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Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer treatment kidney infection purchase oxybutynin now. Concerted action of p62 and Nrf2 protects cells from palmitic acid-induced lipotoxicity. A novel Grb14-mediated cross-talk between insulin and p62/Nrf2 pathways regulates liver lipogenesis and selective insulin resistance. Sustained activation of nuclear erythroid 2related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2. Two-site substrate recognition model for the Keap1-Nrf2 system: A hinge and latch mechanism. Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Association of keap1 and nrf2 genetic mutations and polymorphisms with endometrioid endometrial adenocarcinoma survival. Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Toll-like receptor signaling induces Nrf2 pathway activation through p62-triggered Keap1 degradation. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. From the 18th century until today, much of human anatomy and physiology has been well defined under healthy or disease states. In a simplistic sense, an important physical element keeping man "a machine" running is the blood circulation. The blood is the most complex bodily fluid that delivers oxygen, nutrients, and endocrine factors to cells and tissues, while transporting metabolic byproducts and secreted molecules or vesicles away. Whereas normal physiological and metabolic functions require unobstructed blood flow through the vasculature network embedded in a tissue, ischemia is associated with deficiency of oxygen, nutrients and endocrine factors in target tissues due to restriction of blood supply. Such scenario often results from insufficient blood supply caused by blood vessel obstruction, hemorrhage or hypotensive shock. Prolonged ischemia causes tissue injury and malfunction due to cell death or cell degeneration. In some cases, if the blood supply is reduced but not completely eliminated, particularly when the blockage of a blood vessel occurs over a period of time, downstream tissues can adapt and survive, but altered biochemical metabolism ensues. Acute ischemia in the cardiovascular system is one of the most common causes of a life-threatening situation. Blood vessel obstruction occurs due to atherosclerosis, thrombus, embolism, vasculature spasm or sometimes, but rarely, vasculitis. Interruption of the arterial blood flow affords a substantial or total blockage of blood flow to downstream tissues, resulting in medical emergencies such as stroke, i. Cerebral infarction and myocardial infarction together represent the number one cause of natural death worldwide. For myocardial infarction, a typical scenario involves rupture of an atherosclerotic plaque with subsequent activation of the blood clotting cascade, inducing partial or total occlusion of a coronary artery. Obstruction of myocardial blood flow can also result from an embolism due to thrombi originating in the left atrium by atrial fibrillation, where it is transported into the branches of the coronary arterial tree by the circulation, thereby blocking arterial inflow. Similar pathophysiological events can occur in the brain, leading to cerebral infarction. Ischemia can also take place in the lung, liver, kidney, and intestines, adding to common causes for hospitalization. Hypotensive shock, often a result of sepsis, severe bleeding, severe dehydration, or sudden decrease in cardiac output due to myocardial infarction, fatal arrhythmia or cerebral infarction, can produce widespread systemic ischemia with injury to a vast array of organs including the limbs. Animal models of ischemia in each of the above mentioned organs have been well established, allowing for studies of cellular and organismic changes consequential to ischemia. The myocardium contains mainly two cell types: cardiomyocytes and fibroblasts, in addition to the blood vessels. The mitochondria occupy about 40% of cell volume in cardiomyocytes, entitling the cells with the highest content of mitochondria among all cell types (Barth et al. Such high content of mitochondria correlates with high metabolic activity, making cardiomyocytes highly sensitive to hypoxia and ischemia. At the cellular level, ischemia or hypoxia leads to inhibition of mitochondrial respiration and major alterations of biochemical metabolism. Cardiomyocytes surviving myocardial ischemia undergo adaptation, repair, and hypertrophic growth. In the clinic, the efficiency of care is measured by how quickly blood flow is restored, since the fate of the ischemic myocardium is dependent on the speed of reperfusion, in addition to the metabolic demand of the ischemic zone and adequacy of removal of noxious metabolites. Timely reperfusion limits infarct size and the severity of ventricular dysfunction, the major cardiac adverse events, as well as long-term morbidity and mortality. Currently the most effective method for protecting tissues from ischemic or ischemic reperfusion injury is pre- or post- conditioning. The protective effect of pre- or post- conditioning was first observed in animal models and has been translated into the clinic for the management of acute ischemic heart disease by percutaneous coronary interventions (Heusch, 2013). Ischemic pre-conditioning is a phenomenon during which transient repetitive cycles of minor or mild ischemia and reperfusion provide protection against tissue injury from subsequent severe or prolonged ischemia. Repetitive cycles of brief reperfusion and ischemia at the end of a period of prolonged ischemia, such as 1 h, are termed ischemic post-conditioning, which also offers tissue protection (Zhao et al. Pre- or post-conditioning mediated tissue protection has been observed with multiple organ systems. Although the mechanisms of such protection remain an intensive area of research interest, a list of signaling molecules has been shown to function as important mediators, for example, adenosine and adenosine A1 receptor, inhibition of which blunts the organ protective effect of preconditioning. In the myocardium, protection by ischemic preconditioning has two temporal phases: immediate protection (less than 2 h) and delayed protection (24 to 48 h). Immediate protection involves modification of signaling for existing protective molecules, whereas delayed protection often results from increased expression of protective genes. Similar two-phase protection has been observed in other organs, although the time course may vary. Because of the lack of pharmacological agents that can offer similar degrees of protection, such as those seen with pre- or post-conditioning, understanding the signaling transduction pathways of ischemia and reperfusion is critical for identifying targets for future drug development. It is expected that a drug might provide tissue protection without introducing additional damage such as by reperfusion. Normal hearts utilize fatty acids preferentially over carbohydrates as the main source for energy production via oxidative metabolism. Supply of oxygen to the heart stops within 10 s of the onset of ischemia (Jennings et al.

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The parameters where a plausible direct impact of protein synthesis inhibition is anticipated are represented by * medicine cards order 2.5mg oxybutynin fast delivery. The maximum tolerable levels of mycotoxins in foods should not be as low as to prohibit legitimate international trade of food, but these levels must protect consumers from the toxic and carcinogenic effects of mycotoxins. Despite extensive efforts, the mechanism of carcinogenicity of most mycotoxins remains to be elucidated. Some mycotoxins (such as aflatoxins) are proven carcinogens in humans whereas others (fumonisins and ochratoxins) are suspected to be human carcinogens based on data from experimental animals. One particular issue to address is that humans are very frequently exposed to different mycotoxins with additive or even synergistic adverse effects in experimental animals or on cell cultures. The possible interaction of mycotoxins with genotoxic and/or tumor-promoting features is an area requiring significant research effort, as are epidemiological studies on exposure to specific mycotoxins. Modulation of key regulators of mitosis linked to chromosomal instability in an early event in ochratoxin A carcinogenicity. Aflatoxin B1 induces the transversion of G/T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. A foodborne disease outbreak due to the consumption of moldy sorghum and maize containing fumonisin mycotoxins. Development of a molecular detection and differentiation system for ochratoxin A producing Penicillium species and its application to analyze the occurrence of Penicillium nordicum in cured meat. Exposure assessment to mycotoxins in workplace: aflatoxins and ochratoxin A occurrence in airborne dusts and human sera. Hepatic tumours and other chronic liver changes in rats following a single oral administration of aflatoxin. Outbreak of aflatoxin poisoningdeastern and central provinces Kenya, January-July 2004. Analysis of the p53 tumor-suppressor gene in hepatocellular carcinomas from Britain. Prenatal exposure of mice to human liver carcinogen aflatoxin B1 reveals a critical window of susceptibility to genetic change. Perturbation of mitosis through inhibition of histone acetyltransferases: the key to ochratoxin A toxicity and carcinogenicity Fumonisin B1 inhibits mitochondrial respiration and deregulates calcium homeostasisdimplication to mechanism of cell toxicity. Standard and Fpg-modified comet assay in kidney cells of ochratoxin A and fumonisin B1 treated rats. A review on ochratoxin A occurrence and effect of processing of cereals and cereal derived food products. Alleviative effect of myricetin on ochratoxin A-induced oxidative stress in rat renal cortex: Histological and biochemical study. Hepatocellular carcinoma and food contamination: aflatoxins and ochratoxin A as great prompter. Serum albumin adducts in the molecular epidemiology of aflatoxin carcinogenesis: correlation with aflatoxin B1 intake and urinary excretion of aftatoxin M1. Toxicity and carcinogenicity of the Fusarium moniliforme metabolite, fumonisin B1, in rats. Interaction of fumonisin B1 and aflatoxin B1 in a short-term carcinogenesis model in rat liver. Maternal fumonisin exposure and risk for neural tube defect: mechanism in an in vivo mouse model. Revision of ochratoxin a production capacity by the main species of Aspergillus section Circumdati. The low intestinal and hepatic toxicity of hydrolyzed fumonisin B1 correlates with its inability to alter the metabolism of sphingolipids. Molecular dosimetry of aflatoxin-N7-guanine in human urine obtained in the Gambia, West Africa. Molecular dosimetry in rat urine of aflatoxin-N7-guanine and other aflatoxin metabolites by multiple monoclonal antibody affinity chromatography and immunoaffinity/high performance chromatography. Cytochrome P450 oxidations in the generation of the reactive electrophiles: epoxidation and related reactions. Effects of ochratoxin A on muse oocyte maturation and fertilization, and apoptosis during fetal development. Case report evidence of relationship between hepatocellular carcinoma and ochratoxicosis. Prospective detection of codon 249 mutations in plasma of hepatocellular carcinoma patients. In Endemic NephropathyProceedings of the Second International Symposium on Endemic Nephropathy, Sofia, Bulgaria (pp. Specific mutations of hepatitis B virus in plasma predict liver cancer development. A review of the evidence that ochratoxin A is an Nrf2 inhibitor: implication for nephrotoxicity and renal carcinogenicity. Fumonisin B1- induced hepatocellular and cholangiocellular tumors in male Fischer 344 rats: potentiating effect of 2-acetylaminofluorene on oval cell proliferation and neoplastic development in a discontinued feeding study. Aflatoxins and fumonisins in corn from the high-incidence area for human hepatocellular carcinoma in Guangxi, China. Ochratoxin A and mitotic disruption: mode of action analysis of renal tumor formation by ochratoxin A. Lifetime, low-dose ochratoxin A dietary study on renal carcinogenesis in male Fisher rats. Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: a potential risk factor for human neural tube defects among population consuming fumonisin-contaminated maize. Daily intake estimates of fumonisins in corn-based food products in the population of Parana, Brasil. Reactive oxygen species sources and biomolecular oxidative damage induced by aflatoxin B1 and fumonisin B1 in rat spleen mononuclear cells. Mycotoxins are conventional and novel risk biomarkers for hepatocellular carcinoma. Comparative acute and combinative toxicity of aflatoxin B1and fumonisin B1 in animals and human cells. Climate change factors and Aspergillus flavus: Effects on gene expression, growth and aflatoxin production. Sphingolipid metabolism: roles in signal transduction and disruption by fumonisins. Exposure to fumonisins and the occurrence of neural tube defects along the Texas-Mexico border. Up-regulation of nucleotide excision repair in mouse lung and liver following chronic exposure to aflatoxin B1 and its dependence on p53 genotype. Fumonisin B1 and the kidney: modes of action for renal tumor formation by fumonisin B1 in rodents. Fumonisin B1 treatment acts synergistically with methyl donor deficiency during rat pregnancy to produce alterations of H3- and H4-histone methylation patterns in fetus. Variations of ochratoxin A concentrations in the blood of healthy population in some Croatian cities. New molecular and field evidences for the implication of mycotoxins but not aristolochic acid in human nephropathy and urinary tract tumor. Ochratoxin A contamination of the autochthonous dry-cured meat product "Slavonski kulen" during a six-month production process.

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Laboratories in Hiroshima and Nagasaki are dedicated to studying the acute and chronic effects of the atomic detonations in those cities medications may be administered in which of the following ways purchase oxybutynin australia. Epidemiologic tracking of the survivors has allowed for the study of the relationship between estimated radiation dose and the development of leukemias and solid tumors (Thompson et al. By examining the fate of family members who were located in the same houses during the atomic bomb explosions, it has been estimated that doses of 2. Animal studies have shown that administering various growth factors to stimulate surviving blood-forming stem cells in the bone marrow facilitates more rapid recovery from radiation injury, and the lives of 100% of the exposed population can be saved after a whole-body dose of up to about 10 Gy (1000 rad). An excess risk of leukemia was one of the earliest delayed effects of radiation exposure observed in the victims of the atomic bombs dropped on Hiroshima and Nagasaki in Aug. Now, more than 50 years after these events, this excess risk is widely seen as the most apparent long-term effect of radiation. As of 1990, 176 of the 50, 113 survivors in the Life Span Study who had significant exposures (>0. With regard to other types of cancer, 4687 people in the Life Span Study had died of nonleukemic forms of cancer by 1990, which represents an excess of 381 deaths as compared with an estimated 4306 deaths in a population that had not been exposed (Pierce and Vaeth, 2003; Pierce et al. A comparison of excess deaths in the Life Span Study population between 1950 and 1990, according to radiation dose, is shown in Table 4; the number of deaths sorted by the type of cancer is shown in Table 5. Acute exposure of 600 workers at the Table 4 Cancer deaths between 1950 and 1990 among life span study survivors according to dose 0. The incidence rate was still high more than 10 years after exposure, with 116 reported cases during the 3-year interval from 1996 to 1998 (Rybakov et al. The tumors in these patients were characterized by a shorter latency period and increased aggressiveness at presentation, as measured by the extent of regional and distant metastases (Heidenreich et al. Germline mutations at human minisatellite loci were studied in children born in the heavily polluted areas of the Mogliev district of Belarus after the Chernobyl accident and in a control population. The frequency of mutation was found to be twice as high in the exposed families as in the control group (Dubrova et al. Biodosimetry is now widely used in industry to correlate exposure to a toxicant (radiation, chemical, etc. The sources were mostly g-emitters, with some b-emitters, but included 89Sr, 90Sr, 137Cs, 95Zr, 95Nb, 106Ru, and others, typically with long half-lives (Akleyev et al. The cancer-specific mortality (55 cancer death cases) in the exposed patients with signs and symptoms of chronic radiation syndrome was 274. The older exposed age cohort had the highest cancer death rate at 602 deaths per 100 000 person-years. The largest differences in cancer incidence of the exposed population versus the controls were for leukemiad25 per 100 000 person-years (8. The cancer specific mortality rate was dose dependent, being much higher in exposure doses > 1. In the 1930s, before the effects of ionizing radiation were well understood, a number of people were exposed to radiation for medical purposes (Holm, 2001; Mole, 1987; Mole and Major, 1983). In England, patients with ankylosing spondylitis were treated with ionizing radiation from 1935 until 1954 (Smith and Doll, 1982). These patients were later found to have a fivefold higher incidence of leukemia than expected. In the United States and Israel, ionizing radiation was used until 1960 as a treatment for children with tinea capitis or ringworm (Shore, 1990; Shore et al. Later, as adults, Ionizing Radiation as a Carcinogen 203 these people developed basal cell carcinomas of the skin and thyroid tumors. In Germany, an X-ray contrasting agent called thorotrast, which contained 232Th, was given to patients requiring gall bladder or liver X-ray imaging. This population later developed a very high rate of liver cancer, which is otherwise quite rare in Europe (Travis et al. In Canada, during the 1930s and 1940s, tuberculosis patients received greater than 400 rads of ionizing radiation resulting, eventually, in a 15-fold increase in lung cancer (Myrden and Hiltz, 1988). There are several other examples of medical uses of high doses of ionizing radiation, each of which has resulted in a clearly evident increased incidence of cancer at the target organ (Boice et al. All such treatments were halted in the 1950s or early 1960s after it became apparent that ionizing radiation, apart from its other biological effects, which include cell killing and effects on immune function, was also causing cancer in people exposed to the types of doses given during the course of medical treatments. This recognition came about as a result of one of the most significant exposures of humans to ionizing radiationdthe atomic bomb explosions in Japan in 1945. These enzymes have been shown to have a critical role in a number of cellular processes, such as growth, differentiation, and apoptosis. Because ionizing radiation is a carcinogen in most organs in almost all species, researchers are faced with an enormous array of choices in animal models of radiation-induced carcinogenesis. Questions about radiation-induced carcinogenesis have been studied as whole body irradiation of most laboratory animal species. Animal models used for studying the bioeffects of radiation have included rabbits, mice, rats, and other mammalian and nonmammalian species, including dogs and monkeys flown aboard the Russian Bion satellites. Many of the bioeffects are thought to be universal responses to radiation, whereas others are thought to be specific to cell type or species. Long-term follow-up studies of the exposed animals showed induction of solid tumors and leukemia; however, the observed extent of life shortening and cancer induction depended on dose and not on proton energy level (Dalrymple et al. More focused studies about specific mechanistic questions have been applied to specific organs in different animals. Given the wide range of animals available, determining the ideal animal model for radiation experiments is determined by the experimental question posed. In addition, species-specific peculiarities make some animals ideal for certain studies and poor choices for others. Thoughtful analysis is required to extrapolate the results of 204 Ionizing Radiation as a Carcinogen animal studies into information that is applicable to humans. Although there is considerable debate about ideal animal models to address different research questions, it is generally agreed that careful consideration is required to choose the best available animal model out of the many available choices for radiation carcinogenesis research. Some factors that must be considered include relative dosing, timing, animal life cycle, and intrinsic biological differences and/or responses to injury. Furthermore, animal size and morphology must also be taken into account, since absorbed dose distributions for a given radiation type will vary significantly between different animals and organ systems. Efforts to address these challenges can be seen in a novel technique, which aims to more accurately reproduce dose and dose distribution of different radiation types by using megavoltage electron beam radiation (Cengel et al. These studies elucidated the general characteristics of radiation carcinogenesis, in conjunction with epidemiological studies in humans. These studies have shown that ionizing radiation is universally carcinogenic to living creatures, although there is wide variation in radiation responses according to species, organ, and radiation distribution. A recent evaluation of animal models for radiation-induced carcinogenesis agreed that there is a wide variety of appropriate animal models for research, including rodents, dogs, pigs, and primates (Augustine et al. However, significant uncertainty still exists about the accuracy of extrapolating the carcinogenesis results of animal studies to humans. Genetically modified mice (inbred strains, knockouts, knock-ins, transgenics) are particularly useful tools to determine molecular and cellular mechanisms involved in radiation-induced cancers. Connexin 32-deficient knockout mice exhibited increased radiation-induced carcinogenesis of the lung and liver, compared to wild-type mice (King and Lampe, 2004). The expression of individual genes can be suppressed or activated in various mouse models, which make them particularly useful for dissecting molecular and cellular factors that contribute to the initiation, progression, and treatment of radiation-induced cancers. However, a recent evaluation of animal models identified a need for the development of additional animal models to better understand the underlying mechanisms of radiation-induced carcinogenesis, particularly for the study of radioprotectants (Augustine et al. These findings were supported by various epidemiologic studies in human populations receiving radiation exposure from environmental, occupational, medical, and accident sources (Little, 2000; Pierce et al. The universal nature of radiation as a carcinogen relates to its ability to penetrate cells and to deposit energy within them.

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Radiation-induced p53 mutation has been observed in murine intestinal epithelium (Wilson et al symptoms 1974 order 2.5 mg oxybutynin fast delivery. In addition to mutating the p53 gene, ionizing radiation increased p53 expression in human mammary epithelial cells (Sheen and Dickson, 2002), suggesting a mechanism by which ionizing radiation may amplify the effects of mutated p53. The inactivation of p53 results in a significant decrease in radiation sensitivity in glioblastoma cells (Yount et al. In addition to its more direct contributions to carcinogenic processes, tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo in murine leukemia (Miyashita et al. Interactions between multiple oncogenes, tumor suppressor genes, or both have been implicated in carcinogenesis. Radiosensitivity of cancer cells also relies on the interaction of multiple oncogenes and tumor suppressor genes. Radiosensitivity of head and neck cancer patients depends on the ratio of p53, bcl-2, and bax protein levels (Csuka et al. The loss of erbB2 expression did not affect radiosensitivity in a panel of tumor cell lines, but radiosensitivity dramatically decreased when both erbB2 and erbB3 expression were inhibited (Dote et al. These studies suggest that the modulation of radiation-induced responses in the pathogenesis and treatment of cancer cells is quite complex and involve the interaction of several interactive genes. Genomic instability refers to abnormally high rates of genetic changes that occur spontaneously and are passed onto subsequent generations. The loss of genetic integrity is associated with tumorigenesis (Kinzler and Vogelstein, 1997; Lengauer et al. Shortened telomeres have been associated with accelerated aging and increased lymphoma in mice (Espejel et al. It has also reported that the loss of a single telomere resulted in instability of multiple chromosomes in a human tumor cell line (Sabatier et al. In addition, the same study proposed that multiple genetic dysfunctions promote carcinogenesis, which is consistent with the vulnerable genetic state induced by genomic instability. Yet, only physical measurements of the exposure environment are typically used to derive estimates of cancer risk. This approach assumes that a physical measurement can be equated to a biologically meaningful dose. The risk coefficient that is applied to a personal dose assumes that all individuals exposed respond to radiation in the same way as a theoretically "average" person exposed to typical radiation sources. It is now established that individual radiation response will be governed by genetic makeup. As described above, there are multiple gene products interacting to respond to damage induced by radiation. The genetic heterogeneity in many of these [yet 212 Ionizing Radiation as a Carcinogen unidentified] gene products results in a range of susceptibilities to ionizing radiation. The notion of individual susceptibilities cannot be translated into practical action plans and policies in large terrestrial populations at this time. However, a small cohort of individuals, such as International Space Station astronauts, could be evaluated for individual risk prediction by assessing individual response to radiation exposure. The acceptable risk of a deterministic effect occurring within a radiation worker is zero, and occupational dose limits ensure that these thresholds are not exceeded. Stochastic effects are those effects whose probability of occurrence, but not their severity, is a function of the dose. The dose to radiation-induced cancer risk conversion factors is highly dependent on gender, age at exposure, and tissue type. With regards to hereditary effects, the National Academy of Sciences estimates of the probability that radiation will increase genetic defects, for a dose of 0. The risk rate is mainly due to dominant gene mutations and chromosomal diseases; however, the risks for malformation and growth/developmental retardation are also high, with most sensitive period being between 8 and 25 weeks gestation. Another means of applying dose limitations is based on the risk of "radiation detriment" (Table 6). This more modern approach to dose limitation uses the concept of detriment to measure total risk to an individual. Components of overall radiation exposure detriment are (1) risk of fatal cancer, (2) allowance for relative years of life lost for specific fatal cancers, (3) allowance for morbidity, and (4) allowance for the risk of hereditary diseases. In the case of space-based radiation exposure, projected risks based on the Japanese data are Table 6 Tissue Bladder Bone marrow Breast Colon Liver Lung Esophagus Ovary Skin Stomach Thyroid Gonads Other Total Contribution to detriment for average worker (average worker dose of 0. Information regarding these radiation sources is incomplete and will require a number of years of development before a more complete picture evolves. Excess relative risk is obtained by fitting multiplicative models and is defined as the ratio of cumulative risk at a given age among the exposed to cumulative risk among the nonexposed. Absolute risk is obtained by fitting additive models and represents the difference between cumulative risk among the exposed and the nonexposed groups. Uncertainty in projected cumulative risk is assessed by use of iterative Monte Carlo analysis to "fold" together probability density functions for several risk projection models and bias correction factors. What follows describes life table methods used during each iteration to obtain "quantiles" of excess lifetime risk, xI,r. Methods discussed in the following sections are described in detail elsewhere (Peterson and Cucinotta, 1999). Each iteration starts by randomly selecting the risk projection model to be used for generating a double-decrement life table during the iteration. Excess relative risk coefficients in percent per Sv are from Table X of Thompson et al. After 5000 iterations are performed, the various quantiles of xmix are ranked in ascending order. Central estimates of risk are then based on the median, m(xmix), with 90% subjective confidence limits based on the 5th and 95th percentiles of the ranked quantiles. Overall, risk decreases with increasing age at exposure and approaches 1% for males exposed at age 90. The median risk of leukemia among males showed a similar trend but was greatest for exposure at age 40, where it approached 4. The effect of the short 40-year plateau period during which leukemia risk is accumulated can be noticed in the curve for males exposed at age 20. Cumulative risk of leukemia from exposure at older ages is higher than risk from exposure at younger ages because the excess absolute leukemia risk is added to baseline rates. If plateau periods for leukemia were longer than 40 years, a different picture would emerge (Aguiar, 1998; Preston, 2005; Preston et al. For females, the highest nonleukemic cancer risks observed for exposure at ages 20, 30, 40, 50, 60, and 70 were 4. Lifetime cancer incidence risks approaching 3% for exposure to 1 Sv could be expected for males exposed at age 40 and females exposed at age 50. In principle, this can be achieved by physical shielding, by setting acceptable exposure limits, and by radioprotective agents and/or therapy. There are three means to reduce exposure to ionizing radiation: (1) increasing distance from the radiation source, (2) minimizing the time of exposure, and (3) using shielding. Ionizing Radiation as a Carcinogen 215 the first two means to reduce exposure to radiation are the simplest to implement for terrestrial radiation protection. The most commonly used means of protection for terrestrial radiation workers is shielding; that is, the placement of material between the human and the radiation source to reduce the exposure. By definition, shielding is the use of materials to mitigate the effects of the incident radiation by (1) reducing the intensity of the radiation. Thus, in principle, shielding alone should be able to reduce exposure by attenuating the radiation and reducing the dose rates. The composition and the thickness of a material will affect its ability to shield radiation. This form of radiation characterizes one of the principal health threats to astronauts venturing beyond low earth orbit (Chancellor et al, 2014).

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In general medications xr purchase oxybutynin online pills, increasing the concentration of either or both of the reactants L and R can increase the overall rate of association. These manipulations also will increase the amount of drugreceptor complex formed and thus lengthen the time required to reach equilibrium. Optimal incubation conditions are determined empirically for each system and are chosen to maximize complex formation will minimizing the degradation of L and R. The source of receptor is dependent on the system under study and may include crude extracts, membrane preparations, cytosol, or nuclear extracts. However, in many instances the receptor is expressed in bacteria, yeast or insect cells, if possible. This allows for much higher concentrations of receptor than seen in vivo, often at higher purity (> 1 mg/ml). However, receptors that are multiprotein complexes or require post-translational modifications are difficult to examine using recombinant proteins. When receptors are embedded within membranes, the free and bound forms of drug may be easily separated by filtration or centrifugation. However, if the rate of ligand dissociation is high, the rate of separation may become an important consideration for accurately measuring the amount of drug-receptor complex. In the proceeding section, the basic separation techniques will be briefly discussed. For a more detailed description of these methods see Levitzki (1984) or Limbird (2005). After the solution reaches equilibrium, samples from both chambers are taken and the radioactivity measured. The amount of drug-receptor complex formed is determined based on the assumption that the free drug is equal on the protein and non-protein containing compartments. Equilibrium dialysis is no longer a frequently utilized method in receptor binding assays predominantly due to the long time required to reach equilibrium and secondary increases in the risk of protein or drug breakdown and decreased throughput. There are several variations of centrifugal separation of drug-receptor complexes. If the receptor is membrane bound, the drug-receptor complex may be centrifuged and a tight pellet formed. One minor variation is to layer the receptor-containing solution on a high-density solution (sucrose or oil). In the case of soluble receptors, either the receptor or the drug may be precipitated by centrifugation. In the former situation, an antibody specific to the receptor may be coupled to a large molecule such as sepharose. However nonspecific binding and trapping of the free drug are often major limitations. This procedure can handle a large number of samples and the filtration devices are commercially available. The filters are generally made from glass, nylon or nitrocellulose in order to provide high affinity and capacity for protein binding. As with other methods, the washing of the drug-receptor complex is performed with cold buffer to slow down the dissociation rate of the drug. Non-specific binding and trapping of the radioligand to the filter are potential problems associated with vacuum filtration. In this assay, the receptor is attached to a synthetic bead that contains a scintillin (a material that emits photons when it absorbs radioactive emissions). In most instances the receptor is bacterially expressed, purified and chemically attached to the bead, although it is possible to adhere membrane bound or crude receptor preparations. When a radioactive ligand is added to the medium, only the portion that is bound to the receptor will be close enough in proximity to the scintillin and thereby produce a photon emission. Scintillation proximity assays have become quite popular because of their high-throughput capabilities. However, the production of the synthetic beads containing the receptor of interest may be an arduous task for many laboratories. However, if the tracer is bound by a larger molecule, its effective molecular volume is increased. The bound and free states of the ligand each have an intrinsic polarization value: a high value for the bound state and a low value for the free state. The measured polarization is a weighted average of the two values, thus providing a direct measure of the fraction of tracer bound to receptor. AlphaScreen assays are bead-based proximity assays, based upon an oxygen channeling technology. The screen utilizes beads that are used to label the two interacting molecules; the receptor in this case can be affixed to a bead using specific antibodies. The ligand may be linked to a bead using antibodies (if a peptide ligand) or through a chemical linkage. When a Donor bead containing phthalocyanine is laser excited (at 680 nm) ambient oxygen is converted to singlet oxygen. This is a highly amplified reaction since approximately 60,000 singlet oxygen molecules can be generated and travel at least 200 nm in aqueous solution before decay. Consequently, if the Donor and Acceptor beads are within that proximity, energy transfer occurs. Singlet oxygen molecules react with chemicals in the Acceptor beads to produce a luminescent response. Any interaction with a non-receptor site would be considered nonspecific binding and is found at excess over true, specific interactions with the receptor. The binding of radioligand is examined in the presence of excess, saturating amounts of unlabeled drug. This technique assumes that a 100-fold excess of nonradioactive ligand saturates the specific receptor binding, but has no effect on the nonspecific sites. A useful rule-of-thumb is to use the unlabeled compound at a concentration equal to 100 times its Kd for the receptor, if that is known from previous experiments or estimated from preliminary analyses of the system. The drug used in excess may be the compound used as the radioligand, but unlabeled, or it may be a chemical that is known to bind to the same receptor. Ideally, the same results should be obtained when defining nonspecific binding with a range of concentrations of several drugs. Nonspecific binding is generally proportional to the concentration of radioligand (within the range used) and will not plateau at high concentrations. The desire is to extend the data to a physiologically relevant situation and therefore, the following criteria may be used to assess whether the data generated may indeed to extrapolated to a real-world. The advantage of such transformations is that Kd, and receptor density (Bmax or Rtot) can be easily identified. However, if the drug concentrations examined are insufficient, as define empirically, linear transformations may give a distorted view of the binding phenomena. All plotting methods must meet the following criteria: (1) Assumptions that the law of mass action, as described above, is met; (2) the incubation and separation techniques are appropriate; and (3) Nonspecific binding has been adequately measured. Use of drug concentrations that allow binding to approach saturation is crucial for accurate examination of the interaction between drug and receptor. As mentioned above, a good rule-of-thumb is to use a concentration of unlabeled ligand at 100 times the Kd. One of the criteria stated previously for a physiologically relevant receptor is that the binding sites are saturable. To assess saturability, the characteristics of binding as a function of increasing concentrations of radioligand are determined. An important consequence of this equation representing a rectangular hyperbola is that the horizontal asymptote is Rtot or Bmax. The estimation of Bmax and Kd can be solved by either linear transformation or by non-linear regression, which is described below.

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• Preventing some types of kidney stones.
• Are there any interactions with medications?
• Improving aerobic exercise performance.
• Dosing considerations for Phosphate Salts.
• Sensitive teeth, heartburn, cleaning out the bowels as a laxative preparation for intestinal tests such as colonoscopy when sodium phosphates are used, and other conditions.
• Are there safety concerns?
• Low blood phosphate, when sodium and potassium phosphates are used.

Source: http://www.rxlist.com/script/main/art.asp?articlekey=96719

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Studies of tumor induction by carcinogens in animal models have identified multiple loci that contribute to strain differences in susceptibility for every tumor type studied treatment lichen sclerosis discount 5mg oxybutynin visa. Thus, variants of tumor susceptibility genes are not directly responsible for transformation but influence the rate at which mutations occur and/or accumulate in a cell or influence the probability that a genetically altered cell will clonally expand into a clinically relevant tumor. The combined effects of multiple tumor susceptibility genes determine the overall susceptibility of an individual to the development of a particular type of cancer with each gene acting to either increase or decrease susceptibility. The complexity of genetic control of cancer susceptibility has been demonstrated by Demant and colleagues who reported that cancer susceptibility is complicated by genic interactions (Fijneman et al. However, the two loci interacted with each other with the effect of either locus being dependent upon the genotype of the other locus. In addition, gender and parent-of-origin have been shown to modify the effects of tumor susceptibility genes (Walrath et al. Recent studies have identified susceptibility loci that can act to both increase and decrease risk of cancer development, depending on the tissue involved. A large number of epidemiologic studies have associated cancer risk with genetic variants in candidate tumor susceptibility genes. Identification of genetic variants that modify cancer risk in humans has been complicated by a number of factors including genetic heterogeneity in the population, the multiplicity of genes involved, the low penetrance of each gene, epistatic interactions between tumor susceptibility genes, and variation in environmental exposure. In general, the per allele estimated effect size for each region has been between 1. Animal models are useful experimental tools that can overcome many of the complications of human studies in the identification and characterization of tumor susceptibility genes. Models offer the opportunity to dissect the process of tumor development within a defined system to elucidate the fundamental principles underlying cancer susceptibility. Such models are amenable to intervention at all stages of neoplastic development, allowing investigators to study even the earliest events in this process. In addition, both normal and neoplastic cells and tissues can be readily obtained from donor animals for biochemical and molecular analysis. To date, loci that affect susceptibility to carcinogen exposure have been identified in all models studied. Although the identification of specific genes that underlie these tumor susceptibility loci has been difficult, genes that underlie several modifier loci including Mom1 (Pla2g2a), Pctr1 (Cdkn2a), Skts13 (Aurka), Skts14 (Tgfb1), Mtes1 (Sipa1), Psl1. Importantly, polymorphisms in these genes have been associated with cancer risk in humans, demonstrating the utility of using animal models to identify genes that modify susceptibility to cancer. Interestingly, lymphomas are typically of B-cell origin while leukemias are of T-cell origin. Heterozygous carriers also have an increased risk of cancer development compared to the general population (reviewed in Digweed and Sperling, 2004). The average age at which cancer is diagnosed in Bloom syndrome patients is 24 years (reviewed in Thompson and Schild, 2002). The incidence of Bloom syndrome is quite low in the general population but in some select populations it occurs at a higher frequency. Other tumors are present in some families and these tumors include adenocarcinoma of the endometrium, ovary, small bowel, stomach, pancreas, and bile ducts, along with transitional cell carcinoma of the renal pelvis and ureter (reviewed in Cohen and Leininger, 2014). In addition to colon cancer, Muir-Torre syndrome patients develop skin tumors such as keratoacanthoma, sebaceous adenoma, epithelioma, and carcinoma (reviewed in Ponti and Ponz, 2005). The number of skin tumors can range from one to more than ten tumors per patient (Lucci-Cordisco et al. In addition, an increased risk of colorectal cancer has recently been reported for heterozygous carriers of the G382D variant in individuals aged > 55 years (Farrington et al. The Gln/Gln genotype of this variant has been associated with increased lung cancer risk among light smokers but decreased risk among heavy smokers (Hung et al. The endpoint of carcinogen exposure is often determined by a combination of oxidation, reduction and conjugation reactions. In recent years, a large amount of data has accumulated from genetic epidemiologic studies linking polymorphisms in biotransformation genes to susceptibility to cancers such as leukemia and breast, lung, colon and bladder cancers (Yu et al. Phase I metabolism can lead to reactive intermediates that are responsible for cancer induction or in some cases lead to products with weak or no biologic activity (reviewed in Bag et al. There are conflicting epidemiologic studies suggesting that several of these alleles are associated with cancer risk (reviewed in Bozina et al. A role for genic interactions in determining risk is supported by observations that risk of lung cancer (Shah et al. Inheritance of the c2 allele has been associated with decreased risk of lung cancer in Asians while no association was observed in Caucasians (Xu et al. A meta-analysis concluded that inheritance of the low expression allele significantly decreased risk of lung cancer; however, the inheritance of the polymorphism was only protective in smokers (Taioli et al. Inheritance of the low expression allele was also associated with decreased risk of colorectal cancer (Li et al. The His113 and His139 variants have reduced enzyme activity compared to the Tyr113 and Arg139 variants. A recent meta-analysis found that the Tyr113His polymorphism was associated with decreased risk of lung cancer in Caucasians (Wang et al. In contrast, the polymorphism was associated with increased risk of lung cancer in Asians (Wang et al. Another meta-analysis found that the His139Arg polymorphism was associated with decreased risk of colorectal cancer in Caucasians while the Tyr113His polymorphism was not associated with colorectal cancer risk (Liu et al. These reactions usually render a compound more water soluble, more readily excreted, and less reactive, although some products can have enhanced biologic activity. Polymorphisms in the genes that encode these enzymes have been associated with cancer risk (Bag et al. In this case, N-acetylation may prevent activation of aromatic amines that accumulate due to cigarette smoking or occupational exposures. The process is triggered by the migration of various types of leukocytes to the inflammation site, followed by the activation of a wide spectrum of inflammatory cells which are recruited by cytokines, chemokines, and growth factors. A link between inflammation and cancer was noted over 100 years ago by Rudolf Vichow (Balkwill and Mantovani, 2001) and epidemiologic studies indicate that chronic inflammation is associated with increased risk of cancer (reviewed in Thompson et al. Risk factors include duration of disease, severity of inflammation, and age of diagnosis (reviewed in Zisman and Rubin, 2008). Studies also indicate that patients with lung inflammatory diseases, such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, or sarcoidosis have an elevated lung cancer risk (reviewed in Engels, 2008). It is not clear that inflammation plays a role in elevated cancer risk in all of these diseases. Additional studies found an association of non-steroidal anti-inflammatory drug use and decreased lung tumor risk, supporting the hypothesis that inflammation is involved with lung cancer risk. Other inflammatory diseases associated with cancer include chronic pancreatitis associated with pancreatic cancer (Whitcomb, 2004), prostatitis associated with prostate cancer (De Marzo et al. In addition, chronic inflammation resulting from bacterial or viral agents has been associated with increased cancer risk (reviewed in Schottenfeld and Beebe-Dimmer, 2006). These include human papillomavirus associated with cancer of the uterine cervix, hepatitis B and C viruses associated with hepatocellular carcinogenesis, Helicobacter pylori associated with gastric cancer, Epstein-Barr virus associated with nasopharynx carcinoma and lymphoid tumors, Schitosoma hematobium associated with urinary bladder cancer, and Opisthorchis viverrini and Clonorchis sineasis associated with tumors of the biliary tract. Recent pathway analysis using the mouse two-stage skin tumor model identified a network of inflammatory genes associated with skin tumor promotion susceptibility (Shen et al. Proto-oncogenes have normal functions in regulating cellular processes such as cell division, proliferation, survival, motility, and apoptosis. Activating mutations or over-expression of proto-oncogenes can contribute to tumor initiation and progression. Tumor suppressor genes function to control cellular proliferation by negatively regulating cell growth. Germline and/or somatic mutations of tumor suppressor genes, resulting in loss of function, contribute to transformation. Numerous genes function as tumor suppressor genes and have been associated with both familial cancer syndromes and sporadic cancers. Studies of familial cancer syndromes and their associated gene mutations have led to insight into the mechanisms of carcinogenesis. Recently, greater effort has been invested in determining the impact of polymorphisms within tumor suppressor genes and proto-oncogenes on risk of sporadic cancer. Data from epidemiologic studies suggest that risk of a number of different cancer types is associated with inheritance of polymorphisms within these genes (reviewed in Bag et al. However, these associations are not clear, with other studies suggesting an opposite correlation or no association at all (reviewed in Hiyama et al. The G870A polymorphism occurs at the intron 4/exon 5 boundary and results in functionally different splice variants of the protein.

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A systematic evaluation of the impact of these polymorphisms has been difficult because the processes involved are complex and multifaceted treatment hiatal hernia buy oxybutynin in india. Furthermore, as described above, the impact of a particular polymorphism may be evident only under specific conditions, or a given polymorphism may have no effect whatsoever. In spite of this uncertainty, several clear examples have emerged that illustrate the importance of genetic variation as it relates to toxic exposure and response. Both enzyme classes exhibit considerable polymorphic variation, and some variants have been linked to the development of toxicant-induced cancers (Kadlubar and Badawi, 1995; Oude Ophuis et al. Some of the variants of this gene are associated with increased mutation and disease (for a complete list of genes involved in xenobiotic metabolism, (see "Relevant Websites" section)). Both aromatic and heterocyclic amines are present in the environment from several sources, including cigarette smoke and cooked foods. Variation in these genes has been associated with cancer of the breast, colon, lung, and urinary bladder (Bell et al. Polymorphisms are common in these genes, including nonfunctional alleles that result from the absence or deletion of the entire coding region (Ali-Osman et al. By implication, individuals with similar genotypes may be at increased risk for developing disease after exposure to cigarette smoke. In both cases, however, the precedent is cleardgenetic variation in carcinogen metabolism genes has a significant impact on disease risk. A diversity of repair pathways, including base excision repair, nucleotide excision repair, recombinational repair and mismatch repair, evolved to handle a wide array of lesions. Each of these systems involves multiple, interacting proteins, and significant crosstalk between the various repair pathways. Nucleosomal histones are mostly modified in their N-terminal tailsdregions enriched in positively charged aminoacidic residues that are subject to a large number of covalent posttranslational modifications including, but not limited to , acetylation, methylation, phosphorylation, and ubiquitination (for review, see Kouzarides, 2007; Thomas, 2006; Bojang and Ramos, 2014). These modifications are involved in chromatin function through regulation of gene expression. For example, histone H3 methylation at lysine 4 (H3K4me) activates gene expression (Santos-Rosa et al. This phosphorylation may extend over many kilobases around the site of the damage (Fillingham et al. In general, toxicants or drugs modify specific epigenetic marks that create a tissue or cell type-specific profile (see Navratilova et al. Research into these relationships has revealed strong associations between genotype and risk for these diseases, particularly for genes involved in metabolism of foreign compounds. The authors suggested that a detailed analysis of repair polymorphisms, in conjunction with in vitro assays for repair efficiency and large-scale epidemiology studies, would be valuable for the advancement of the field. However, a large number of genes potentially associated with human disease have not been evaluated for polymorphism content. Identifying polymorphisms is an important first step in understanding the relationship between genetic variation and susceptibility to toxic exposures. Global efforts to sequence the human genome have provided a valuable opportunity to collect information on polymorphic variation among populations. In addition to whole-genome sequencing efforts, several major projects are underway to collect cross-genome datadmany with the specific goal of identifying polymorphisms in human populations (see Table 3). Although these efforts remain poorly integrated, we now have access to large databases representing millions of individual polymorphisms, and the tools to evaluate this data are developing at a similar rapid Table 3. Once polymorphisms are identified, the enormously complex process of ascertaining their significance begins. In the context of toxicology, the polymorphisms must be evaluated under specific conditions of exposure in order to establish their relationship to human health. Although a formidable challenge, these types of studies also hold the potential for tremendous benefit. For example, knowledge of the impact of a given allele should allow the identification of subgroups within the population that are particularly susceptible to exposure. On the bases of these relationships, preventative, regulatory and therapeutic efforts are now being developed to manage toxicity outcomes and to avert or ameliorate disease. On a similar note, it is known that the xenobiotic metabolizing enzymes are important to the metabolism of various therapeutic drugs. It will help researchers to find genes affecting health, disease, and responses to drugs and environmental factors A nonprofit foundation organized for the purpose of providing public genomic data. Similar approaches can be envisioned for a wide variety of exposure-related genetic profiling applications. The large number of genes involved in human responses to toxic challenge, coupled with the high frequency of low-penetrance genotypes, suggests that all of us carry inherent risks for disease and susceptibility. Additionally, each of us likely shares risk-group identity with many people from all ethnic, economic, and geographical groups. Technological advancement and scientific endeavor continue to provide more abundant and reliable information regarding genetic risk, and it is crucial that social and legal development proceed apace. Although we cannot (as yet) change our genotype, we can and should ensure that our environment, lifestyle, and laws incorporate our emerging knowledge of genetic risk in both an ethical and scientifically sound manner. Genetic and Epigenetic Determinants of Environmental Injury and Disease 473 Ilett, K. Conclusions 475 476 476 476 478 478 478 479 479 480 480 480 481 482 482 Glossary Effect size A measurement of the magnitude of the effect that a given genotype (or treatment) has on a specific outcome. Heritability the proportion of phenotypic variance that can be attributed to genetic variation. Heritability estimates range from 0 (no contribution of genetic variation to phenotypic variation) to 1 (phenotypic variation explained entirely by genetic variation). Odds ratio the ratio between the probability that an event will occur in one group and the probability that it will occur in another. Pleiotropy A situation in which a single genetic polymorphism influences two or more distinct traits. In this article we discuss complex diseases and their inherited susceptibility primarily (albeit not exclusively) by taking as an example childhood asthma, one of the most complex among complex diseases (Martinez and Vercelli, 2013). Although a focus on childhood asthma grounds the discussion in compelling real-life examples, Change History: May 2017. One of the most striking characteristics of asthma is its marked heterogeneity in terms of pathophysiology, age of onset, clinical course, and response to treatment (Martinez and Vercelli, 2013). Moreover, asthma exhibits a characteristic age-by-sex interaction, with many more boys diagnosed before puberty but increased prevalence in girls after puberty and throughout adult life. This clinical heterogeneity likely reflects the presence of distinct disease endotypes, i. The marked and rapid increase in asthma prevalence observed over the past 50 years in westernized countries (Bach, 2002; Eder et al. Among environmental risk factors for childhood asthma, maternal asthma remains perhaps the most significant predictor of disease during childhood (Lim et al. In combination, these data highlight the impact of environmental factors on asthma pathogenesis and moreover suggest that the trajectory to the disease is developmentally regulated and begins in early life, possibly even in utero (Bonnelykke and Ober, 2016). In addition to the many environmental exposures implicated in asthma risk (Ober and Vercelli, 2011), twin and family studies suggest that genetic factors are critical for childhood asthma susceptibility. In particular, a recent meta-analysis of 71 twin studies involving 36,903 twin pairs estimated the heritability of asthma to be 0. Heritability estimates are also higher among boys compared with girls and in those with early-onset compared with later-onset asthma (Thomsen et al. These distinct but complementary lines of evidence support the notion that asthma is a bona fide complex disease in which genetic, environmental and developmental factors play a critical pathogenetic role.

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The toxicological significance of olfactory transport of manganese remains controversial medicine ok to take during pregnancy purchase 2.5mg oxybutynin with visa. Although olfactory transport rapidly delivers manganese to brain structures in the olfactory pathway, it appears to be relatively slow (and perhaps inefficient) in delivering inhaled manganese to the rat striatum and other more distant brain structures. Elevated manganese olfactory bulb concentrations can occur following oral exposure as well (Foster et al. One question that remains is whether inhaled manganese delivered to the olfactory bulb produces any adverse neurological effect(s). For example, there is evidence suggesting that olfactory dysfunction occurs in honeybees exposed to pesticides (Palmer et al. In some cases these associations have been evaluated experimentally and await confirmation in wild animal populations. Olfactory toxicity in animals often relies on the 370 Olfactory System assessment of the integrity of the olfactory epithelium at multiple sites. Occupation-related olfactory impairment is often subclinical, and is often only appreciated using olfactory function testing procedures. Improved integration of biochemical and behavioral approaches to the study of toxicant-induced olfactory injury should improve our ability to perform adequate risk assessments for chemicals that affect this system. Collaborative behavioral teratology study: Protocol design and testing procedures. Chemosensory mediated behaviors and gene transcription profiles in wild yellow perch (Perca flavescens) from metal contaminated lakes. Olfactory dysfunction and cognitive impairment in age-related neurodegeneration: Prevalence related to patient selection, diagnostic criteria and therapeutic treatment of aged clients receiving clinical neurology and community-based care. Localization and comparative toxicity of methylsulphonyl-2,5 and 2,6-dichlorobenzene in the olfactory mucosa in mice. Copper-induced olfactory toxicity in salmon and steelhead: Extrapolation across species and rearing environments. Identification and molecular regulation of neural stem cells in the olfactory epithelium. Chronic exposure to rotenone, a dopaminergic toxin, results in peripheral neuropathy associated with dopaminergic damage. Direct olfactory transport of inhaled manganese (54MnCl2) to the rat brain: Toxicokinetic investigations in a unilateral nasal occlusion model. Evidence of an odorant-binding protein in the human olfactory mucus: Location, structural characterization, and odorant-binding properties. Air pollution is associated with brainstem auditory nuclei pathology and delayed brainstem auditory evoked potentials. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Further studies of the metabolic incorporation and covalent binding of inhaled [3H]- and [14C]formaldehyde in Fischer-344 rats: Effects of glutathione depletion. Review of the role and methodology of high resolution approaches in aroma analysis. Comparative risks of aldehyde constituents in cigarette smoke using transient computational fluid dynamics/physiologically based pharmacokinetic models of the rat and human respiratory tracts. Comparative computational modeling of airflows and vapor dosimetry in the respiratory tracts of rat, monkey, and human. Nasal epithelial lesions in F344 rats following a 90-day inhalation exposure to naphthalene. Nasal toxicity of manganese sulfate and manganese phosphate in young male rats following subchronic (13-week) inhalation exposure. Correlation of brain magnetic resonance imaging changes with pallidal manganese concentrations in rhesus monkeys following subchronic manganese inhalation. Assessment of upper respiratory tract and ocular irritative effects of volatile chemicals in humans. Effects of zinc gluconate and 2 other divalent cationic compounds on olfactory function in mice. Phosphatidyl-inositide signalling proteins in a novel class of sensory cells in the mammalian olfactory epithelium. The sense of smell, its signaling pathways, and the dichotomy of cilia and microvilli in olfactory sensory cells. Metabolic activation of the olfactory toxicant, dichlobenil, in rat olfactory microsomes: Comparative studies with p nitrophenol. Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra. Pharmacokinetic evaluation of the equivalency of gavage, dietary, and drinking water exposure to manganese in F344 rats. Isomer-specific bioactivation and toxicity of dichlorophenyl methylsulphone in rat olfactory mucosa. Use of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry comparisons of ester vapors. Acute toxicity of zinc oxide nanoparticles to the rat olfactory system after intranasal instillation. Patient-derived olfactory mucosa for study of the non-neuronal contribution to amyotrophic lateral sclerosis pathology. Update on olfactory mucosal metabolic enzymes: Age-related changes and N-acetyltransferase activities. Drug transporter expression and localization in rat nasal respiratory and olfactory mucosa and olfactory bulb. Distribution and systemic effects of intranasally administered 25 nm silver nanoparticles in adult mice. Characterization of olfactory deficits in the rat following administration of 2,6-dichlorobenzonitrile (dichlobenil), 3,30 -iminodipropionitrile, or methimazole. Anatomical and histological factors affecting intranasal drug and vaccine delivery. The perception of odor is not a surrogate marker for chemical exposure: A review of factors influencing human odor perception. Effects of acute and chronic dimethylamine exposure on the nasal mucociliary apparatus of F-344 rats. Nonoccupational environmental exposure to manganese is linked to deficits in peripheral and central olfactory function. The nose revisited: A brief review of the comparative structure, function, and toxicologic pathology of the nasal epithelium. Odorant-binding proteins and xenobiotic metabolizing enzymes: Implications in olfactory perireceptor events. The utility of magnetic resonance imaging in the diagnostic evaluation of idiopathic olfactory loss. International comparison of odor threshold values of several odorants in Japan and in the Netherlands. Evaluation of the toxicity of zinc in the rat olfactory neuronal cell line, Odora. Degeneration and regeneration of the olfactory epithelium following inhalation exposure to methyl bromide: Pathology, cell kinetics, and olfactory function. Label-retaining, quiescent globose basal cells are found in the olfactory epithelium. Cellular and molecular mechanisms regulating embryonic neurogenesis in the rodent olfactory epithelium. Demonstration of an olfactory bulb-brain translocation pathway for ZnO nanoparticles in rodent cells in vitro and in vivo. Nasal dosimetry of inhaled gases and particles: Where do inhaled agents go in the nose Dosimetry modeling of inhaled formaldehyde: Comparisons of local flux predictions in the rat, monkey, and human nasal passages. Effect of acute copper sulfate exposure on olfactory responses to amino acids and pheromones in goldfish (Carassius auratus). Ethanol impairs memory of a simple discrimination in adolescent rats at doses that leave adult memory unaffected. Olfactory discrimination and generalization of ammonium nitrate and structurally related odorants in Labrador retrievers.

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Hundreds of variants clustered in genomic loci and biological pathways affect human height medicine 0027 v cheap oxybutynin 5mg with mastercard. Risk for asthma in offspring of asthmatic mothers versus fathers: A meta-analysis. Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Functional impact of global rare copy number variation in autism spectrum disorders. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Relative impact of nucleotide and copy number variation on gene expression phenotypes. The power of regional heritability analysis for rare and common variant detection: Simulations and application to eye biometrical traits. A virtuous duplicity: 17q21 variants at the intersection between asthma protection and risk. The Faustian bargain of genetic association studies: Bigger might not be better, or at least it might not be good enough. Gene set analysis of genome-wide association studies: Methodological issues and perspectives. Fish and fish oil intake in relation to risk of asthma: A systematic review and meta-analysis. Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index. A Veith, C Chu, B Moorthy updated all sections and included new sections and figures from R. Geoghegan, Modeling Genetic Susceptibility to Disease, Comprehensive Toxicology, Second Edition. Pharmaceutical and toxicological research today must incorporate the effect of genetic variation on drug dosage, efficacy, bioavailability and toxicity (Blais et al. Additionally, novel gene editing technologies have been developed that allow for an unprecedented ability to generate animal models harboring these types of genetic variation. These animals serve as preclinical platforms for a wide range of toxicology applications, such as drug toxicity testing to understanding how exposure to xenobiotics impact different individuals. Animal models also play a role in the bench-to-bedside spectrum, from driving basic science discoveries to serving as preclinical models. Animal models provide an unparalleled insight into understanding complex physiological systems and modeling human disease. The development of genetically modified animal models has facilitated the ability to interrogate gene expression and function in both biological and pathological processes. Recent technological advances have enabled the rapid generation of genetically engineered animal models at a rate that not previously possible. Coupled with the increased availability of large-scale genomic datasets and bioinformatics tools, toxicologists now have the unparalleled ability to model genetic susceptibility to disease. This article focuses on advances in genetic engineering that have provided an unprecedented ability to generate animals that can model genetic susceptibility to disease. Novel methods have been developed to allow investigators to generate genetic animal models for their disease or gene of interest at an incredible pace. Moreover, these advances have allowed for the generation of genetically engineered animal models of other species. There are a growing number of databases and resources available to investigators to help identify candidate genes or previously generated genetic animal models for their research. This article also highlights novel gene targeting methods and approaches as well as screening methods. The goal is to provide the reader an understanding of what is currently being done in animals to model genetic susceptibility to disease. The importance of gene targeting in biology and medicine was recognized in 2007 with the Nobel Prize in Physiology and Medicine to Mario Capecchi, Martin Evans, and Oliver Smithies. The pioneering approach utilized homologous recombination in embryonic stem cells, however novel endonuclease-based gene editing technologies are quickly supplanting gene targeting. This discussion primarily features mice, in part due their wide popularity among 486 Modeling Genetic Susceptibility to Disease biomedical investigators. Subsequent gene targeting approaches may also highlight different aspects of vector design. Original efforts to create transgenic mice were done with viruses, such as Simian Virus 40, and while the transgene was able to pass on to subsequent generations, the integration site was random (Costantini and Lacy, 1981; Gordon and Ruddle, 1981; Jaenisch and Mintz, 1974). Black indicates nucleotide sequence, blue indicates amino acid sequence, red indicates mutations. In this example, endogenous exon 2 is replaced with a mutant exon 2 containing a point mutation. Recombination between A and B at regions of homology produce (C) successful incorporation of mutant exon 2 targeting vector. These regions of homology are often >1 kilobase pair (Kb) in length and flank the 50 and 30 end of the desired mutation. It is important that the homologous sequences between the endogenous genome and the gene- targeting vector be isogenic, and able to match the strain of mouse being used. Linearization of the targeting vector increases the low frequency of homologous recombination (Brenner et al. Despite linearization of the targeting vector and efficient transfection methods, the frequency of homologous recombination remains low. Therefore, positive and negative selection criteria are often utilized to enrich for cells that incorporate the transgene successfully. A common positive selection marker is a neomycin-resistance gene (neo) which provides cells resistance against the antibiotic G418 (Sedivy and Sharp, 1989). Addition of the antibiotic G418 allows only cells which express neo to survive, therefore, the neo cassette or other positive selection markers, are positioned between the regions of homology. It is also possible for the gene-targeting vector to randomly insert into the genome. There are a number of other reviews available to highlight the basic principles of gene targeting (Hall et al. This was first shown by introduction of a modified b-globin gene into the endogenous human b-globin locus (Smithies et al. In this approach, a minimum of two generations is needed to obtain mice with ubiquitous incorporation of the transgene and can take several months. However, recent advances have allowed for the development of endonuclease-based methods to precisely and rapidly create mutant animals. With previous methods, this would have taken multiple generations of breeding to obtain homozygous knockouts for multiple genes. There are also a number of reviews highlighting the future of this system in genome engineering that may be of interest (Doudna and Charpentier, 2014; Sander and Joung, 2014). Different mutations and alleles can have different effects on a given gene expression and function. Modeling Genetic Susceptibility to Disease 489 Table 1 Gene targeting approach cheat sheet. As previously mentioned, the examples focus on murine models, but these types of alleles are applicable in other animal models as well. Table 1 contains an abbreviated summary of the gene targeting approaches, impact on gene expression, and possible research questions that allele can address. Early strategies often used selection markers, such as neo, to disrupt the gene of interest, creating null alleles (Doetschman et al. However, as sequencing of model organisms has grown, more gene targeting vector schemes can be used to create null alleles. These types of alleles traditionally provide investigators insight into the relevance and function of the gene target in biological and pathological processes. The results from this study identified Cyp1a1 as playing a protective role against hyperoxic toxicity.

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Genetically based Nacetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens 97140 treatment code generic oxybutynin 2.5mg free shipping. Diet, physical activity, and colorectal cancer among Chinese in North America and China. Human hepatocytes support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogen sodium phenobarbital in an in vivo study using a chimeric mouse with humanized liver. The investigation of these involves both knowledge of the source and nature of the hazard and an understanding of the relationship of the exposure to the disease. A distinction is often made between conditions from which individuals may have no or only partial control and those for which some element of personal choice exists. Exposure encountered at work and to substances in the environment would, for example, tend to fall in the former category, whilst lifestyle factors such as smoking, eating a high-fat diet, and drinking alcohol would fall in the latter category. The working environment should not be a place where there is a risk of disease of injury, yet many thousands of workers worldwide are exposed to hazardous substances at work every day. In the public mind substances related to occupational cancer are often associated with chemical exposures, especially manmade (Higginson, 1993), although the research community would generally consider a much broader set of factors, encompassing all that might impact on human cancer, for example, shift working. For human data, sufficient evidence is defined as the establishment of a causal relationship between exposure to the agent and human cancer. Limited evidence is defined as the observation of a positive association between exposure to the agent and human cancer, for which a causal interpretation is considered credible, but chance, bias, or confounding could not be ruled out with reasonable confidence. Toxicological studies conducted on experimental animals can rigorously assess the biological response to a range of levels of exposure to a given substance or Table 1 Group 1 2A 2B Carcinogenicity defined by the International Agency for Research on Cancer Definition Carcinogenic to humans Probably carcinogenic to humans Possibly carcinogenic to humans Used when Sufficient evidence in humans Limited evidence in humans, and sufficient evidence in experimental animals Limited evidence in humans, and absence of sufficient evidence in experimental animals, or inadequate evidence in humans or human data nonexistent and sufficient evidence in experimental animals Inadequate or unavailable evidence in humans and inadequate or limited evidence in animals Evidence suggests a lack of carcinogenicity in humans and in experimental animals 3 4 Not classifiable as carcinogenic to humans Probably not carcinogenic to humans 250 Occupational Carcinogenesis combination of substances. This has the advantage of specificity but presents a problem when extrapolating to humans, both because of species differences and because high doses are often used in an experimental setting in animals, whereas typically humans will be exposed to low doses of pollutants. This can partially be overcome through clinical studies employing human volunteers. However, for ethical reasons these are generally limited to a narrow range of low exposure levels, which cause a mild and reversible health effects. Epidemiological designs, such as cross-sectional, case-control and cohort studies (Rothman and Greenland, 1998), have thus been widely used to test causal hypotheses in human cancer in studies of individuals. Temporal or geographical ecological studies have also played an important part in identifying potential causal associations between exposures and adverse health effects (Elliott et al. Important issues are those of (1) confounding, where an association between the exposure of concern and the disease of interest is partially explained by the association of both of these with another variable, the confounder, which itself is either a cause or closely related to a cause of the disease, for example, many diseases and exposures will vary by age, and (2) effect modification or interaction, where the risk due to an occupational exposure is modified by levels of another exposure, for example, asbestos and smoking in lung cancer (Berry and Liddell, 2004). The presence of possible confounding has to be taken into account in the interpretation of results, particularly where the exposure levels and hence the magnitude of any expected risk is relatively low. The assessment of all the evidence, from animal and human experimental studies as well as epidemiological studies, is thus essential when making judgments as to causality. There is also increasing interest in estimating and comparing burdens of disease generally (Lopez et al. Estimates can identify major risk factors and highrisk populations, support decisions on priority actions for risk reduction, and provide an understanding of important contributions to health inequalities. Since then several other estimates of occupational cancer burden have been made for selected cancers (Table 2). A recent update of the total burden of occupational death worldwide estimated that over 850 000 deaths occurred in 2010 due to occupational causes, of which over half were estimated to be due occupational injuries, a further 25% due to particulate matter, gases and fumes leading to chronic obstructive pulmonary disease and nearly 14% due occupational carcinogens (Lim et al. Some of the differences between the results could be due to differences in the numbers of agents considered or differences between countries in the occupational situations in which exposures occur or different methodological approaches used. Occupation also contributed 2% or more overall to cancers of the larynx, oesophagus, and stomach, and soft tissue sarcoma with, in addition for men, melanoma of the eye (due to welding), and non-Hodgkin lymphoma. Both the British and Global Burden of Disease studies draw attention to the important issues of: (1) multiple occupational carcinogens causing specific types of cancer, for example, the British study evaluated 21 lung carcinogens; and (2) specific carcinogens causing several different cancers, for example. These issues require careful consideration for burden estimation and for prioritizing risk reduction strategies. Table 2 Estimates of attributable fraction for occupational causes of selected cancers Cancer site Lung M 15% 21. In the United Kingdom, for example, the Industrial Injuries Benefit Scheme includes cancers from established carcinogens such as asbestos (mesothelioma and lung cancer), wood dust (sinonasal and nasopharyngeal cancers), aromatic amines (bladder cancer), arsenic, tars, soots and mineral oils (skin cancer), benzene (acute nonlymphocytic leukaemia), and chromates and silica (lung cancer). The United Kingdom adopts a list approach as does France, India, the Philippines, Malaysia, Cameroon, Zambia, and Canada. This avoids the need to develop a generic proof of causality between the disease and occupation and allows a presumption of causality for the occupations and cancers on the lists. In practice, this means that any disease can be recognized as an occupational disease if the causal link is proven. Countries such as Germany, Italy, Belgium, Switzerland, and Mexico adopt a mixed approach (Lauterbach and Von Tautphoeus, 2002). There is a paucity of information about latency periods, but evidence suggests that for diseases such as leukaemia and other blood cancers, exposure in the 20 years before diagnosis is important whereas for solid tumors the risk exposure period can be up to 50 years before diagnosis. Steeper rates of decline were found for Japan and eastern Europe compared with North America and western Europe, for manufacturing industries compared with mining and other industries, and for aerosols and metals compared with vapours. Reductions in exposure may be achieved through introduction of engineering controls, substitution of materials, and improved hygiene measures with differences between countries arising because of differences in factors such as legislation, technology, attitudes to risk, and geographical structure. Some exposures have all but disappeared due to the decline of the industry or the substitution of hazardous substances by other noncarcinogenic agents. Other carcinogens such as naturally occurring radon could also easily be eliminated from workplaces. For some carcinogenic agents exposures remain high, for example, silica and wood dust exposure in the construction industry, in which the number of employees is increasing (Kauppinen et al. Epidemiological studies have consistently reported elevated risks associated with smoking and alcohol consumption. A total of 5498 male chimney sweeps from Denmark, Finland, Norway and Sweden were identified in the cohort. Statistically significant excesses of cancers of the lung, oesophagus, pharynx, bladder, and colon were found. Almost all the epidemiological studies have been carried out in dry cleaners and tetrachloroethylene has been consistently associated with an increased risk of esophageal cancer with many risk estimates being more than doubled (Blair et al. The strongest factor associated with stomach cancer is chronic infection with Helicobacter pylori with other suggestive factors including high dietary intake of irritant substances, such as salts and nitrates (Lambert and Hainaut, 2007) and alcohol consumption (Forman and Burley, 2006). Occupations and geographical areas with the highest risks tend to be those associated with heavy past asbestos exposures, for example, asbestos mining, manufacture, and shipbuilding. These industries have now declined and workers with the highest risks today are likely to be those subject to incidental exposures, for example, construction workers. There have been a large number of studies reporting on associations between asbestos exposure and stomach and other gastrointestinal tract cancers (Gamble, 2008; Goodman et al. The risk estimates for both stomach and colorectal cancers vary but are generally modest. Numerous studies have been carried out that show excess lung cancers related to asbestos exposure. Exposure to diesel engine emissions occurs in many occupational settings, and it is often difficult to evaluate separately from other combustion fumes, notably gasoline engine emissions. Both showed positive trends in lung cancer risk with increasing exposure to diesel exhaust, as quantified via estimated elemental carbon as a proxy of exposure. Exposure to inorganic arsenic, especially in mining and copper smelting, has consistently been associated with an increased risk of lung cancer with an almost 10-fold increase in risk in the most heavily exposed (Lee-Feldstein, 1986). Beryllium: Exposure to beryllium occurs mainly in mining, refining, and in the manufacture of ceramics, and electronic and aerospace equipment. Increased risk has also been observed among battery workers (Sorahan and Esmen, 2004), smelter workers (Ades and Kazantzis, 1988), alloy workers (Sorahan et al. Chromium: It adds rust and acid resistance properties as well as hardness to alloys. Cobalt: this metal is used to make corrosion- and wear-resistant alloys used in aircraft engines, magnets and high-strength steels, and other alloys.