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For the chemical with the short elimination half-life of 8 hours bacteria 40x discount flagyl 400mg amex, minimal accumulation occurs from day to treatment for uti bactrim dose order flagyl canada day over the work days virus ebola espanol purchase flagyl amex. Near complete washout of the chemical is observed when work resumes on Monday (see arrow). For the chemical with the long elimination half-life of 24 hours, progressive accumulation is observed over the five work days. Washout of the longer half-life chemical over the weekend is incomplete; a significant residual is carried into the next work week. In classic kinetics, the rate constants are defined by the data; thus, these models are often referred to as data-based models. In physiologic models, the rate constants represent known or hypothesized biological processes, and these models are commonly referred to as physiologically based models. The concept of incorporating biological realism into the analysis of drug or xenobiotic distribution and elimination is not new. This model contained all the important determinants in chemical disposition that are considered valid today. Unfortunately, the computational tools required to solve the underlying equations were not available at that time. With advances in computer science, the software and hardware needed to implement physiological models are now well within the reach of toxicologists. The advantages of physiologically based models compared with classic models are that (1) these models can describe the time course of distribution of toxicants to any organ or tissue, (2) they allow estimation of the effects of changing physiologic parameters on tissue concentrations, (3) the same model can predict the toxicokinetics of chemicals across species by allometric scaling, and (4) complex dosing regimes and saturable processes such as metabolism and binding are easily accommodated (Gargas and Andersen, 1988). The disadvantages are that (1) much more information is needed to implement these models compared with classic models, (2) the mathematics can be difficult for many toxicologists to handle, and (3) values for parameters are often ill defined in various species, strains, and disease states. Nevertheless, physiologically based toxicokinetic models are conceptually sound and are potentially useful tools for gaining rich insight into the kinetics of toxicants beyond what classic toxicokinetic models can provide. This hypothetical chemical is eliminated through metabolism in the liver (K m ), biliary excretion (K b ), renal excretion (K r ) into the urine, and fecal excretion (K f ). Perfusion-limited compartments are noted in blue and diffusionlimited compartments are noted in white. Km Basic Model Structure Physiologic models are fundamentally complex compartmental models; it generally consists of a system of tissue or organ compartments that are interconnected by the circulatory network. If necessary, each tissue or organ compartments can further be divided into extracellular and intracellular compartments to describe movement of toxicant at the cellular level. The exact model structure, or how the compartments are organized and linked together, depends on both the chemical and the organism being studied. For example, a physiologic model describing the disposition of a chemical in fish would require a description of the gills (Nichols et al. For example, a model for a non-volatile, water-soluble chemical, which might be administered by intravenous injection (Fig. For example, the first model has a compartment for the intestines, because biliary excretion, fecal elimination, and enterohepatic circulation are presumed important in the disposition of this chemical. The second model has a compartment for fat because fat is an important storage organ for organics. Both contain a liver compartment because the hepatic metabolism of each chemical is an important element of its disposition. Models are simplifications of reality and should contain elements believed to represent the essential disposition features of a chemical. In view of the fact that physiologic modeling requires more effort than does classic compartmental modeling, what then accounts for the popularity of this approach among toxicologists? Toxicologists are constantly faced with the issue of extrapolation in risk assessments-from laboratory animals to humans, from high to low doses, from occasional to continuous exposure, and from single chemicals to mixtures. Because the kinetic constants in physiologic models represent measurable biological or chemical processes, the resultant physiologic models have the potential for extrapolation from observed data to predicted scenarios. Because the parameters underlying the model structure represent measurable biological and chemical determinants, the appropriate values for those parameters can be chosen for each species, forming the basis for successful interspecies extrapolation. Even though the same model structure is used for both rodents and humans, the simulated and the observed kinetics of both chemicals differ between rats and humans. The terminal half-life of both organics is longer in the human compared with the rat. This longer half-life for humans is due to the fact that clearance rates for smaller species are faster than those for larger ones. Even though the larger species breathes more air or pumps more blood per unit of time than does the smaller species, blood flows and ventilation rates per unit of body mass are greater for the smaller species. The smaller species has more breaths per minute or heartbeats per minute than does the larger species, even though each breath or stroke volume is smaller. The faster flows per unit mass result in a more efficient delivery of a chemical to organs responsible for elimination. Because the parameters in physiologic models represent real, measurable values, such as blood flows and ventilation rates; the same model structure can resolve such disparate kinetic behaviors among species. Transport of chemical throughout the body by blood is depicted by the black arrows. Elimination of chemical as depicted by the model includes metabolism (dashed arrow) and exhalation (black arrow). Compartments the basic unit of the physiologic model is the lumped compartment, which is often depicted as a box in a graphical scheme (Fig. A compartment represents a definable anatomical site or tissue type in the body that acts as a unit in effecting a measurable kinetic process (Rowland, 1984, 1985). A compartment may represent a particular structure or functional portion of an organ, a segment of blood vessel with surrounding tissue, an entire discrete organ such as the liver or kidney, or a widely distributed tissue type such as fat or skin. Compartments usually consist of three individual well-mixed regions, or sub-compartments, that correspond to specific physiologic spaces or regions of the organ or tissue. These sub-compartments are: (1) the vascular space through which the compartment is perfused with blood, (2) the interstitial space that forms the matrix for the cells, and (3) the intracellular space consisting of the cells in the tissue (Gerlowski and Jain, 1983). The rate of entry is a product of the blood flow rate to the tissue (Q t in L/h) and the concentration of the toxicant in the blood entering the tissue (Cin in mg/L). Within the compartment, the toxicant moves from the vascular space to the interstitial space at a certain net rate (Flux1 ) and moves from the interstitial space to the intracellular space at different net rate (Flux2 ). Some toxicants can bind to cell components; thus, within a compartment there may be both free and bound toxicants. Cout is equal to the concentration of the toxicant in the vascular space assuming a well-mixed compartment. One of the best illustrations of the predictive power of physiologic models is their ability to extrapolate kinetic behavior from laboratory animals to humans. For example, physiologic models developed for styrene and benzene correctly simulate the concentration of each chemical in the blood of both rodents and humans (Ramsey and Andersen, 1984; Travis et al. Both styrene and benzene are volatile organic chemicals; thus, the model structures for the kinetics of both chemicals in rodents and humans are identical to that shown in Fig.
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This deceptively slim volume covers a tremendous amount of material bacteria ua rare purchase 500 mg flagyl otc, and repetition will be a key aid as you progress in your studies antibiotics tired discount 500mg flagyl fast delivery. An effort has been made to virus killing robot flagyl 250mg on-line emphasize concepts and principles over random facts, the forest rather than the trees. Attention to the same by the student will provide a deeper, more meaningful understanding of human disease. We must always remind ourselves that ultimately our goal is to learn, to share, and to serve. To begin with, I would like to acknowledge Shaykh Zulfiqar Ahmad, whose clear vision has guided me to horizons I would never have known. My family is to be acknowledged for their limitless sacrifice, in particular the constant encouragement and support of my wife Amina, who has proved through the years to be the wind under my wings. Williams (Class of 2013, Pritzker School of Medicine, University of Chicago) for their extensive review. Finally, I would be remiss without acknowledging my students, who give meaning to what I do. An increase, decrease, or change in stress on an organ can result in growth adaptations. Occurs via an increase in the size (hypertrophy) and/or the number (hyperplasia) of cells B. Hypertrophy involves gene activation, protein synthesis, and production of organelles. For example, cardiac myocytes undergo hypertrophy, not hyperplasia, in response to systemic hypertension (Fig. Decrease in cell size occurs via ubiquitin-proteosome degradation of the cytoskeleton and autophagy of cellular components. In ubiquitin-proteosome degradation, intermediate filaments of the cytoskeleton are "tagged" with ubiquitin and destroyed by proteosomes. These vacuoles fuse with lysosomes whose hydrolytic enzymes breakdown cellular components. Most commonly involves change of one type of surface epithelium (squamous, columnar, or urothelial) to another 2. Esophagus is normally lined by nonkeratinizing squamous epithelium (suited to handle friction of a food bolus). Acid reflux from the stomach causes metaplasia to nonciliated, mucin-producing columnar cells (better able to handle the stress of acid, Fig. Metaplasia occurs via reprogramming of stem cells, which then produce the new cell type. Under persistent stress, metaplasia can progress to dysplasia and eventually result in cancer. A notable exception is apocrine metaplasia of breast, which carries no increased risk for cancer. Vitamin A is necessary for differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye. In vitamin A deficiency, the thin squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium. A classic example is myositis ossificans in which muscle tissue changes to bone during healing after trauma (Fig. Hypoplasia is a decrease in cell production during embryogenesis, resulting in a relatively small organ (e. The likelihood of injury depends on the type of stress, its severity, and the type of cell affected. Neurons are highly susceptible to ischemic injury; whereas, skeletal muscle is relatively more resistant. Common causes of cellular injury include inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations. Low oxygen delivery to tissue; important cause of cellular injury Oxygen is the final electron acceptor in the electron transport chain of oxidative phosphorylation. Causes of hypoxia include ischemia, hypoxemia, and decreased 0 2-carrying capacity of blood. Hypoxemia is a low partial pressure of oxygen in the blood (Pao 2 60 mm Hg, Sao2 90%). Lysosome membrane damage results in hydrolytic enzymes leaking into the cytosol, which, in turn, are activated by the high intracellular calcium. The morphologic hallmark of cell death is loss of the nucleus, which occurs via nuclear condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis). Area of infarcted tissue is often wedge-shaped (pointing to focus of vascular occlusion) and pale. Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction. Characteristic of granulomatous inflammation due to tuberculous or fungal infection Fig. Necrotic adipose tissue with chalky-white appearance due to deposition of calcium (Fig. Saponification is an example of dystrophic calcification in which calcium deposits on dead tissues. In dystrophic calcification, the necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate. Dystrophic calcification is distinct from metastatic calcification, in which high serum calcium or phosphate levels lead to calcium deposition in normal tissues (e. Leaking of proteins (including fibrin) into vessel wall results in bright pink staining of the wall microscopically (Fig. Apoptotic bodies fall from the cell and are removed by macrophages; apoptosis is not followed by inflammation. Lack of Bcl2 allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases. Free radicals are chemical species with an unpaired electron in their outer orbit. Return of blood to ischemic tissue results in production of0 2 -derived free radicals, which further damage tissue. Amyloid is a misfolded protein that deposits in the extracellular space, thereby damaging tissues. Congo red staining and apple-green birefringence when viewed microscopically under polarized light (Fig. Presents with episodes offever and acute serosal inflammation (can mimic appendicitis, arthritis, or myocardial infarction) ii. Clinical findings of systemic amyloidosis include Nephrotic syndrome; kidney is the most common organ involved. Familial amyloid cardiomyopathy Mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy. Ap amyloid (derived from p-amyloid precursor protein) deposits in the brain forming amyloid plaques.
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Although the majority of a solvent spilled onto the ground evaporates virus outbreak purchase discount flagyl on line, some may permeate the soil and migrate through it until reaching groundwater or an impermeable material treatment for uti from e coli order 500mg flagyl otc. In years past antibiotics for uti caused by e coli cheap flagyl 200mg with amex, the more lipophilic solvents were generally regarded as water insoluble. Maximum solubilities of some common hydrocarbon solvents range from 10 mg/L (ppm) for n-hexane to 24,000 mg/L for bromochloromethane. Concentrations in well water are rarely high enough for acute or subacute toxicity to be of concern. The very low levels of some solvents typically found in water have, however, caused a great deal of concern and debate about their carcinogenic potential. Potential health effects of solvent contaminants of water have received considerable attention over the past 30+ years. The finding of some 76 synthetic organic chemicals, many of which were solvents, prompted passage of the Safe Drinking Water Act in 1974. It and certain other trihalomethanes are formed by reaction of the chlorine added as a disinfectant with natural organic compounds present in the water. Of the thousands of chemicals found at hazardous waste sites, six of the ten most commonly present in groundwater are solvents (Fay and Mumtaz, 1996; Fay, 2006). People are subjected to solvents in environmental media by inhalation, ingestion, and skin contact. Thus, they pass freely through membranes from areas of high-to-low concentration by passive diffusion. Gases in the alveoli are thought to equilibrate almost instantaneously with blood in the pulmonary capillaries (Goldstein et al. Systemic uptake of solvents during ongoing inhalation exposures is dependent on tissue loading and metabolism, in addition to the factors noted above. Percent uptake is initially high, but progressively declines as the chemical accumulates in tissues, and the level of chemical in venous blood returning to the pulmonary circulation increases. A near steady state, or equilibrium will soon be reached upon inhalation of a fixed concentration of lipophilic solvents. Despite continued inhalation of lipophilic solvents, levels in the blood and tissues (other than fat) generally only increase modestly. Percent uptake remains relatively constant for the duration of exposure, with metabolism and accumulation in adipose tissue largely responsible for the continuing absorption. Hydrophilic solvents take considerably longer to reach steady-state, due to the extended time required for equilibration of chemical in the inspired air with that in the total body water (Goldstein et al. It is now usually assumed that 100% of an oral dose of most solvents is absorbed systemically. Absorption of solvents through the skin can result in both local and systemic effects. Skin contact with vapors and concentrated solutions of solvents is a common occurrence in the workplace. A related concept is that the tissue dose in a given target organ in one species will have the same degree of effect as an equivalent target organ dose in a second species. Gaining an understanding of how the processes that govern solvent kinetics vary with dose, route of exposure, species, and even different individuals greatly reduces the number of assumptions that have to be made in assessment of health risks from exposure and toxicity/carcinogenicity data. Volatility and lipophilicity are two of the most important properties of solvents that govern their absorption and deposition in the body. Most solvents are volatile under normal usage conditions, though volatility varies from compound to compound. Skin penetration can be quantified in laboratory animals and humans by a variety of in vitro and in vivo techniques (Morgan et al. Dermal permeability constants are typically two to four times lower for human than for rodent skin (McDougal et al. The extent of dermal absorption in occupational and environmental exposure settings should be taken into account when conducting risk assessments of solvents. Blood in the portal venous circulation passes through the liver before reentering the venous circulation. Solvents are also subject to exhalation by the lungs during their first pass through the pulmonary circulation. Those solvents that are well metabolized and quite volatile are most efficiently eliminated before they enter the arterial blood. The efficiency of the hepatic first-pass elimination is thus dependent on the chemical, as well as the rate at which it arrives in the liver. This hypothesis, if demonstrated experimentally, could have a profound effect on extrahepatic cancer and noncancer risk estimates of environmentally encountered levels of solvents in ingested media. Nevertheless, as much as 50% of such compounds may still be carried by erythrocytes (Lam et al. These researchers found that lipophilic solvents do not bind appreciably to plasma proteins or hemoglobin, but partition into hydrophobic sites in these molecules. Lipophilic solvents also partition into phospholipids, lipoproteins, and cholesterol present in the blood. The brain is an example of a rapidly perfused tissue with a relatively high lipid content. Lipophilic solvents therefore quickly accumulate in the brain after the initiation of exposures (Warren et al. Route of exposure can significantly influence target organ deposition and toxicity of solvents. Much of the pre-1980s toxicology database for solvents comprised results of inhalation studies. Such a practice is obviously not scientifically valid, when physiological differences in the absorption pathways are taken into account. For convenience, test chemicals are typically given daily to animals as a single bolus by gavage in short- and long-term oral toxicity and carcinogenicity studies. Actual human exposures to solvents in drinking water are quite different, in that people typically ingest water in divided doses. No evidence of hepatic tumorigenesis was seen, however, when these mice were given the same doses of the chemical in their drinking water (Jorgenson et al. Oral bolus doses of solvents can cause damage by exceeding the capacity of hepatic and pulmonary first-pass elimination, as well as protection and repair processes of cells. This can be attributed to redistribution of toluene from the brain to body fat and other tissues, as well as to relatively rapid metabolism and exhalation. In contrast, recovery from acetone narcosis does not occur for at least 9 hours post exposure. It is instead distributed in the considerable volume of the blood and other body water.
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Whereas apoptosis is orderly bacteria water test 200mg flagyl with amex, necrosis is a disorderly process that ends with cell debris in the extracellular environment virus 72 hours buy flagyl 400mg without prescription. The constituents of the necrotic cells attract aggressive inflammatory cells virus 71 generic 250mg flagyl free shipping, and the ensuing inflammation amplifies cell injury (see further on). This function of apoptosis is discussed in more detail in the final section of this chapter. It must be emphasized, however, that apoptosis of damaged cells has a full value as a tissue repair process only for tissues that are made up of constantly renewing cells (e. Apoptosis in the pulmonary alveolar epithelium, an extremely tight barrier, could cause flooding of the alveolar space with interstitial fluid, a potentially lethal outcome. Proliferation: Regeneration of Tissue Tissues are composed of various cells and the extracellular matrix. Therefore, repair of injured tissues involves not only regeneration of lost cells and the extracellular matrix but also reintegration of the newly formed elements. In parenchymal organs such as liver, kidney, and lung, various types of cells are involved in the process of tissue restoration. Nonparenchymal cells of mesenchymal origin residing in the tissue, such as resident macrophages and endothelial cells, and those migrating to the site of injury, such as blood monocytes, produce factors that stimulate parenchymal cells to divide and stimulate some specialized cells (e. Replacement of Lost Cells by Mitosis Soon after injury, cells adjacent to the damaged area enter the cell division cycle (Fig. As early as 2 to 4 hours after administration of a low dose of carbon tetrachloride to rats, the mitotic index in the liver increases dramatically, indicating that cells already in the G2 phase progress rapidly to the M phase. The mitotic activity of the hepatocytes culminates at 36 to 48 hours, after a full transit through the cycle, indicating that quiescent cells residing in G0 enter and progress to mitosis (M). Peak mitosis of nonparenchymal cells occurs later, after activation and replication of parenchymal cells. In some tissues, such as intestinal mucosa and bone marrow, stem cells first divide to provide self-renewal and then differentiate to replace more mature cells lost through injury. Stem cell-derived cells, called oval cells, are also located in the liver, in the bile ductules. As these cells produce -fetoprotein, the level of serum -fetoprotein correlates with improved outcome of acetaminophen-induced injury. Sequential changes in gene expression occur in the cells that are destined to divide. In rats subjected to partial hepatectomy to study the regeneration of the liver, oligonucleotide microarray analysis revealed that more than 150 genes involved in the early gene response with up or down-regulation (Su et al. The overexpressed genes include those that code for transcription factors important in proliferative signaling, such as c-fos, c-jun, Egr1, and c-myc (see Fig. Interestingly, some genes whose products decelerate the cell cycle also become temporarily overexpressed (e. The cell division cycle and the participating cyclins and cyclin-dependent protein kinases. Areas representing phases of the cycle are meant to be proportional to the number of cells in each phase. After receiving signals to divide, they progress into the G1 phase of the cell division cycle. G0 /G1 transition involves activation of immediate early genes so that cells acquire replicative competence. Mitosis (M) is the shortest phase of the cell cycle (approximately 40 min out of the 40-h-long cycle of hepatocytes) and most likely requires the largest energy expenditure per unit of time. The daughter cells produced may differentiate and enter into the pool of quiescent cells (G0 ), substituting for those which had been lost. During the cycle, the levels of various cyclins temporarily surge by synthesis and degradation (see figure). In addition to cyclines, phosphorylation also regulate the activity of Cdks: phosphorylation by Wee1 protein kinase inactivates Cdk 1 and Cdk 2, whereas dephosphorylation by cdc25 phosphatases activates them. After tissue necrosis, the number of cells entering the cell division cycle markedly increases at areas adjacent to the injury. The proportion of cells that are in S phase in a given period is reflected by the labeling index, whereas the percentage of cells under going mitosis is the mitotic index (see text). It has been speculated that the regenerative process is initiated by the release of chemical mediators from damaged cells. The nonparenchymal cells, such as resident macrophages and endothelial cells, are receptive to these chemical signals and produce a host of secondary signaling molecules, cytokines, and growth factors that promote and propagate the regenerative process (Fig. Cells presented are E = endothelial cells; G = granulocyte; H = hepatocyte; M = macrophage (Kupffer cell); S = stellate cell (also called perisinusoidal, Ito or fat-storing cell). Solid arrows represent effects of growth factors on cell division, whereas the dashed arrow shows the effect on extracellular matrix formation. This cytokine acts on these macrophages in an autocrine manner, activating its receptor (item 2 in Fig. This cytokine network promotes transition of the quiescent liver cells (G0 ) into cell cycle (G1 ) and makes them receptive to growth factors ("priming"). It is produced by resident macrophages and endothelial cells of various organs-including liver, lung, and kidney-and in a paracrine manner activates receptors on neighboring parenchymal cells (Fig. The communication between parenchymal and nonparenchymal cells during tissue repair is mutual. These among others, induce cyclins and the protein phosphatase cdc25, two groups of short-lived regulatory proteins. This in turn releases the transcription factor E2F, which induces enzymes and regulatory proteins needed for cell cycle progression (Fig. Although the cytotokine- and growth factor-controlled mitotic cell replacement is likely an essential part in the repair of most tissues built up of cells with proliferative capacity, there are also tissue specific features of tissue repair. Epithelia composed of a single cell layer form important barriers; therefore replacement of mortally injured epithelial cells, which become detached from the basement membrane, is an urgent need. This can be achieved more rapidly by cell migration than by mitotic cell replacement. For example, in the damaged mucosa of the gastrointestinal tract, cells of the residual epithelium rapidly migrate to the site of injury as well as elongate and thin to reestablish the continuity of the surface even before this could be achieved by cell replication. Normal mice exposed to dextran sodium sulfate in the drinking water develop diffuse colonic mucosal injury some exhibiting bloody diarrhea. Migration of the surviving cells also precedes mitotic cell replacement in the tubular epithelium of the injured kidney. Replacement of the Extracellular Matrix the extracellular matrix is composed of proteins, glycosaminoglycans, and the glycoprotein and proteoglycan glycoconjugates (Gressner, 1992). In liver, these molecules are synthesized by stellate or fat storing cells located in the space of Disse, between the hepatic sinusoid and the hepatocytes (Fig.
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In some European countries antibiotic 1338 discount flagyl 250mg mastercard, as a domestic remedy antimicrobial liquid soap order flagyl, the flax seeds are soaked overnight and the extract is used as a laxative virus que esta en santo domingo generic flagyl 200 mg on line, possibly exposing these individuals to cyanide from the linamarin (Rosling, 1993). Nervous System Historically, some of the most useful drugs have been plant-derived chemicals that act on the nervous system. However, some unintended serious neurotoxic syndromes may result from ingestion of certain plants. Epileptiform Seizures the parsley family of plants (Apiaceae) contains some of the most edible (e. The fleshy tubers of Cicuta maculata (water hemlock) may be mistaken for other edible wild tubers. Several members of the mint family (Labiatae) are noted for their essential oils, such as pennyroyal (Hedeoma), sage (Salvia), and hyssop (Hyssopus). Several species of Strychnos (Loganaceae) contain strychnine and brucine (dimethoxystrychnine). Cases of unintentional poisoning from seeds of Strychnos nux vomica have been reported (Wang et al. Seeds of Strychnos ignatii in the Phillipine islands have caused similar toxic effects. Excitatory Amino Acids Widely divergent species of plants produce amino acids that mimic the action of glutamate on the central nervous system. Most fast excitatory transmission in the mammalian brain is mediated by inotropic receptors for the amino acid, glutamate, on specialized neurons. Different types of glutamate receptors respond to different excitatory amino acids from plants, acting on one or more of these glutamate receptor subtypes. The consequence of ingestion of excitatory amino acids is excessive stimulation that may result in death of neurons. One of these acids, kainic acid, is present in the marine red alga Digenia simplex. The alga produces domoic acid, an analog of glutamate, as do several species of the marine diatom Nitzschia (Kotaki et al. Acute symptoms are gastrointestinal distress, headache, hemiparesis, confusion, and seizures. Prolonged effects are severe memory deficits and sensorimotor neuropathy (Teitelbaum et al. The fungus Amanita muscaria (fly agaric) got its name from its poisonous actions on flies. Poisoning from this woodland mushroom and from Amanita pantherian (panther agaric, common in western United States) is due to the content of the excitatory amino acid, ibotenic acid (isoxazole amino acid), and to its derivative, muscimol (Li and Oberlies, 2005). The effects are somewhat variable: central nervous system depression, ataxia, hysteria, and hallucinations. The content of ibotenic acid varies with the time of year; more has been reported in spring than in fall. Several other genera of fungi have hallucinogenic actions, notably Psilocybe, containing the indoles, psilocin, and psilocybin (Tsujikawa et al. The pea family (Leguminosae) contains several species that produce excitatory amino acids in the seeds. Willardiine [1-(2-amino2-carboxyethyl)pyrimidine-2,4-dione] has been isolated from Acacia willardiana, Acacia lemmoni, Acacia millefolia, and Mimosa asperata (Gmelin, 1961). Lathyrus sylvestris (flat pea) is a perennial indigenous to Europe and central Asia and naturalized in Canada and northern United States. An acute neurologic condition in sheep begins with weakness and progresses to tremors and prostration, sometimes with clonic movements and seizures (Rasmussen et al. Seeds of Lathyrus sativus (grass pea) are used as food in several countries, including India and Ethiopia. Affected individuals have corticospinal motor neuron degeneration with severe spastic muscle weakness and atrophy but little sensory involvement (Spencer et al. Motor Neuron Demyelination Paralysis develops from some toxins without primary excitation of neurons. Karwinskia humboldtiana, family Rhamnaceae, is a shrub of southwestern United States, Mexico, and Central America. Anthracenones are found in the seeds, the amount varying with stage of growth; green fruit may be more toxic than ripe fruit (Bermudez et al. The clinical syndrome that develops after a latency of several days is ascending flaccid paralysis, beginning with demyelination of large motor neurons in the legs and, in fatal cases, leading to bulbar paralysis (Martinez et al. In addition to neurotoxicity, the anthracenones in Karwinskia, especially peroxisomicine A2, [3,39-dimethyl-3,39,8,89,9,99-hexahydroxy-3,30,4,49-tetrahydro(7,10-bianthracene)-1,19-2H,29H -dione], causes lung atelectasis and emphysema and massive liver necrosis. Inhibition of catalase in peroxisomes has been proposed as the mechanism of cell toxicity (Martinez et al. The common name comes from the most obvious consequence of ingestion of locoweeds: aberrant behavior with hyperexcitability and locomotor difficulty. In animals dying from locoweed poisoning, there is cytoplasmic foamy vacuolation of cerebellar neurons. Inhibition of the Golgi enzyme results in abnormal brain glycoproteins and accumulation of mannose-rich oligosaccharides (Tulsiani et al. The pathology is not limited to the nervous system and the effects of swainsonine poisoning are found in several tissues. A species of the fungus Embellisia, an endophyte on locoweeds, may also produce swainsonine (McLainRomero et al. Parasympathetic Stimulation Several plant alkaloids affect the autonomic nervous system, mimicking the transmitter acetylcholine at autonomic ganglia (nicotinic receptors) or the peripheral endings of the parasympathetic system (muscarinic receptors). The postsynaptic receptors at terminations of the parasympathetic nerve fibers are called "muscarinic" after the selective stimulation of these receptors by muscarine, a quaternary ammonium furan, that was first extracted from the mushroom A. However, this mushroom contains only trace amounts of muscarine, and poisoning is due to its content of ibotenic acid. Some mushrooms of the genera Inocybe, Clitocybe, and Omphalatus contain significant amounts of muscarine, and consumption of toxic species causes diarrhea, sweating, salivation, and lacrimation, all referable to stimulation of parasympathetic receptors (de Haro et al. Parasympathetic Block the belladonna alkaloids (atropine, lhyoscyamine, and scopolamine), known for their block of muscarinic receptors, are found in several genera of Solanaceae, the nightshade family. Datura stramonium (jimson weed) is native to India and contains primarily scopolamine; Hyoscyamus niger (henbane) is native to Europe and contains primarily l-hyoscyamine; Atropa belladonna (deadly nightshade), also native to Europe, contains atropine; Duboisia myoporoides (pituri) in Australia contains l-hyoscyamine. The effects of modest doses of l-hyoscyamine or atropine are referable to muscarinic receptor block: tachycardia, dry mouth, dilated pupils, and decreased gastrointestinal motility.
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Histologic sections of a kidney reveal patchy necrosis of epithelial cells of both the proximal and distal tubules with flattening of the epithelial cells vyrus 987 c3 2v discount 250 mg flagyl otc, rupture of the basement membrane (tubulorrhexis) antibiotics used for lower uti buy flagyl 200mg amex, and marked interstitial edema bacteria in space buy flagyl amex. Acute pyelonephritis Acute tubular necrosis Chronic glomerulonephritis Chronic pyelonephritis Diffuse cortical necrosis Urinary System 363 344. The gross appearance of the kidney shown below is most compatible with which of the following conditions? Cystic renal dysplasia Acute pyelonephritis Chronic pyelonephritis Acute glomerulonephritis Chronic glomerulonephritis 345. During a routine physical examination, a 42-year-old female is found to have an elevated blood pressure of 150/100 mmHg. Further workup reveals that renal vein renin levels are increased on the left but decreased on the right. Atherosclerotic narrowing of the left renal artery Atherosclerotic narrowing of the right renal artery Fibromuscular hyperplasia of the left renal artery Fibromuscular hyperplasia of the right renal artery Hyaline arteriolosclerosis 364 Pathology 346. Which one of the following gross appearances of a kidney is most characteristic of malignant nephrosclerosis? Broad U-shaped cortical scars overlying dilated calyces in renal poles Depressed cortical areas overlying necrotic papillae of varying stages Multiple small petechial hemorrhages on the surface Multiple small white areas on the surface Wedge-shaped (i. The combination of severe acute flank pain and microscopic hematuria is suggestive of a. Cholelithiasis Choledocholithiasis Kidney tumor Urinary bladder tumor Urolithiasis Urinary System 365 348. The kidney shown in the photomicrograph below exhibits a tumor that originated in the upper pole. Clear cell carcinoma Signet cell carcinoma Small cell carcinoma Squamous cell carcinoma Transitional cell carcinoma 349. Which one of the listed individuals is most likely to have a tumor that has a histologic appearance characterized by undifferentiated mesenchymal cells with immature tubules and abortive glomerular formation? Physical examination of a 3-day-old male infant reveals urine leaking from the area of the umbilicus. Microscopic examination of the discharge reveals numerous neutrophils, but no bacteria are present. Which one of the following is the best diagnosis for this individual given only this information? Acute cystitis Acute prostatitis Gonococcal urethritis Interstitial cystitis Nongonococcal urethritis 352. A biopsy of the mucosa of the urinary bladder from an individual with acute cystitis due to infection with Escherichia coli would most likely reveal a. An infiltrate of lymphocytes and plasma cells An infiltrate of neutrophils Inflammation with eosinophils Noncaseating granulomas Sheets of macrophages with granular cytoplasm Urinary System 367 353. A 49-year-old male who is a long-term smoker presents with frequency and hematuria. Histologic examination of sections taken from an exophytic lesion of the urinary bladder reveal groups of atypical cells with frequent mitoses forming finger-like projections that have thin, fibrovascular cores. These groups of atypical cells do not extend into the lamina propria and muscularis. Bicarbonate levels in metabolic acidosis are <21 mM, while those in metabolic alkalosis are >28 mM. In metabolic acidosis, increased serum acid (increased hydrogen ion concentration) causes a decrease in serum pH and a decrease in serum bicarbonate concentration. The causes of metabolic acidosis are broken down clinically into two groups: those with a normal anion gap and those with an increased anion gap. A normal anion gap metabolic acidosis may result from either loss of bicarbonate (diarrhea) or loss of renal regeneration of bicarbonate, seen with renal tubular acidosis type 1 (decreased excretion of titratable acid, i. The body also compensates through renal mechanisms that increase H+ excretion and increase bicarbonate reabsorption. Causes of metabolic alkalosis include vomiting (losing gastric acid), increased aldosterone secretion (which causes increased [H+] excretion by the kidneys), and certain diuretics. Causes of respiratory alkalosis include diseases or states that cause hypoxemia (such as living at high altitude), psychogenic causes, and ingestion of salicylates (which can cause a mixed respiratory alkalosis and metabolic acidosis). The fetus swallows amniotic fluid (about 400 mL/day), and 370 Pathology then absorbs it in the respiratory and digestive tracts. Waste products cross the placental membrane and enter maternal blood in the intervillous space. The oligohydramnios leads to characteristic facial features that include wide-set eyes; low-set, floppy ears; and a broad, flat nose. In two types of cystic renal disease, the numerous cysts are found in both the cortex and medulla. These two types of polycystic disease of the kidney are the infantile type and the adult type. Adult polycystic kidney disease typically presents in adulthood and has an autosomal dominant inheritance pattern. Histologically, the cysts are lined by tubular epithelium, while the stroma between the cysts is normal. Adult polycystic renal disease is associated with liver cysts and berry aneurysms, which may rupture and cause a subarachnoid hemorrhage. About one-half of patients with adult polycystic renal disease eventually develop uremia. Infantile polycystic kidney disease typically presents in newborns, has an autosomal recessive pattern of inheritance, and is associated with hepatic cysts (microhamartomas) and congenital hepatic fibrosis. Medullary sponge kidney is usually asymptomatic, is not familial, and is characterized by normal-sized kidneys with small cysts in the renal papillae. In medullary cystic disease complex (nephronophthisis), kidneys are small and sclerotic with multiple cysts at the corticomedullary junction. Individuals with this abnormality present in the first two decades of life with salt-wasting polyuria and progressive renal failure. Most cases are familial and display both recessive and dominant inheritance patterns. Two other types of cysts that are not limited to the medulla are simple cysts and acquired cysts. Simple cortical cysts are single, unilateral cysts, found in adults, that are benign. Patients are usually asymptomatic, but they may present with microscopic hematuria. Acquired polycystic renal disease is Urinary System Answers 371 associated with chronic renal dialysis. Nephrotic syndrome is characterized by marked proteinuria, that is, proteinuria greater than 3. Because of this marked proteinuria, patients lose albumin (hypoalbuminemia), which leads to peripheral edema.
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The first meiotic division occurs within the ovary just before ovulation virus que crea accesos directos generic flagyl 250mg amex, and the second occurs just after the sperm fuses with the egg horse antibiotics for dogs order flagyl cheap. Before separation antibiotics for acne how long should i take it order flagyl on line amex, the homologous pairs of chromosomes exchange genetic material by a process known as crossing over. Subsequent meiotic stages distribute the members of the tetrads to the daughter cells in such a way that each cell receives the haploid number of chromosomes. At telophase, one secondary oocyte and a polar body have been formed, which are no longer genetically identical. The secondary oocyte enters the next cycle of division very rapidly; each chromosome splits longitudinally; the ovum and the three polar bodies now contain the haploid number of chromosomes and half the amount of genetic material. Although the nuclei of all four eggs are equivalent, the cytoplasm is divided unequally. The end products are one large ovum and three rudimentary ova (polar bodies), which subsequently degenerate. The ovum is released from the ovary at the secondary oocyte stage; the second stage of meiotic division is triggered in the oviduct by the entry of the sperm. Although ovarian weight, unlike uterine weight, in the rat does not fluctuate during the estrous cycle, ovarian weight and histology can provide very useful information about the effects of toxicants on the female reproductive system. Toxicants affect ovarian histology inducing a variety of lesions, including polyovular follicles, oocyte depletion, interstitial cell hyperplasia, corpora albanicans, and absence of corpora lutea, for example. In addition, ovarian tissue can be cultured ex vivo after in vivo treatment or in vitro at different stages of the estrous cycle or during pregnancy to assess their steroidogenic capacity (Berman and Laskey, 1993; Calafat et al. Case Study-Busulphan the drug busulfan is an alkylating agent used to treat several diseases in humans including chronic myelogenous leukemia, certain myeloproliferative disorders such as severe thrombocytosis and polycythemia vera and busulfan is also used in combination with other drugs to treat myelofibrosis. Busulfan has been used in very high doses and in combination with other drugs to destroy the bone marrow in preparation for a bone marrow transplant. Busulfan may interfere with the normal menstrual cycles in women and block sperm production in men. In addition, busulfan causes ovarian failure and prevents or delays the onset of puberty in girls. In the rat, busulfan produces a similar profile of reproductive effects, the most dramatic occuring in utero. In rodents, endocrine function during adulthood can be altered by prenatal exposure to fetal germ cell toxicants. The ovary of the treated female offspring, lacking oocytes, developing follicles (the source of most serum estradiol) or corpora lutea (the major source of progesterone) fails to produce sex hormones. The most severely affected females do not display estrous cycles or spontaneous sexual behavior as a consequence of this effect. In addition to these reproductive effects, brain weight was reduced in both sexes all dosage groups, even though body and other nonreproductive organ weights were only affected in the high-dose group (10 mg). Even though the gonads of both sexes were affected at similar dosage levels, fertility and gonadal hormone production were much more easily disrupted in female than male offspring, because the steroid producing cells in the ovary fail to differentiate in the absence of the oocyte. In the male, Leydig cell numbers and steroidogenesis are not so dependent upon normal gametogenesis. Hence, the lack of oocytes in the female progeny results in a lack of estrous cyclicity and the spontaneous display of female mating behavior at proestrus. However, this classification is of little import because in their absence, ovarian thecal and granulosa cell endocrine functions are severely impaired. In addition to busulfan, several environmental chemicals have been shown to disrupt ovarian development and oocyte numbers in the rat or mouse. Low levels of occupational exposure have been measured during the production and use of 1,3-butadiene. A diagrammatic representation of the sites of actions of female reproductive toxicants is presented in Fig. Ovarian Cycle the cyclic release of pituitary gonadotropins involving the secretion of ovarian progesterone and estrogen is depicted in Fig. These female sex steroids determine ovulation and prepare the female accessory sex organs to receive the male sperm. Sperm, ejaculated into the vagina, must make their way through the cervix into the uterus, where they are capacitated. The conceptus then returns from the oviducts to the uterus and implants into the endometrium. This axis can be disrupted, resulting in infertility at any level of the endocrine system. Postovarian Processes Female accessory sex organs function to bring together the ovulated ovum and the ejaculated sperm. The chemical composition and viscosity of reproductive tract fluids, as well as the epithelial morphology of these organs, are controlled by ovarian (and trophoblastic) hormones (see Fig. Oviducts the oviducts provide the taxis of the fimbria, which is under muscular control. The involvement of the autonomic nervous system in this process, as well as in oviductal transport of both the male and female gametes, raises the possibility that drugs known to alter the autonomic nervous system may alter function and therefore fertility. The progression of the fertilized eggs through the oviduct and uterus is under hormonal regulation and chemicals like the estrogens can stimulate oviductal transport and interfere with uterine endometrial function, precluding implantation (Cummings and Perreault, 1990). Uterine weight and fluid content increase many folds during proestrus under the influence of estrogen. The vaginal cytology also changes daily throughout the estrous cycle and this can be monitored by examining the cytology of the cells sloughed from the vaginal epithelium into the lumen with daily vaginal lavages. Uterine weight is a very useful index of estrogenicity in the immature or adult ovariectomized female rat. Since uterine weight and histology fluctuate greatly during the estrous cycle, studies which necropsy females at different stages of the cycle will often be too variable to detect anything but the most profound effects on these endpoints, but nonetheless it can still be a useful endpoint and should be measured. A single vaginal lavage, taken at necropsy could be used as a covariate to analyze for treatment effects. Uterus Uterine endometrium reflects the cyclicity of the ovary as it is prepared to receive the conceptus. In primates, at the end of menstruation, all but the deep layers of the endometrium are sloughed. Under the influence of estrogens from the developing follicle, the endometrium increases rapidly in thickness. After ovulation, the endometrium becomes slightly edematous, and the actively secreting glands become tightly coiled and folded under the influence of estrogen and progesterone from the corpus luteum. When fertilization fails to occur, the endometrium is shed and a new cycle begins. In considering these processes there are numerous potential targets for the action of chemicals upon the system (see Fig. So for example, there are a number of examples of nutritional deficits (and overexposures) of critical vitamins and minerals (e.
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Tetracyclines have chelating property-form insoluble and unabsorbable complexes with calcium and other metals klebsiella oxytoca antibiotic resistance buy 250 mg flagyl. Milk light antibiotics for acne buy 400 mg flagyl fast delivery, iron preparations infection lung flagyl 250 mg generic, nonsystemic antacids and sucralfate reduce their absorption. Administration of these substances and tetracyclines should be staggered, if they cannot be avoided altogether. Tetracyclines are widely distributed in the body (volume of distribution > 1 L/kg). They are concentrated in liver, spleen and bind to the connective tissue in bone and teeth. Most tetracyclines are primarily excreted in urine by glomerular filtration; dose has to be reduced in renal failure; doxycycline is an exception to this. They are partly metabolized and significant amounts enter bile-some degree of enterohepatic circulation occurs. Administration Oral capsule is the dosage form in which tetracyclines are most commonly administered. Odynophagia and esophageal ulceration has occurred by release of the material from capsules in the esophagus during swallowing, especially with doxycycline. Intramuscular injection of tetracyclines is very painful; thrombophlebitis of the injected vein can occur, especially on repeated i. Tetracyclines are risky in pregnant women; can precipitate acute hepatic necrosis which may be fatal. A reversible Fanconi syndrome like condition is produced by outdated tetracyclines. This is caused by degraded products-epitetracycline, anhydrotetracycline and epianhydrotetracycline which damage proximal tubules. Phototoxicity A sunburn-like or other severe skin reaction on exposed parts is seen in some individuals. Given from midpregnancy to 5 months of extrauterine life, the deciduous teeth are affected: brown discolouration, ill-formed teeth which are more susceptible to caries. Tetracyclines given between 3 months and 6 years of age affect the crown of permanent anterior dentition. Given during late pregnancy or childhood, tetracyclines can cause temporary suppression of bone growth. The ultimate effect on stature is mostly insignificant, but deformities and reduction in height are a possibility with prolonged use. Antianabolic effect Tetracyclines reduce protein synthesis and have an overall catabolic effect. Empirical therapy Tetracyclines are often employed when the nature and sensitivity of the infecting organism cannot be reasonably guessed. However, they are not dependable for empirical treatment of serious/life-threatening infections. They may also be used for initial treatment of mixed infections, although a combination of -lactam and an aminoglycoside antibiotic or a third generation cephalosporin or a fluoroquinolone are now preferred. Vestibular toxicity Minocycline can cause ataxia, vertigo and nystagmus, which subside when the drug is discontinued. Skin rashes, urticaria, glossitis, pruritus ani and vulvae, even exfoliative dermatitis have been reported. Superinfection Tetracyclines are frequently responsible for superinfections, because they cause more marked suppression of the resident flora. Though mouth, skin or vagina may be involved, intestinal superinfection by Candida albicans is most prominent (for details see p. Higher doses suppress the flora more completely-greater chance of superinfection: doses on the lower side of the range should be used whenever possible. The tetracycline should be discontinued at the first sign of superinfection and appropriate therapy instituted. Doxycycline and minocycline are less liable to cause diarrhoea, because only small amounts reach the lower bowel in the active form. They should be avoided in patients on diuretics: blood urea may rise in such patients. They are preferred for blind/mass treatment of suspected cases during an epidemic, though streptomycin often acts faster. Tetracyclines are second choice drugs: (a) To penicillin/ampicillin for tetanus, anthrax, actinomycosis and Listeria infections. Weekly doxycycline (200 mg) has been used as prophylactic in subjects at risk during an epidemic. Other situations in which tetracyclines may be used are: (a) Urinary tract infections: Odd cases in which the organism has been found sensitive. Tigecycline It is the first member of a new class of synthetic tetracycline analogues (glycyl-cyclines) which are active against most bacteria that have developed resistance to the classical tetracyclines. Tigecycline is active against most grampositive and gram-negative cocci and anaerobes, including tetracycline resistant strains of Strep. The lack of cross resistance between the two groups is mainly because the tetracycline efflux pumps acquired by many resistant bacteria have low affinity for tigecycline and are unable to pump it out. In other resistant bacteria, the ribosomal protection protein against tetracycline is less active in protecting the ribosomal binding site from tigecycline. Thus, the two most important mechanisms of tetracycline resistance do not operate against tigecycline. It is eliminated mainly in the bile; dose adjustment is not needed in renal insufficiency. It is not recommended for hospital acquired/ ventilator-associated chest infections, because in a comparative trial, all cause mortality was higher in tigecycline group than in the comparator group receiving other antibiotics. It is also not suitable for urinary tract infection, because only low concentrations are attained in urine. The clinical efficacy of tigecycline in other infective conditions is still to be established. It specifically attaches to the 50S ribosome near the acceptor (A) site and prevents peptide bond formation between the newly attached aminoacid and the nascent peptide chain (see Fig. Antimicrobial spectrum Chloramphenicol is primarily bacteriostatic, though high concentrations have been shown to exert cidal effect on some bacteria, e. It is a broad-spectrum antibiotic, active against nearly the same range of organisms (gram-positive and negative cocci and bacilli, rickettsiae, mycoplasma) as tetracyclines. Notable differences between these two are: (a) Chloramphenicol was highly active against Salmonella including S. Like tetracyclines, it is ineffective against Mycobacteria, Pseudomonas, many Proteus, viruses and fungi. Resistance Most bacteria are capable of developing resistance to chloramphenicol, which generally emerges in a graded manner, as with tetracyclines.
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Potassium iodide is secreted by bronchial glands and can irritate the airway mucosa antibiotics for uti didn't work 200mg flagyl visa. Acetylcysteine It opens disulfide bonds in mucoproteins present in sputum-makes it less viscid antibiotic eye drops over the counter discount 400 mg flagyl overnight delivery, but has to virus 68 ny order flagyl without prescription be administered directly into the respiratory tract. A variety of expectorant formulations containing an assortment of the above ingredients, often in combination with antitussives/antihistaminics are marketed and briskly promoted, but objective evidence of efficacy of these is non-conclusive. Steam inhalation and proper hydration may be more helpful in clearing airway mucus. Mucolytics Bromhexine A derivative of the alkaloid vasicine obtained from Adhatoda vasica (Vasaka), is a potent mucolytic and mucokinetic, capable of inducing thin copious bronchial secretion. It depolymerises mucopolysaccharides directly as well as by liberating lysosomal enzymes-network of fibres in tenacious sputum is broken. Side effects are rhinorrhoea and lacrimation, nausea, gastric irritation, hypersensitivity. It may break gastric mucosal barrier; is contraindicated in peptic ulcer patients. It is available in combination with amoxicillin or cephalexin for treatment of bronchitis, bronchiectasis, sinusitis, etc. Ambroxol A metabolite of bromhexine having similar mucolytic action, uses and side effects. Because they aim to control rather than eliminate cough, antitussives should be used only for dry nonproductive cough or if cough is unduly tiring, disturbs sleep or is hazardous (hernia, piles, cardiac disease, ocular surgery). Side effect: Dizziness, nausea, drowsiness; at high doses hallucinations and ataxia may occur. It is a common ingredient of many proprietary cough formulations (see antitussive combinations below). Codeine is regarded as the standard antitussive; suppresses cough for about 6 hours. The antitussive action is blocked by naloxone indicating that it is exerted through opioid receptors in the brain. At higher doses respiratory depression and drowsiness can occur, especially in children. Like morphine, it is contraindicated in asthmatics and in patients with diminished respiratory reserve; should be avoided in children. Chlophedianol It is a centrally acting antitussive with slow onset and longer duration of action. Antihistamines Many H1 antihistamines have been conventionally added to antitussive/expectorant formulations (see below). They afford relief in cough due to their sedative and anticholinergic actions, but lack selectivity for the cough centre. They have no expectorant property, may even reduce secretions by anticholinergic action. They have been specially promoted for cough in respiratory allergic states, though their lack of efficacy in asthma is legendary. Peripherally acting antitussives Prenoxdiazine In contrast to other antitussives, it acts peripherally; desensitizes the pulmonary stretch receptors and reduces tussal impulses originating in the lungs. Though an old drug developed in Hungary, it has been introduced recently in India. Ethylmorphine It is closely related to codeine which is methylmorphine, and has antitussive, respiratory depressant properties like it, but is believed to be less constipating. Nonopioids Noscapine (Narcotine) An opium alkaloid of the benzoisoquinoline series (see Ch. It depresses cough but has no narcotic, analgesic or dependence inducing properties. It is nearly equipotent antitussive as codeine, especially useful in spasmodic cough. Dextromethorphan does not depress mucociliary function of the airway mucosa and is practically devoid of constipating action. The antitussive action of Bronchodilators Bronchospasm can induce or aggravate cough. Bronchodilators relieve cough in such individuals and improve the effectiveness of cough in clearing secretions by increasing surface velocity of airflow during the act of coughing. They should be used only when an element of bronchoconstriction is present and not routinely. Their fixed dose combinations with antitussives are not satisfactory because of differences in time course of action of the components and liability for indiscriminate use. Fixed dose combinations of a centrally acting antitussive with a bronchodilator or with an antihistaminic having high atropinic activity have been banned in India, but many are still marketed. Though it has been shown to reduce experimentally induced cough in healthy volunteers, there is no evidence of benefit in pathological cough. Asthma is now recognized to be a primarily inflammatory condition: inflammation underlying hyperreactivity. An allergic basis can be demonstrated in many adult, and higher percentage of pediatric patients. In others, a variety of trigger factors (infection, irritants, pollution, exercise, exposure to cold air, psychogenic) may be involved: Extrinsic asthma: It is mostly episodic, less prone to status asthmaticus. These mediators together constrict bronchial smooth muscle, cause mucosal edema, hyperemia and produce viscid secretions, all resulting in reversible airway obstruction. The inflammation perpetuates itself by cell-to-cell communication and recruitment of more and more inflammatory cells. Bronchial smooth muscle hypertrophy, increase in the population of mucus secreting cells and blood vessels occurs over time and damage to bronchial epithelium accentuates the hyperreactivity. Loss of bronchiolar elasticity leads to closure of smaller air tubes during expiration. The airway obstruction is accentuated during exercise causing shortness of breath. The expiratory airflow limitation does not fluctuate markedly over long periods of time, but there are exacerbations precipitated by respiratory infections, pollutants, etc. It is clearly related to smoking and characteristically starts after the age of 40. Methylxanthines: Theophylline (anhydrous), Aminophylline, Choline theophyllinate, Hydroxyethyl theophylline, Theophylline ethanolate of piperazine, Doxophylline. Inhalational: Beclomethasone dipropionate, Budesonide, Fluticasone propionate, Flunisolide, Ciclesonide. Since 2 receptors on inflammatory cells desensitize quickly, the contribution of this action to the beneficial effect of 2 agonists in asthma where airway inflammmation is chronic, is uncertain, and at best minimal. Though adrenaline (1+2+ receptor agonist) and isoprenaline (1+2 agonist) are effective bronchodilators, it is the selective 2 agonists that are now used in asthma to minimize cardiac side effects.
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Reiter syndrome is characterized by the triad of arthritis antibiotics for canine ear infection flagyl 400 mg on-line, urethritis antibiotic resistance review cheap 400mg flagyl with mastercard, and conjunctivitis antibiotics for acne with no side effects order flagyl 500 mg on line. Due to hyperuricemia; related to overproduction or decreased excretion of uric acid 1. Leukemia and myeloproliferative disorders-Increased cell turnover leads to hyperuricemia. Development of tophi-white, chalky aggregates of uric acid crystals with fibrosis and giant cell reaction in the soft tissue and joints (Fig. Laboratory findings include hyperuricemia; synovial fluid shows needle-shaped crystals with negative birefringence under polarized light (Fig. Bilateral proximal muscle weakness; distal involvement can develop late in disease. Degenerative disorder characterized by muscle wasting and replacement of skeletal muscle by adipose tissue B. Dystrophin is important for anchoring the muscle cytoskeleton to the extracellular matrix. Mutations are often spontaneous; large gene size predisposes to high rate of mutation. Presents as proximal muscle weakness at 1 year of age; progresses to involve distal m us des i. Death results from cardiac or respiratory failure; myocardium is commonly involved. Autoantibodies against the postsynaptic acetylcholine receptor at the neuromuscular junction B. Muscle weakness that worsens with use and improves with rest; classically involves the eyes, leading to ptosis and diplopia 2. Arises as a paraneoplastic syndrome, most commonly due to small cell carcinoma of the lung C. Malignant tumor of skeletal muscle Most common malignant soft tissue tumor in children Rhabdomyoblast is the characteristic cell; desmin positive Most common site is the head and neck; vagina is the classic site in young girls. Dermis consists of connective tissue, nerve endings, blood and lymphatic vessels, and adnexal structures (e. Pruritic, erythematous, oozing rash with vesicles and edema; often involves the face and flexor surfaces B. Treatment involves removal of the offending agent and topical glucocorticoids, if needed. Comedones (whiteheads and blackheads), pustules (pimples), and nodules; extremely common, especially in adolescents B. Hormone-associated increase in sebum production (sebaceous glands have androgen receptors) and excess keratin production block follicles, forming comedones. Propionibacterium acnes infection produces lipases that break down sebum, releasing proinflammatory fatty acids; results in pustule or nodule formation C. Well-circumscribed, salmon-colored plaques with silvery scale, usually on extensor surfaces and the scalp (Fig. Parakeratosis (hyperkeratosis with retention of keratinocyte nuclei in the stratum corneum) 3. Thinning of the epidermis above elongated dermal papillae; results in bleeding when scale is picked off (Auspitz sign) E. Acantholysis (separation) of stratum spinosum keratinocytes (normally connected by desmosomes) results in suprabasal blisters. Thin-walled bullae rupture easily (Nikolsky sign), leading to shallow erosions with dried crust. Autoimmune destruction ofhemidesmosomes between basal cells and the underlying basement membrane B. Presents as an elevated nodule with a central, ulcerated crater surrounded by dilated (telangiectatic) vessels (Fig. Malignant proliferation of squamous cells characterized by formation of keratin pearls. Additional risk factors include immunosuppressive therapy, arsenic exposure, and chronic inflammation (e. Presents as an ulcerated, nodular mass, usually on the face (classically involving the lower lip) D. Actinic keratosis is a precursor lesion of squamous cell carcinoma and presents as a hyperkeratotic, scaly plaque, often on the face, back, or neck. Melanocytes are responsible for skin pigmentation and are present in the basal layer of the epidermis. May involve the eyes (ocular form) or both the eyes and skin (oculocutaneous form) D. Begins as nests of melanocytes at the dermal-epidermal junction (junctional nevus); most common mole in children 2. Junctional component is eventually lost resulting in an intradermal nevus, which is the most common mole in adults. Characterized by a flat macule or raised papule with symmetry, sharp borders, evenly distributed color, and small diameter(< 6 mm) E. Radial growth horizontally along the epidermis and superficial dermis; low risk of metastasis 2. Increased risk of metastasis; depth of extension (Breslow thickness) is the most important prognostic factor in predicting metastasis. Superficial spreading-most common subtype; dominant early radial growth results in good prognosis. Lentigo maligna melanoma-lentiginous proliferation (radial growth); good prognosis 3. Presents as erythematous macules that progress to pustules, usually on the face; rupture of pustules results in erosions and dry, crusted, honey-colored serum. Deeper (dermal and subcutaneous) infection, usually due to S au reus or S pyogenes B. Sloughing of skin with erythematous rash and fever; leads to significant skin loss B. Due to S aureus infection; exfoliative A and B toxins result in epidermolysis of the stratum granulosum. Firm, pink, umbilicated papules due to poxvirus; affected keratinocytes show cytoplasmic inclusions (molluscum bodies, Fig. Klinefelter syndrome, 153, 176 Knudson two-hit hypothesis, 27 Krabbe disease, 182 K-ras oncogene, 112 Krukenberg tumor, 106, 147 Kussmaul respirations, 167 Lobar pneumonia, 87, 881 Lobular carcinoma in situ, 175 Locked in syndrome, 184 Loeffler syndrome, 83 Lower urinary tract carcinoma, 135 Lumbar puncture, 180 Inflammatory dermatoses, 201-202 Influenza virus, 88! Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Your right to use the work may be terminated if you fail to comply with these terms.