose-response was found with risk estimates consistent with zero risk below 2.2 Gy based on 90% confidence intervals. The MMI approach described here resolves a dilemma in practical radiation protection when one is forced to select between models with profoundly different dose-responses for risk estimates. (orig.)

  17. The alanine detector in BNCT dosimetry: Dose response in thermal and epithermal neutron fields

    Energy Technology Data Exchange (ETDEWEB)

    Schmitz, T., E-mail: schmito@uni-mainz.de [Institute for nuclear chemistry, Johannes Gutenberg-University, Mainz D-55128 (Germany); Bassler, N. [Department of Physics and Astronomy, Aarhus University, Ny Munkegade 120, Aarhus C, Aarhus 8000 (Denmark); Blaickner, M. [AIT Austrian Institute of Technology GmbH, Vienna A-1220 (Austria); Ziegner, M. [AIT Austrian Institute of Technology GmbH, Vienna A-1220, Austria and TU Wien, Vienna University of Technology, Vienna A-1020 (Austria); Hsiao, M. C. [Insitute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Liu, Y. H. [Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Koivunoro, H. [Department of Physics, University of Helsinki, POB 64, FI-00014, Finland and HUS Medical Imaging Center, Helsinki University Central Hospital, FI-00029 HUS (Finland); Auterinen, I.; Serén, T.; Kotiluoto, P. [VTT Technical Research Centre of Finland, Espoo (Finland); Palmans, H. [National Physical Laboratory, Acoustics and Ionising Radiation Division, Teddington TW11 0LW, United Kingdom and Medical Physics Group, EBG MedAustron GmbH, Wiener Neustadt A-2700 (Austria); Sharpe, P. [National Physical Laboratory, Acoustics and Ionising Radiation Division, Teddington TW11 0LW (United Kingdom); Langguth, P. [Department of Pharmacy and Toxicology, University of Mainz, Mainz D-55128 (Germany); Hampel, G. [Institut für Kernchemie, Johannes Gutenberg-Universität, Mainz D-55128 (Germany)

    2015-01-15

    Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a {sup 60}Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes FLUKA and MCNP. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen and Olsen alanine response model. Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. Conclusions: The

  18. Habitual Chocolate Consumption May Increase Body Weight in a Dose-Response Manner

    Science.gov (United States)

    Greenberg, James A.; Buijsse, Brian

    2013-01-01

    Objective Habitual chocolate intake was recently found to be associated with lower body weight in three cross-sectional epidemiological studies. Our objective was to assess whether these cross-sectional results hold up in a more rigorous prospective analysis. Methods We used data from the Atherosclerosis Risk in Communities cohort. Usual dietary intake was assessed by questionnaire at baseline (1987–98), and after six years. Participants reported usual chocolate intake as the frequency of eating a 1-oz (∼28 g) serving. Body weight and height were measured at the two visits. Missing data were replaced by multiple imputation. Linear mixed-effects models were used to evaluate cross-sectional and prospective associations between chocolate intake and adiposity. Results Data were from 15,732 and 12,830 participants at the first and second visit, respectively. More frequent chocolate consumption was associated with a significantly greater prospective weight gain over time, in a dose-response manner. For instance, compared to participants who ate a chocolate serving less often than monthly, those who ate it 1–4 times a month and at least weekly experienced an increase in Body Mass Index (kg/m2) of 0.26 (95% CI 0.08, 0.44) and 0.39 (0.23, 0.55), respectively, during the six-year study period. In cross-sectional analyses the frequency of chocolate consumption was inversely associated with body weight. This inverse association was attenuated after excluding participants with preexisting obesity-related illness. Compared to participants without such illness, those with it had higher BMI and reported less frequent chocolate intake, lower caloric intake, and diets richer in fruits and vegetables. They tended to make these dietary changes after becoming ill. Conclusions Our prospective analysis found that a chocolate habit was associated with long-term weight gain, in a dose-response manner. Our cross-sectional finding that chocolate intake was associated with lower body

  19. Linearization of dose-response curve of the radiochromic film dosimetry system

    Energy Technology Data Exchange (ETDEWEB)

    Devic, Slobodan; Tomic, Nada; Aldelaijan, Saad; DeBlois, Francois; Seuntjens, Jan; Chan, Maria F.; Lewis, Dave [Medical Physics Unit, McGill University, Montreal, Quebec H3G 1A4 (Canada) and Department of Radiation Oncology, SMBD Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2 (Canada); Executive Administration for Radiation Protection and Safety Medical Devices Sector, Saudi Food and Drug Authority, Riyadh, Kingdom of Saudi Arabia 13312 (Saudi Arabia); Medical Physics Unit, McGill University, Montreal, Quebec H3G 1A4 (Canada) and Department of Radiation Oncology, SMBD Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2 (Canada); Medical Physics Unit, McGill University, Montreal, Quebec H3G 1A4 (Canada); Department of Medical Physics, Memorial Sloan-Kettering Cancer Center Basking Ridge, New Jersey 07920 (United States); Ashland Inc., Wayne, New Jersey 07470 (United States)

    2012-08-15

    Purpose: Despite numerous advantages of radiochromic film dosimeter (high spatial resolution, near tissue equivalence, low energy dependence) to measure a relative dose distribution with film, one needs to first measure an absolute dose (following previously established reference dosimetry protocol) and then convert measured absolute dose values into relative doses. In this work, we present result of our efforts to obtain a functional form that would linearize the inherently nonlinear dose-response curve of the radiochromic film dosimetry system. Methods: Functional form [{zeta}= (-1){center_dot}netOD{sup (2/3)}/ln(netOD)] was derived from calibration curves of various previously established radiochromic film dosimetry systems. In order to test the invariance of the proposed functional form with respect to the film model used we tested it with three different GAFCHROMIC Trade-Mark-Sign film models (EBT, EBT2, and EBT3) irradiated to various doses and scanned on a same scanner. For one of the film models (EBT2), we tested the invariance of the functional form to the scanner model used by scanning irradiated film pieces with three different flatbed scanner models (Epson V700, 1680, and 10000XL). To test our hypothesis that the proposed functional argument linearizes the response of the radiochromic film dosimetry system, verification tests have been performed in clinical applications: percent depth dose measurements, IMRT quality assurance (QA), and brachytherapy QA. Results: Obtained R{sup 2} values indicate that the choice of the functional form of the new argument appropriately linearizes the dose response of the radiochromic film dosimetry system we used. The linear behavior was insensitive to both film model and flatbed scanner model used. Measured PDD values using the green channel response of the GAFCHROMIC Trade-Mark-Sign EBT3 film model are well within {+-}2% window of the local relative dose value when compared to the tabulated Cobalt-60 data. It was also

  20. Quantitative Models of the Dose-Response and Time Course of Inhalational Anthrax in Humans

    Science.gov (United States)

    Schell, Wiley A.; Bulmahn, Kenneth; Walton, Thomas E.; Woods, Christopher W.; Coghill, Catherine; Gallegos, Frank; Samore, Matthew H.; Adler, Frederick R.

    2013-01-01

    Anthrax poses a community health risk due to accidental or intentional aerosol release. Reliable quantitative dose-response analyses are required to estimate the magnitude and timeline of potential consequences and the effect of public health intervention strategies under specific scenarios. Analyses of available data from exposures and infections of humans and non-human primates are often contradictory. We review existing quantitative inhalational anthrax dose-response models in light of criteria we propose for a model to be useful and defensible. To satisfy these criteria, we extend an existing mechanistic competing-risks model to create a novel Exposure–Infection–Symptomatic illness–Death (EISD) model and use experimental non-human primate data and human epidemiological data to optimize parameter values. The best fit to these data leads to estimates of a dose leading to infection in 50% of susceptible humans (ID50) of 11,000 spores (95% confidence interval 7,200–17,000), ID10 of 1,700 (1,100–2,600), and ID1 of 160 (100–250). These estimates suggest that use of a threshold to human infection of 600 spores (as suggested in the literature) underestimates the infectivity of low doses, while an existing estimate of a 1% infection rate for a single spore overestimates low dose infectivity. We estimate the median time from exposure to onset of symptoms (incubation period) among untreated cases to be 9.9 days (7.7–13.1) for exposure to ID50, 11.8 days (9.5–15.0) for ID10, and 12.1 days (9.9–15.3) for ID1. Our model is the first to provide incubation period estimates that are independently consistent with data from the largest known human outbreak. This model refines previous estimates of the distribution of early onset cases after a release and provides support for the recommended 60-day course of prophylactic antibiotic treatment for individuals exposed to low doses. PMID:24058320

  1. Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity.

    Science.gov (United States)

    Calabrese, Vittorio; Cornelius, Carolin; Cuzzocrea, Salvatore; Iavicoli, Ivo; Rizzarelli, Enrico; Calabrese, Edward J

    2011-08-01

    Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by co-ordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as carnosine, carnitines or polyphenols, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response, challenges long-standing beliefs about the nature of the dose-response in a lowdose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. In this review we discuss the most current and up to date

  2. Nano-silver induces dose-response effects on the nematode Caenorhabditis elegans

    DEFF Research Database (Denmark)

    Ellegaard-Jensen, Lea; Alstrup Jensen, Keld; Johansen, Anders

    2012-01-01

    adverse dose-response effects and mortality on C. elegans. LC50 for AgNP28 was lower than for AgNP1 and, hence, at the present test conditions the PVP-coated AgNP28 was more toxic than AgNP1. Including E. coil in the test medium as a food source increased AgNPs toxicity towards nematodes compared to when......Toxicity of nano-formulated silver to eukaryotes was assessed by exposing nematodes (Caenorhabditis elegans) to two types of silver nanoparticles (AgNPs): with average primary particle diameters of 1 nm (AgNP1) and 28 nm (AgNP28, PVP coated), respectively. Tests were performed with and without...... and AgNP28. Higher toxicity of AgNP28 than AgNP1 may be explained by a combination of effects of coating, Ag-solubility and higher uptake rates due to agglomeration into mu m-size agglomerates in the exposure medium. (C) 2012 Elsevier Inc. All rights reserved....

  3. Dose-Response Effect of Sunlight on Vitamin D2 Production in Agaricus bisporus Mushrooms

    DEFF Research Database (Denmark)

    Urbain, Paul; Jakobsen, Jette

    2015-01-01

    The dose response effect of UV-B irradiation from sunlight on vitamin D2 content of sliced Agaricus bisporus (white button mushroom) during the process of sun-drying was investigated.Real-time UV-B and UV-A data were obtained using a high-performance spectroradiometer. During the first hour...... of sunlight exposure, the vitamin D2 content of the mushrooms increased in a linear manner, with concentrations increasing from 0.1 μg/g up to 3.9 ± 0.8 μg/g dry weight (DW). At the subsequent two measurements one and 3 h later, respectively, a plateau was reached. Two hours of additional exposure triggered...... a significant decline in vitamin D2 content. After just 15 min of sun exposure and an UV-B dose of 0.13 J/cm(2), the vitamin D2 content increased significantly to 2.2 ± 0.5 μg/g DW (P vitamin D2 per 100 g of fresh mushrooms and comparable to levels found...

  4. DOSE RESPONSE EFFECT OF Paracoccidioides brasiliensis IN AN EXPERIMENTAL MODEL OF ARTHRITIS

    Directory of Open Access Journals (Sweden)

    Eduardo Alexandre Loth

    2014-06-01

    Full Text Available Paracoccidioidomycosis (PCM is caused by the dimorphic fungus Paracoccidioides brasiliensis (Pb and corresponds to prevalent systemic mycosis in Latin America. The aim of the present work was to evaluate the dose response effect of the fungal yeast phase for the standardization of an experimental model of septic arthritis. The experiments were performed with groups of 14 rats that received doses of 103, 104 or 105 P. brasiliensis (Pb18 cells. The fungi were injected in 50 µL of phosphate-buffered saline (PBS directly into the knee joints of the animals. The following parameters were analyzed in this work: the formation of swelling in knees infused with yeast cells and the radiological and anatomopathological alterations, besides antibody titer by ELISA. After 15 days of infection, signs of inflammation were evident. At 45 days, some features of damage and necrosis were observed in the articular cartilage. The systemic dissemination of the fungus was observed in 11% of the inoculated animals, and it was concluded that the experimental model is able to mimic articular PCM in humans and that the dose of 105 yeast cells can be used as standard in this model.

  5. Dose response effect of Paracoccidioides brasiliensis in an experimental model of arthritis.

    Science.gov (United States)

    Loth, Eduardo Alexandre; Biazim, Samia Khalil; Dos Santos, José Henrique Fermino Ferreira; Puccia, Rosana; Brancalhão, Rosimeire Costa; Chasco, Lucinéia de Fátima; Gandra, Rinaldo Ferreira; Simão, Rita de Cássia Garcia; de Franco, Marcello Fabiano

    2014-01-01

    Paracoccidioidomycosis (PCM) is caused by the dimorphic fungus Paracoccidioides brasiliensis (Pb) and corresponds to prevalent systemic mycosis in Latin America. The aim of the present work was to evaluate the dose response effect of the fungal yeast phase for the standardization of an experimental model of septic arthritis. The experiments were performed with groups of 14 rats that received doses of 103, 104 or 105 P. brasiliensis (Pb18) cells. The fungi were injected in 50 µL of phosphate-buffered saline (PBS) directly into the knee joints of the animals. The following parameters were analyzed in this work: the formation of swelling in knees infused with yeast cells and the radiological and anatomopathological alterations, besides antibody titer by ELISA. After 15 days of infection, signs of inflammation were evident. At 45 days, some features of damage and necrosis were observed in the articular cartilage. The systemic dissemination of the fungus was observed in 11% of the inoculated animals, and it was concluded that the experimental model is able to mimic articular PCM in humans and that the dose of 105 yeast cells can be used as standard in this model.

  6. Ordered multiple comparisons with the best and their applications to dose-response studies.

    Science.gov (United States)

    Strassburger, K; Bretz, F; Finner, H

    2007-12-01

    This article considers the problem of comparing several treatments (dose levels, interventions, etc.) with the best, where the best treatment is unknown and the treatments are ordered in some sense. Order relations among treatments often occur quite naturally in practice. They may be ordered according to increasing risks, such as tolerability or safety problems with increasing dose levels in a dose-response study, for example. We tackle the problem of constructing a lower confidence bound for the smallest index of all treatments being at most marginally less effective than the (best) treatment having the largest effect. Such a bound ensures at confidence level 1 -alpha that all treatments with lower indices are relevantly less effective than the best competitor. We derive a multiple testing strategy that results in sharp confidence bounds. The proposed lower confidence bound is compared with those derived from other testing strategies. We further derive closed-form expressions for power and sample size calculations. Finally, we investigate several real data sets to illustrate various applications of our methods.

  7. Dose-Response Effect of Sunlight on Vitamin D2 Production in Agaricus bisporus Mushrooms.

    Science.gov (United States)

    Urbain, Paul; Jakobsen, Jette

    2015-09-23

    The dose response effect of UV-B irradiation from sunlight on vitamin D2 content of sliced Agaricus bisporus (white button mushroom) during the process of sun-drying was investigated.Real-time UV-B and UV-A data were obtained using a high-performance spectroradiometer. During the first hour of sunlight exposure, the vitamin D2 content of the mushrooms increased in a linear manner, with concentrations increasing from 0.1 μg/g up to 3.9 ± 0.8 μg/g dry weight (DW). At the subsequent two measurements one and 3 h later, respectively, a plateau was reached. Two hours of additional exposure triggered a significant decline in vitamin D2 content. After just 15 min of sun exposure and an UV-B dose of 0.13 J/cm(2), the vitamin D2 content increased significantly to 2.2 ± 0.5 μg/g DW (P < 0.0001), which is equivalent to 17.6 μg (704 IU) vitamin D2 per 100 g of fresh mushrooms and comparable to levels found in fatty fish like the Atlantic salmon.

  8. Threshold estimation based on a p-value framework in dose-response and regression settings

    CERN Document Server

    Mallik, Atul; Banerjee, Moulinath; Michailidis, George

    2011-01-01

    We use p-values to identify the threshold level at which a regression function takes off from its baseline value, a problem motivated by applications in toxicological and pharmacological dose-response studies and environmental statistics. We study the problem in two sampling settings: one where multiple responses can be obtained at a number of different covariate-levels and the other the standard regression setting involving limited number of response values at each covariate. Our procedure involves testing the hypothesis that the regression function is at its baseline at each covariate value and then computing the potentially approximate p-value of the test. An estimate of the threshold is obtained by fitting a piecewise constant function with a single jump discontinuity, otherwise known as a stump, to these observed p-values, as they behave in markedly different ways on the two sides of the threshold. The estimate is shown to be consistent and its finite sample properties are studied through simulations. Ou...

  9. Inhibition of food-stimulated acid secretion (intragastric titration) by roxatidine acetate. Dose-response study.

    Science.gov (United States)

    Bonfils, S; Chen, W W; Vatier, J

    1988-01-01

    In 10 healthy male volunteers a dose-response study was carried out with roxatidine acetate, 75, 150, 300, and 600 mg, and placebo on food-stimulated gastric acid secretion (intragastric titration (IGT]. The design of the study, with drug intake 150 min before starting IGT, enabled stable inhibition over the 90-min observation period of the test. Cumulative secretory results showed a dose-related acid secretion inhibition (67% for 75 mg; 87.6% for 150 mg; 98.8% for 300 mg; 99.6% for 600 mg). The results were statistically significantly different from placebo and from each other, except for 300 mg versus 600 mg. With a Lineweaver-Burk plot, the ED50 was 41 mg and r = 0.98. Peak concentrations of roxatidine were observed either at T 150 or T 180. Significant correlation (r = 0.7; p less than 0.001) was obtained for the percentage inhibition with 75 mg and 150 mg together versus peak concentrations. Antisecretory potency with the IGT model applied to normal subjects appears to be of the same order for roxatidine acetate and for ranitidine.

  10. Increasing food deprivation relative to baseline influences D-amphetamine dose-response gradients.

    Science.gov (United States)

    Lotfizadeh, Amin D; Zimmermann, Zachary J; Watkins, Erin E; Edwards, Timothy L; Poling, Alan

    2014-10-01

    Several studies using non-pharmacological discriminative stimuli have found that stimulus control, as evident in generalization gradients, changes when motivation for (i.e., deprivation of) the relevant reinforcer is altered. Drug-discrimination studies, however, have not consistently revealed such an effect. A procedural detail that may account for the lack of a reliable effect in drug-discrimination studies is that motivation was characteristically reduced relative to the training condition in these studies. The present experiment examined how substantially increasing motivation affects D-amphetamine discrimination. Rats initially were trained to discriminate D-amphetamine (1.0 mg/kg) from vehicle (0 mg/kg) injections under 22-h food deprivation conditions. Dose-response gradients were then obtained under 22-h and 46-h deprivation levels. The ED50 was significantly higher with greater deprivation. This finding suggests that increasing motivation relative to the training condition may reduce stimulus control by drugs, while decreasing it may sharpen stimulus control. Copyright © 2014. Published by Elsevier Inc.

  11. Melatonin entrains free-running blind people according to a physiological dose-response curve.

    Science.gov (United States)

    Lewy, Alfred J; Emens, Jonathan S; Lefler, Bryan J; Yuhas, Krista; Jackman, Angela R

    2005-01-01

    The specific circadian role proposed for endogenous melatonin production was based on a study of sighted people who took low pharmacological doses (500 microg) of this chemical signal for the "biological night": the magnitude and direction of the induced phase shifts were dependent on what time of day exogenous melatonin was administered and were described by a phase-response curve that turned out to be the opposite of that for light. We now report that lower (physiological) doses of up to 300 microg can entrain (synchronize) free-running circadian rhythms of 10 totally blind subjects that would otherwise drift later each day. The resulting log-linear dose-response curve in the physiological range adds support for a circadian function of endogenous melatonin in humans. Efficacy of exogenous doses in the physiological range are of clinical significance for totally blind people who will need to take melatonin daily over their entire lifetimes in order to remain entrained to the 24 h day. Left untreated, their free-running endocrine, metabolic, behavioral, and sleep/wake cycles can be almost as burdensome as not having vision.

  12. Dose-response modeling in mental health using stein-like estimators with instrumental variables.

    Science.gov (United States)

    Ginestet, Cedric E; Emsley, Richard; Landau, Sabine

    2017-02-21

    A mental health trial is analyzed using a dose-response model, in which the number of sessions attended by the patients is deemed indicative of the dose of psychotherapeutic treatment. Here, the parameter of interest is the difference in causal treatment effects between the subpopulations that take part in different numbers of therapy sessions. For this data set, interactions between random treatment allocation and prognostic baseline variables provide the requisite instrumental variables. While the corresponding two-stage least squares (TSLS) estimator tends to have smaller bias than the ordinary least squares (OLS) estimator; the TSLS suffers from larger variance. It is therefore appealing to combine the desirable properties of the OLS and TSLS estimators. Such a trade-off is achieved through an affine combination of these two estimators, using mean squared error as a criterion. This produces the semi-parametric Stein-like (SPSL) estimator as introduced by Judge and Mittelhammer (2004). The SPSL estimator is used in conjunction with multiple imputation with chained equations, to provide an estimator that can exploit all available information. Simulated data are also generated to illustrate the superiority of the SPSL estimator over its OLS and TSLS counterparts. A package entitled SteinIV implementing these methods has been made available through the R platform. © 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

  13. Linearization of EBT3 film dose response and virtual film dosimetry for SBRT quality assurance

    Science.gov (United States)

    Cai, M.; Archibald-Heeren, B.; Wang, Y.; Metcalfe, P.

    2017-01-01

    EBT3 film offers high spatial resolution and low energy dependence, making it a suitable choice for quality assurance where high dose gradients are present, such as the case for SBRT. This work presents a simple method to adjust scanner settings so that dose response becomes linear. This linearity eliminates the need to obtain a calibration curve and associated uncertainties in curve fitting. Relative dosimetry can be performed after dose normalization to a reference point. Linearity is also a more robust condition than calibration curve with respect to scanner warm-up conditions, resulting in reduced uncertainty in dose measurement. An in-house developed program reads the film scan and a 2D dose map then constructs both to virtual films using grayscale values. Film intensity value was normalized to dose at reference point. Relative dosimetry was performed by comparing the two resulting images. Patient specific quality assurance was conducted for two SBRT cases. In both plans more than 95% gamma function points passed the gamma criteria of 2%/3mm.

  14. Aldrin and dieldrin: a reevaluation of the cancer and noncancer dose-response assessments.

    Science.gov (United States)

    Hooker, Eric P; Fulcher, Keri G; Gibb, Herman J

    2014-05-01

    The dose-response analyses of cancer and noncancer health effects of aldrin and dieldrin were evaluated using current methodology, including benchmark dose analysis and the current U.S. Environmental Protection Agency (U.S. EPA) guidance on body weight scaling and uncertainty factors. A literature review was performed to determine the most appropriate adverse effect endpoints. Using current methodology and information, the estimated reference dose values were 0.0001 and 0.00008 mg/kg-day for aldrin and dieldrin, respectively. The estimated cancer slope factors for aldrin and dieldrin were 3.4 and 7.0 (mg/kg-day)(-1), respectively (i.e., about 5- and 2.3-fold lower risk than the 1987 U.S. EPA assessments). Because aldrin and dieldrin are no longer used as pesticides in the United States, they are presumed to be a low priority for additional review by the U.S. EPA. However, because they are persistent and still detected in environmental samples, quantitative risk assessments based on the best available methods are required. Recent epidemiologic studies do not demonstrate a causal association between aldrin and dieldrin and human cancer risk. The proposed reevaluations suggest that these two compounds pose a lower human health risk than currently reported by the U.S. EPA. © 2013 Society for Risk Analysis.

  15. Herbicide toxicity, selectivity and hormesis of nicosulfuron on 10 Trichogrammatidae (Hymenoptera) species parasitizing Anagasta ( = Ephestia) kuehniella (Lepidoptera: Pyralidae) eggs.

    Science.gov (United States)

    Leite, Germano L D; de Paulo, Paula D; Zanuncio, José C; Tavares, Wagner De S; Alvarenga, Anarelly C; Dourado, Luan R; Bispo, Edilson P R; Soares, Marcus A

    2017-01-02

    Selective agrochemicals including herbicides that do not affect non-target organisms such as natural enemies are important in the integrated pest management (IPM) programs. The aim of this study was to evaluate the herbicide toxicity, selectivity and hormesis of nicosulfuron, recommended for the corn Zea mays L. (Poaceae) crop, on 10 Trichogrammatidae (Hymenoptera) species. A female of each Trichogramma spp. or Trichogrammatoidea annulata De Santis, 1972 was individually placed in plastic test tubes (no choice) with a cardboard containing 45 flour moth Anagasta ( = Ephestia) kuehniella Zeller, 1879 (Lepidoptera: Pyralidae) eggs. Parasitism by these natural enemies was allowed for 48 h and the cardboards were sprayed with the herbicide nicosulfuron at 1.50 L.ha(-1), along with the control (only distilled water). Nicosulfuron reduced the emergence rate of Trichogramma bruni Nagaraja, 1983 females, but increased that of Trichogramma pretiosum Riley, 1879, Trichogramma acacioi Brun, Moraes and Smith, 1984 and T. annulata females. Conversely, this herbicide increased the emergence rate of Trichogramma brasiliensis Ashmead, 1904, T. bruni, Trichogramma galloi Zucchi, 1988 and Trichogramma soaresi Nagaraja, 1983 males and decreased those of T. acacioi, Trichogramma atopovilia Oatman and Platner, 1983 and T. pretiosum males. In addition, nicosulfuron reduced the sex ratio of T. galloi, Trichogramma bennetti Nagaraja and Nagarkatti, 1973 and T. pretiosum and increased that of T. acacioi, T. bruni, T. annulata, Trichogramma demoraesi Nagaraja, 1983, T. soaresi and T. brasiliensis. The herbicide nicosulfuron was "harmless" (class 1, <30% reduction) for females and the sex ratio of all Trichogrammatidae species based on the International Organization for Biological Control (IOBC) classification. The possible hormesis effect of nicosulfuron on Trichogrammatidae species and on the bacterium Wolbachia sp. (Rickettsiales: Rickettsiaceae) was also discussed.

  16. Dairy Consumption and Incidence of Hypertension : A Dose-Response Meta-Analysis of Prospective Cohort Studies

    NARCIS (Netherlands)

    Soedamah-Muthu, S.S.; Verberne, L.D.M.; Ding, E.L.; Engberink, M.F.; Geleijnse, J.M.

    2012-01-01

    Dairy Consumption and Incidence of Hypertension : A Dose-Response Meta-Analysis Prospective Cohort Studies Sabita S. Soedamah-Muthu, Lisa D.M. Verberne, Eric L. Ding, Mariëlle F. Engberink and Johanna M. Geleijnse Hypertension. published online September 17, 2012; Hypertension is published by the Am

  17. Low dose effects and non-monotonic dose responses for endocrine active chemicals: Science to practice workshop: Workshop summary

    DEFF Research Database (Denmark)

    Beausoleil, Claire; Ormsby, Jean-Nicolas; Gies, Andreas

    2013-01-01

    A workshop was held in Berlin September 12–14th 2012 to assess the state of the science of the data supporting low dose effects and non-monotonic dose responses (“low dose hypothesis”) for chemicals with endocrine activity (endocrine disrupting chemicals or EDCs). This workshop consisted...

  18. Dose-Response Analysis of RNA-Seq Profiles in Archival Formalin-Fixed Paraffin-Embedded (FFPE) Samples.

    Science.gov (United States)

    Use of archival resources has been limited to date by inconsistent methods for genomic profiling of degraded RNA from formalin-fixed paraffin-embedded (FFPE) samples. RNA-sequencing offers a promising way to address this problem. Here we evaluated transcriptomic dose responses us...

  19. Dose-Response Analysis of RNA-Seq Profiles in Archival Formalin-fixed paraffin-embedded (FFPE) Samples

    Science.gov (United States)

    Formalin-fixed paraffin-embedded (FFPE) samples provide a vast untapped resource for chemical safety and translational science. To date, genomic profiling of FFPE samples has been limited by poor RNA quality and inconsistent results with limited utility in dose-response assessmen...

  20. Nonmonotonic Dose Responses as They Apply to Estrogen, Androgen, and Thyroid Pathways and EPA Testing and Assessment Procedures

    Science.gov (United States)

    A state of the science document providing a judgment on the degree to which nonmonotonic dose-responses are evidenced in the scientific literature and to evaluate the extent to which they may impact U.S. EPA’s chemical testing and risk assessment.

  1. Fundamental investigations of natural and laboratory generated SAR dose response curves for quartz OSL in the high dose range

    DEFF Research Database (Denmark)

    Timar-Gabor, Alida; Constantin, Daniela; Buylaert, Jan-Pieter;

    2015-01-01

    SAR-OSL investigations on quartz from Romanian loess resulted in non concordant fine and coarse-grain ages for equivalent doses higher than ~100 Gy. The laboratory dose response for both grain sizes is well represented by a sum of two saturating exponential functions, fine and coarse grains chara...

  2. Dairy consumption is inversely associated with type 2 diabetes: dose-response meta-analysis of prospective cohort studies

    NARCIS (Netherlands)

    Gijsbers, L.; Geleijnse, J.M.; Soedamah-Muthu, S.S.

    2011-01-01

    Observational studies suggest an inverse association between dairy intake and incident type 2 diabetes, but the quantity of dairy is not known. Previous meta-analyses did not take into account the type of dairy product. Therefore, we examined dose-response associations between the intake of total

  3. Dose-response relations between occupational exposures to physical and psychosocial factors and the risk of low back pain.

    NARCIS (Netherlands)

    H. Morgenstern; A. Burdorf (Alex); J.P. Jansen (Jeroen)

    2004-01-01

    textabstractAIMS: To assess dose-response relations between occupational exposures to physical and psychosocial factors and the risk of low back pain. METHODS: A cohort of 523 subjects, working in nursing homes and homes for the elderly, was followed prospectively for one year. Phy

  4. Influence of lung parenchymal destruction on the different indexes of the methacholine dose-response curve in COPD patients

    NARCIS (Netherlands)

    G.T. Verhoeven; A.F.M. Verbraak (Anton); S. Boere-van der Straat; H.C. Hoogsteden (Henk); J.M. Bogaard (Jan)

    2000-01-01

    textabstractSTUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose-response curves in COPD is still a matter of debate. Bronchial hyperresponsiveness (BHR) in patients with COPD could be influenced by the destruction of the parenchyma and the aug

  5. Dose-Response Analysis of RNA-Seq Profiles in Archival Formalin-Fixed Paraffin-Embedded (FFPE) Samples.

    Science.gov (United States)

    Use of archival resources has been limited to date by inconsistent methods for genomic profiling of degraded RNA from formalin-fixed paraffin-embedded (FFPE) samples. RNA-sequencing offers a promising way to address this problem. Here we evaluated transcriptomic dose responses us...

  6. Construction and validation of a dose-response curve using the comet assay to determine human radiosensitivity to ionizing radiation.

    Science.gov (United States)

    Güerci, A; Zúñiga, L; Marcos, R

    2011-01-01

    Individual radiosensitivity is an individual characteristic associated with an increased reaction to ionizing radiation. The purpose of our work is to establish a dose-response curve useful to classify individuals as radiosensitive or radioresistant. Thus, a dose-response curve was constructed by measuring in vitro responses to increasing doses (0 to 8 Gy) of gamma radiation in the comet assay. The obtained curve fit well with a linear equation in the range of 0 to 8 Gy. The overall dose-response curve was constructed for percent DNA in tail, as a measure of the genetic damage induced by irradiation. To probe the goodness of the constructed curve, a validation study was carried out with whole blood from two donors in a blind study. Results show that, for the two applied doses (2 and 6 Gy), the obtained values fit well inside the interval of confidence of the curve. In conclusion, our results demonstrate the usefulness of the comet assay in determining individual responses to defined doses of gamma radiation. The standard dose-response curve constructed may be used to detect individuals departing from reference values.

  7. Dose response on the 110 °C thermoluminescence peak of un-heated, synthetic Merck quartz

    Energy Technology Data Exchange (ETDEWEB)

    Kaya Keleş, Şule, E-mail: sule.kaya@ankara.edu.tr; Meriç, Niyazi; Polymeris, George S.

    2016-07-15

    Studies on 110 °C TL peak have been carried out using natural quartz from different origins and synthetic quartz produced by different suppliers. The interest in quartz is due to its usage in dating and retrospective dosimetry as a main material; both synthetic and natural types of quartz yield the 110 °C TL peak in their glow curve. In most studies to understand the physical mechanism behind the TL system, synthetic quartz samples are used and there are many investigations about dose response, in both low and high radiation dose region. In these studies generally synthetic quartz samples produced by Sawyer Research Products are used and the studies showed that both heated and un-heated synthetic quartz samples have intense supra-linear responses. Supra-linearity was enhanced by applying a pre-irradiation while several models have been developed towards an explanation to these supra-linearity effects. In this study commercially available synthetic Merck quartz was used. Different combinations of optical filters were used to obtain dose response curves upto 266 Gy and the effect of pre-dose to these dose response curves was studied. Un-pre-dosed Merck quartz samples dose supra-linearity index is below 1 independently on the optical filters; so Merck quartz showed linear or sub-linear dose response.

  8. Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose response (BBDR) Model***

    Science.gov (United States)

    A biologically-based dose response (BBDR) model for the hypothalamic-pituitary thyroid (HPT) axis in the lactating rat and nursing pup was developed to describe the perturbations caused by iodide deficiency on the 1-IPT axis. Model calibrations, carried out by adjusting key model...

  9. Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model

    Science.gov (United States)

    A biologically-based dose response (BBDR) model for the hypothalamic-pituitary thyroid (BPT) axis in the lactating rat and nursing pup was developed to describe the perturbations caused by iodide deficiency on the HPT axis. Model calibrations, carried out by adjusting key model p...

  10. Dose-response and concentration-response relation of rocuronium infusion during propofol nitrous oxide and isoflurane nitrous oxide anaesthesia

    NARCIS (Netherlands)

    Kansanaho, M; Olkkola, KT; Wierda, JMKH

    1997-01-01

    The dose-response and concentration-response relation of rocuronium infusion was studied in 20 adult surgical patients during proporfol-nitrous oxide and isoflurane (1 MAC) -nitrous oxide anaesthesia. Neuromuscular block was kept constant, initially at 90% and then at 50% with a closed-loop feedback

  11. Effects of the pre-irradiation storage procedure on the dose response of a Fricke xylenol orange gel dosimeter

    Directory of Open Access Journals (Sweden)

    Liosi Giulia Maria

    2015-09-01

    Full Text Available The Fricke xylenol orange (FX gel system is a chemical dosimeter characterized by good sensitivity, linear dose response, tissue equivalence, no toxicity, easy preparation, reproducibility and low cost. Thanks to the presence of the gelatinous matrix, the system is particularly suitable to perform reliable 3D mapping of the absorbed dose spatial distribution via magnetic resonance imaging (MRI or optical techniques. The aim of this work is to study in a systematic way the influence of the pre-irradiation storage procedure upon sensitivity, dose response stability and lifetime of use of a FX gel system made with gelatin from porcine skin subjected to homogeneous irradiation. For this purpose, different pre-irradiation storage procedures, in terms of temperature and duration of each storage step, were investigated. In order to evaluate the dose response stability, the optical analyses of the samples were performed up to 6 hours after irradiation. Moreover, the samples were irradiated at time intervals of 24 hours for up to 7 days after preparation in order to evaluate the system lifetime of use. Regardless of their thermal and temporal life, the samples show linear dose responses in the investigated dose range (3-24 Gy and an increase of sensitivity with the time elapsed between preparation and irradiation. Among the three pre-irradiation storage procedures considered here, a procedure that provides the best dose response stability and lifetime of use was identified and recommended for further use. The analyzed dosimetric system possesses good properties that make it promising for medical application, particularly concerning the evaluation of pre-treatment plan quality assurance within the conformational external beam radiotherapy

  12. Parity and pancreatic cancer risk: a dose-response meta-analysis of epidemiologic studies.

    Directory of Open Access Journals (Sweden)

    Hong-Bo Guan

    Full Text Available BACKGROUND: Previous epidemiologic studies have reported inconsistent results between parity and pancreatic cancer (PC risk. To our knowledge, a comprehensive and quantitative assessment of this association has not been conducted. METHODS: Relevant published studies of parity and PC were identified using MEDLINE (PubMed and Web of Science databases until November 2013. Two authors (H-BG and LW independently assessed eligibility and extracted data. Eleven prospective and 11 case-control studies reported relative risk (RR estimates and 95% confidence intervals (CIs of PC associated with parity. Fixed- and random-effects models were used to estimate the summary RR depending on the heterogeneity of effects. RESULTS: The summary RR for PC comparing the highest versus lowest parity was 0.86 (95% CI: 0.73-1.02; Q = 50.49, P<0.001, I2 = 58.4%. Significant inverse associations were also observed in the studies that adjusted for cigarette smoking (RR = 0.81; 95% CI: 0.68-0.98, Type 2 diabetes mellitus (RR = 0.83; 95% CI: 0.75-0.93, and those that included all confounders or important risk factors (RR = 0.85; 95% CI: 0.76-0.96. Additionally, in the dose-response analysis, the summary RR for per one live birth was 0.97 (95% CI: 0.94-1.01; Q = 62.83, P<0.001, I2 = 69.8%, which also indicated a borderline statistically significant inverse effect of parity on PC risk. No evidence of publication bias and significant heterogeneity between subgroups were detected by meta-regression analyses. CONCLUSION: In summary, these findings suggest that higher parity is associated with a decreased risk of PC. Future large consortia or pooled studies are warranted to fully adjust for potential confounders to confirm this association.

  13. Qualitative and quantitative approaches in the dose-response assessment of genotoxic carcinogens.

    Science.gov (United States)

    Fukushima, Shoji; Gi, Min; Kakehashi, Anna; Wanibuchi, Hideki; Matsumoto, Michiharu

    2016-05-01

    Qualitative and quantitative approaches are important issues in field of carcinogenic risk assessment of the genotoxic carcinogens. Herein, we provide quantitative data on low-dose hepatocarcinogenicity studies for three genotoxic hepatocarcinogens: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN). Hepatocarcinogenicity was examined by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, which are the preneoplastic lesions in rat hepatocarcinogenesis and the endpoint carcinogenic marker in the rat liver medium-term carcinogenicity bioassay. We also examined DNA damage and gene mutations which occurred through the initiation stage of carcinogenesis. For the establishment of points of departure (PoD) from which the cancer-related risk can be estimated, we analyzed the above events by quantitative no-observed-effect level and benchmark dose approaches. MeIQx at low doses induced formation of DNA-MeIQx adducts; somewhat higher doses caused elevation of 8-hydroxy-2'-deoxyquanosine levels; at still higher doses gene mutations occurred; and the highest dose induced formation of GST-P positive foci. These data indicate that early genotoxic events in the pathway to carcinogenesis showed the expected trend of lower PoDs for earlier events in the carcinogenic process. Similarly, only the highest dose of IQ caused an increase in the number of GST-P positive foci in the liver, while IQ-DNA adduct formation was observed with low doses. Moreover, treatment with DEN at low doses had no effect on development of GST-P positive foci in the liver. These data on PoDs for the markers contribute to understand whether genotoxic carcinogens have a threshold for their carcinogenicity. The most appropriate approach to use in low dose-response assessment must be approved on the basis of scientific judgment.

  14. Energy crop (Sida hermaphrodita) fertilization using digestate under marginal soil conditions: A dose-response experiment

    Science.gov (United States)

    Nabel, Moritz; Bueno Piaz Barbosa, Daniela; Horsch, David; Jablonowski, Nicolai David

    2014-05-01

    The global demand for energy security and the mitigation of climate change are the main drivers pushing energy-plant production in Germany. However, the cultivation of these plants can cause land use conflicts since agricultural soil is mostly used for plant production. A sustainable alternative to the conventional cultivation of food-based energy-crops is the cultivation of special adopted energy-plants on marginal lands. To further increase the sustainability of energy-plant cultivation systems the dependency on synthetic fertilizers needs to be reduced via closed nutrient loops. In the presented study the energy-plant Sida hermaphrodita (Malvaceae) will be used to evaluate the potential to grow this high potential energy-crop on a marginal sandy soil in combination with fertilization via digestate from biogas production. With this dose-response experiment we will further identify an optimum dose, which will be compared to equivalent doses of NPK-fertilizer. Further, lethal doses and deficiency doses will be observed. Two weeks old Sida seedlings were transplanted to 1L pots and fertilized with six doses of digestate (equivalent to a field application of 5, 10, 20, 40, 80, 160t/ha) and three equivalent doses of NPK-fertilizer. Control plants were left untreated. Sida plants will grow for 45 days under greenhouse conditions. We hypothesize that the nutrient status of the marginal soil can be increased and maintained by defined digestate applications, compared to control plants suffering of nutrient deficiency due to the low nutrient status in the marginal substrate. The dose of 40t/ha is expected to give a maximum biomass yield without causing toxicity symptoms. Results shall be used as basis for further experiments on the field scale in a field trial that was set up to investigate sustainable production systems for energy crop production under marginal soil conditions.

  15. Dose-response effects of atropine and HI-6 treatment of organophosphorus poisoning in guinea pigs

    Energy Technology Data Exchange (ETDEWEB)

    Koplovitz, I.; Menton, R.; Matthews, C.; Shutz, M.; Nalls, C.

    1995-12-31

    H1-6 (1-2-hydrnxyiminomethyl-1 pyridino-3-(4-carbameyl- 1--pyddino)-2- oxaprnpane dichioride) has been evaluated as an oxime alternative to pralidoxime, and toxogonin in the treatment of organophosphorus (OP) poisoning. The dose response effects of atropine (ATR) and HI-6 were investigated to more fully explore the interaction of these compounds in the treatment of OP poisoning. ATR, HI-6 and various combinations of the two drugs were evaluated against lethal poisoning by soman (GD) and tabun (GA) in guinea pigs. The effect of adjunctive diazepam treatment on the efficacy of atropine and HI-6 against soman was also investigated. Animals of either sex were challenged s.c. with OP and treated i.m. 1 min later with ATR and/or HI-6. When used, diazepam was injected immediately after ATR+HI6. LD50s of each treatment were calculated from probit models based on 24-hour survival against 5 levels of nerve agent and 6 animals per challenge level. A protective index (PI) was calculated by dividing the nerve agent LD50 in the presence of treatment by the LD50 in the absence of treatment. Treatment with HI-6 alone had little effect on the toxicity of either OP. Treatment with ATR alone was more effective than HI-6 alone and was significantly more effective against soman than against tabun. When used in combination atropine and HI-6 had a strong synergistic effect against both agents. The dose of atropine used with HI-6 was critical in determining the efficacy of HI-6 against either agent. The slopes of the dose-lethality curves were minimally affected by the dose of ATR or HI-6. Adjunctive treatment with diazepam enhanced the efficacy of HI-6 and atropine against soman.

  16. Dose-response of EBT3 radiochromic films to proton and carbon ion clinical beams

    Science.gov (United States)

    Castriconi, Roberta; Ciocca, Mario; Mirandola, Alfredo; Sini, Carla; Broggi, Sara; Schwarz, Marco; Fracchiolla, Francesco; Martišíková, Mária; Aricò, Giulia; Mettivier, Giovanni; Russo, Paolo

    2017-01-01

    We investigated the dose-response of the external beam therapy 3 (EBT3) films for proton and carbon ion clinical beams, in comparison with conventional radiotherapy beams; we also measured the film response along the energy deposition-curve in water. We performed measurements at three hadrontherapy centres by delivering monoenergetic pencil beams (protons: 63-230 MeV; carbon ions: 115-400 MeV/u), at 0.4-20 Gy dose to water, in the plateau of the depth-dose curve. We also irradiated the films to clinical MV-photon and electron beams. We placed the EBT3 films in water along the whole depth-dose curve for 148.8 MeV protons and 398.9 MeV/u carbon ions, in comparison with measurements provided by a plane-parallel ionization chamber. For protons, the response of EBT3 in the plateau of the depth-dose curve is not different from that of photons, within experimental uncertainties. For carbon ions, we observed an energy dependent under-response of EBT3 film, from 16% to 29% with respect to photon beams. Moreover, we observed an under-response in the Bragg peak region of about 10% for 148.8 MeV protons and of about 42% for 398.9 MeV/u carbon ions. For proton and carbon ion clinical beams, an under-response occurs at the Bragg peak. For carbon ions, we also observed an under-response of the EBT3 in the plateau of the depth-dose curve. This effect is the highest at the lowest initial energy of the clinical beams, a phenomenon related to the corresponding higher LET in the film sensitive layer. This behavior should be properly modeled when using EBT3 films for accurate 3D dosimetry.

  17. Dose-response study of sodium cromoglycate in exercise-induced asthma.

    Science.gov (United States)

    Patel, K R; Berkin, K E; Kerr, J W

    1982-01-01

    Ten patients with exercise-induced asthma participated in a single-blind dose-response study comparing the protective effect of inhaled sodium cromoglycate in increasing concentrations from 2 to 40 mg/ml. Saline was used as a control. Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second (FEV1) after the patients had run on a treadmill for eight minutes. There was slight bronchodilation evident from the increase in baseline FEV1 after inhalation of sodium cromoglycate, the difference reaching statistical significance with the highest concentration (5.7%, p less than 0.05). After exercise the maximal percentage falls in FEV1 (means and SEM) after saline and after sodium cromoglycate at 2, 10, 20, and 40 mg/ml were 37.3 +/- 4.7, 17.3 +/- 4.1, 10 +/- 3.3, 7.6 +/- 2.4, and 12 +/- 2.9. Sodium cromoglycate inhibited the exercise-induced fall in FEV1 at all the concentrations used in the study (p less than 0.001) and its inhibitory effect increased from 2 to 20 mg/ml. The mean FEV1 returned to baseline values within 15 minutes at higher concentrations of sodium cromoglycate (20 and 40 mg/ml) and a small bronchodilator effect was noted at 30 minutes. The findings suggest that the protective effect of sodium cromoglycate in exercise asthma is dose related. At higher concentration the drug suppresses chemical mediator release from the lung mast cells and may also modify the bronchial reactivity to release mediators. PMID:6818707

  18. Paradigmenwechsel in der Anti-Aging-Medizin: Hormesis, Target-of-Rapamycin-Komplex und erste Anti-Aging-Pillen // Paradigm Shift in Anti-Aging Medicine: Hormesis, Target of Rapamycin Complex and First Human Anti-Aging-Pills

    Directory of Open Access Journals (Sweden)

    Römmler A

    2016-01-01

    Full Text Available Studies in model organisms have shown that some drugs and lifestyle practices (calorie-restricted diets, regular exercise, e.g. can extend life and health span and protect against the onset of age-related chronic diseases by targeting physiological pathways.brA common mode of action was found via mTOR (mechanistic Target Of Rapamycin pathway signalling. This intracellular protein kinase complex plays a key role in stimulating anabolic and cell growth promoting processes, while inhibiting autophagy. On the other hand, downregulation results in antiproliferative, anticancer and intensive cell-repairing effects leading to life and health span extension and stress resistance. The mTOR complex regulates such basic cell activities and integrates signals from nutrition sensing, energy metabolism, insulin and growth factors, stress and hypoxia.brImportantly, mTOR can be inhibited by some molecules and their analogs (rapamycin, resveratrol, metformin, e.g., which are released naturally from plants, yeast or bacteria to protect against natural enemies. Its dosage resembles an adaptive hormetic response relationship, as high concentrations are toxic and mild doses are associated with anticancer and antiaging effects. This opens up new avenues for their use as „anti-aging pills“ in humans.brRecent human data suggest that metformin, rapamycin and other mTOR-inhibitors could delay heart disease, cancer, cognitive decline and improve survival time in people with diabetes mellitus. In addition, response to influenca vaccine was enhanced by rapamycin in adults with immunosenescence, indicating beneficial anti-aging effects in the elderly.br“Treat aging” is an actual call to recognize aging as an indication appropriate for clinical trials and treatments, as it was recently approved by the Federal Drug Administration (FDA USA. p bKurzfassung/b: Die ansteigende Morbidität und Invalidität in alternden Industrienationen stößt an die Grenzen der Ressourcen

  19. Fat Intake Is Not Linked to Prostate Cancer: A Systematic Review and Dose-Response Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Chang Xu

    Full Text Available Since the late 1960s, the average global supply of fat has increased by 20 g per capita per day. While fat intake has been considered a potential risk factor for prostate cancer (Pca, the hypothesis from previous epidemiologic studies remained equivocal.Relevant cohort studies were identified through a literature search in PubMed, ScienceDirect and Wiley Online Library up to March 1, 2015. A systematic review and dose-response meta-analysis were used to assess the relationship between fat intake and the risk for Pca.We identified 14 cohort studies, which included 37,349 cases and a total of 751,030 participants. We found no evidence of a non-linear association between fat intake and the risk for Pca. Overall, the summarized relative risks for every 28.35 g increment a day was 0.99 (95%CI: 0.98, 1.01; P=0.94; n=13 for total fat intake, 1.00 (95%CI: 1.00, 1.00; P=0.72; n=9 for saturated fat, 0.99 (95%CI: 0.95, 1.03; P=0.55; n=7 for polyunsaturated fat, and 1.00 (95%CI: 0.95, 1.04; P=0.85; n=8 for monounsaturated fat. Additionally, there was no link to the risk for advanced stage Pca regarding total fat intake (RR=1.02, 95%CI: 0.96, 1.08; P=0.63; n=5, saturated fat (RR=0.96, 95%CI: 0.84, 1.11; P=0.61; n=6, polyunsaturated fat (RR=0.96, 95%CI: 0.79, 1.17; P=0.68; n=6, or monounsaturated fat (RR=0.96, 95%CI: 0.86, 1.07; P=0.42; n=6. Subgroup and sensitively analyses showed consistent results.Little evidence from published cohort studies supports the statement that total fat, saturated fat or unsaturated fat intake increases the risk for Pca or advanced stage Pca.

  20. Hormesis, cellular stress response and neuroinflammation in schizophrenia: Early onset versus late onset state.

    Science.gov (United States)

    Calabrese, Vittorio; Giordano, James; Crupi, Rosalia; Di Paola, Rosanna; Ruggieri, Martino; Bianchini, Rio; Ontario, Maria Laura; Cuzzocrea, Salvatore; Calabrese, Edward J

    2017-05-01

    Abnormal redox homeostasis and oxidative stress have been proposed to play a role in the etiology of several neuropsychiatric spectrum disorders. Emerging interest has recently focused on markers of oxidative stress and neuroinflammation in schizophrenic spectrum disorders, at least in particular subgroups of patients. Altered expression of genes related to oxidative stress, oxidative damage to DNA, protein and lipids, as well as reduced glutathione levels in central and peripheral tissues could act synergistically, and contribute to the course of the disease.  Herein, we discuss cellular mechanisms that may be operative in neuroinflammation and contributory to schizophrenia. We address modulation of endogenous cellular defense mechanisms as a potentially innovative approach to therapeutics for schizophrenia, and other neuropsychiatric conditions that are associated with neuroinflammation. Specifically, we discuss the emerging role of heme oxygenase as prominent member of neuroprotective network in redox stress responsive mechanisms, as well as the importance of glutathione relevant in schizophrenia pathophysiology. Finally we introduce the hormetic dose response concept as relevant and important to neuroprotection, and review hormetic mechanisms as possible approaches to manipulation of neuroinflammatory targets that may be viable for treating schizophrenia spectrum disorders. © 2016 Wiley Periodicals, Inc.

  1. Obesity has multifaceted impact on biochemical recurrence of prostate cancer: a dose-response meta-analysis of 36,927 patients.

    Science.gov (United States)

    Hu, Meng-Bo; Xu, Hua; Bai, Pei-De; Jiang, Hao-Wen; Ding, Qiang

    2014-02-01

    Obesity is inconsistently related to biochemical recurrence (BCR) of prostate cancer (PCa) in different epidemiological studies. We conducted a systematic review and dose-response meta-analysis of published studies from MEDLINE and EMBASE in order to determine the relationship between body mass index (BMI) and BCR of PCa. We identified a total of 26 studies including 36,927 individuals. Pooled estimates of relative risk (RR) and confidence interval (CI) were computed, and dose-response meta-analysis was subsequently performed. Based on the random-effects approach, a 5 kg/m(2) increase in BMI was associated with 16 % (RR 1.16, 95 % CI 1.08-1.24) higher risk of BCR for entire set of 26 studies. Significantly higher rates of BCR were also observed in radical prostatectomy series (RR 1.17, 95 % CI 1.07-1.28) and external beam radiation therapy series (RR 1.19, 95 % CI 1.10-1.28), while no significant correlation was observed in brachytherapy series (RR 0.91, 95 % CI 0.64-1.28). Different BCR outcomes came out for studies held in USA (RR 1.18, 95 % CI 1.10-1.28), Europe (RR 1.04 95 % CI 0.91-1.17) and Asia (RR 1.83 95 % CI 0.85-3.97), respectively. There was limited evidence of a nonlinear association between BMI and BCR, which showed a critical point of 33 in BMI. The findings from meta-analysis showed that excess BMI was positively correlated with BCR of PCa multifacetedly, indicating good weight control and detailed attention to treating obese patients might improve the prognosis of PCa.

  2. Dose-response effects of atropine and HI-6 treatment of organophosphorus poisoning in guinea pigs.

    Science.gov (United States)

    Koplovitz, I; Menton, R; Matthews, C; Shutz, M; Nalls, C; Kelly, S

    1995-01-01

    HI-6 (1-2-hydroxyiminomethyl-1-pyridino-3-(4-carbamoyl-1-pyridino -2- oxapropane dichloride) has been evaluated as an oxime alternative to pralidoxime, and toxogonin in the treatment of organophosphorus (OP) poisoning. The dose response effects of atropine (ATR) and HI-6 were investigated to more fully explore the interaction of these compounds in the treatment of OP poisoning. ATR, HI-6 and various combinations of the two drugs were evaluated against lethal poisoning by soman (GD) and tabun (GA) in guinea pigs. The effect of adjunctive diazepam treatment on the efficacy of atropine and HI-6 against soman was also investigated. Animals of either sex were challenged s.c. with OP and treated i.m. 1 min later with ATR and/or HI-6. When used, diazepam was injected immediately after ATR+HI6. LD50s of each treatment were calculated from probit models based on 24-hour survival against 5 levels of nerve agent and 6 animals per challenge level. A protective index (PI) was calculated by dividing the nerve agent LD50 in the presence of treatment by the LD50 in the absence of treatment. Treatment with HI6 alone had little effect on the toxicity of either OP. Treatment with ATR alone was more effective than HI-6 alone and was significantly more effective against soman than against tabun. When used in combination atropine and HI-6 had a strong synergistic effect against both agents. The dose of atropine used with HI-6 was critical in determining the efficacy of HI-6 against either agent. The slopes of the dose-lethality curves were minimally affected by the dose of ATR or HI-6. Adjunctive treatment with diazepam enhanced the efficacy of HI-6 and atropine against soman. It is concluded that 1) ATR has a large effect on the efficacy of HI-6 against OP poisoning, 2) the dose of ATR must be carefully selected in studies investigating the efficacy of HI-6 against OP poisoning, 3) the effective dose of ATR in the guinea pig is approximately 16 mg/kg, and 4) diazepam is a useful

  3. Lipid metabolic dose response to dietary alpha-linolenic acid in monk parrot (Myiopsitta monachus).

    Science.gov (United States)

    Petzinger, Christina; Heatley, J J; Bailey, Christopher A; Bauer, John E

    2014-03-01

    Monk parrots (Myiopsitta monachus) are susceptible to atherosclerosis, a progressive disease characterized by the formation of plaques in the arteries accompanied by underlying chronic inflammation. The family of n-3 fatty acids, especially eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA), have consistently been shown to reduce atherosclerotic risk factors in humans and other mammals. Some avian species have been observed to convert α-linolenic acid (18:3n-3, ALA) to EPA and DHA (Htin et al. in Arch Geflugelk 71:258-266, 2007; Petzinger et al. in J Anim Physiol Anim Nutr, 2013). Therefore, the metabolic effects of including flaxseed oil, as a source of ALA, in the diet at three different levels (low, medium, and high) on the lipid metabolism of Monk parrots was evaluated through measuring plasma total cholesterol (TC), free cholesterol (FC), triacylglycerols (TAG), and phospholipid fatty acids. Feed intake, body weight, and body condition score were also assessed. Thus the dose and possible saturation response of increasing dietary ALA at constant linoleic acid (18:2n-6, LNA) concentration on lipid metabolism in Monk parrots (M. monachus) was evaluated. Calculated esterified cholesterol in addition to plasma TC, FC, and TAG were unaltered by increasing dietary ALA. The high ALA group had elevated levels of plasma phospholipid ALA, EPA, and docosapentaenoic acid (DPAn-3, 22:5n-3). The medium and high ALA groups had suppressed plasma phospholipid 20:2n-6 and adrenic acid (22:4n-6, ADA) compared to the low ALA group. When the present data were combined with data from a previous study (Petzinger et al. in J Anim Physiol Anim Nutr, 2013) a dose response to dietary ALA was observed when LNA was constant. Plasma phospholipid ALA, EPA, DPAn-3, DHA, and total n-3 were positively correlated while 20:2n-6, di-homo-gamma-linoleic acid (20:3n-6Δ7), arachidonic acid (20:4n-6), ADA, and total n-6 were inversely correlated with dietary en% ALA.

  4. Dose-response relationship for fractionated irradiation in the treatment of spinal meningeal melanocytomas: a review of the literature.

    Science.gov (United States)

    Rades, Dirk; Schild, Steven E

    2006-05-01

    Complete resection (CTR) of meningeal melanocytomas results in better outcome than incomplete resection (ITR). After ITR, outcome is improved by radiotherapy. CTR is less frequent with spinal melanocytomas than with cerebral melanocytomas. This study of 49 spinal melanocytoma patients was performed to define an appropriate radiation dose after ITR. All reported spinal melanocytoma cases were reviewed for extent of surgery, radiotherapy (total dose, dose per fraction), and outcome. CTR was compared to ITR for local control (LC) and overall survival (OS). ITR alone was compared to ITR plus radiotherapy (ITR + RT). In the ITR + RT group, doses of 50-52.2 Gy (1.8-2.0 Gy per fraction) were compared to doses meningeal melanocytoma cases. Our results should be confirmed in a larger series of patients when available.

  5. A different view on indoor environment: Focus on people and situations rather than single-dose response relationships

    NARCIS (Netherlands)

    Bluyssen, P.M.

    2012-01-01

    A different view on indoor environment quality (IEQ) is required. A view in which IEQ is approached in an integrative multi-disciplinary way, in which the focus is on users (situations) in stead of single components and in which the focus is an improving quality of life as opposed to only prevent pe

  6. In Situ Dose-Response Relationships for a Mammalian Multiparameter Model for Assessing Petrochemical-Induced Ecotoxicity.

    Science.gov (United States)

    2007-11-02

    over non-pollutant environmental variables (climate, nutrition , etc.), which can frequently confound interpretation of biomarker response profiles...globulin nephropathy . Toxicologic Pathology (in press).Lochmiller, R. L 1995. Testing the immunocompetence handicap theory. Trends Ecol. Evol. 10

  7. Comparison of Two Dose-response Relationship of Noise Exposure Evaluation Results with High Frequency Hearing Loss

    Institute of Scientific and Technical Information of China (English)

    Hua Zhang; Nan Li; Qiu-Ling Yang; Wei Qiu; Liang-Liang Zhu; Li-Yuan Tao; Robert I Davis

    2015-01-01

    Background:Complex noise and its relation to hearing loss are difficult to measure and evaluate.In complex noise measurement,individual exposure results may not accurately represent lifetime noise exposure.Thus,the mean LAeq,8 h values of individuals in the same workgroup were also used to represent LAeq,8h in our study.Our study aimed to explore whether the mean exposure levels of workers in the same workgroup represented real noise exposure better than individual exposure levels did.Methods:A cross-sectional study was conducted to establish a model for cumulative noise exposure (CNE) and hearing loss in 205 occupational noise-exposed workers who were recruited from two large automobile manufacturers in China.We used a personal noise dosimeter and a questionnaire to determine the workers' occupational noise exposure levels and exposure times,respectively.A qualified audiologist used standardized audiometric procedures to assess hearing acuity after at least 16 h of noise avoidance.Results:We observed that 88.3% of workers were exposed to more than 85 dB(A) of occupational noise (mean:89.3 ± 4.2 dB(A)).The personal CNE (CNEp) and workgroup CNE (CNEg) were 100.5 ± 4.7 dB(A) and 100.5 ± 2.9 dB(A),respectively.In the binary logistic regression analysis,we established a regression model with high-frequency hearing loss as the dependent variable and CNE as the independent variable.The Wald value was 5.014 with CNEp as the independent variable and 8.653 with CNEg as the independent variable.Furthermore,we found that the figure for CNEg was more similar to the stationary noise reference than CNEp was.The CNEg model was better than the CNEp model.In this circumstance,we can measure some subjects instead of the whole workgroup and save manpower.Conclusions:In a complex noise environment,the measurements of average noise exposure level of the workgroup can improve the accuracy and save manpower.

  8. Comparison of Two Dose-response Relationship of Noise Exposure Evaluation Results with High Frequency Hearing Loss

    Directory of Open Access Journals (Sweden)

    Hua Zhang

    2015-01-01

    Full Text Available Background: Complex noise and its relation to hearing loss are difficult to measure and evaluate. In complex noise measurement, individual exposure results may not accurately represent lifetime noise exposure. Thus, the mean L Aeq,8 h values of individuals in the same workgroup were also used to represent L Aeq,8 h in our study. Our study aimed to explore whether the mean exposure levels of workers in the same workgroup represented real noise exposure better than individual exposure levels did. Methods: A cross-sectional study was conducted to establish a model for cumulative noise exposure (CNE and hearing loss in 205 occupational noise-exposed workers who were recruited from two large automobile manufacturers in China. We used a personal noise dosimeter and a questionnaire to determine the workers′ occupational noise exposure levels and exposure times, respectively. A qualified audiologist used standardized audiometric procedures to assess hearing acuity after at least 16 h of noise avoidance. Results: We observed that 88.3% of workers were exposed to more than 85 dB(A of occupational noise (mean: 89.3 ± 4.2 dB(A. The personal CNE (CNEp and workgroup CNE (CNEg were 100.5 ± 4.7 dB(A and 100.5 ± 2.9 dB(A, respectively. In the binary logistic regression analysis, we established a regression model with high-frequency hearing loss as the dependent variable and CNE as the independent variable. The Wald value was 5.014 with CNEp as the independent variable and 8.653 with CNEg as the independent variable. Furthermore, we found that the figure for CNEg was more similar to the stationary noise reference than CNEp was. The CNEg model was better than the CNEp model. In this circumstance, we can measure some subjects instead of the whole workgroup and save manpower. Conclusions: In a complex noise environment, the measurements of average noise exposure level of the workgroup can improve the accuracy and save manpower.

  9. A Dose-Response Relationship between Organic Mercury Exposure from Thimerosal-Containing Vaccines and Neurodevelopmental Disorders

    Directory of Open Access Journals (Sweden)

    David A. Geier

    2014-09-01

    Full Text Available A hypothesis testing case-control study evaluated concerns about the toxic effects of organic-mercury (Hg exposure from thimerosal-containing (49.55% Hg by weight vaccines on the risk of neurodevelopmental disorders (NDs. Automated medical records were examined to identify cases and controls enrolled from their date-of-birth (1991–2000 in the Vaccine Safety Datalink (VSD project. ND cases were diagnosed with pervasive developmental disorder (PDD, specific developmental delay, tic disorder or hyperkinetic syndrome of childhood. In addition, putative non-thimerosal-related outcomes of febrile seizure, failure to thrive and cerebral degenerations were examined. The cumulative total dose of Hg exposure from thimerosal-containing hepatitis B vaccine (T-HBV administered within the first six months of life was calculated. On a per microgram of organic-Hg basis, PDD (odds ratio (OR = 1.054, specific developmental delay (OR = 1.035, tic disorder (OR = 1.034 and hyperkinetic syndrome of childhood (OR = 1.05 cases were significantly more likely than controls to receive increased organic-Hg exposure. By contrast, none of the non-thimerosal related outcomes were significantly more likely than the controls to have received increased organic-Hg exposure. Routine childhood vaccination may be an important public health tool to reduce infectious disease-associated morbidity/mortality, but the present study significantly associates organic-Hg exposure from T-HBV with an increased risk of an ND diagnosis.

  10. Establishment of radiation dose-response curve based on in vitro irradiation of peripheral blood samples by X-ray%离体人外周血血X射线照射后剂量效应曲线的建立

    Institute of Scientific and Technical Information of China (English)

    李广伟; 李峰生

    2012-01-01

    目的 建立准确估算受辐射照射者辐射剂量的方法.方法 采用X射线照射离体人外周血,一步法培养外周血淋巴细胞56 h后收获制片,检测染色体"双着丝粒(dic)+环(r)"畸变率,拟合剂量效应曲线.结果 畸变率随照射剂量增加而增加,存在明显的剂量效应,剂量效应曲线回归方程为y=0.020 8x2+0.102 8x-0.024 8,r2=0.995 3(P<0.05).结论 通过建立X射线照射离体人外周血后的剂量效应曲线,能准确估算受照辐射剂量.%Objective To establish the method of estimating accurately radiation dose of the individuals exposed to ionizing-radi-ation. Methods The blood samples in vitro were irradiated by X-ray,then cultured using one-step method for 56 hours. According to the chromosomal aberration rate(including dicentric chromosome and ring) , radiation dose-response curve was fitted. Results The chromosomal aberration rate induced by the different radiation doses increased along with the increase of radiation dose, and there was an apparent dose-response relationship,the radiation dose-response curve regression equation:y=0. 020 8x2+0. 102 8x-0. 024 8. Conclusion The dose of the individual exposed to ionizing-radiation could be estimated accurately according to the radiation dose-response curve that might be fitted by the blood samples in vitro irradiated by X-ray.

  11. The dose-response relation in human volunteers for gastro-intestinal pathogens

    NARCIS (Netherlands)

    Teunis PFM; Heijden OG van der; Giessen JWB van der; Havelaar AH; MGB

    1996-01-01

    Published data on infection of human hosts with various protozoa, bacteria, and viruses causing gastro-enteritis are used to establish a quantitative relationship between ingested dose and the risk of infection. For all data sets analysed, this relationship is determined by fitting either an exponen

  12. Dose response of commercially available optically stimulated luminescent detector, Al2O3:C for megavoltage photons and electrons.

    Science.gov (United States)

    Kim, Dong Wook; Chung, Weon Kuu; Shin, Dong Oh; Yoon, Myonggeun; Hwang, Ui-Jung; Rah, Jeong-Eun; Jeong, Hojin; Lee, Sang Yeob; Shin, Dongho; Lee, Se Byeong; Park, Sung Yong

    2012-04-01

    This study examined the dose response of an optically stimulated luminescence dosemeter (OSLD) to megavoltage photon and electron beams. A nanoDot™ dosemeter was used to measure the dose response of the OSLD. Photons of 6-15 MV and electrons of 9-20 MeV were delivered by a Varian 21iX machine (Varian Medical System, Inc. Milpitas, CA, USA). The energy dependency was photons, the dose was linear until 200 cGy. The superficial dose measurements revealed photon irradiation to have an angular dependency. The nanoDot™ dosemeter has potential use as an in vivo dosimetric tool that is independent of the energy, has dose linearity and a rapid response compared with normal in vivo dosimetric tools, such as thermoluminescence detectors. However, the OSLD must be treated very carefully due to the high angular dependency of the photon beam.

  13. The relationship between sound insulation and acoustic quality in dwellings

    DEFF Research Database (Denmark)

    Rindel, Jens Holger

    1998-01-01

    the different findings are discussed. It is tried to establish dose-response relationships between airborne sound insulation or impact sound pressure level according to ISO 717 and the percentage of people being annoyed by noise from neighbours. The slopes of the dose-response curves vary from one investigation...

  14. Dose-Response Association Between Physical Activity and Incident Hypertension: A Systematic Review and Meta-Analysis of Cohort Studies.

    Science.gov (United States)

    Liu, Xuejiao; Zhang, Dongdong; Liu, Yu; Sun, Xizhuo; Han, Chengyi; Wang, Bingyuan; Ren, Yongcheng; Zhou, Junmei; Zhao, Yang; Shi, Yuanyuan; Hu, Dongsheng; Zhang, Ming

    2017-05-01

    Despite the inverse association between physical activity (PA) and incident hypertension, a comprehensive assessment of the quantitative dose-response association between PA and hypertension has not been reported. We performed a meta-analysis, including dose-response