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• Associate Professor of Surgery, Director of Surgical Education and Curriculum
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For reasons not well understood prostate cancer kaiser buy eulexin 250mg on line, spontaneous pheochromocytomas are largely observed in aging male laboratory rats mens health nottingham best 250mg eulexin, but are relatively rare in mice (Greim et al prostate enlargement treatment generic eulexin 250mg otc. The differences between rats and mice have led to the suggestion that the mouse is a more suitable model for humans as regards adrenal medullary risk assessment man health tips in urdu buy discount eulexin online. These medullary lesions mens health 10k glasgow 2013 eulexin 250 mg lowest price, more frequently observed in males prostate implant buy on line eulexin, can be induced by a variety of xenobiotic agents (Tischler et al. Pheochromocytomas in rats differ from those in all other species in that they are common, often bilateral, and can be induced by many chemicals. An extensive listing of chemicals that are effective at producing proliferative lesions in rats and mice has been provided in reviews by Greim et al. Vitamin D is the most powerful mitogenic stimulus to cause chromaffin cell proliferation in the adrenal medulla in rats (Greim et al. Because the vitamin D effect has been seen in vivo, but not in vitro, it is thought to result from impaired calcium homeostasis, resulting in hypercalcemia. In animals, there is no indication as yet that pheochromocytomas are induced by chemicals working through genotoxic mechanisms (Ozaki et al. Proliferation of chromaffin cells in male rats occurred following exposure to aromatic amines such as p-chloroaniline (Chhabra et al. Rather, proliferation of chromaffin cells in rats can be stimulated by chemicals that induce uncoupling of mitochondrial respiration, hypoxia, disturbances in calcium homeostasis, acute stress, and overfeeding (Greim et al. Many of the chemicals that induce pheochromocytoma in animals are uncouplers of oxidative phosphorylation, for example, acrylamide (Howland and Alli, 1986) or furan (Mugford et al. Unlike in humans, in which they secrete high levels of epinephrine, rat pheochromocytomas are usually characterized by predominant or exclusive production of norepinephrine. Chemicals that induce pheochromocytomas in rats are pharmacologically diverse, and usually stimulate chromaffin cell proliferation by neutrally derived signals, or agents that regulate catecholamine synthesis and release. An important class of compounds that affects the rat adrenal medulla includes sugars and sugar alcohols, such as lactitol, xylitol, and sorbitol (Lynch et al. Both nicotine and reserpine have been implicated in the development of adrenal medullary proliferative lesions in rats. Both chemicals act by a shared mechanism, because nicotine directly stimulates nicotinic acetylcholine receptors whereas reserpine causes a reflex increase in the activity of cholinergic nerve endings in the adrenal. A short dosing regimen of reserpine administration in vivo stimulates proliferation of chromaffin cells in the adult rat, and the mechanism may involve a reflex increase in neurogenic stimulation via the splanchnic nerve. Roe and Bar (1985) have suggested that environmental and dietary factors may be more important than genetic factors as determinants of the incidence of adrenal medullary proliferative lesions in rats because the incidence of adrenal medullary lesions can be reduced by lowering the carbohydrate content of the diet. Several of the chemicals that increase the incidence of adrenal medullary lesions, such as sugar alcohols, increase absorption of calcium from the gut. Calcium ions as well as cyclic nucleotides and prostaglandins may act as mediators capable of stimulating both hormonal secretion and cellular proliferation. In summary, three dietary factors have been suggested to lead to an increased incidence of adrenal medullary proliferative lesions in chronic toxicity studies in rats (Roe and Bar, 1985). These are excessive intake of (1) food associated with feeding ad libitum; (2) calcium and phosphorus; and (3) other food components (eg, vitamin D and poorly absorbable carbohydrates), which increase calcium absorption. This striking difference in sensitivity to mitogenic stimuli may explain the lower frequency of adrenal medullary proliferative lesions in mice compared to many rat strains. The human adrenal medulla, as in mice, has a low spontaneous incidence of proliferative lesions of chromaffin cells. Human chromaffin cells also failed to respond to a variety of mitogenic stimuli in culture (Tischler and Riseberg, 1993). These findings and others suggest that chromaffin cells of the rat represent an inappropriate model to assess the potential effects of xenobiotic chemicals on chromaffin cells of the human adrenal medulla. A relationship exists between adenohypophyseal (anterior pituitary) hormones and the development of adrenal medullary proliferative lesions. For example, the long-term administration of growth hormone is associated with an increased incidence of pheochromocytomas as well as the development of tumors at other sites. Prolactin-secreting pituitary tumors, which occur commonly in many rat strains, also play a role in the development of proliferative medullary lesions. In addition, several neuroleptic compounds that increase prolactin secretion by inhibiting dopamine production have been associated with an increased incidence of proliferative lesions of medullary cells in chronic toxicity studies in rats. In long-term animal studies, pheochromocytomas often are accompanied by tumors or toxic effects in other organs. They often are seen in cases involving renal, lung, and hepatic toxicity, in addition to endocrine disturbances (Greim et al. They are associated with the following conditions: hypoxia, uncoupling of oxidative phosphorylation, disturbances of calcium homeostasis, or disturbances of the hypothalamic endocrine axis (Greim et al. At this time, there are no human chromaffin cell lines, despite numerous efforts to establish such a cell line (Tischler et al. This is thought to be dependent upon Ca++ influx through voltage-gated channels (Taylor et al. Proliferation of chromaffin cells can also be induced in vitro by activators of adenylate cyclase that stimulates neuropeptide receptors, as well as stimulators of protein kinase C, which stimulates muscarinic cholinergic receptors. The interstitial compartment is composed of C cells, the site of synthesis, and secretion of calcitonin (Modified from Porterfield, 2007). A second cell type is also present, the C-cells, or parafollicular cells composing the intrafollicular spaces (Capen and Martin, 1989; Capen, 2001). The thyroid secretes two hormones known as thyroxine (T4) and triiodothyronine (T3) (Capen and Martin, 1989; Capen, 2001; Hedge et al. Both of these hormones are produced in epithelial cells in the basic functional unit of the thyroid known as the follicle. Each follicle consists of a sphere of epithelial cells surrounding a colloidal core. Generally, the level of secretory activity of follicular cells can be estimated as a direct function of their height. Cells involved in synthesizing thyroid hormone are columnar in shape, whereas quiescent cells are cuboidal (Capen and Martin, 1989; Capen, 2001). T4 and T3 are important regulators of overall metabolism, and their effects are regulated within a long time frame (Capen, 2001; Hedge et al. However, the primary target tissues for thyroid hormone include the liver, kidney, heart, brain, pituitary, gonads, and spleen (Capen and Martin, 1989; Capen, 2001; Zoeller et al. Some studies indicate that xenobiotics directly affect the structure of the thyroid gland (Capen, 2001). For example, some environmental chemicals such as heavy metals and red dye #3 are known to decrease the size of the colloid space (Bronnikov et al. This is thought to reduce the space required for storing hormones, leading to an impaired ability of the thyroid gland to synthesize and store thyroid hormones. The schematic shows the thyroid gland in humans, which consists of two lobes of endocrine tissue, located just below the larynx on each side of the trachea with an isthmus connecting the two lobes (Modified from Porterfield, 2007). Thyroid hormones are composed of two modified, covalently linked tyrosine amino acids. T4 contains two iodides on each aromatic ring for a total of four, while T3 contains two iodides on the tyrosine closest to the amino acid moiety (amino and carboxy groups), and one iodide on the outer aromatic ring (Capen, 2001; Hedge et al. While the thyroid gland synthesizes and secretes both T4, and T3, it primarily releases T4. In fact, about 90% of thyroid hormone secreted by the thyroid gland is in the form of T4 in humans (Hedge et al. T4 from the thyroid gland can be peripherally converted to T3 (active hormone) or rT3 (inactive metabolite), then successively deiodinated by the monodeiodinases (Modified from Hedge et al. Iodine in the form of iodide (I-) is actively transported in to the epithelial cell, where it is oxidized to I2 by thyroid peroxidase. T4 from the thyroid gland can be peripherally converted to T3 (active hormone) or reverse T3 (rT3, the inactive metabolite) then successively deiodinated by the monodeiodinases (Capen, 2001; Hedge et al. About 40% of circulating T4 is metabolized to T3 by 5-monodeiodinase, and 40% is converted to rT3 by 5-monodeiodinase (Capen, 2001; Hedge et al. Additionally, about two-thirds of T3 and all rT3 in circulation are produced from T4 by peripheral conversion (Capen, 2001; Hedge et al. As a result, the ratio of circulating T4 and T3 does not reflect the ratio of these two substances when they were released from the thyroid gland. Based on a variety of observations, it appears that circulating T4 levels provide a "sink" of prohormone that can serve as a ready supply for peripheral conversion to T3 (the active form; Hedge et al. Several studies indicate that xenobiotics can interfere with thyroid gland function by adversely affecting the process of thyroid hormone synthesis (Jugan et al. For example, environmental chemicals such as perchlorate, chlorate, and bromate inhibit uptake of iodide and thus, decrease thyroid hormone synthesis (Crofton, 2008). Further, some chemicals may interfere with monodeiodinases, leading to decreased levels of thyroid hormones. Specifically, studies have shown that red dye #3 and propylthiouracil inhibit 5-monodeiodinase, leading to reduced serum levels of T3 (Capen, 2001; Crofton, 2008). Some studies indicate that some xenobiotics may increase the clearance of thyroid hormones from the serum, limiting the availability of thyroid hormones to act on tissues and often resulting in symptoms of hypothyroidism (Brouwer et al. Thyroid Hormone Binding Proteins Once released in to the blood, thyroid hormones are rapidly bound to high affinity serum binding proteins (Capen, 2001; Hedge et al. Only the small unbound fraction of the total hormone pool has access to receptors in target cells, and thus only the unbound fraction can exert biological activity. The displacement of thyroid hormones from the binding proteins often leads to a rapid decline in serum thyroid hormone levels. The homodimers and heterodimers bind to thyroid hormone response elements located in target genes and interact with coactivators and corepressors to regulate transcription. While all three isoforms are present in most tissues, their expression differs spatially and temporally during development (Zoeller, 2005). Second, some environmental chemicals interfere with thyroid hormone binding to receptors via indirect mechanisms (Zoeller, 2005). In such cases, it is thought that the chemicals exert their effects by promoting coactivators or inhibiting corepressors. Interestingly, most inhibition by thyroid hormones is by T4, although T3 can also provide some degree of inhibition (Hedge et al. Further, the feedback effect is mediated primarily at the level of the anterior pituitary, although some degree of negative feedback occurs at the level of the hypothalamus (Hedge et al. Overall, the thyroid axis responds rapidly at the hypothalamo-pituitary unit, but beyond this level, the system is governed by processes that have extremely long time constants. As a result, this rhythm is not reflected in circulating thyroid hormone concentrations. Physiological Effects Thyroid hormones influence nearly every tissue in the body, in a variety of ways (Capen, 2001; Hedge et al. In spite of complexities of hormone action on target tissues, it is reasonably accurate to simply view thyroid hormone as the primary determinant of the overall metabolic rate of the body. The effects are exaggerated in states of thyroid excess (hyperthyroidism) or deficiency (hypothyroidism) and produce the clinical and biochemical manifestations of these disorders. In general, thyroid hormone stimulates both anabolic and catabolic biochemical pathways; however, its over-riding effect is catabolism (energy mobilization). Thyroid hormone also produces significant effects on growth and development (Capen, 2001; Hedge et al. A deficiency of thyroid hormone in early life leads to a delay in development of the brain in animal models and humans (Dickerson and Gore, 2007; Gore, 2011; Zoeller et al. Brain development is especially dependent on thyroid hormone during the first several months after birth in humans (Zoeller, 2005). If thyroid hormone levels are inadequate during this period, severe irreversible mental retardation in the form of cretinism occurs. Early diagnosis and immediate replacement with thyroid hormones can prevent these effects, and are; therefore, essential. They are made of two phenyl rings with varying degrees of chlorination, resulting in 209 different congeners. These chemicals are flame retardants that are used in a variety of products, including electric equipment, clothing, furniture, carpeting, plastics, and paints. Perchlorate Perchlorate is another thyroid disrupting chemical (Crofton, 2008; Jugan et al. This chemical is widely used as a rocket propellant as well as a chemical in fireworks and airbag deployment systems. It is a highly stable and water-soluble compound and thus, it is known to persist in the environment, particularly in the water and food supply. The mechanism of action of perchlorate is thought to be primarily by reducing iodide uptake, which ultimately reduces thyroid hormone synthesis (Patrick, 2009). It is important to note, however, that the effects of perchlorate on the thyroid gland have not been well studied and the results to date in humans are equivocal. Thyroid Toxicity Given the influence of thyroid hormones on numerous tissues in the body, it is not surprising that xenobiotics that affect thyroid hormone levels often cause symptoms of hypothyroidism, hyperthyroidism, or lead to significant impairment in brain development and function. Below are some specific examples of environmental chemicals that have been shown to affect thyroid hormone levels through a variety of mechanisms, resulting in adverse physiological outcomes. A few rodent studies have shown that a phthalate known as di-n-butyl phthalate decreases T3 and T4 in a dose-dependent manner (Boas et al. The consequences of phthalate-induced changes in thyroid hormone levels in humans or rodents are unclear at this time and should be investigated in future studies. Humans have four parathyroid glands, which are located on the back of side of the thyroid gland (Hedge et al. The parathyroid glands are composed of chief cells and oxyphil cells (Capen and Rosol, 1989; Hedge et al. In humans, oxyphil cells are absent at birth, appear around puberty, and increase in number with age.

Methyl tertiary butyl ether lacks tumor-promoting activity in N-nitrosodiethylamine-initiated B6C3F1 female mouse liver prostate cancer 80 year old order eulexin 250mg on-line. The Determination of Whether Dithiocarbamate Pesticides Share a Common Mechanism of Toxicity prostate test psa purchase 250mg eulexin with mastercard. Critical review of the epidemiological literature on occupational exposure to perchloroethylene and cancer prostate cancer urologist vs oncologist order eulexin 250 mg otc. Inhalation carcinogenicity and chronic toxicity of carbon tetrachloride in rats and mice prostate oncology specialists uk purchase eulexin online from canada. Penetration of chloroform prostate oncology 360 eulexin 250 mg on-line, trichloroethylene mens health getting abs pdf buy generic eulexin on-line, and tetrachloroethylene through human skin. Cytochrome P450 isoforms and the metabolism of volatile hydrocarbons of low relative molecular mass. Different contributions of cytochrome P450 2E1 and P450 2B1/2 to chloroform hepatotoxicity in rat. Dietary modification of metabolism and toxicity of chemical substances-with special reference to carbohydrate. Effects of ethanol and phenobarbital administration on the metabolism and toxicity of benzene. A comparative study on the contribution of cytochrome P450 isozymes to metabolism of benzene, toluene and trichloroethylene in rat liver. Mouse Liver Tumors: Benefits and Constraints on Use in Human Health Risk Assessment, Qualitative and Quantitative Aspects. Toxicological Research of Methanol as a Fuel for Power Station: Summary Report on Test with Monkeys, Rats and Mice. Effects of 2-methoxyethanol on fetal development, postnatal behavior, and embryonic intracellular pH of rats. A comprehensive evaluation of the carcinogenic potential of middle distillate fuels. The role of dermal irritation in the skin tumor promoting activity of petroleum middle distillates. Sensory irritation, pulmonary irritation, and respiratory stimulation by airborne benzene and alkylbenzenes: prediction of safe industrial exposure levels and correlation with their thermodynamic properties. Kinetics and metabolism of inhaled methyl chloroform (1,1,1-trichloroethane) in male volunteers. Manganese distribution in the brain and neurobehavioral changes following inhalation exposure of rats to three chemical forms of manganese. Toxicology and Carcinogenesis Studies of Tetrachloroethylene (Perchloroethylene) in F344/N Rats and B6C3F1 Mice. Carcinogenesis Studies of Trichloroethylene (Without Epichlorohydrin) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Toxicity Studies of a Chemical Mixture of 25 Groundwater Contaminants Administered in Drinking Water to F344/N Rats and B6C3F1 Mice. Toxicology and Carcinogenesis Studies of Ethylene Glycol in B6C3F1 Mice (Feed Studies). Toxicology and Carcinogenesis Studies of t-Butyl Alcohol in F344/N Rats and B6C3F1 Mice. Toxicology and Carcinogenesis Studies of Ethylbenzene in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Influence of tap water quality and household water use activities on indoor air and internal dose levels of trihalomethanes. Disseminated thrombosis and bone infarction in female rats following inhalation exposure to 2-butoxyethanol. Epidemic of pediatric deaths from acute renal failure caused by diethylene glycol poisoning. Accumulation of 2u-globulin in the renal proximal tubules of male rats exposed to unleaded gasoline. Leupeptin-mediated alteration of renal phagolysosomes: similarity to hyaline droplet nephropathy of male rats exposed to unleaded gasoline. Decreases in protein kinase and phosphatase activities in the liver nuclei of rats exposed to carbon tetrachloride. In vivo and in vitro evaluations of spermatotoxicity induced by 2-ethoxyethanol treatment. Depression of liver microsomal glucose 6-phosphatase activity in carbon tetrachloride-poisoned rats. Potential synergistic effects of lipid peroxidation and of covalent binding of haloalkane-derived free radicals to cellular components in the process. Dose-dependent protein adduct formation in liver, kidney, and blood of rats and in human blood after perchloroethylene inhalation. Application of a physiologically based pharmacokinetic model to estimate the bioavailability of ethanol in male rats: distinction between gastric and hepatic pathways of metabolic clearance. Genetic polymorphisms in ethanol metabolism: issues and goals for physiologically based pharmacokinetic modeling. Tetrachloroethylene-contaminated drinking water in Massachusetts and the risk of colon-rectum, lung, and other cancers. Route of administration determines whether chloroform enhances or inhibits cell proliferation in the liver of B6C3F1 mice. Chloroform in drinking water prevents hepatic cell proliferation induced by chloroform administered by gavage in corn oil to mice. Effect of chloroform on dichloroacetic acid and trichloroacetic acid-induced hypomethylation and expression of c-myc gene and on their promotion of liver and kidney tumors in mice. Subchronic chloroform priming protects mice from a subsequently administered lethal dose of chloroform. Impact of repeated exposure on toxicity of perchloroethylene in Swiss Webster mice. Detection of carbon disulfide in breath and air: a possible new risk factor for coronary artery disease. Influence of several factors on blood alcohol concentrations after drinking alcohol. Mode of action and pharmacokinetic studies of 2-butoxyethanol in the mouse with an emphasis on forestomach dosimetry. Chemical exposures at hazardous waste sites: experiences from the United States and Poland. Ethylene glycol-mediated tubular injury: identification of critical metabolites and injury pathways. Short-term inhalation toxicity of methanol, gasoline, and methanol/gasoline in the rat. Methyl tertbutyl ether causes 2u-globulin nephropathy and enhanced renal cell proliferation in male Fischer-344 rats. A review of carbon disulphide exposure data and the association between carbon disulfide exposure and ischemic heart disease mortality. Interactive effects of toluene and hexane on behavior and neurophysiologic responses in Fischer-344 rats. Mechanisms of alcohol-induced hepatic fibrosis: a summary of the Ron Thurman Symposium. Mechanisms of alcohol-associated cancers: introduction and summary of the symposium. Bayesian analysis of a physiologically based model for perchloroethylene in humans. Cancer risk among workers at Danish companies using trichloroethylene: a cohort study. Platelet activating factor receptor binding plays a critical role in jet fuel-induced immune suppression. Diagnosis of polymorphisms in carcinogen-activating and inactivating enzymes and cancer susceptibility: a review. Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. Repeated exposure to the abused inhalant toluene alters levels of neurotransmitters and generates peroxynitrite in nigrostriatal and mesolimbic nuclei in rat. Abused inhalants and central reward pathways: electrophysiological and behavioral studies in the rat. Epinephrine-induced cardiac arrhythmia potential of some common industrial solvents. Physiologically-based pharmacokinetic modeling with methylchloroform: implications for interspecies, high dose/low dose, and dose route extrapolations. In vitro metabolism of methylene chloride in human and animal tissues: use in physiologically based pharmacokinetic models. Degeneration of the basal ganglia in monkeys from chronic carbon disulfide poisoning. Gestational exposure to ethanol suppresses msx2 expression in developing mouse embryos. Assessment of exposure to carbon disulfide in viscose production workers from urinary 2-thiothiazolidine4-carboxylic acid determinations. Major molecular differences between mammalian sexes are involved in drug metabolism and renal function. Biological and health effects of exposure to kerosene-based jet fuels and performance additives. Modulation of bronchial epithelial cell barrier function by in vitro jet propulsion fuel 8 exposure. Predicting age-appropriate pharmacokinetics of six volatile organic compounds in the rat utilizing physiologically based pharmacokinetic modeling. Central nervous system effects of chronic toluene abuse-clinical, brainstem evoked response and magnetic resonance imaging studies. Induction of necrosis in skin fibroblasts and keratinocytes and modulation of levels of Bcl-2 family members. Cell-specific activation and detoxification of benzene metabolites in mouse and human bone marrow: identification of target cells and potential role for modulation of apoptosis in benzene toxicity. Is exposure to bacterial endotoxin a determinant of susceptibility to intoxication from xenobiotic agents Occurrence and potential humanhealth relevance of volatile organic compounds in drinking water from domestic wells. Evaluation of the psychological functions in humans exposed to the threshold limit value of 1,1,1-trichloroethane. Effect of route and pattern of exposure on the pharmacokinetics and acute hepatotoxicity of carbon tetrachloride. Uptake, distribution, and elimination of carbon tetrachloride in rat tissues following inhalation and ingestion exposures. Evaluation of the potential impact of age- and gender-specific lung morphology and ventilation rate on the dosimetry of vapors. Physiologically based pharmacokinetic modeling of styrene and styrene oxide respiratory-tract dosimetry in rodents and humans. Effects of consumption of ethanol on the biological monitoring of exposure to organic solvent vapors: a simulation study with trichloroethylene. Enhanced metabolism of volatile hydrocarbons in rat liver following food deprivation, restricted carbohydrate intake, and administration of ethanol, phenobarbital, polychlorinated biphenyl and 3-methylcholanthrene: a comparative study. Kinetic studies on sex difference in susceptibility to chronic benzene intoxication with special reference to body fat content. Potentiation of carbon tetrachloride hepatotoxicity and lethality in type 2 diabetic rats. Association of spontaneous abortion and other reproductive effects with work in the semiconductor industry. Teratologic potential of 2-methoxyethanol and transplacental distribution of its metabolite, 2-methoxyacetic acid, in non-human primates. Benzene metabolism by human liver microsomes in relation to cytochrome P450 2E1 activity. Dose excretion relationship in tetrachloroethylene-exposed workers and the effect of tetrachloroethylene co-exposure on trichloroethylene exposure. Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Interindividual variations in human liver P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. Promoting effects of unleaded gasoline and 2,2,4-trimethylpentane on the development of atypical cell foci and renal tubular cell tumors in rats exposed to N-ethyl-N hydroxyethylnitrosamine. Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate. Interdisciplinary neurotoxicity inhalation studies: carbon disulfide and carbonyl sulfide research in F344 rats. Setting occupational health standards: toxicokinetic differences among and between men and women. Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. Immunotoxicity of 2-methoxyethanol following oral administration in Fischer 344 rats. Evaluation of the immunotoxicity of orally administered 2-methoxyacetic acid in Fischer 344 rats.

In other patients with ulcerative colitis prostate oncology specialists los angeles cheap eulexin generic, active disease is associated with increased epithelial cell and lymphocyte apoptosis [20] prostate cancer 185 safe 250mg eulexin. Another possible explanation is the use of sulphasalazine androgenic hormone baldness purchase eulexin overnight delivery, which induces microscopic colitis (and presumed increased epithelial apoptosis) in a small number of patients mens health 10k glasgow eulexin 250mg free shipping. Muciphages Muciphages were first described as mucin-containing macrophages in the colorectal lamina propria by Azzopardi and Evans in 1966 [21] prostate cancer spread to bones eulexin 250mg. They may occur in normal and abnormal colorectal mucosal biopsies [22] and they not regarded as pathological in themselves: they can be found in up to 50% of rectal biopsies [21] man health 50 buy 250mg eulexin with amex. Muciphages are probably related to previous epithelial damage, usually subtle and clinically insignificant, that releases mucin in to the lamina propria. Pneumatosis coli this condition in the colon is identical to pneumatosis cystoides intestinalis of the small intestine and the aetiology is discussed in Chapter 27. It is characterised by gas cysts in the submucosal and subserosal layers of the large bowel wall and can affect the entire colon and rectum or just one part [26]. The disease is often symptomless but can present with diarrhoea, rectal bleeding due to mucosal erosion over the cysts or rarely pneumo-peritoneum from rupture of a gas cyst in to the peritoneal cavity. It is also possible that pneumatosis coli can lead to intestinal obstruction and clinical simulation of a neoplastic stricture, especially if the mucosa is also involved. The mucosal surface has a coarse cobblestone appearance due right side of the colon more than the left, and it is seen in the appendix but not in the terminal ileum [16,17]. The lymphoid follicles in the colonic mucosa are not affected and may stand out as pale spots on endoscopy. Paradoxically, pigment-containing histiocytes may be found in the sinuses of lymph nodes draining an area of melanosis coli [18]. Although melanosis coli remains an important marker for anthraquinone laxative abuse, it has to be remembered that it is an end-product of apoptosis and several other drugs cause excess apoptosis and melanosis 752 Large intestine Table 40. These diseases are primarily submucosal accumulations but may be seen within the lamina propria. The gas seems to be under some pressure, because rupture of the cysts during endoscopic biopsy or in fresh surgical specimens may cause a popping sound. The connective tissue between the cysts, which are often multi-locular, shows little inflammation. Pseudo-lipomatosis this is a mucosal accumulation of microscopic gas bubbles, manifested as multiple spherical empty spaces of variable size in the lamina propria that resemble fat cells in paraffin sections. There is no epithelial or histiocytic lining to the spaces and some are seen within lymphoid aggregates [28]. Pseudolipomatosis is effectively part of the spectrum of changes seen in pneumatosis coli [29,30,31]. The gas spaces are thought usually to arise as a consequence of air entering the lamina propria through minute breaches in the surface epithelium during insufflation at endoscopy. Although this may sometimes occur in normal mucosa, it may be that atrophic mucosa such as that found in inactive longstanding inflammatory bowel disease is more susceptible. Miscellaneous disorders of the large intestine 753 Pseudo-lipomatosis has also been described after inadequate washing of endoscopes following hydrogen peroxide endoscope disinfection, when residual peroxide reacts with normal tissues to release oxygen [29,32]. Stercoral ulceration Stercoral ulcers result from pressure of abnormally hard faecal masses on the mucosa of the large bowel, most commonly at the rectosigmoid junction where there is a narrow lumen whose expansion is restricted by the presence of neighbouring structures. They are usually a consequence of intractable constipation and are an uncommon cause of perforation and faecal peritonitis, which may be initiated with straining at stool. Non-absorbable antacids containing aluminium salts and cation exchange resins, used to treat hyperkalaemia in renal patients, appear to be contributory [33,34]. Stercoral ulcers appear as well demarcated, irregular, longitudinal tears and perforations through which hard stool may be seen to protrude. Histologically the appearances are of ulceration with focal ischaemic features and intense acute and chronic inflammation penetrating the bowel wall [35]. The differential diagnosis may include diverticular disease and the latter should be excluded, primarily by very careful macroscopic examination of the resection specimen. The large bowel (along with the skin, remainder of the gastrointestinal tract and biliary system) is a well recognised site of involvement in affected individuals, usually resulting in watery diarrhoea or rectal bleeding, and rectal biopsy is often used as a convenient method of confirming the clinical diagnosis. In early cases this may be the only abnormality and, as it may be patchy, several levels taken through the biopsy may be necessary to identify it with confidence. There may also be more overt epithelial cell necrosis in the upper reaches of the crypt and on the luminal surface, which may result in crypts lined by flattened degenerate cells and distended by necrotic cells. Cord colitis syndrome this term has recently been given to a newly recognised condition characterised by culture-negative diarrhoea (usually watery), fever and weight loss that occurs in approximately 10% of recipients of haematopoietic stem cell transplants, specifically with umbilical cord blood [40]. It has not been reported after allogeneic peripheral blood or bone marrow transplantations. Colorectal biopsies typically show a chronic active colitis of variable degree with a mixed inflammatory cell infiltrate in the lamina propria, focal neutrophilic cryptitis and Paneth cell metaplasia, but little crypt distortion. Granulomas, either compact epithelioid forms or looser histiocytic collections related to ruptured crypts, are common. Ileal biopsies from one recorded patient had pseudo-pyloric metaplasia, suggesting that there may also be a chronic ileitis. In view of the dramatic response to antibiotic therapy, the possibility remains that cord colitis is caused by a hither to unrecognised infective agent. Chronic inflammatory cells in the lamina propria may be slightly increased, but this is rarely pronounced. These clusters are often composed entirely of endocrine cells, probably reflecting the slower turnover of this cell population compared with colonocytes and goblet cells [38]. Residual crypts undergo regeneration by epithelial proliferation and crypt fission, resulting in a markedly distorted mucosal architecture that may suggest longstanding inactive chronic ulcerative colitis. However, in chronic Effects of bowel preparation Old-fashioned hyperosmolar bowel preparations for colonoscopy have been recorded to cause considerable oedema and mucin depletion in the absence of inflammation [41]. Miscellaneous disorders of the large intestine 755 Torsion of appendices epiploicae Appendices epiploicae come to the notice of histopathologists when they undergo torsion. They may also autoamputate and present as peritoneal loose bodies (see Chapter 48). These tumours, and the possible role of human papillomavirus in their causation, are discussed in Chapter 38. Intestinal pseudoobstruction and ischemia secondary to both 2-microglobulin and serum A amyloid deposition. Development of gastrointestinal beta2-microglobulin amyloidosis correlates with time on dialysis. Successful laparoscopic treatment of ileo-cecal endometriosis producing large bowel obstruction. Melanosis coli is associated with an increase in colonic epithelial apoptosis and not with laxative abuse. Yellow-brown spindle bodies in mesenteric lymph nodes: a possible relationship with melanosis coli. The importance of apoptosis in the histopathology of drug related lesions of the large intestine. Barium granuloma Barium granulomas result from extravasation of radiological contrast material in to the bowel wall via mucosal tears or diverticula. They may present as polypoid or ulcerated lesions that can closely mimic a tumour endoscopically, especially when they are not discovered until some considerable time after the causative barium enema examination. On rare occasions they may penetrate in to the bowel wall, resulting in barium abscesses and barium peritonitis (see Chapter 46). Barium granulomas are made up of macrophages containing light green/grey barium sulphate crystals that may vary in size and shape from small granular crystals to large rhomboidal forms. They are anisotropic in polarised light and may be identified histochemically by the rhodizonate method and characterised further by energy dispersive X-ray analysis [46]. Malakoplakia Malakoplakia involving the large intestine may be seen in association with ulcerative colitis, in patients with coexisting debilitating illnesses or malignancy, or rarely in isolation. It may present as ulcers with sentinel polyps, as a tumour-like mass or even as diffuse thickening of the bowel wall. Squamous metaplasia of the colorectum Squamous metaplasia occurring within the colon and rectum is rare. Squamous metaplasia has also been described within colonic adenomas, and both adenosquamous and pure invasive squamous cell carci- 756 Large intestine 40. Golytely lavage versus a standard colonoscopy preparation: effect on a normal colonic mucosal histology. An electron microscopic study: demonstration of bacilliform organisms in malakoplakic macrophages. Colonic squamous cell carcinoma in ulcerative colitis: report of a case and review of the literature. Squamous metaplasia of the rectum associated with ulcerative colitis diagnosed using narrow-band imaging. Squamous-cell carcinoma developing after an ileoanal pouch procedure: report of a case. Assessment of histopathologic changes in the colonic biopsy in acute graft-versus-host disease. Selective sparing of enterochromaffin cells in graft versus host disease affecting the colonic mucosa. Chronic graftversus-host syndrome in man: a long-term clinicopathologic study of 20 Seattle patients. In general terms it is an anteroposterior slit situated between the rectum above and the perianal skin below [1]. Different groups tend to use different anatomical landmarks to define the precise upper and lower limits of the rectum. Surgeons and physicians, however, usually regard the level of the levator ani muscle as the upper limit and the anal orifice as the lower limit. Anatomists, on the other hand, use the levels of the anal valves and the anal orifice, respectively, to mark the upper and lower borders of the anus [3]. The anal canal is separated from the tip of the coccyx by a mass of fibromuscular tissue known as the anococcygeal ligament. Lying immediately anterior to the anus is the perineal body, beyond which are the membranous part of the urethra and the bulb of the penis in the male or the lower end of the vagina in the female. The lower ends of these are joined at approximately the mid-point of the internal sphincter by the anal valves, which are small transverse crescents of mucosa marking the position of the pectinate or dentate line. The submucosal tissue of the pecten is dense and firmly anchors the epithelium to the underlying internal sphincter. Above the dentate line, however, the submucosal connective tissue is loose, which allows prolapse to occur. The arterial supply to the anus comes from the superior middle and inferior rectal arteries. The internal rectal venous plexus lies beneath the mucosa in the upper twothirds of the anal canal. In the left lateral, right anterior and right posterior zones the plexus is modified in to three specialised vascular anal cushions, consisting of submucosal and anastomosing networks of arterioles and venules with arteriovenous communications showing similar features to erectile tissue. When the vessels of the anal cushions become engorged and prolapse downwards they give rise to haemorrhoids [5]. It was previously believed that the internal rectal plexus drained in to the portal system via the superior rectal vein, whereas the external venous plexus drained in to the systemic circulation by the middle and inferior rectal veins. However, more recent studies suggest that there are usually free communications of the superior, middle and inferior rectal veins and that the venous drainage from the anal cushions is primarily to the systemic circulation [6,7]. These are, in fact, barely distinguishable from each other and their existence as distinct entities has been questioned. The internal and external sphincters and the puborectalis muscle are responsible for maintaining continence, providing what has been described as triple security. It is likely that these three structures act in a coordinated manner with each serving slightly different roles [9]. The uppermost of these is the colorectal zone which differs from the normal rectal mucosa by virtue of a predominance of sialo-mucins over sulpho-mucins and the splaying of the fibres of the muscularis mucosae, which extend upwards in to the lamina propria between crypts. In the rectum these features are associated with mucosal prolapse but in the colorectal zone of the anus they may be regarded as normal. There is wide variation between the histological zones of the anus and the gross anatomical landmarks. The lower pecten of the anal canal corresponds the lymphatic drainage of the anal canal above the dentate line passes to the superior rectal group of lymph nodes. Lymphatic drainage below the dentate line passes to the superficial inguinal lymph nodes. However more recent studies suggest that the attempt to separate precisely different parts of the anus on embryological grounds is artificial and it is better regarded as a single, albeit complex, structure [8]. There are differences in innervation of the anus above and below the dentate line. The mucosa below the dentate line has a somatic type of nerve supply in keeping with its ectodermal origin. The anal mucosa above the dentate line is insensitive with an autonomic nerve supply typical of endodermally derived tissues. The internal anal sphincter is composed of smooth muscle and represents an enlargement of the circular muscle of the rectum, with which it is in continuity. Specimen handling the entire anus is received as part of an abdomino-perineal excision of the rectum for rectal adenocarcinoma.

Cellular mechanisms for developmental toxicity of chlorpyrifos: targeting the adenylate cyclase signaling cascade prostate over the counter supplements order eulexin 250 mg otc. Chronic toxicity and oncogenicity studies of ingested 1 prostate knotweed control order generic eulexin line, 3-dichloropropene in rats and mice prostate cancer tests 250 mg eulexin visa. The role of P-glycoprotein in preventing developmental and neurotoxicity: avermectins-a case study prostate cancer quotes order cheap eulexin on-line. Occupational exposure limits for organophosphate pesticides based on inhibition of red blood cell acetylcholinesterase androgen hormone vaginal dryness buy generic eulexin line. Organochlorine pesticide residues in human milk of a Hmong hill tribe living in Northern Thailand androgen hormone used to induce buy discount eulexin 250 mg line. Minimum concentrations of N-methylpyridinium-2-aldoxime methane sulphonate (P2S) which reverse neuromuscular block. The clastogenic potential of triazine herbicide combinations found in potable water supplies. Acute poisoning with a glyphosate surfactant herbicide (Roundup): a review of 93 cases. Interaction of organophosphate pesticides and related compounds with the androgen receptor. Metabolism of chlorpyrifos by human cytochrome P450 isoforms and human, mouse and rat liver microsomes. Severe toxic reactions and death following the ingestion of diethyltoluamide-containing insect repellents. Lasting behavioral consequences of organophosphate pesticide exposure during development. The Use of Data on Cholinesterase Inhibition for Risk Assessments of Organophosphorus and Carbamate Pesticides. Triazine Cumulative Risk Assessment and Atrazine, Simazine and Propazine Decisions. Atrazine in municipal drinking water and risk of low birth weight, pre-term delivery, and small-forgestational-age status. Comparison of organochlorine pesticide levels in adipose tissue and human milk of mothers living in Veracruz, Mexico. A review of pesticide exposure and cancer incidence in the Agricultural Health Study cohort. Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans. Organochlorine hydrocarbons in human breast milk collected in Hong Kong and Guangzhou. Dimethylphosphoryl-inhibited human cholinesterases: inhibition, reactivation and aging kinetics. Neuropathy target esterase and its yeast homologue degrade phosphatidylcholine to glycerophosphocholine in living cells. Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction. Metals as Toxicants Movement of Metals in the Environment Chemical Mechanisms of Metal Toxicology Factors Impacting Metal Toxicity Biomarkers of Metal Exposure Molecular Responses to Metal Exposure Metal-Binding Proteins and Metal Transporters Pharmacology of Metals Toxic Effects of Metals Erik J. What defines a "metal" is not always obvious and the differences between metallic and nonmetallic elements may be subtle (Vouk, 1986). Metals are typically defined by physical properties of the element in the solid state, but can vary widely with the metallic element. General metal properties include high reflectivity (luster), high electrical conductivity, high thermal conductivity, and mechanical ductility and strength. A characteristic of metals of toxicological importance is that they may often react in biological systems by losing one or more electrons to form cations (Vouk, 1986). Various names are applied to subsets of metallic elements including alkali metals (eg, lithium and sodium), the alkaline earth metals (eg, beryllium and magnesium), the transition (or "heavy") metals (eg, cadmium), and the metalloids (eg, arsenic and antimony), the latter of which show characteristics of metals and nonmetals. Over 75% of the elements in the periodic table are regarded as metals and several are considered metalloids. This chapter discusses Environmental cycling Global distribution Biotransformation Biomagnification Occurrence Natural anthropogenic Chemistry Chemical form Speciation Essentiality metals, and certain metal complexes or molecules, that have been reported to produce significant toxicity in humans. The discussion includes major toxic metals (eg, lead, cadmium), essential metals (eg, zinc, copper), medicinal metals (eg, platinum, bismuth), and minor toxic metals including metals of technological significance (eg, indium, uranium). This chapter will also discuss toxic metalloids (eg, arsenic, antimony) and certain nonmetallic elemental toxicants (eg, selenium, fluoride). Metals as Toxicants It cannot be stressed enough that the use of metals has been critical to the progress and success of human civilization. It is difficult to imagine an advanced civilization without extensive use of metals and metal compounds. However, metals are unique among pollutant toxicants in that they are all naturally occurring and, in many cases, are already ubiquitous to some level within the human environment. Thus, regardless of how safely metals are used in industrial processes or consumer endpoint products, some level of human exposure is inevitable. Furthermore, life evolved in the presence of metals and organisms have been forced to deal with these potentially toxic, yet omnipresent, elements. With essentiality there is intentional bioaccumulation that involves safe transport and storage. Nonetheless, even essential metals can be toxic with increasing exposure, as they overwhelm biological systems and bind to unwanted sites. It is repeatedly seen that the nonessential toxicant metals mimic essential metals and thereby gain access to , and potentially disrupt, key cellular functions. This can also account for bioaccumulation of toxic metals without known biological function. Metals differ from other toxic substances because, as elements, they are neither created nor destroyed by human endeavors. What human industry and civilization generally do accomplish is to concentrate metals in the biosphere. The anthropogenic contribution to the levels of metals in air, water, soil, and food is well recognized (Beijer and Jernelov, 1986). Human use of metals can also alter the chemical form or speciation of an element and thereby impact toxic potential. With a few very notable exceptions, most metals are only sparingly recycled once used. These factors combine together and tend to make metals persistent in the human environment, often resulting in protracted exposures. Due to their very early use, metals are one of the oldest toxicants known to humans. For instance, human use of lead probably started prior to 2000 bc, when abundant supplies were obtained from ores as a by-product of smelting silver. The first description of abdominal colic in a man who extracted metals is credited to Hippocrates in 370 bc. Arsenic was used early on for decoration in Egyptian tombs and as a "secret poison," whereas mercury assumed almost a mystical stature in early science and was a large focus of alchemy. However, most of the use of the metals has occurred since the onset of the industrial revolution. In this regard, many of the metals of toxicological concern today were only relatively recently discovered. For instance, cadmium was first recognized in the early 1800s, and it was much later before the metal was widely used. The toxicological importance of some of the rarer or lesser used metals has increased with new applications, such as chemotherapy and microelectronics, or other emerging technologies. Historically, metal toxicology usually concerned acute or overt, high-dose effects, such as abdominal colic from lead or the bloody diarrhea and uropenia after mercury exposures. Due to advances in our understanding of toxic potential of metals, and the accompanying improvements in industrial hygiene and stricter environmental standards, acute high-dose effects of metals are now very uncommon in the Western world. Metal toxicology has shifted focus to more subtle, chronic, low-dose effects, in which causeand-effect relationships may not be immediately clear. Other important chronic toxic effects include carcinogenesis, and several metals have emerged as human carcinogens (Straif et al. In humans, defining the responsible agent for such toxicological effects can often be difficult, particularly when the endpoint disease may have a complex etiology caused by a number of different chemicals or even combinations of chemicals. In addition, humans are never exposed to only a single metal, but rather to complex mixtures. Rodent or cellular/molecular models are helpful but the metals as a class of toxicants clearly present many challenges in toxicological research. The elemental nature of metals impacts their biotransformation and toxicity, as detoxication by destructive metabolism to subcomponents of lesser toxicity cannot occur with these atomic species. This level of indestructibility combined with the bioaccumulation that can often occur contributes to the high concern for metals as toxicants. However, biological conjugation to form organometallic compounds can occur for various metals (Dopp et al. The redox capacity of a given metal or metallic compound should also be considered as part of its metabolism. The metabolism of metals is intricate and subtle but directly impacts toxic potential. Rainwater dissolves rocks and ores and transports materials, including metals, to rivers and underground water (eg, arsenic), depositing and stripping materials from adjacent soil and eventually transporting these substances to the ocean to be precipitated as sediment or taken up in to forming rainwater to be relocated elsewhere. Biological cycles moving metals include biomagnification by plants and animals resulting in incorporation in to food cycles. In comparison, human activity often intentionally shortens the residence time of metals in ore deposits, and can result in the formation of new, non-naturally occurring metallic compounds. Human industry greatly enhances metal distribution in the global environment by discharge to soil, water, and air, as exemplified by the 200-fold increase in lead content of Greenland ice since the onset of the industrial revolution. Mercury undergoes global cycling with elevated levels being found far from points of discharge, as, for example, with mercury in the Arctic Ocean. Increased distribution of metals and metal compounds in the environment, especially through anthropogenic activities, raises increasing concern for ecotoxicological effects. Reports of metal intoxication are common in plants, aquatic organisms, invertebrates, fish, sea mammals, birds, and domestic animals. Mercury poisoning from consumption of fish containing high levels of methylmercury and cadmium poisoning from consumption of rice grown in soils contaminated with cadmium from industrial discharges are examples of human consequences from environmental pollution. Not all human toxicity occurs from metals deposited in the biosphere by human activity. For example, chronic arsenic poisoning from high levels of naturally occurring inorganic arsenic in drinking water is a major health issue in many parts of the world. Endemic intoxication from excess fluoride, selenium, or thallium can all occur from natural high environmental levels. Chemical Mechanisms of Metal Toxicology the precise chemical basis of metal toxicology is inadequately understood but a uniform mechanism for all toxic metals is implausible because of the great variation in chemical properties and toxic end points. Chemically, metals in their ionic form can be very reactive and can interact with biological systems in a large variety of ways. For instance, metals such as cadmium and mercury readily attach to sulfur in proteins as a preferred bioligand. Such adventitious binding is an important chemical mechanism by which 984 exogenous metals exert toxic effects that can result in steric rearrangement that impairs the function of biomolecules (Kasprzak, 2002). An example would be the inhibition of enzyme activity by metal interaction at sites other than the active center, such as the inhibition of heme synthesis enzymes by lead. The inhibition of biologically critical enzymes is an important molecular mechanism of metal toxicology. In this regard the toxic metals may act as mimics of essential metals, binding to physiological sites that normally are reserved for an essential element. Owing to their rich chemistry, essential metals control, or are involved in, a variety of key metabolic and signaling functions (Kasprzak, 2002; Cousins et al. Through mimicry, the toxic metals may gain access to , and potentially disrupt, a variety of important or even critical metal-mediated cellular functions. For example, mimicry for, and replacement of, zinc is a mechanism of toxicity for cadmium, copper, and nickel. Thallium mimics potassium and manganese mimics iron as a critical factor in their toxicity. Mimicry of arsenate and vanadate for phosphate allows for cellular transport of these toxic elements, whereas selenate, molybdate, and chromate mimic sulfate and can compete for sulfate carriers and in chemical sulfation reactions (Bridges and Zalpus, 2005). Organometallic compounds can also act as mimics of biological chemicals, as, for example, with methylmercury, which is transported by amino acid or organic anion transporters (Bridges and Zalpus, 2005). Indeed, molecular or ionic mimicry at the level of transport is often a key event in metal toxicity. Another key chemical reaction in metal toxicology is metalmediated oxidative damage. Alternatively, metals may displace redox active essential elements from their normal cellular ligands, which, in turn, may result in oxidative cellular damage. For instance, cadmium, which is not redox active, may well cause oxidative stress through the release of endogenous iron, an element with high redox activity (Valko et al. Metals can also induce an array of aberrant gene expression, which, in turn, produces adverse effects. An array of aberrant hepatic gene expressions occurs in adult mice after in utero arsenic exposure, which could be an important molecular event in arsenic hepatocarcinogenesis (Liu et al.

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