Aarti Umranikar MRCOG MFFP

• Senior Registrar in Obstetrics and Gynaecology, Princess Anne
• Hospital, Southampton

Transfer of ochratoxin A from lactating rats to their offspring: a short-term study first line antibiotics for acne purchase cheap ethambutol line. Gender and geographical variability in the exposure pattern and metabolism of deoxynivalenol in humans: a review virus 7g7 ethambutol 400 mg for sale. Clinical and pathologic changes in acute bovine aflatoxicosis: rumen motility and tissue and fluid concentrations of aflatoxins B1 and M1 virus 99 800 mg ethambutol otc. Preliminary study of the pharmacokinetics and toxicopathy of deoxynivalenol (vomitoxin) in swine antibiotic with steroid buy ethambutol online now. Efficacy of a new ochratoxin-binding agent (OcraTox) to counteract the deleterious effects of ochratoxin A in laying hens antibiotic wound infection order discount ethambutol line. Comparative toxicokinetics, absolute oral bioavailability, and biotransformation of zearalenone in different poultry species. Metabolism of aflatoxins: key enzymes and interindividual as well as interspecies differences. Scientific opinion on the risk for public and animal health related to the presence of sterigmatocystin in food and feed. Measurement of sterigmatocystin concentrations in urine for monitoring the contamination of cattle feed. Comparative pathologic changes in broiler chicks on feed amended with Fusarium proliferatum culture material or purified fumonisin B1 and moniliformin. Effects of chlorophyll and chlorophyllin on low-dose aflatoxin B(1) pharmacokinetics in human volunteers. Elevation of sphinganine 1-phosphate as a predictive biomarker for fumonisin exposure and toxicity in mice. Ochratoxin A: molecular interactions, mechanisms of toxicity and prevention at the molecular level. Worldwide occurrence of mycotoxins in cereals and cereal-derived food products: public health perspectives of their co-occurrence. Abuse of anabolic agents in beef cattle: could bile be a possible alternative matrix Fumonisin B1 contamination in breast milk and its exposure in infants under 6 months of age in Rombo, Northern Tanzania. Biomonitoring of the mycotoxin zearalenone: current state-of-the art and application to human exposure assessment. Fusarium diseases of maize associated with mycotoxin contamination of agricultural products intended to be used for food and feed. Bioavailability of aflatoxin B1 and ochratoxin A, but not fumonisin B1 or deoxynivalenol, is increased in starch-induced low ruminal pH in nonlactating dairy cows. Investigation of noncovalent interactions of aflatoxins (B1, B2, G1, G2, and M1) with serum albumin. Toxicopathological studies on the effects of aflatoxin B(1), ochratoxin A and their interaction in New Zealand white rabbits. Physiologically based toxicokinetics of serum aflatoxin B1-lysine adduct in F344 rats. The kinetics of urinary fumonisin B1 excretion in humans consuming maize-based diets. Evidence for fumonisin inhibition of ceramide synthase in humans consuming maize-based foods and living in high exposure communities in Guatemala. Blood, breast milk and urine: potential biomarkers of exposure and estimated daily intake of ochratoxin A: a review. Determination of fumonisin B1 levels in body fluids and hair from piglets fed fumonisin B1-contaminated diets. Experimental mycotoxic nephropathy in pigs provoked by a mouldy diet containing ochratoxin A and fumonisin B1. Mycotoxin occurrence in feed and feed raw materials worldwide: long-term analysis with special focus on Europe and Asia. Kinetic parameters and intraindividual fluctuations of ochratoxin A plasma levels in humans. Measurement of urinary concentrations of the mycotoxins zearalenone and sterigmatocystin as biomarkers of exposure in mares. Ergosterol and mycotoxins in grain dusts from fourteen Belgian cereal storages: a preliminary screening survey. Toxicokinetics of fumonisin B1 in Turkey poults and tissue persistence after exposure to a diet containing the maximum European tolerance for fumonisins in avian feeds. Tissue persistence of fumonisin B1 in ducks and after exposure to a diet containing the maximum European tolerance for fumonisins in avian feeds. Gas chromatography-mass spectrometry for metabolite profiling of Japanese Black cattle naturally contaminated with zearalenone and sterigmatocystin. Fumonisin B1 as a urinary biomarker of exposure in a maize intervention study among South African subsistence farmers. Biomonitoring of mycotoxins in human breast milk: current state and future perspectives. Individual and combined effects of feeding Fusarium moniliforme culture material, containing known levels of fumonisin B1, and aflatoxin B1 in the young Turkey poult. Effect of a hay and a grain diet on the rate of hydrolysis of ochratoxin A in the rumen of sheep. Evaluation of fumonisin biomarkers in a cross-sectional study with two high-risk populations in China. Metabolic profile of zearalenone in liver microsomes from different species and its in vivo metabolism in rats and chickens using ultra high-pressure liquid chromatography-quadrupole/time-of-flight mass spectrometry. Effects of individual and combined administration of ochratoxin A and aflatoxin B1 in tissues and eggs of White Leghorn breeder hens. In the 17 western United States, it was estimated that more than $340 million in annual losses were attributed to poisonous plants (Nielsen et al. This cost estimate used 1989 figures and only considered death losses and measureable reproductive losses in cattle and sheep. A revised estimate of over $500 million annually using more current animal prices was recently reported (Holechek, 2002). Less obvious costs such as lost grazing opportunities, additional feed costs, increased healthcare costs, management adjustments, increased culling costs, lost weight gains, delayed or failed reproduction, and the emotional stress accompanying many poisonous plant cases were not included in the Nielsen and James or Holechek analyses. When one considers these other costs, inflation, and current animal values, and when all pastures and ranges in the United States are factored in, the economic cost of poisonous plants to the livestock industry is significant. In addition, an often ignored cost is the environmental impact on plant biodiversity from invasive species, many of which are poisonous. These invasive and poisonous species are often aggressive invaders and reduce optimum utilization of private, federal, and state-managed forest, range, and pasture lands. This aspect alone has far-reaching implications, not only for livestock producers but also for many other segments of society. For example, in the arid and semiarid livestock-producing regions of the world, such as the western United States, regions of South Africa, Australia, China, South America, and others, browsing or grazing animals may have limited access to high-quality forage at certain times of the year and are forced to survive by grazing some poisonous species. In other instances, hay or harvested forages from areas where poisonous plants are abundant may be contaminated with a high percentage of poisonous plants, and when animals are fed contaminated hay, they may be poisoned. Poisonous plant problems are often exacerbated during periods of below normal rainfall when the abundance of grasses is reduced. In other instances, poisoning occurs early in the season when poisonous plants such as lupine or death camas have emerged ahead of grasses. To restate the obvious, poisoning by plants only occurs when animals eat too much too fast or graze it over extended periods. Therefore, management strategies utilizing multiple factors are required to minimize losses from poisonous plants. Part of this research has emphasized identifying biomarkers of poisoning for diagnostics and research. This article is not intended to be all inclusive but focuses on some of the most economically important and geographically widespread poisonous plants to livestock producers in the United States. There are three toxic syndromes associated with these species: (1) locoweed poisoning caused by species containing the indolizidine alkaloid swainsonine (w24 species); (2) species containing nitrotoxins (w356 species and varieties); and (3) selenium accumulators (w22 species). In the final stages of locoism, central nervous system tissue shows swelling of axonal hillocks (meganeurites) and growth of new dendrites and synapses. This altered synaptic formation in nervous tissue in severely affected animals is permanent and may be the cause of some irreversible neurological signs. Because of neurological dysfunction and apparent permanence of some lesions in the nervous system, horses are believed to be unpredictable and therefore unsafe to use for riding or draft, but they may remain reproductively sound once they have recovered from the poisoning. Toxin the indolizidine alkaloid swainsonine (1) was first isolated from the Australian plant Swainsona canescens (Colegate et al. There are about 24 known species of Astragalus and Oxytropis that contain swainsonine and have been implicated in livestock poisonings. The term "loco" is Spanish, meaning crazy, and colloquially describes the aberrant behavior of locoweed-poisoned animals. All species of Astragalus and Oxytropis containing swainsonine are collectively referred to as locoweeds. Toxicology There are numerous effects of locoweed on animals, but the classic syndrome from which the term "locoism" derived is one of the central neurological dysfunctions, resulting in aberrant and often aggressive and unpredictable behavior. The disease is chronic, developing after weeks of ingesting locoweeds, and begins with depression, dull-appearing eyes, and incoordination, progressing to uncharacteristic behavior, including aggression, staggering, solitary behavior, wasting, and eventually death if continued consumption is allowed. Other problems associated with locoweed ingestion include reproductive failure, abortion, birth defects, weight loss, and enhanced susceptibility to brisket disease at high elevations (Panter et al. A positive correlation was shown to exist between swainsonine concentrations found in the plant and concentrations of swainsonine produced by the endophytic fungus cultured from the same plant (Ralphs et al. This same correlation was demonstrated for Oxytropis glabra, an important poisonous plant in the Inner Mongolia steppe (Ping et al. Research results have shown that inhibition of a-mannosidase is relatively transient and quickly reversible once animals stop eating locoweed (Stegelmeier et al. Blood serum clearance of swainsonine is rapid (half-life of w20 h); thus, the effects of locoweed should be reversible if tissue damage has not become extensive and permanent. This suggests that intermittent grazing of locoweed could be an effective means of reducing locoweed poisoning. There is also an apparent threshold dosage where severity of cell damage is more timedependent than dosage-dependent. Therefore, increasing animal numbers on loco pastures and reducing time of grazing is also a logical method to reduce economic impact yet utilize infested pastures. Many locoweeds are biennials or perennials that flourish periodically under optimum environmental conditions. Historically, losses are regional and sporadic, with large regional economic impact. Individual cases of significant losses are frequent, and some historical cases are reported in James and Nielsen (1988). Conditions of Grazing In cows, preference to graze locoweed is relative to the amount and condition of other available forage. Many locoweeds are cool-season species that green up and start growth early in the spring, flower, set seed, and go dormant in summer, and then resume growth in fall. Sheep preferred the regrowth foliage of Green River milkvetch to dormant grasses during late fall and early winter on the desert range in eastern Utah (Ralphs et al. Horses selected green spotted locoweed instead of dormant grasses in the spring in Arizona (Pfister et al. Cattle readily grazed Wahweap milkvetch in proportion to its availability on desert winter range in southeastern Utah. In a series of grazing studies in northeast New Mexico, cattle readily grazed white locoweed in Marche May but stopped grazing it in June as warm-season grasses became abundant and white locoweed matured and became coarse and rank. Stocker cattle grazed white-point locoweed on shortgrass prairies in May and early June, but weight losses continued throughout the summer, even though they had stopped eating locoweed. On mixed-grass prairies on the eastern foothills of the Rocky Mountains in northern Colorado, cattle ceased grazing white-point locoweed when it matured following flowering in mid-June and became rank and less palatable. However, they continued to graze it throughout the subsequent summer when abundant summer precipitation caused the locoweed to remain green and succulent (Ralphs et al. Evaluation of serum swainsonine versus serum alpha mannosidase will indicate recent exposure to locoweed; however, elimination kinetics of swainsonine is short (t½ elimination of 20 h) and recovery rate of a-mannosidase is relative to disappearance of swainsonine. Therefore, serum evaluation of swainsonine or a-mannosidase is of limited value in diagnosis. However, these are not pathognomonic to locoweed poisoning and without a history of locoweed ingestion would be of limited value as biomarkers. Currently, the best diagnosis for locoweed poisoning can only be obtained after necropsy and follow-up histopathology. Although there are few gross lesions seen in locoweed poisoned animals, there are many characteristic microscopic lesions. Most organ systems are affected; however, the nervous and endocrine systems are extremely sensitive and diseased cells of these organs are swollen and filled with dilated vacuoles described as cellular constipation. This cellular foamy vacuolation is readily observed in thyroid, pancreas, kidneys, testes, ovaries, and macrophages in nearly all tissues. Research at the Poisonous Plant Research Laboratory is focused on identifying selected abnormal proteins with a slow elimination kinetics as a biomarker to diagnose locoweed exposure and also as measure of prognosis for recovery. Prevention of Poisoning and Management Recommendations Prevention of poisoning remains a matter of management strategy adapted to individual grazing programs to minimize grazing of locoweed plants (Graham et al. Livestock should be denied access to locoweeds during critical periods when they are relatively more palatable than associated forages. On shortgrass prairies of northeastern New Mexico, stocker cattle should not be turned onto locoweed-infested rangelands until warm-season grasses start growth in late May or early June. Cattle on rangeland year-round should be removed from locoweed-infested areas in the spring when it is green and growing and warm-season grasses remain dormant. They can be returned to locoweedinfested pastures in summer when warm-season grasses are abundant. Most locoweed species are endemic, growing only in certain habitats or on specific soils. Reserving locoweed-free pastures for grazing during critical periods in spring and fall can prevent locoweed poisoning.

The analysis of antioxidants antimicrobial wound cleanser 800 mg ethambutol for sale, cytokines antimicrobial lighting purchase 800 mg ethambutol with visa, and inflammatory cells can often provide mechanistic insights into the underlying disease antibiotic resistance and livestock buy ethambutol paypal. This technique is typically used in cases where the pollutant is known to primarily affect the nasal passages and upper airways (Snow et al script virus ethambutol 400 mg purchase otc. The high degree of variability hampers its utility in identifying exposure- and pathologyrelated biomarkers (Rosias antibiotic invention cheap ethambutol 400 mg free shipping, 2012). Mainly, the issues with methodologies involve differences in the conditions of the subjects, condenser devices, and preservation/storage of the samples. Based on the interest in identifying biomarkers in exhaled breath, the American Thoracic Society and the European Respiratory Society organized a task force to develop guidelines on collection and analysis of biomarkers in exhaled breath (Ahmadzai et al. Recently, more sophisticated devices and controlled exhalation techniques have provided fairly consistent sampling of exhaled breath for assessment of biomarkers (Pleil et al. In animals, blood is generally drawn into the syringe directly from the abdominal aorta, vein, or by cardiac puncture at necropsy. Often, orbital, tail, or other surface bleeding techniques are employed for repeated sampling of blood for biomarker analysis in animals. For the collection of urine, special metabolic cages are used to collect samples in a noninvasive manner; however, urine also can be collected directly from the bladder during necropsy. On the other hand, toxicity biomarkers that involve disease-specific proteins, metabolites, or nucleic acids that are detected in the collection samples will need to be further assessed to gain knowledge about the dynamic nature of the injury or disease to develop therapeutic approaches. In this section, the biomarkers of inhalation exposure, lung toxicity, and diseases will be described. This is particularly important in regard to injuries and diseases caused by environmental and occupational exposures. Perhaps, the most commonly studied biomarkers of exposure are the plasma levels of cotinine (a metabolite of nicotine) and carboxyhemoglobin in smokers (Liu et al. These exposure biomarkers can provide evidence of the type and degree of exposure and, often, information about the temporality of lung changes. Exposure biomarkers can also yield information about the likely pathologies in the lung. Translocation of an essential metal, zinc, was confirmed by exposing rats to 70Zn, a stable zinc isotope (Wallenborn et al. There is evidence that some manufactured nanomaterials can be detected in the circulation on pulmonary exposure; however, often the concentration of nanomaterials has been very small (Choi et al. Translocation of reactive polycyclic aromatic hydrocarbons of diesel exhaust into the systemic circulation has been shown in a few studies. For example, a significant portion of diesel sooteassociated benzo[a]pyrene adherent to carbon core, as would be expected for components of diesel exhaust, rapidly translocated systemically after pulmonary exposure in dogs (Gerde et al. However, the detection methods for organic constituents in biological tissue samples are often inadequate and lack sensitivity. Nevertheless, there are many opportunities for identification of exposure biomarkers, especially when exposures are expected to contain metals and nanomaterials. Depending on the sample being analyzed, the type of biomarker examined could vary somewhat. This section covers the description of biomarkers shown to be altered in lung toxicity and pathology (Table 13. It also provides evidence of their relation to lung injury and their pathophysiological roles. This section does not include every known biomarker of lung toxicity and its biology, but rather the most commonly used biomarkers are described, with an emphasis on their functional correlation with lung toxicity and disease. This technique, however, is used less extensively in laboratory animals because of the difficulties with adequate sample collection and data interpretation. The levels of ferritin and superoxide dismutase, indicators of oxidative stress, are suggested as potential biomarkers of lung cancer (Carpagnano et al. Recent recommendations for standardization of sampling, analysis, and reporting of data were created by a task force set up by the European Respiratory Society to address this issue (Horvath et al. Total Protein and Albumin In healthy individuals and animals, there is limited protein in the alveolar lining; however, injury to the airways and alveolar structures leads to leakage of vascular protein into the alveolar space. Increased synthesis of cellular protein can also leak proteins from epithelial cells into the apical side of the airways. Because albumin is present at extremely low concentrations in the alveolar lining of healthy individuals and animals but can leak into the airspace on injury, the measure of albumin can provide evidence of the presence of blood proteins. Analyses of protein and albumin are made in numerous toxicological studies and in human clinical studies involving lung injuries and diseases. In clinical situations, these assays are modified for automated analysis of multiple samples. Their increases following chronic lung injuries or diseases will need to be examined with caution because not all chronic injuries are likely to be associated with active cell damage. When the activities of all these enzymes are measured, a more comprehensive assessment of lung cell injury can be made. In occupational and acute injuries, this marker is useful; however, in chronic lung diseases, it might not be consistently increased in all types of pathologies. This lysosomal enzyme is involved in the degradation of polysaccharides and glycoconjugates containing N-acetyl glucosamine residues. It has been shown to be released from alveolar macrophages during phagocytosis of foreign particles (WereszczynskaSiemiatkowska et al. Note that asbestos induces acute lung inflammation and injury (pathology not shown) that resulted in long-term fibrosis. Alkaline phosphatase, which is present in type 2 alveolar epithelial cells, can be released in the alveolar lining and serve as a biomarker of type 2 cell damage (Aiso et al. Especially in cases of cigarette smokeeinduced lung disease, increases in proteases can cause protease/antiproteinase imbalance (Nyunoya et al. However, because a given protease might be involved in many different diseases and injuries, the diagnostic values for these biomarkers are limited (Vuorinen et al. Determination of their proteolytic activity by special gel-based assays can provide insight into the signaling pathways and the type of pathology. Oxidation By-Products and Antioxidants Because the lung is exposed continuously to high levels of molecular oxygen, the potential for oxidation of structural macromolecules exists, especially in a disease condition where appropriate antioxidant homeostasis cannot be maintained. When the balance between oxidants and antioxidants is shifted to increased oxidation, lung injury ensues. Humans, primates, and guinea pigs lack the mechanism to synthesize ascorbate in the body and, thus, require dietary supplementation, whereas laboratory rodents (rats and mice) can produce ascorbic acid. Specialized transporters exist on cells to transport ascorbate at the apical surface of the airway lining (Wilson, 2005). The levels of ascorbate in experimental cigarette smoke exposure are decreased because of increased oxidative burden (Ghio et al. Generally, biological samples can be stabilized by acidic deproteinization with perchloric and metaphosphoric acid (Roginsky et al. Other airway lining antioxidants include extracellular superoxide dismutase, which is normally present within interstitial spaces and alveolar lining where it is a scavenger of superoxide radicals (Fattman et al. Following stress, the activity of extracellular superoxide dismutase has been shown to increase. Iron is the most abundant metal component of the body, is redox active, and is regulated precisely by tightly controlled transport mechanisms. Iron-binding proteins play a critical role in maintaining antioxidant homeostasis and removal of nonheme iron. Because these proteins are changed in a number of pathological conditions and after acute lung injury, the specificity of these proteins for a given lung disease cannot be ascertained. A number of studies have also shown increases in levels of malondialdehyde, which is produced by oxidative modification of lipids. Accurate measurement of its levels is challenging; however, increases have been shown in some lung injuries (Nemmar et al. Because oxidative stress and increased oxidation of macromolecules are associated with almost all lung pathologies and injuries, the changes in these markers will not provide specific insights into the type of disease or injury. Cytokines, Chemokines, and Growth Factors Cytokines and chemokines are secreted by lung epithelial, smooth muscle, interstitial, and endothelial cells and alveolar macrophages. The ability to analyze the pattern of change among many functionally related cytokines, as opposed to individual ones, allows for a more accurate prediction of the type of disease and its progression and severity. For example, increased secretion of Th2 cytokines will be indicative of an asthma phenotype (Hartl et al. The increased secretion of these cytokines is noted during an immune response and can also occur in injuries not mediated by immune mechanisms. Some of these cytokines and chemokines serve to stimulate proinflammatory reaction, whereas others are involved in the maintenance of homeostasis. Therefore, proteins released into the airway lining fluid can serve as biomarkers of underlying lung inflammation, infection, or chronic disease. Bronchoalveolar Lavage Fluid Cells as a Determinant of Lung Inflammation Lung injury leads to recruitment of inflammatory cells from blood to the lung compartments through highly regulated immunological processes. These cells can be mounted on a slide using cytospin centrifugation and stained for their microscopic examination and identification. Quantification of relative cell types is used for assessment of lung inflammation in many inhalation toxicological and human exposure studies. In lung diseases, these cells provide information on the nature of pathology, whereas the surface characterization of receptors can predict molecular mechanisms. Lung injuries and pathologies associated with inhalation exposure to particulate and fibrous materials result in macrophage phagocytosis of these inhaled materials. Macrophages undergo phagocytosis and pinocytosis, leading to activation (Zhang and Kaminski, 2012). Inflammatory cells are recruited into the alveolar space following lung injury through elaboration of cytokines and chemokines from activated macrophages and epithelial cells. The type and the degree of cell infiltration depend on the physicochemical property of the inhalant and the degree of initial injury. The identification and quantification of inflammatory cells can provide insight into the type of pathology. Flow cytometry analysis for surface markers is often used to determine immunological mechanisms. In many cases, these cells recovered from healthy and diseased patients are cultured to study their potential to secrete cytokines on stimulation and their pathobiologic mechanisms. Often, sloughed-off ciliated epithelial cells are present because of procedural injury. The blood sample collection is performed routinely in any clinical setting and in experimental studies. New approaches and discoveries have led to significant advances in global assessment of biomarkers in the blood. Here, we will discuss several lung toxicity biomarkers individually and as a group to enable a pattern of change to be examined. Therefore, their detection in the circulation can provide highly specific information concerning lung injury and pathology. Because these proteins are secreted in limited quantities, their detection sensitivity is critical in determining the correlation between the severity of lung injury and the degree by which the protein level increases in the circulation. Many of these biomarkers are likely to be changed with multiple lung diseases, often limiting their specificity and predictive value for a given pulmonary disease. Smokers who have demonstrated reduced diffusion capacity at the capillary barrier have been shown to have increased blood lysozyme, a marker of inflammatory cells. This has been shown to correlate with the degree of impairment in lung diffusion capacity (Schmekel et al. Increased levels of cytokeratin-18 immune complexes were present in patients with pulmonary fibrosis (Dobashi et al. Some immunological mediators have the potential for being considered as biomarkers for infections. These studies suggest that there are likely a number of immune responsee related biomarkers that can be considered for further validation. The type of any immune biomarker change, however, can depend on the type of lung damage or infection. Collagen and Elastin Fragments Collagen and elastin are present at high levels in the lung and provide a unique structural framework. Injury to the structural components of the lung results in proteolytic degradation of extracellular matrixeassociated collagen and elastin. Some of the fragments of collagen and elastin are highly reactive and have been shown to induce inflammatory responses within the lung (Overbeek et al. Desmosine and isodesmosine, degradation products of elastin, have been identified in circulation and are considered fairly specific markers of emphysematous changes in the lung (Viglio et al. Other elastin degradation products have also been identified and are named elastokines based on their ability to cause inflammatory reactions (Cantor and Shteyngart, 2004). These fragments can serve as biomarkers of underlying lung disease (Ostroff et al. Because other organ injuries can also fragment collagen and elastin, the analysis of by-products in plasma should accompany additional measures of lung injury. The determination of these fragments is limited to the availability of specific antibodies. Circulating cytokines as biomarkers have been implicated in a number of pulmonary diseases (Tzortzaki et al. Increased levels of circulating cytokines have also been implicated in coal miners (Zou et al. A number of experimental air pollution studies have shown changes in circulating cytokines; however, the increases have been inconsistent relative to the degree of lung injury. It is likely that animal strain, temporality, and other host factors, in addition to the types of lung injuries, play important roles. Thus, the use of circulating cytokines and other proteins in experimental lung toxicity or lung diseases as biomarkers should be considered in conjunction with other types of disease measures. Many of these cell surface receptors have their soluble form present in the circulation and are involved in regulatory mechanisms.

With practice antibiotics for uti infection symptoms discount ethambutol 400 mg fast delivery, the toxicologist can feel the needle penetrate into the sc space antibiotics for uti planned parenthood purchase cheap ethambutol, if that happens by accident antibiotic resistance livestock feed purchase discount ethambutol on line, and can relocate the needle prior to injection virus - ruchki zippy generic ethambutol 800 mg visa. A properly administered id dose will appear as a small bleb on the surface of the skin buy antibiotics for sinus infection ethambutol 400 mg buy fast delivery. A dose administered into the sc space will not appear as a bleb, as the dose will be distributed over a larger area. Washing excess test article from the treatment site after a prescribed time will limit the exposure period to a known interval. The appropriate choices for the above (and other variables) in topical toxicity study design are a function of the specific objectives of the study, and the physical and chemical characteristics of the test article. The solvent is allowed to dry using a warm air blower if necessary, and the animal is returned to its cage. On subsequent treatment days the tape-stripping operation can be reduced to about 5e10 applications of adhesive tape to achieve the shinny appearance. Topical Administration the topical route of administration is occasionally used for toxicity testing. This choice of route may be appropriate for testing the systemic and local toxic effects of substances intended for human topical administration or which are likely to come into accidental contact with human skin. Data suggest that the mouse is one of the less appropriate species for extrapolation of percutaneous toxicity to the human, as the permeability of mouse skin (as well as rat and rabbit skin) is substantially higher than the permeability of human skin (Maibach and Wester, 1989). It is now clear that lipophilic compounds are readily absorbed into and across the skin, and also that the skin may be a source of significant metabolism of some chemicals (Maibach and Wester, 1989). Variables, in addition to lipophilicity, that are likely to affect dermal absorption include the integrity of the skin at the treatment site, the vehicle employed for dosing, occlusion, and/or restraint of the mouse after treatment, and whether the test article is washed off after some prescribed period. Variations on the integrity of the skin include totally intact skin, skin from which the outer epidermal layers have been tape stripped using a surgical adhesive tape. The presumption is that nonlipophilic test articles will penetrate stripped (thinned) or abraded (interrupted) skin more extensively than they would in intact skin. The proper choice of a vehicle may enhance the permeability of the skin to a nonlipophilic chemical. Occlusion of the treatment site and/or restraint of the mouse after application of a topical dose improve retention of the dose in contact with the skin and reduce the probability that the animal will orally ingest the topical Inhalation the inhalation route of administration offers the most rapid absorption of most test articles, with systemic availability second only to iv injection. Efficiency of absorption by the inhalation route is conferred by the large surface area of the respiratory system, the close proximity of the inner alveolar surface to the blood circulating through the lungs, and the fact that the entire cardiac output passes through the lungs with each circuit of the blood through the body. Absorption of inhaled agents proceeds via one or more of the following mechanisms depending on specific characteristics of the agent: direct absorption into the blood stream, absorption from the gastrointestinal tract following deposit in the nasopharynx or transport by mucociliary escalation and swallowing, and/or lymphatic uptake following deposit in the alveoli. Inhalation studies are particularly useful in estimating the risk of accidental or occupational exposure to a gas, vapor, dust, fume, or mist as well as in evaluating the toxicity of agents that are intended to be administered by inhalation. Administration by inhalation is the most technologically complex means of routine exposure, and a comprehensive description of the procedures is beyond the scope of this chapter. Rather, this discussion will be limited to some of the advantages, disadvantages, and variables to be considered in inhalation testing. The primary disadvantage is the technological complexity of the method, with the associated risk of technical error and disregard of an important variable. For a mouse to inhale a test article, the mouse must be placed in an environment that contains the test article in the form of a gas, vapor, dust, fume, or mist. The test article must exist in a particle size that is inspirable, generally having an aerodynamic diameter from 1 to about 10 A. Particle size dictates the location where the test article will be deposited and absorbed in the respiratory tract. Larger particles are deposited in the nasopharyngeal region, with successively smaller particles deposited in the trachea, bronchial, bronchiolar, and finally the alveolar region for particles of about 1 m or less. The technology of particle generation and uniform distribution through the exposure apparatus is complex in itself. In addition to generating and uniformly distributing the test atmosphere, care must be exercised to capture the exhaust from the exposure apparatus, such that the test article can be contained without contamination of the laboratory or environment. Exposure periods can range from a few minutes, appropriate for test articles that may pose only an acute exposure risk to continuous exposure over a prolonged period, appropriate for test articles that may pose a risk of long-term environmental or occupational exposure. Exposure apparatus generally takes the form of a chamber that contains the whole animal or groups of animals, or a device that exposes only the head or nose of the animal(s) to the experimental atmosphere. Chamber (Whole Body) Inhalation chambers allow relatively large numbers of mice to be exposed simultaneously without restraint. The aerodynamic considerations are complex, but simpler than for a head-only or nose-only exposure system. The flow rate through a chamber must be adequate to provide temperature and humidity control. Disadvantages of whole body chambers include the tendency for test article to accumulate in the fur, from which it can be ingested; on the skin and eyes, which may interfere with the intended route of exposure and the difficulty in monitoring respiratory volume and rate of individual animals. Head/Nose Exposure (Head Only/Nose Only) Head- or nose-only exposure apparatus limits exposure of the mouse to the test article by routes, other than inhalation, as only a small amount of skin and fur are exposed to the test environment. In addition, it is possible to monitor respiratory volume and rate of individual animals with some of the head-or-nose-only equipment. Disadvantages to this equipment include the fact that only a relatively small number of animals can be simultaneously exposed, and those animals must be restrained in a position that keeps their heads or noses in close contact with the exposure apparatus. This restraint imposes stress on the animals and virtually precludes continuous exposure, as the processes of eating and drinking are not possible with most of this equipment. Heart rates in awake mice have been measured in the range of 300 to more than 800 beats/min (Hoyt et al. Reliable blood pressure measurements are best made by cannulation of a major artery, such as the carotid. Such procedures require anesthesia and surgery, neither of which is especially desirable during the course of a study that may be of long duration and involve many animals. Clinical Observations and Physical Examinations Clinical observations entail the recording of effects that can be detected by direct observation, such as abnormal gait and body weight. For the sake of this discussion, a variety of parameters that can be observed or measured directly will be discussed in this section. Clinical observations often provide the first indication of which physiological systems are being affected by the test article. Mice should be observed regularly throughout the in-life portion of a toxicity study. The type and frequency of these observations should be tailored to meet the scientific objectives of the specific study. Most effects observed following administration of acute (single) doses occur within a relatively short time after dosing. As acute iv doses are often associated with almost immediate effects, it might be appropriate to observe treated mice within 5 min, at about 15, 30, and 60 min, and again at 2 and 4 h after dosing. Observations should be repeated at least once daily on all subsequent study days throughout the postdosing I. This schedule should provide information on the times of onset, peak activity, and remission from toxic effects as well as information on the sequence and severity of effects observed. The high intensity of data collection on the day of dosing in acute studies requires that the system for conducting and recording observations be simple and time efficient. Typically, a system of "exception reporting" is used, in which observations of exceptions from the norm are recorded, and the absence of comment on a system. Clinical observations in repeated dose studies should be conducted at approximately the same time each day to assure that changes in findings over the course of the study can be attributed to the accumulation of or adaptation to toxic effects rather than incidental changes attributable to circadian rhythm or time after dosing. Minimally, all animals should be observed early in the day, prior to daily dosing, and it is highly desirable to conduct at least one additional daily observation at 2e4 h after dosing (or late in the day) to be aware of effects that may be associated with higher blood levels of test article usually found from a few minutes to a few hours after dosing. The simplest form of clinical observation is an observation for survival and moribundity. This or a higher level of observation must be conducted at least once daily in all toxicity studies. The next level of observation is an observation for clinical signs of toxicity, such as abnormal level of spontaneous motor activity, abnormal gait, abnormal respiration, and abnormal quantity or quality of fecal output. During the conduct of a physical examination, specific parameters are evaluated, such as quality of coat, body orifices (for excessive or unusual discharges), eyes, respiratory sounds, and in studies longer than about 26 weeks, animals are examined carefully for evidence of visible or palpable masses. Body weight and feed consumption are typically monitored in studies longer than a few days. An appropriate interval for measuring body weight and feed consumption is about a week. These two parameters should be measured concurrently, such that changes in one can be compared directly to changes in the other. In longer studies, in which the mice have reached maturity and body weight gain has approached zero, the frequency at which body weight and feed consumption are measured can be reduced to as infrequently as once per month. Clinical Laboratory Evaluations Clinical laboratory evaluations of mice refer to evaluations of blood and urine. Blood is routinely collected at sacrifice in repeated dose studies, and small quantities. Interim (nonterminal) blood samples can be collected by retro-orbital venous plexus puncture, cardiac puncture, and tail snip, among other techniques. Retro-orbital puncture is technically difficult and may require anesthesia or immobilization of the animal. Cardiac puncture typically requires anesthesia, and cardiac injury may compromise the histological evaluation of cardiac tissue. Tail snip often yields samples that are contaminated with extravascular, extracellular fluids. Any administration of anesthetic agents during the study of a test article that is not thoroughly understood engenders some risk to the interpretation of the study, as potential interactions of the anesthetic with the metabolism or direct effect of the test article are nearly impossible to predict. Blood collected at the time of sacrifice is typically drawn from the inferior vena cava or the abdominal aorta while the mouse is under anesthesia. In the case of terminal blood collection, potential interaction of the anesthetic agent with the test article, induction of liver enzymes, etc. In addition, bone marrow smears may be prepared but are usually only prepared at sacrifice in mice. Caution should be exercised in comparing experimental data with results obtained from the literature or with results obtained on different instrumentation or by different procedures. For greatest utility, a set of normal values should be compiled for the laboratory procedures and equipment used to produce the data in the toxicity study. As a practical matter, urine is not usually collected in routine toxicity studies. The primary difficulty in conducting urinalysis is that the mouse produces a very small volume of urine during a reasonable collection period. As a result, attempts to evaluate urinary concentrations of practically anything can be very misleading. Postmortem Procedures Postmortem procedures, literally those procedures performed after the death of the animal, include confirmation of the identification number and sex of the animal, an external examination, examination of the significant internal organs in place prior to removal, and then removal, weighing of appropriate organs, and collection of tissue specimens for histological processing and microscopic examination. The microscopic examination of tissue specimens by a qualified veterinary pathologist may be the single most important source of information in understanding the toxicity of a test article. Ordinarily, the list of tissues to be routinely weighed, collected, and processed for histological examination will be specified in the study protocol. In addition to the tissues specified in the protocol, specimens are usually collected of all lesions or target organs that have been identified during the course of the study or at gross necropsy. It is important to provide the necropsy staff with a current list of abnormal clinical observations, especially any evidence of visible or palpable masses, as this is the time when the visible and palpable lesions can be linked to the histopathological evaluation of those lesions. Every effort should be made to locate all lesions described and collect representative tissue from those sites. A detailed description of necropsy procedures is beyond the scope of this discussion. It should be emphasized that the necropsy process, particularly when conducted on a large number of animals at the scheduled termination of a study, is a process in which a large number of tissue samples may be collected and a similarly large quantity of data may be gathered during a short period of time. As such, this process presents many opportunities for loss or misidentification of samples and data. A rigorous system of accounting for which tissues have been collected from each animal, and for tracking the samples and data collected is critical to the accurate interpretation of the toxicity study. It is often possible to select a strain for testing that is particularly vulnerable or resistant to either the test article or a particular type of lesion that might be expected to be associated with that test article. The small size of the mouse confers economy in acquisition, husbandry, handling, and test article consumption. The relatively short gestation period and life span of the mouse are useful in conducting reproductive studies, or studies in which the test article will be administered for a high percentage of the lifetime of the animal. The small size of the mouse is responsible for most of the disadvantages of the species as well. Small size and blood volume makes it difficult or impossible to collect multiple samples of blood and urine over short periods of time. Certain physiological evaluations, such as electrocardiograms, are difficult owing to the small size and high activity level of the species. The Hamster the hamster is the third most frequently used laboratory animal following the rat and mouse at a level of w146,000/year (Renshaw et al. Although historically the hamster saw extensive use in carcinogenesis testing, as will be overviewed, this has changed. It has many attractive features as a laboratory animal because of its reproduction ease, unique anatomical and physical features, rapid physiological development, short life span, low incidence of spontaneous diseases, and a high susceptibility to induced pathological agents. Hamsters historically have been used in several fields, especially in carcinogenesis because of its low incidence of spontaneous tumors, but currently most of their use is seen in testing associated with buccal delivery of drugs (Gad, 2016). Hamsters have also played an important role in blood vessel physiology because their cheek pouches with thin vascularized walls are very accessible. The remaining 20% are primarily Chinese, followed distantly by European, Armenian, Rumanian, Turkish, South African, and Dzungarian hamsters.

Virtually every gas antibiotic resistance methods 400 mg ethambutol with mastercard, excluding oxygen virus not alive ethambutol 600 mg buy, can act as a simple asphyxiant by replacing oxygen from ambient air and interfering with oxygen delivery (Goldfranks antibiotic resistance can boost bacterial fitness cheap ethambutol 400 mg fast delivery, 2015) antibiotics buy online order generic ethambutol canada. Unlike simple asphyxiants antibiotics for sinus infection in babies purchase ethambutol with visa, chemical asphyxiants act by producing cellular hypoxia (interference with cellular respiration). Exposure to toxic gases may be the result of the intentional release of chemical warfare agents. The accidental release of methyl isocyanate (liquid below but a gas above 39 C) in Bhopal, India, resulted in the immediate death of at least 3800 people in 1984 (Broughton, 2005). It also caused significant morbidity and early death for many more; the combined number of injured or dead is estimated to be over 250,000. The measurement of urinary excretion of unmodified solvents has numerous advantages such as, but not limited to , having a noninvasive sample collection procedure (compared with blood and tissue sampling), being specific and sensitive (able to detect low levels of exposure), and analytical techniques for their detection are widely available and/or easily developable (Gobba et al. Moreover, the correlation between environmental timeweighted average concentration (an index of the external dose of solvents) and the levels of unchanged solvents in the urine of individuals exposed via inhalation is generally good. The correlation between the ambient air and urine levels of selected toxic solvents and gases (as indicated by their r-values) is listed in Table 34. The alveoli are at the end Correlation Coefficients of the Ambient Air and Urine Levels of Toxic Solvents and Gases Name of Solvent or Gas Benzene Toluene Xylenes r 0. The concentration of volatile compounds in the end-tidal air (the last portion of expired air) is in constant equilibrium with that in the blood (Caro and Gallego, 2009). Consequently, the end-tidal air can be used to detect and measure exposure to volatile compounds. The correlation coefficient between alveolar air levels and environmental air concentrations of these solvents ranged from 0. When the breath of dry cleaning workers was monitored for tetrachloroethylene exposure, a solvent also known as "dry cleaning fluid" because of its wide use in dry cleaning, it was found that exposure to tetrachloroethylene can be reliably monitored from breath (Droz and Guillemin, 1986). Numerous other articles discuss the use of breath for biomonitoring solvent and gas exposure. It is clear, based on these publications, that in addition to the use of urine for biomonitoring exposure to unmetabolized solvents and gases, breath can also be used to detect and measure exposure to these compounds. Like the collection of urine samples, the collection of breath samples is rapid and noninvasive. The correlation factors of ambient air and breath levels of selected toxic solvents are listed in Table 34. In addition to urine and breath, blood may also be used for measuring biomarkers of toxic solvent exposure. Because it requires an invasive procedure to obtain and may expose those who collect it to blood-borne diseases, it is less preferred. For example, in a study of toluene, the correlation coefficients for toluene levels in the air of occupational environment and concentrations of toluene in alveolar air, blood, and urine were comparable, i. Using blood for monitoring exposure in some cases may be superior and in other cases inferior compared with using breath or urine. In the case of acetone, monitoring exposure in blood was less useful than monitoring exposure using breath or urine. A search of the currently available literature yielded correlation coefficients of up to 0. The Use of Metabolites of Toxic Solvents or Gases as Biomarkers of Exposure the metabolites of toxic solvents and gases can also be used to monitor exposures to these chemicals. Unfortunately, certain metabolites may form from more than one compound, rendering them nonspecific biomarkers of the parent compounds. For instance, n-hexane and 2hexanone are both commonly used solvents that share the highly neurotoxic 2,5-hexanedione metabolite that is excreted in the urine and is used for monitoring exposure to these two solvents (Cardona et al. Consequently, when the source of 2,5-hexanedione is unknown, determination of the parent compound from breath may be preferable (Periago et al. Other factors that may complicate the use of metabolites as biomarkers of exposure are changes in metabolism resulting from co-exposure to other solvents or gases or from metabolizing enzyme induction because of repeated exposure. In the case of n-hexane, after short-term, acute co-exposure with methyl ethyl ketone, a decrease in the concentration of 2,5-hexanedione was observed, whereas after repeated, chronic co-exposure with the methyl ethyl ketone, the urinary excretion of 2,5-hexanedione increased (Cardona et al. Repeated co-exposure of n-hexane with toluene tended to reduce and repeated co-exposure with acetone tended to increase the urinary excretion of 2,5-hexanedione (Cardona et al. Isopropanol is another example where a metabolite could be used for biomonitoring. Not only was the correlation between alveolar and environmental concentrations of unmetabolized isopropanol found to be high. Additionally, the urinary acetone concentration was found to increase in proportion to the isopropanol exposure intensity (r ¼ 0. Hence, in addition to isopropanol itself, acetone may be used as a biomarker of isopropanol exposure. Unfortunately, as acetone can also signal acetone exposure, caution must be exercised when it used as a biomarker of isopropanol exposure (Lauwerys and Hoet, 2001). In addition to the parent compound, the metabolites of toluene, one of the most widely used organic solvents, are also used as biomarkers of toluene exposure (Cosnier et al. Numerous articles reported good correlation between alveolar air toluene concentrations and environmental air toluene concentrations. In addition, highly significant correlations between the urinary metabolites of toluene and the concentration of toluene in both blood and ambient air ¨ were found (Angerer and Kramer, 1996). The highest correlation coefficient was obtained for o-cresol, a metabolite of toluene, and toluene in ambient air. Therefore, in addition to employing toluene as a biomarker of toluene exposure, its o-cresol metabolite can also be used for this purpose. Unfortunately, when coexposure to other solvents sharing similar metabolic pathways with toluene occurs. For instance, at high toluene exposure levels, there was a good correlation (r ¼ 0. Like toluene, some of its metabolites are also suitable biomarkers of its exposure, while others are not. Because of their lack of specificity, phenol, hydroquinone, and catechol (metabolites of benzene) are not suitable biomarkers for the assessment of environmental or even occupational benzene exposure (Arnold et al. Like other mercapturates, it is unstable in alkaline urine, and as such, freezing or acidification of the sample is required. Other examples of metabolites of some toxic solvents utilized as possible biomarkers of exposure are listed in Table 34. The human body is able to Metabolites of Toxic Solvents Used as Possible Biomarkers of Exposure Biomarker Metabolite(s) S-Phenylmercapturic acid tt-Muconic acid References Boogaard (2009), Inoue et al. Hence, their use as biomarkers of exposure or effect may be limited (Needham et al. On the other hand, hemoglobin (Hb) adducts, especially smaller ones, may not impact the life span of the erythrocyte. Furthermore, these adducts may accumulate in the body, and large quantities of Hb can be easily isolated from small volumes of blood for analysis. Consequently, Hb adducts can be utilized as biomarkers of exposure (Angerer et al. Albumin adducts are very useful for this purpose, as albumin is present in large quantities in the blood. The above-mentioned adducts are also employed for biomonitoring exposure to toxic solvents and gases. It is commonly used for numerous industrial processes as an intermediate, as a sterilizing agent for medical supplies and foods, as a fumigant, and as an insecticide. In the case of this toxic gas, its 2-hydroxyethyl adduct with Hb can be used as a biomarker of ethylene oxide exposure ´ (Csanady et al. Unfortunately, it is also a biomarker of ethylene exposure, as ethylene is biotransformed to ethylene oxide. Hb and plasma protein adducts of benzene oxide are also potential markers of benzene exposure, though Hb adducts might be diagnostically less sensitive than adducts of plasma proteins. Regrettably, currently available methods are not sensitive enough to monitor environmental benzene exposure using these Hb and plasma protein adducts, and they are also unsuitable for routine applications. Furthermore, the Hb and albumin adducts of 1,2- and 1,4-benzoquinone were found to be nonspecific biomarkers of benzene exposure. Hence, further development of even more sensitive methods for the detection and quantitation of benzene oxide adducts is desirable. The Use of Novel Biomarkers of Toxic Solvent and Gas Exposure Alterations in gene expression can serve both as biomarkers of exposure and as early effects of exposure. Chronic industrial benzene exposure has been associated with an increased incidence of aplastic anemia (deficiency of platelets and red and white blood cells) because of bone marrow damage (Snyder, 2012). In addition, it is a leukemogen; the first reports of the association between benzene and leukemia are about a century old. The mechanisms of leukemogenesis and development of aplastic anemia have been the subjects of much research. Furthermore, these biomarkers of effects could also serve as biomarkers of benzene exposure. Numerous genes were found to be affected by benzene, four of which were the most significantly and consistently affected and could be used as potential biomarkers of exposure. In summary, identification of novel biomarkers may serve as biomarkers of both exposure and effect and may help us understand the mechanisms of toxicity. Consequently, urinary albumin levels may be used to monitor effects of nephrotoxic solvents. However, this biomarker and other biomarkers of effects of nephrotoxic solvents are not specific to a solvent or to kidney injury due to solvent exposure. Nonetheless, periodic determination of urinary albumin levels is a useful tool for monitoring kidney damage in solvent-exposed workers. For a more detailed discussion on biomarkers of different target organs of chemicals, refer to the chapters in the Systems Toxicity Biomarkers section of this book. Unfortunately, as the selected examples below demonstrate, these biomarkers of effects are specific neither to a solvent nor to solvent or gas exposure. As biomarkers of effects are nonspecific in nature and humans are exposed to a variety of chemicals in their everyday lives that may or may not interact, relating these biomarkers of effects to a specific exposure is either challenging or outright impossible, and as such, they have limited use for health risk assessment (Boogaard, 2009). The liver transaminases alanine transaminase and aspartate transaminase are sensitive markers of liver injury and therefore can be used to monitor liver ¨ damage after solvent exposure (Silins and Hogberg, 2011). Increased bilirubin, sorbitol dehydrogenase, gamma-glutamyl transpeptidase, and serum bile acid levels, along with other markers, may also signal liver injury after solvent exposure. Unfortunately, these biomarkers of effects are specific neither to a solvent nor to liver damage resulting from toxic solvent exposure and may be elevated because of various diseases and disorders. Numerous markers of kidney damage, such as increased urinary albumin and N-acetyl-beta-D-glucosaminidase levels, have been identified. To interpret the data and derive quantitative reference or guidance values, knowledge of the quality of the analytical data and understanding of toxicokinetics of the toxic solvent or gas are necessary (Boogaard, 2009). Comprehension of the toxicokinetics of the substance of interest is essential, as some metabolites may form endogenously or from dietary ingredients or may originate from other chemicals that share the same metabolite with it. As the presence of a biomarker simply indicates exposure, one also needs to know the doseeresponse relationship to assess health risk; biomonitoring data must be correlated with toxicity data. Information on toxicity usually comes from animals, and sometimes humans, exposed to very high levels of toxic solvents or gases. Unfortunately, this method makes it hard to predict effects at low or very low levels of exposure. For a general discussion of how biomarkers fit into toxicological evaluation and risk assessment considerations and how risk assessment with the potential use of biomarkers is integrated into the development of chemical regulations, refer to Chapter 67. Nonetheless, it is not without limitations, and still much work is left to be done. Moreover, most of the currently used biomarkers of toxic solvent and gas exposure are only suitable for detecting fairly recent exposures. Finding biomarkers for detecting exposures from months, years, or decades ago is an area with much left to accomplish. In addition, exposure to mixtures, rather than to a single substance, is commonplace. Simultaneous exposure to multiple solvents and/or gases complicates biomonitoring of exposure and effects of a specific substance. More information is needed on co-exposure to multiple chemicals and their effects on specific biomarker(s) and the toxicity of a solvent or gas. Finally, ethical issues (such as confidentiality) in human biomonitoring also need to be addressed. Breath air analysis and its use as a biomarker in biological monitoring of occupational and environmental exposure to chemical agents. Two serious and challenging medical complications associated with volatile substance misuse: sudden sniffing death and fetal solvent syndrome. Isopropanol exposure: environmental and biological monitoring in a printing works. Concentration of ethylene oxide in the alveolar air of occupationally exposed workers. Biological monitoring of occupational exposure ton-hexane by measurement of urinary 2, 5-hexanedione. Behaviour of urinary 2, 5-hexanedione in occupational co-exposure to n-hexane and acetone. Alveolar air and urine analyses as biomarkers of exposure to trihalomethanes in an indoor swimming pool. Environmental and biological monitoring of volatile organic compounds in the workplace.

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