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The proximal tubule contains numerous transport systems capable of driving concentrative transport of many metabolic substrates, including amino acids, glucose, and citric acid cycle intermediates. The proximal tubule also reabsorbs virtually all the filtered lowmolecular-weight proteins by specific endocytotic protein reabsorption processes. In addition, small linear peptides may be hydrolyzed by peptidases associated with the proximal tubular brush border. An important excretory function of the proximal tubule is secretion of weak organic anions and cations by specialized transporters that drive concentrative movement of these ions from postglomerular blood into proximal tubular cells, followed by secretion into tubular fluid. Toxicant-induced interruptions in the production of energy for any of these active transport mechanisms or the function of critical membrane-bound enzymes or transporters can profoundly affect proximal tubular and whole-kidney function. The different segments of the proximal tubule exhibit marked biochemical and physiologic heterogeneity (Goldstein, 1993). Transport capacities for these substances in the S2 and S3 segments are appreciably less; for example, glucose reabsorption in the S2 and S3 segments is about 50% and 10% of that in the S1 segment, respectively. In contrast, the principal site of organic anion and cation secretion is in the S2 and S1 /S2 segments, respectively. Cross-section of the glomerular capillary membrane with the capillary endothelium, basement membrane, and epithelium podocytes. Although the glomerular capillary wall permits a high rate of fluid filtration (approximately 20% of blood entering the glomerulus is filtered), it provides a significant barrier to the transglomerular passage of macromolecules. Experiments using a variety of charged and neutral tracers have established that this barrier function is based on the ability of the glomerulus to act as a size-selective and chargeselective filter (Brenner et al. Filtration of anionic molecules tends to be restricted compared to that of neutral or cationic molecules of the same size. These permselective properties of the glomerulus appear to be directly related to the physicochemical properties of the different cell types within the glomerulus (Kanwar et al. These highly anionic components produce electrostatic repulsion and hinder the circulation of polyanionic macromolecules, thereby markedly retarding passage of these molecules across the filtration barrier. Chemically induced injury to distinct proximal tubular segments therefore may be related in part to their segmental differences in biochemical properties (see section "Site-Selective Injury"). Loop of Henle the thin descending and ascending limbs and the thick ascending limb of the loop of Henle are critical to the processes involved in urinary concentration. Approximately 25% of the filtered Na+ and K+ and 20% of the filtered water are reabsorbed by the segments of the loop of Henle. The tubular fluid entering the thin descending limb is iso-osmotic to the renal interstitium; water is freely permeable and solutes, such as electrolytes and urea, may enter from the interstitium. In contrast, the thin ascending limb is relatively impermeable to water and urea, and Na+ and Cl are reabsorbed by passive diffusion. Conversely, increasing the tubular workload (via the ionophore amphotericin B) exacerbates hypoxic injury to this segment (Brezis et al. The distal tubular cells contain numerous mitochondria but lack a well-developed brush border and an endocytotic apparatus characteristic of the pars convoluta of the proximal tubule. The early distal tubule reabsorbs most of the remaining intraluminal Na+, K+, and Cl but is relatively impermeable to water. The late distal tubule, cortical collecting tubule, and medullary collecting duct perform the final regulation and fine-tuning of urinary volume and composition. The remaining Na+ is reabsorbed in conjunction with K+ and H+ secretion in the late distal tubule and cortical collecting tubule. Additionally, because urinary concentrating ability is dependent upon medullary and papillary hypertonicity, agents that increase medullary blood flow may impair concentrating ability by dissipating the medullary osmotic gradient. Table 14-1 illustrates the efficiency of the nephrons in the conservation of electrolytes, substrates, and water and excretion of nitrogenous wastes (urea). Distal Tubule and Collecting Duct the macula densa comprises specialized cells located between the end of the thick ascending limb and the early distal tubule, in close proximity to the afferent arteriole. This anatomic arrangement is ideally suited for a feedback system whereby a stimulus received at the macula densa is transmitted to the arterioles of the same nephron. Obstruction of the tubular lumen by cast formation increases tubular pressure; when tubular pressure exceeds glomerular capillary pressure, filtration decreases or ceases.
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One other factor contributing to fecal excretion is intestinal secretion, which likely occurs by passive diffusion out of enterocytes or via exfoliation of intestinal cells during the normal turnover of this epithelium. Biliary Excretion the biliary route of elimination is perhaps the most significant source contributing to the fecal excretion of xenobiotics and is even more important for the excretion of metabolites. A compound can be extracted by the liver, thereby preventing its distribution to other parts of the body. The liver is also the main site for biotransformation of toxicants, and metabolites may be excreted directly into bile. In this manner, the liver can remove xenobiotics and their metabolites before entering the general circulation. Furthermore, xenobiotics and/or their metabolites excreted into bile enter the intestine and may be excreted with feces. However, if the physicochemical properties favor reabsorption, an enterohepatic circulation may ensue (discussed below). Toxic chemicals bound to plasma proteins are fully available for active biliary excretion. The factors that determine whether a chemical will be excreted into bile or into urine are not fully understood. However, as a general rule, low-molecular-weight compounds (<325) are poorly excreted into bile whereas compounds or their conjugates with molecular weights exceeding about 325 can be excreted in appreciable quantities. Glutathione and glucuronide conjugates have a high predilection for excretion into bile, but there are marked species differences in the biliary excretion of foreign compounds with consequences for the biological half-life of a compound and its toxicity (Klaassen et al. Table 5-12 provides examples of species differences in biliary excretion, and demonstrates that species variation in biliary excretion is also compound specific. It is therefore difficult to categorize species into "good" or "poor" biliary excretors but, in general, rats and mice tend to be better biliary excretors than are other species (Klaassen and Watkins, 1984). Foreign compounds excreted into bile are often divided into three classes on the basis of the ratio of their concentration in bile versus that in plasma. Class A substances have a ratio of nearly 1 oatp1a1 Blood (sinusoidal) rp Bc oatp1a4 Mrp4 oatp1b2 ep Bs M rp 2 Mrp6 oat2 Ntcp oct1 Figure 5-14. Class B substances have a ratio of bile to plasma greater than 1 (usually between 10 and 1000). However, a compound does not have to be highly concentrated in bile for biliary excretion to be of quantitative importance. For example, mercury is not concentrated in bile, yet bile is the main route of excretion for this slowly eliminated substance. Biliary excretion is regulated predominantly by xenobiotic transporters present on the canalicular membrane. Transporters present on the sinusoidal membranes of hepatocytes also contribute to hepatic uptake and efflux, and thereby contribute to hepatobiliary clearance of xenobiotics. There are four known transporters expressed on the canalicular membrane that are directly involved in biliary excretion. Mrp2 is extremely important in biliary excretion because it is largely responsible for the transport of organic anions including the glucuronide and glutathione conjugates of many xenobiotics. The mutant rats also present with conjugated hyperbilirubinemia, show reduced biliary excretion of glutathione, and are defective in the normal biliary excretion of glucuronide and glutathione conjugates of many xenobiotics. An Mrp2-/- null mouse has been developed, and like its mutant rat counterparts, shows marked reductions in bile flow, biliary glutathione concentrations, and reduced ability to eliminate xenobiotics. Finally, species differences in Mrp2 function may contribute to the qualitative differences observed across species in biliary excretion. Such differences are likely to contribute to the observed species differences in biliary excretion illustrated in Table 5-12. Although the highest levels of Bcrp are found in the placenta, the transporter is expressed on the bile canalicular membrane of hepatocytes where it preferentially transports sulfate conjugates of xenobiotics. P-gp is important in the biliary elimination of compounds such as doxorubicin and vinblastine. The biliary excretion of xenobiotics mediated by Mrp2, Bcrp, and P-gp usually results in increased excretion of toxicants out of hepatocytes and into bile. In doing so, these transporters increase excretion of xenobiotics and generally limit the likelihood of toxicity in the liver.
- Mastroiacovo Gambi Segni syndrome
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- Microcephaly mesobrachyphalangy tracheoesophageal fistula syndrome
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Epidemiological studies of epileptic patients treated for more than 35 years with phenobarbital or phenytoin have established that chronic liver microsomal enzyme induction in humans does not increase the incidence of liver or thyroid tumor formation (Singh et al. This high-affinity binding protein is not present in rodents, for which reason T4 is rapidly conjugated and excreted in bile. Accordingly, the plasma half-life of thyroxine in rats (1224 h) is considerably shorter than in humans (59 d). It is estimated that rats require a tenfold higher rate of thyroxine production (on a per kilogram body weight basis) than do humans to maintain physiological T4 levels. Other key events include increased oxidant production (such as increased peroxisomal H2 O2 production), increased cell proliferation (which fixes mutations), and suppression of apoptosis (which prevents the removal of genetically damaged cells and permits clonal expansion) (Klaunig et al. Clofibrate has been reported to cause a statistically significant increase in cancer mortality rate during a 5- to 8-year treatment period. However, there were no significant increase in cancer rate in a follow-up study, which included a posttreatment period (Lai, 2004). Enzyme Induction and Porphyria Due to the increased demand for heme, persistent induction of cytochrome P450 can lead to porphyria, a disorder characterized by excessive accumulation of intermediates in the heme biosynthetic pathway. In 1956, widespread consumption of wheat contaminated with the fungicide hexachlorobenzene caused an epidemic of porphyria cutanea tarda in Turkey. Another outbreak occurred in 1964 among workers at a factory in the United States manufacturing 2,4,5trichlorophenoxyacetic acid (the active ingredient in several herbicides and in the defoliant, Agent Orange). With the exception of methylation and acetylation, conjugation reactions result in a large increase in xenobiotic hydrophilicity, so they greatly promote the excretion of foreign chemicals. Glucuronidation, sulfonation, acetylation, and methylation involve reactions with activated or "high-energy" cofactors, whereas conjugation with amino acids or glutathione involves reactions with activated xenobiotics. Glucuronidation Glucuronidation is a major pathway of xenobiotic biotransformation in mammalian species except for members of the cat family (lions, lynxes, civets, and domestic cats) (Tukey and Strassburg, 2000). The site of glucuronidation is generally an electron-rich nucleophilic O, N, or S heteroatom. Therefore, substrates for glucuronidation contain functional groups such as aliphatic alcohols and phenols (which form Oglucuronide ethers), carboxylic acids (which form O-glucuronide esters), primary and secondary aromatic and aliphatic amines (which form N -glucuronides), and free sulfhydryl groups (which form S-glucuronides). In humans and monkeys, more than 30 tertiary amines (including tripelennamine, cyclobenzaprine, and imipramine) are substrates for N -glucuronidation, which leads to the formation of positively charged quaternary glucuronides, some of which may be carcinogenic (see below) (Hawes, 1998). Certain xenobiotics, such as phenylbutazone, sulfinpyrazone, suxibuzone, ethchlorvynol, 6 - tetrahydrocannabinol, and feprazone, contain carbon atoms that are sufficiently nucleophilic to form C-glucuronides. Coumarin and certain other carbonyl-containing compounds are glucuronidated to form arylenol-glucuronides. In a series of twenty four 4substituted phenols, a methyl or ether in any position increases the rate of glucuronidation compared with phenol itself. In addition to numerous xenobiotics, substrates for glucuronidation include several endogenous compounds, such as bilirubin, steroid hormones, and thyroid hormones. Glucuronide conjugates of xenobiotics and endogenous compounds are polar, water-soluble metabolites that are eliminated from the body in urine or bile. Whether glucuronides are excreted from the body in bile or urine depends, in part, on the size of the aglycone (parent compound or unconjugated metabolite). In rat, glucuronides are preferentially excreted in urine if the molecular weight of the aglycone is less than 250, whereas glucuronides of larger molecules (aglycones with molecular weight >350) are preferentially excreted in bile. Molecular weight cutoffs for the preferred route of excretion vary among mammalian species. The carboxylic acid moiety of glucuronic acid, which is ionized at physiological pH, promotes excretion because (1) it increases the aqueous solubility of the xenobiotic and (2) it is recognized by the biliary and renal organic anion transport systems, which enable glucuronides to be secreted into urine and bile. Although present in the lysosomes of some mammalian tissues, considerable glucuronidase activity is present in the intestinal microflora. The intestinal enzyme can release the aglycone, which can be reabsorbed and thereby enters a cycle called enterohepatic circulation, which delays the elimination of xenobiotics. N -Glucuronides are more slowly hydrolyzed by -glucuronidase than O- or S-glucuronides, whereas O-glucuronides tend to be more stable to acid-catalyzed hydrolysis than N - or S-glucuronides. The functional group that reacts with or is transferred to the xenobiotic is shown in blue. The enzyme faces the lumen of the endoplasmic reticulum, where it is ideally placed to conjugate lipophilic xenobiotics and their metabolites generated by oxidation, reduction, or hydrolysis. Other studies have shown that sulfoconjugates, phenolphthalein glucuronide, and estradiol 3glucuronide are transported across the rat liver endoplasmic reticulum by facilitated diffusion, whereas 4-nitrophenyl glucuronide and 4-acetamidophenyl glucuronide are not, which suggests the presence of at least three microsomal glucuronide transporters with partially overlapping substrate specificity (Csala et al. In vitro, the glucuronidation of xenobiotics by liver microsomes can be stimulated by detergents.
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The mean tumor size increases progressively with age as does the frequency of bilateral and multicentric occurrence. A variety of techniques may be used for the demonstration of catecholamines in tissue sections. The chromaffin reaction is the oxidation of catecholamines by potassium dichromate solutions and results in the formation of a brown-to-yellow pigment in medullary tissue. The chromaffin reaction as traditionally performed possesses a low level of sensitivity and should not be used for the definitive demonstration of the presence of catecholamines in tissues. Similarly, both the argentaffin and argyrophil reactions, which have been used extensively in the past for the demonstration of chromaffin cells, also possess low sensitivity and specificity. Fluorescence techniques using formaldehyde or glyoxylic acid represent the methods of choice for the demonstration of catecholamines at the cellular level. Immunohistochemistry provides an alternative approach for the localization of catecholamines in chromaffin cells and other cell types. Antibodies are available that permit epinephrine- and norepinephrine-containing cells to be distinguished in routinely fixed and embedded tissue samples. Several of the important enzymes involved in the biosynthesis of catecholamine hormones also may be demonstrated by immunohistochemical procedures. Antibodies to chromogranin-A can be used for the demonstration of this unique protein in chromaffin cells (Puchacz et al. Pheochromocytomas in rats and human beings are both composed of chromaffin cells with variable numbers of hormonecontaining secretory granules. These tumors in rats usually do not secrete excess amounts of catecholamines whereas human pheochromocytomas episodically secrete increased amounts of catecholamines leading to hypertension and other clinical disturbances. There appears to be a striking species difference in the response of medullary chromaffin cells to mitogenic stimuli with rats being very sensitive compared to humans. This striking difference in sensitivity to mitogenic stimuli may explain the lower frequency of adrenal medullary proliferative lesions in humans compared to many rat strains (Tischler and Riseberg, 1993). The mouse adrenal medulla, which like humans has a low spontaneous incidence of proliferative lesions of chromaffin cells, also failed to respond to a variety of mitogenic stimuli. 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 (Lynch et al. Species differences in mitogenic responses of chromaffin cells in vitro from adult rat, human, bovine, and mouse adrenals. Chemically Induced Medullary Toxicity Medullary chromaffin cells in rats are susceptible to acute necrosis and cytolysis by salinomycin, which occurs in less than 10 hours (Chen-Pan et al. However, the adrenal medulla is capable of replenishing the chromaffin cells in as little as 24 hours by an unknown mechanism. It appears that the adrenal medulla recruits undifferentiated chromaffin cells to repopulate the medulla by a rapid and orderly process of differentiation. Therefore, chemically induced acute necrosis of the adrenal medulla may be easily overlooked if short experimental time points (<24 hours) were not examined. Schwann cells actively functioned as phagocytes and appeared to indirectly stimulate the differentiation of undifferentiated chromaffin cells. Inflammatory cells were rare with only a few lymphocytes evident inside the clusters of necrotic medullary cells. The synthesis of thyroid hormones is unique among endocrine glands because the final assembly of hormone occurs extracellularly within the follicular lumen. Essential raw materials, such as iodide ion (I-), are trapped by follicular cells from plasma, transported rapidly against a concentration gradient to the lumen of the follicle, and oxidized by a peroxidase enzyme in the microvillar membranes to iodine (I2). Biosynthesis of Thyroid Hormones the assembly of thyroid hormones within the follicular lumen is made possible by a unique protein, thyroglobulin, synthesized by follicular cells. Thyroglobulin is a high molecular-weight glycoprotein synthesized in successive subunits on the ribosomes of the endoplasmic reticulum in follicular cells. The constituent amino acids (tyrosine and others) and carbohydrates (mannose, fructose, galactose) are derived from the circulation. Recently synthesized thyroglobulin leaving the Golgi apparatus is packaged into apical vesicles which are extruded into the follicular lumen. The amino acid tyrosine, an essential component of thyroid hormones, is incorporated within the molecular structure of thyroglobulin. These biologically inactive iodothyronines subsequently are coupled together under the influence of the thyroperoxidase to form the two biologically active iodothyronines (thyroxine-T4, triiodothyronine-T3) secreted by the thyroid gland.
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In the average adult, most particles larger than 10 m in aerodynamic diameter are deposited in the nose or oral pharynx and cannot penetrate to tissues distal to the larynx. Particles that penetrate beyond the upper airways are available to be deposited in the bronchial region and the deep-lying airways. Therefore, the alveolar region has significant deposition efficiencies for particles smaller than 5 m and larger than 0. Sedimentation brings about deposition in the smaller bronchi, the bronchioles, and the alveolar spaces, where the airways are small and the velocity of airflow is low. As a particle moves through air, buoyancy and the resistance of air act on the particle in an upward direction while gravitational force acts on the particle in a downward direction. Eventually, the gravitational force equilibrates with the sum of the buoyancy and the air resistance, and the particle continues to settle with a constant velocity known as the terminal settling velocity. Sedimentation is not a significant route of particle deposition when the aerodynamic diameter is below 0. This Brownian motion increases with decreasing particle size, so diffusion is an important deposition mechanism in the nose and in other airways and alveoli for particles smaller than about 0. During exercise, when larger volumes are inhaled at higher velocities, impaction in the large airways and sedimentation and diffusion in the smaller airways and alveoli increase. Factors that modify the diameter of the conducting airways can alter particle deposition. In patients with chronic bronchitis, the mucous layer is greatly thickened and extended peripherally and may partially block the airways in some areas. Jets formed by air flowing through such partially occluded airways have the potential to increase the deposition of particles by impaction and diffusion in the small airways. Irritant materials that produce bronchoconstriction tend to increase the tracheobronchial deposition of particles. Tracheobronchial Clearance the mucus layer covering the tracheobronchial tree is moved upward by the beating of the underlying cilia. Mucociliary clearance is relatively rapid in healthy individuals and is completed within 2448 hours for particles deposited in the lower airways. Pulmonary Clearance There are several ways by which particulate material is removed from the lower respiratory tract once it has been deposited: 1. Particles may be directly trapped on the lining layer of the conducting airways by impaction and cleared upward in the tracheobronchial tree via the mucociliary escalator. Particles may be phagocytized by macrophages and cleared via the mucociliary escalator. Particles may be phagocytized by alveolar macrophages and removed via the lymphatic drainage. Materials may dissolve from the surfaces of particles and be removed via the bloodstream or lymphatics. Insoluble particles, especially long narrow fibers, may be sequestered in the lung for very long periods, often in macrophages located in the interstitium. The sites of interaction of toxicants in the respiratory tract have important implications for evaluation of the risk to humans posed by inhalants. For example, rats have much more nasal surface on a per body weight basis than do humans. Because the breathing pattern of humans resembles that of monkeys more than that of rats, it was concluded that extrapolation of tumor data from rats to humans on the basis of formaldehyde concentration may overestimate doses of formaldehyde to humans. Patterns of animal activity can affect dose to the lung; nocturnally active animals such as rats receive a greater dose per unit of exposure at night than during the day, whereas humans show the opposite diurnal relationships of exposure concentration to dose. Certain gases and vapors stimulate nerve endings in the nose, particularly those of the trigeminal nerve (Alarie et al. The result is holding of the breath or changes in breathing patterns, to avoid or reduce further exposure. If continued exposure cannot be avoided, many acidic or alkaline irritants produce cell necrosis and increased permeability of the alveolar walls. The epithelial barrier in the alveolar zone, after a latency period of several hours, begins to leak, Particle Clearance the clearance of deposited particles is an important aspect of lung defense (see. Rapid removal lessens the time available to cause damage to the pulmonary tissues or permit local absorption.
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Prostaglandin synthase (Cyclooxygenase1,-2) ++ Basal and ciliated cells (cox-1 and cox-2) Glutathione S-Transferases + Olfactory epithelium ++ Cell types vary with isoform & include ciliated and Clara cells? Code for labels: +++, most isoforms expressed highly; +/-, some expression in some studies but not in others, generally low; ++, some isoforms expressed highly;? The mu isoform demonstrates a zonal pattern of expression increased in the lateral olfactory turbinates of the mouse (WhitbyLogan et al. The glutathione transferases have recently been the focus of acute interest because of widespread polymorphisms in their expression in humans and the potential for correlation of this with lung cancer, particularly in smokers. A key point to keep in mind is that these enzyme systems work in concert with one another. The size distribution of many aerosols approximates a log-normal distribution that may be described by the median or geometric mean and the geometric standard deviation. A plot of the frequency of occurrence of a given size against the log of the size produces a bell-shaped probability curve. Particle data frequently are analyzed by plotting the cumulative percentage of particles smaller than a stated size on log-probability paper. In actual practice, it is not unusual to have some deviation from a straight line at the largest or smallest particle sizes measured. Particles that are nonspherical in shape are frequently characterized in terms of equivalent spheres on the basis of equal mass, volume, or aerodynamic drag. It represents the diameter of a unit density sphere with the same terminal settling velocity as the particle, regardless of its size, shape, and density. Aerodynamic diameter is the proper measurement for particles that are deposited by impaction and sedimentation. For very small particles, which are deposited primarily by diffusion, the critical factor is particle size, not density. It must be kept in mind that the size of a particle may change before its deposition in the respiratory tract. Materials that are hygroscopic, such as sodium chloride, sulfuric acid, and glycerol, take on water and grow in size in the warm, saturated atmosphere of the upper and lower respiratory tract. Water solubility is the critical factor in determining how deeply a given gas penetrates into the lung. Mathematical models of gas entry and deposition in the lung that are based solely on the aqueous solubility of a gas predict sites of lung lesions fairly accurately. These models may be useful for extrapolating findings made in laboratory animals to humans (Kimball and Miller, 1999; Medinsky et al. Nanotoxicology Particle Deposition Particle size is usually the critical factor that determines the region of the respiratory tract in which a particle or an aerosol will be deposited. Deposition of particles on the surface of the lung and airways is brought about by a combination of lung anatomy and the patterns of airflow in the respiratory system (Raabe, 1999; Miller, 1999). There is intense current interest in the lung toxicity of nanoparticles, particles with diameters of <100 nm (Oberdorster et al. Ultrafine particles of this size range are increasingly being used in manufactured products, and synthesis and release of particles of this size to the environment, and exposure of individuals in the workplace, is increasing exponentially. In addition, emissions control devices on internal combustion engines, diesel engines, and industrial furnaces and burners can efficiently trap larger particles; however, technology that decreases emissions of larger particles (which contain most of the mass of the particulate fraction) generally produces greater amounts of ultrafine particles (on a particle number basis). If more particles actually reach the deep lung, the higher is the probability of a toxic effect. Particle surface area is of special importance when toxic materials are adsorbed on particles and thus are carried into the lung. Several major working groups have been convened to formulate appropriate strategies for risk assessment of nanoparticles, and their recommendations provide guidance for future studies in this area (Oberdorster et al. Additional concern about potential toxicity of nanoparticles is triggered by the large body of epidemiological evidence linking exposure to ultrafine particles as air pollutants and increased mortality in sensitive populations (Dockery et al. There is, as yet, no defined mechanistic basis for the observed epidemiological associations, and this is a very active field of current research in inhalation toxicology.
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Increasingly sensitive analytical methods are now providing evidence to challenge the historical view, particularly for cytochrome P450-dependent monooxygenases, that the early embryo has low metabolic capabilities (Juchau et al. These investigators later showed that embryos could further metabolize the 7-hydroxy metabolite to an even more toxic catechol. No previous induction was necessary for this activation step, demonstrating the presence of constitutive metabolizing enzymes in the embryo. Although the rates of metabolism for these activation steps may be low relative to the maternal liver, they occur close to the target site of the embryo or even within it, and thus are significant in terms of inducing embryotoxicity. Physiologically based pharmacokinetic models provide the framework to integrate what is known about physiologic changes during pregnancy, both within and between species, with aspects of drug metabolism and embryonic development into a quantitative description of the events. Gabrielson and co-workers (Gabrielson and Paalkow, 1983; Gabrielson and Larsson, 1990) were among the first investigators to develop physiologically based models of pregnancy, and others (Fisher et al. It takes into account the growth of various compartments during pregnancy (including the embryo itself), as well as changes in blood flow and the stage-dependent pH gradients between maternal and embryonic plasma. The solvent 2-methoxyethanol is embryotoxic and teratogenic in all species tested to date. A physiologically based pharmacokinetic model has been developed for the pregnant mouse (Terry et al. Although the blood-flow limited model best predicted gestation day 8 dosimetry, the active transport models better described dosimetry on gestation days 11 and 13. The next step was to extrapolate this model to the inhalation route of exposure, and to model both rats and humans (Gargas et al. Maternal metabolism of xenobiotics is an important and variable determinant of developmental toxicity. As for other health endpoints, the developing field of pharmacogenomics offers hope for increasing our ability to predict susceptible subpopulations based on empirical relationships between maternal genotype and fetal phenotype. These relationships will hopefully guide further work to elucidate mechanisms of toxicant-induced abnormal development. Maternal physiological conditions capable of adversely affecting the developing organism include decreased uterine blood flow, maternal anemia, altered nutritional status, toxemia, altered organ function, autoimmune states, diabetes, electrolyte or acid-base disturbances, decreased milk quantity or quality, and abnormal behavior (Chernoff et al. Induction or exacerbation of such maternal conditions by toxic agents and the degree to which they manifest in abnormal development are dependent on maternal genetic background, age, parity, size, nutrition, disease, stress, and other health parameters and exposures (DeSesso, 1987; Chernoff et al. Interrelationships between maternal susceptibility factors, metabolism, induction of maternal physiologic or functional alterations, placental transfer and toxicity, and developmental toxicity. A developmental toxicant can cause abnormal development through any one or a combination of these pathways. Maternal susceptibility factors determine the predisposition of the mother to respond to a toxic insult, and the maternal effects listed can adversely affect the developing conceptus. Most chemicals traverse the placenta in some form, and the placenta can also be a target for toxicity. In most cases, developmental toxicity is probably mediated through a combination of these pathways. The distinction between direct and indirect developmental toxicity is important for interpreting safety assessment results in pregnant animals, as the highest dosage levels in these experiments are chosen based on their ability to produce some maternal toxicity. However, maternal toxicity defined only by such crude manifestations gives little insight to the toxic actions of a xenobiotic. When developmental toxicity is observed only in the presence of maternal toxicity, the developmental effects may be indirect; however, understanding of the physiologic changes underlying the observed maternal toxicity and elucidation of the association with developmental effects is needed before one can begin to address the relevance of the observations to human safety assessment. Many known human developmental toxicants, including ethanol and cocaine, adversely affect the embryo/fetus predominately at maternally toxic levels, and part of their developmental toxicity may be ascribed to secondary effects of maternal physiological disturbances. For example, the nutritional status of alcoholics is generally poor, and effects on the conceptus may be exacerbated by effects of alcohol on placental transfer of nutrients. Effects of chronic alcohol abuse on maternal folate and zinc metabolism may be particularly important in the induction of fetal alcohol syndrome (Dreosti, 1993). Among experimental animals, the "A" family of inbred mice has a high spontaneous occurrence of cleft lip and palate (Kalter, 1979). The response to vitamin A of murine embryos heterozygous for the curly-tail mutation depends on the genotype of the mother (Seller et al. The teratogenicity of phenytoin has been compared in several inbred strains of mice. New genomic approaches have begun to identify genes associated with differential susceptibility of mouse strains to valproic acid (Finnell et al.
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The occurrence of nocturnal or early-morning erections implies that the neurologic and circulatory pathways involved in attaining an erection are intact and suggests the possibility of a psychological cause. Normal penile erection depends upon the relaxation of smooth muscles in the corpora cavernosa. In the rat, prenatal exposure to the antiandrogenic fungicide vinclozolin induces a significant reduction of erections at all dose levels during the ex copula penile reflex tests in male offspring (Colbert et al. Note multinucleate giant cells and germ cell debris sloughed into the tubular lumen. The earliest studies using a 10week dosing regime (5 d/wk by gavage in corn oil) reported effects at 6 mg/kg/d (Linder et al. Foster (1989) showed that 5-day dosing with 5 mg/kg/d produced a minimal to moderate testicular lesion within 2 weeks and 10 mg/kg/d a moderate to severe lesion. Testicular weight remained reduced for many weeks after the treatment period with significant dose-related effects on fertility (measured by pregnancy rate and implantation success). Detailed electron microscopic evaluation has shown initial lesions to be present in the Sertoli cells of the testis, which results rapidly in germ cell apoptosis and death. A number of studies have described the pathogen- 100 80 60 40 20 0 1 2 3 ** * * ** ** 0 mg/kg/d 5 mg/kg/d 10 mg/kg/d * ** ** ** 4 5 6 7 8 16 Weeks post-dosing Figure 20-22. Effect of m-dinitrobenzene on percentage of females pregnant in a serial mating study design. Note range of germ cell types affected consequent to the Sertoli cell injury produced by the compound. And the reversibility of the effects after 16 weeks (two spermatogenic waves see. The earliest features of these studies after a single dose (250 or 500 mg/kg/d) were that there are Sertoli cell vacuoles and swollen germ cell mitochondria, followed by (or concurrent with) a breakdown of the membrane between the Sertoli cell and the pachytene spermatocyte in a spermatogenic stage-specific manner. This is followed quickly (within hours) by the death of (probably those) pachytene spermatocytes (Creasy et al. Effect of Ethylene glycol monomethyl ether (or its metabolite mehtoxyacetic acid) 24 hours after a single oral dose (100 mg/kg/d). Note the damaged spermatocytes (arrows) in lower tubule compared to the upper normal tubule. As with other testis toxicants, higher dose levels produce a more widespread lesion involving other cell types (Foster et al. The Sertoli cell vacuolization regresses after about 12 hours and is not a prominent feature of this lesion as it is with other agents like hexanedione, or some of the phthalate esters. Some weak evidence of involvement of this cell type also comes from some in vitro data with isolated seminiferous tubules. The lesion is not characteristic of a low-androgen testicular lesion, and reduced accessory sex organ weights are not a prominent feature associated with the early testicular pathology. Male and female rat mating behavior is sufficiently stereotyped that it can be easily quantified to assess the effects of toxicants on these behaviors (Gray and Ostby 1998; Gray et al. During mating, the female rat displays proceptive behaviors like ear wiggling and darting to induce the male to mount, and when mounted the female is "receptive" displaying a lordosis posture characterized by a raised head and tail and fully arched back. In experienced male rats, the latency to the first mount is usually on a few seconds, but inexperienced males may take much longer. When the male rat mounts the lordosing female he will display a single pelvic thrust which may or may not result in intromission of the penis into the vagina. Within a few seconds, the male mounts again and this series continues until the male ejaculates. At the beginning of the second series, the male dislodges the copulatory plug, formed from the seminal secretions. The copulatory plug normally fits close to the cervix and it is necessary to facilitate sperm entry into the uterus. It is not unusual to find seven to eight copulatory plugs in the breeding cage the day after mating (Gray et al. If mating does not occur, then the brief rise in serum progesterone declines by the next day.
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For those with refractory disease, thiopurines, such as azathioprine and 6-mercaptopurine, are used. Intensive therapy (>2 sessions per week) resulted in a higher remission rate when compared to patients treated weekly. A post-hoc analysis of this study demonstrated that the treated subset of patients with microscopic erosions/ulcerations had a significantly higher remission rate when compared to the sham group (Kruis, 2015). It is possible that this accounts for positive outcomes for adsorptive cytapheresis found in Asian, but not North American studies. For Cellsorba, venous whole blood is processed at 50 mL/min through the column for 60 minutes. The Adacolumn is relatively selective for removing activated granulocytes and monocytes. Duration and discontinuation/number of procedures the typical length of treatment is 5-10 weeks for Adacolumn and 5 weeks for Cellsorba. Effects of preoperative leukocytapheresis on inflammatory cytokines following surgery for ulcerative colitis: a prospective randomized study. Effect of intensive granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis positive for cytomegalovirus. Adsorptive granulocyte/ monocyte apheresis for the maintenance of remission in patients with ulcerative colitis: a prospective randomized, double blind, sham-controlled clinical trial. Adsorptive Depletion of Myeloid Lineage Leucocytes as Remission Induction Therapy in Patients with Ulcerative Colitis after Failure of First-Line Medications: Results from a Three-Year Real World, Clinical Practice. Granulocyte/Monocyte Adsorptive Apheresis in Moderate to Severe Ulcerative Colitis - Effective or Not? Granulocytapheresis in steroiddependent and steroid-resistant patients with inflammatory bowel disease: a prospective observational study. Adacolumn leucocytapheresis for ulcerative colitis: clinical and endoscopic features of responders and unresponders. Comparison of the efficacy of granulocyte and monocyte/macrophage adsorptive apheresis and leukocytapheresis in active ulcerative colitis patients: a prospective randomized study. A randomized, double-blind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis. Treating inflammatory bowel disease by adsorptive leucocytapheresis: a desire to treat without drugs. Efficacy, safety and cost analyses in ulcerative colitis patients undergoing granulocyte and monocyte adsorption or receiving prednisolone. A large-scale, prospective, observational study of leukocytapheresis for ulcerative colitis: treatment outcomes of 847 patients in clinical practice. Factors associated with treatment outcome, and long-term prognosis of patients with ulcerative colitis undergoing selective depletion of myeloid lineage leucocytes: a prospective multicenter study. Efficacy and safety of granulocyte and monocyte adsorption apheresis for ulcerative colitis: a meta-analysis. Its classical clinical triad includes muscle weakness (most prominent in proximal muscles of the lower extremities), hyporeflexia and autonomic dysfunction. Rapid onset and progression of symptoms over weeks or months should heighten suspicion of underlying malignancy. The antibodies are believed to cause insufficient release of acetylcholine quanta by action potentials arriving at motor nerve terminals. Antibody levels do not correlate with severity but may decrease as the disease improves in response to immunosuppressive therapy. These medications block fast voltage-gated potassium channels, prolonging presynaptic depolarization and thus the action potential, resulting in increased calcium entry into presynaptic neurons and increased release of acetylcholine. Studies have reported significant improvement following the combination treatment of corticosteroids and azathioprine. Repeated courses may be applied in case of neurological relapse, but the effect can be expected to last only up to 6 weeks in the absence of immunosuppressive therapy. LambertEaton myasthenic syndrome: epidemiology and therapeutic response in the national Veterans Affairs population. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Myasthenic syndrome: effect of choline, plasmapheresis and tests for circulating factor.
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Endomysium Epimysium Perimysium Endomysium Muscle fibre Fasciculus the three envelopes (sheaths) are made up of connective tissue richly endowed with blood vessels and fat cells (lipocytes). The cell also contains mitochondria, endoplasmic reticulum and microsomes the usual cellular constituents. Fats, glycogen, enzymes and myoglobin lie within the sarcoplasm and related structures. Each myofibril is 1 m in diameter and contains filaments of myosin and actin interdigitating with each other between each Z line. When muscle contracts or relaxes these filaments slide over each other producing shortening and lengthening of the muscle fibre. The striated appearance of skeletal muscle is a consequence of differing concentrations of actin and myosin. The distribution of muscle fibre types differ in specific muscles within the body according to function the muscles of the erector spinae are rich in oxidative, fatigue resistant fibres while the converse is true in triceps. Neuromuscular junction Each muscle fibre receives a nerve branch from the motor cell body in the anterior horn of the spinal cord or cranial nerve motor nuclei. When a nerve fibre reaches the muscle it loses its myelin sheath and its neurilemma then merges with the sarcolemma under which the axon spreads out to form the motor endplate. The number of muscle fibres in a motor unit varies: in the eye muscles it is small (510), whereas in the limb muscles the number is large (in the gastrocnemius about 1800). The neuromuscular junction is the point at which neuromuscular transmission is effected. Schwann cell Neurilemma Sarcolemma Axo n Synaptic cleft Synaptic vesicles Physiology Muscle contraction results from the following: 1) A depolarisation wave arrives at the axon terminus and opens voltage sensitive Ca2+ Sarcochannels plasmic 2) Ca2+ entry triggers fusion of synaptic vesicles reticulum with the axon membrane which then release acetylcholine into the synaptic cleft 3) Acetylcholine attaches to end-plate receptors with Na+ entry into muscle. Post synaptic depolarisation initiates an action potential that spreads along the sarcolemmal membrane. The enzyme cholinesterase, found in high concentration at motor endplates, destroys acetylcholine so that normally a single nerve impulse only gives rise to a single muscle contraction. This may be generated either by carbohydrate breakdown (glycogenolysis and glycolysis,) or lipid breakdown (betaoxidation). Parents describe delay in early motor milestones or a history of poor athletic abilities. These are often used to describe symptoms distinct from their strict medical definitions. Proximal weakness will produce difficulty in descending stairs or rising from a low chair or drying hair. Distal weakness causes difficulty with latch keys, ascending stairs and scuffing toes. In disorders of glycolysis a cramp develops in the exercising muscle after a minute or so whereas in Carnitinepalmityl transferase deficiency cramp and rhabdomyolysis follows some hours later. Examination this must assess Walking here a waddling or foot drop gait is noted or other neurological problems such as Parkinsonism identified. Involvement of anatomically adjacent muscles is a feature of the muscular dystrophies. The face must be carefully examined for minor bilateral facial weakness; mild ptosis and limitation of extraocular movements. Muscle weakness should be graded using a standard scale (Medical Research Council scale page 19). High levels are associated with Muscular Dystrophies and Rhabdomyolysis but normal values do not exclude milder muscle disease (benign recessive dystrophies, mitochondrial and some metabolic disorders). The choice between needle and open biopsy is difficult the former is simpler but no less painful; the latter may be preferable to avoid sampling error. Facio-scapulo-humeral muscular dystrophy) they are now defined on the basis of known gene loci and protein product. This is not yet possible in all dystrophies but a continuing reclassification is taking place. Many disorders are associated with abnormalities in the dystrophin associated glycoprotein complex. Congenital myopathies are associated with morphological muscle abnormalities without necrosis and with a more benign prognosis.