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The atypical antipsychotics, except risperidone, do not appreciably raise prolactin levels. Like other drugs of the class, it benefits both positive and negative symptoms of schizophrenia, but is rated less effective than clozapine. Extrapyramidal side effects are less prominent than with typical neuroleptics, but more than clozapine. Zotepine lowers seizure threshold and incidence of seizures is increased at high doses. Zotepine is available in India for use in schizophrenia, but does not offer any specific advantage. Metabolic effects Elevation of blood sugar and triglyceride levels as a consequence of chronic therapy with certain antipsychotics is a major concern now. High potency drugs like trifluperazine, fluphenazine, haloperidol and atypical antipsychotics like risperidone, aripiprazole and ziprasidone have low/no risk. The mechanism of this effect is not clear; may be due to weight gain and/or accentuation of insulin resistance. Cardiovascular mortality among schizophrenics is higher; increased use of atypical antipsychotics may be a contributory factor. Extrapyramidal disturbances these are the major dose-limiting side effects; more prominent with high potency drugs like fluphenazine, haloperidol, pimozide, etc. If that is not possible, one of the anticholinergic antiparkinsonian drugs may be given concurrently. Though quite effective, routine combination of the anticholinergic from the start of therapy in all cases is not justified, because they tend to worsen memory and impair intellect, in addition to dry mouth and urinary retention. It is more common in children below 10 years and in girls, particularly after parenteral administration; overall incidence is 2%. The mechanism of this complication is not understood; no specific antidote is available. A central anticholinergic may reduce the intensity in some cases; but a benzodiazepine like clonazepam or diazepam is the first choice treatment of the motor restlessness. Most patients respond to reduction in dose of the neuroleptic or changeover to an atypical antipsychotic like quetiapine. Though, antidopaminergic action of the neuroleptic may be involved in the causation of this syndrome; anticholinergics are of no help.
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By the end of 2007, 171 (of which two in part of the country) member states had introduced hepatitis B vaccine into their routine immunization programme compared to 31 Member States in 1992, the year of the World Health Assembly resolution recommending global vaccination against hepatitis B . This has to do with the lack or partial introduction of hepatitis B vaccination in large population countries. One hundred and seventy eight (92%) member states introduced hepatitis B vaccination by the end of 2008. However, whereas much progress has been made with the routine use of hepatitis B vaccine, this has taken 15 years since the World Health Assembly recommended its universal use. A similar time lag is unfortunately being experienced with Haemophilus influenzae type b (Hib) vaccine, for which global coverage remains low at 26% in 2007 (Figure 4). One hundred and thirty five states (70%) introduced Hib vaccination by the end of 2008 and a further nine countries are expected to introduce the vaccine before the end of 2009. This pooled procurement mechanism has helped supply nearly 40 countries with a range of affordable quality vaccines and syringes for over 30 years. These developments are accompanied by member states increasing uptake of newly licensed vaccines against rotavirus diarrhoea and human papillomavirus infection and of the pneumococcal conjugate vaccine. This marks the first time that the introduction of a vaccine has occurred simultaneously in both developed and developing countries. By the end of 2008, pneumococcal conjugate vaccine was in universal use in 21 countries (four with partial introduction). In addition, vaccines against human papillomavirus infection could prevent nearly 250,000 annual deaths of women from cervical cancer. The introduction of new vaccines poses challenges to the existing logistics and cold chain requirements due to their current presentations. In particular, the high volume of the pre-filled glass syringe presentation of the 7-valent pneumococcal conjugate vaccine is exceeding the central cold chain storage capacity of some countries and the safe use and disposal of used glass syringes and needles poses a waste management challenge. These issues are being addressed through assistance to countries to improve vaccine and waste management and through interaction with industry to seek more suitable formulations and presentations of new vaccines. Many activities are also ongoing in the area of surveillance of diseases targeted by new vaccines including enhanced laboratory networks and centres of excellence. Work has begun on the implementation of this action plan, including the development of strategic options to support the introduction of more expensive new vaccines in low middle-income countries. First is the need to develop integrated strategies, whereby immunization is implemented as one element of a comprehensive approach to disease control, be it meningitis/pneumonia control, diarrhoeal diseases control, cancer control or epidemic/pandemic prevention and control. Second, the delivery of routine immunization must be seen by all as the basis and the foundation of immunization programmes and must be given attention and dedicated resources. Indeed, reaping the full potential of immunization and including the full benefit of new vaccines can only occur with increasing overall protection and reducing coverage inequities. More vaccines will soon become available on a large scale for use, among others, against meningococcal diseases, Japanese encephalitis and typhoid [22-24]. In addition, governments, multilateral agencies, foundations, and research institutions, among others, have substantially increased their investment in the development of new vaccines.
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Hugo P, Bernier J, Krzystyniak K, Fournier M: Transient inhibition of mixed lymphocyte reactivity by dieldrin in mice. Jirova D, Sperlingova I, Halaskova M, Bendova H, Dabrowska L: Immunotoxic effects of carbon tetrachloride-the effect on morphology and function of the immune system in mice. Kalland T: Alterations of antibody response in female mice after neonatal exposure to diethylstilbestrol. Kim J, Jeong H: Suppression of inducible nitric oxide synthase and tumor necrosis a expression by bisphenol A via nuclear factor-B inactivation in macrophages. Krzystyniak K, Hugo P, Flipo D, Fournier M: Increased susceptibility to mouse hepatitis virus 3 of peritoneal macrophages exposed to dieldrin. Lemarie A, Morzadec C, Merino D, Micheau O, Fardel O, Vernhet L: Arsenic trioxide induces apoptosis of human monocytes during macrophagic differentiation through nuclear factor-kappaB-related survival pathway down-regulation. Maurice T and Romieu P: Involvement of the sigma1 receptor in the appetitive effects of cocaine. Pathak N, Khandelwal S: Oxidative stress and apoptotic changes in murine splenocytes exposed to cadmium. Patterson R, Vega L, Trouba K, Bortner C, Germolec D: Arsenic-induced alterations in the contact hypersensitivity response in Balb/c mice. Ritz B, Heinrich J, Wjst M, Wichmann E, Krause C: Effect of cadmium body burden on immune response of school children. Rodgers K, Klykken P, Jacobs J, Frondoza C, Tomazic V, Zelikoff J: Immunotoxicity of medical devices. Sinigaglia F, Scheidegger D, Garotta G, Scheper R, Pletscher M, Lanzavecchia A: Isolation and characterization of Ni-specific T cell clones from patients with Ni-contact dermatitis. Tarkowski M, Lutz W, Birindelli S: the lymphocytic cholinergic system and its modulation by organophosphorus pesticides. Thomsen M, Yacoub-Youssef H, Marcheix B: Reconstitution of a human immune system in immunodeficient mice: models of human alloreaction in vivo. Van Loveren H, Piersma A: Immunotoxicological consequences of perinatal chemical exposures. Veldman C, Nagel A, Hertl M: Type I regulatory T cells in autoimmunity and inflammatory diseases. Vial T, Choquet-Kastylevsky G, Descotes J: Adverse effects of immunotherapeutics involving the immune system. Suppression of thymusdependent immune responses and of parameters of nonspecific resistance after short-term exposure. Xu D, Liu H, Komai-Koma M: Direct and indirect role of Toll-like receptors in T cell mediated immunity. As a consequence, liver cells are exposed to significant concentrations of these chemicals, which can result in liver dysfunction, cell injury, and even organ failure. In the pharmaceutical industry, adverse effects on the liver are one of the most frequently cited reasons for discontinuing the development of drug candidates. In addition, hepatotoxicity recognized during the postmarketing phase is one of the main causes for withdrawing drugs from the market (Temple and Himmel, 2002).
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Consequently, as illustrated by the comparative absorption of malathion across different human skin sites (Table 5-7), toxicants are likely to readily cross scrotal skin, whereas absorption across forehead skin is less extensive, and penetration across the palm is lowest because of the thickness of the stratum corneum and the lack of dermal appendages. The second phase of percutaneous absorption consists of diffusion of the toxicant through the lower layers of the epidermis (stratum granulosum, spinosum, and germinativum) and the dermis. Despite possessing tight intercellular junctions, these cell layers are far inferior to the stratum corneum as diffusion barriers. In contrast to the stratum corneum, they contain a porous, nonselective, aqueous diffusion medium. Toxicants pass through this area by diffusion and enter the systemic circulation through the numerous venous and lymphatic capillaries in the dermis. The rate of diffusion depends on Table 5-7 Absorption of Malathion Across Different Human Skin Regions anatomical region Scrotum Forehead Hand (back) Palm Figure 5-7. There are several factors that can influence the absorption of toxicants through the skin, including: (1) the integrity of the stratum corneum, (2) the hydration state of the stratum corneum, (3) temperature, (4) solvents as carriers, and (5) molecular size. Because the stratum corneum plays a critical role in determining cutaneous permeability, removal of this layer causes a dramatic increase in the permeability of the epidermis for a variety of large or small molecules, both lipid-soluble and water-soluble (Poet and McDougal, 2002). Caustic agents such as acids and alkalis that damage the stratum corneum increase its permeability. The most frequently encountered penetration-enhancing damage to the skin results from burns and various skin diseases. Under normal conditions, the stratum corneum is partially hydrated, containing about 7% water by weight. This amount of water increases the permeability of the stratum corneum approximately 10-fold over the permeability that exists when it is completely dry. On contact with water, the stratum corneum can increase its weight of tightly bound water up to fivefold, and this can increase permeability an additional twoto threefold. In many studies, the site of application will be covered with plastic wrap (occlusive application), as originally described by Draize et al. Similarly, an increase in temperature will increase dermal penetration by increasing dermal blood flow. This is particularly important for occupational exposures to agents such as insecticides in which agricultural workers are likely to be working strenuously at relatively high temperatures. Such environmental conditions increase dermal penetration and may increase the risk of systemic toxicity. Solvents used to dissolve compounds of interest can also influence dermal penetration. In general, lower absorption will be observed if a toxicant is highly soluble in the vehicle, whereas low solubility of the toxicant in the vehicle will tend to increase dermal penetration. Finally, it is generally recognized that compounds with molecular weights greater than 400 Da will exhibit poor dermal penetration.
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Syphilitic meningitis is characterized by perivascular infiltrates of lymphocytes and plasma cells that cause obliterative endarteritis and meningeal fibrosis. Tabes dorsalis is the result of degeneration of the posterior columns of the spinal cord. This is caused by compression atrophy of the posterior spinal sensory nerves, which produces impaired joint position sensation, ataxia, loss of pain sensation (leading to joint damage, i. The virus is transmitted through peripheral nerves to the brain, where it forms characteristic inclusions within neurons (Negri bodies). Symptoms related to destruction of neurons in the brainstem include irritability, difficulty in swallowing and spasms of the throat (these two resulting in "hydrophobia"), seizures, and delirium. Poliomyelitis is caused by an enterovirus that produces a nonspecific gastroenteritis and then secondarily invades the anterior horn motor neurons of the spinal cord, where it causes muscular paralysis. Microscopy reveals characteristic neuronophagia of anterior horn neurons; the dorsal roots are not affected. Infection causes acute muscular paralysis (atrophy, fasciculations, fibrillation, and hyporeflexia). Postpolio syndrome occurs more than 25 years later, with progressive weakness, decreased muscle mass, and pain. The arthropod-borne viruses (arboviruses) are transmitted by blood-sucking vectors such as ticks and mosquitoes. These viruses represent a heterogenous group of diseases responsible for most outbreaks of epidemic encephalitis, examples being eastern and western equine encephalitis and St. Disease results from alternate folding (normal helix to abnormal pleated sheet) of the normally present PrPc. They are characterized by long incubation periods followed by slowly progressive ataxia and dementia. Microscopically, there is characteristic spongiform change in the gray matter ("cluster of grapes" vacuolation) without inflammation. It primarily affects young adults between 20 and 40 years of age, with the onset of symptoms such as abnormalities of vision, tremors, paresthesias, and incoordination. Early findings include weakness of the lower extremities and visual abnormalities with retrobulbar pain. It results in medial rectus palsy on attempted lateral gaze and monocular nystagmus in abducting eye with convergence. Early symptoms include weakness and cramping, then muscle atrophy and fasciculations. Reflexes are hyperactive in upper and lower extremities, and a positive extensor plantar (Babinski) reflex develops because of the loss of upper motor neu- 510 Pathology rons.
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Rodenticides are also highly toxic to rats, but do not present the same hazard to humans. Indeed, warfarin, one of the most widely used rodenticides, is the same chemical used as an effective "blood thinner" (anticoagulant) for prevention of stroke and other blood clot related conditions. Herbicides, again as a class, have generally moderate to low acute toxicity, one exception being paraquat (which has a low dermal toxicity but causes fatal effects when ingested). In Costa Rica between 1980 and 1986, 3330 individuals were hospitalized for pesticide poisoning, and 429 died. Cholinesterase inhibitors (organophosphates and carbamates) caused 63% of hospitalizations and 36% of deaths, while paraquat accounted for 24% of hospitalizations and 60% of deaths. Cholinesterase inhibitors also caused more than 70% of occupational accidents (Wesseling et al. Of 335 poisoning deaths in Manipal, India, in the 1990s, 70% were due to cholinesterase inhibitors (Mohanty et al. Organophosphates and the organochlorine insecticide endosulfan (which was banned in 1998), were the compounds most commonly involved. Organophosphates, carbamates and paraquat were again involved in the majority of cases (Bertsias et al. In a four year period in Japan, 346 cases of pesticide poisoning were reported; in this case 70% were due to suicide attempts. Again, cholinesterase inhibitors and paraquat were involved in more than 60% of poisonings. Death rate from poisoning with paraquat was over 70%, whereas it was <10% with the herbicides glyphosate or glufosinate (Nagami et al. Regulatory Mandate the awareness that the misuse of pesticides may pose potential health hazards has led to a realm of regulatory measures to ensure their safe use and the protection of the population. In the United States, the primary authority for pesticide regulation resides with the U. The first legislation passed in the United States was the Federal Insecticide Act of 1910, which only prohibited the manufacture of any insecticide or fungicide that was adulterated or misbranded. The Agency must assess aggregate risks based on dietary consumption patterns of children, possible susceptibility of infants and children to pesticides, and cumulative effects of compounds that share the same mechanism of toxicity. Additional regulations concerning pesticides are present in other laws, such as the Safe Drinking Water Act or the Clean Air Act. To register a pesticide or a formulated product, a large number of studies (over 140) are required, a process that takes several years and anywhere between $50 and $100 million. The data base should include information on product and residue chemistry, environmental fate, toxicology, biotransformation/degradation, occupational exposure and reentry protection, spray drift, environmental impact on nontarget species (birds, mammals, aquatic organisms, plants, soil), environmental persistence and bioaccumulation, as well as product performance and efficacy.
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A detailed description of the specific enzymes known to be involved can be found in Shinohara and Ogawa (1995) and Cahill et al. Detailed reviews can be found in Kolodner (1995), Jiricny (1998), Modrich and Lahue (1996), and Jun et al. The question of whether or not strand-specific mismatch repair occurs in mammalian cells has not been resolved, although some evidence does point to its occurrence (Modrich, 1997). The adducted base is reverted to a normal one by the enzyme, which is itself inactivated by the reaction. The preceding sections, together with the references provided, should assist in this assessment. Base substitutions are the replacement of the correct nucleotide by an incorrect one; they can be further subdivided as transitions where the change is purine for purine or pyrimidine for pyrimidine; and transversions where the change is purine for pyrimidine and vice versa. Frameshift mutations are strictly the addition or deletion of one or a few base pairs (not in multiples of three) in protein-coding regions. For the discussion of the mechanism of induction of gene mutations and chromosomal alterations, it is necessary to distinguish chemicals by their general mode of action. Chemicals that produce genetic alterations far more effectively in the S phase of the cell cycle are described as nonradiomimetic. The great majority of chemicals are nonradiomimetic; the radiomimetic group includes bleomycin, streptonigrin, neocarzinostatin, and 8-ethoxycaffeine. Gene mutations can arise in the absence of specific exogenous exposures to radiations and chemicals. The great majority of socalled spontaneous (background) mutations arise from replication of an altered template. Mutations induced by ionizing radiations tend to be deletions ranging in size from a few bases to multilocus events (Thacker, 1992). Gene mutations produced by a majority of chemicals and nonionizing radiations are base substitutions, frameshifts, and small deletions. Thus, relative mutation frequency will be the outcome of the race between repair and replication, i. However, in the case of translesion bypass, discussed above, gene mutations can be produced at relatively high frequencies. Germ Cells the mechanism of production of gene mutations in germ cells is basically the same as in somatic cells. The spermatogonial stem cell in humans and rodents has a long cell cycle time, 8 days or longer, with only a small fraction being occupied by the S phase. However, for considerations of genetic risk, it is the spermatogonial stem cell that is the major contributor because it is present, in general, throughout the reproductive lifetime of an individual.
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Starting in the mid-1940s several other chlorinated insecticides were commercialized, including chlordane, heptachlor, aldrin, and dieldrin. The organophosphorus insecticides were first synthesized in Germany in the late 1930s. FarbenIndustrie in Germany, is considered the "father" of organophosphorus insecticides. Several thousand molecules were synthesized by Schrader, and one (code name E605) was eventually introduced into the agricultural market under the trade name parathion, to become one of the most widely employed insecticides in this class. During those years, compounds of much greater toxicity than parathion, such as sarin, soman, and tabun, were also synthesized as potential chemical warfare agents. This alkaloid had been isolated in 1864 from Calabar beans, the seeds of Physostigma venenosum, a perennial plant in tropical West Africa, and its mode of action as a cholinesterase inhibitor was identified in 1926 (Casida, 1964). Despite the early studies on physostigmine, the carbamates were introduced as insecticides only in the early 1950s. Though pyrethrum flower and extracts had been used for several centuries, pyrethrins were characterized only between 1910 and 1924 (Casida, 1980). This led then to the development of synthetic pyrethroids, the first of which, allethrin, was followed by several others in the early 1970s, particularly because of the work of Michael Elliott in England and of scientists at Sumitomo Chemical Company in Japan. The past 60 years have also seen the development of hundreds of other chemicals used as herbicides, fungicides, and rodenticides. A few years later, two important fumigants were introduced, 1,2dichloropropene and methyl bromide. In the 1950s, phenylureas and chlorophenoxy compounds were developed as herbicides, together with the fungicides captan and folpet. Triazines, chloroacetanilides and paraquat, all widely used herbicides, came to the market in the 1960s, and so did the important class of dithiocarbamate fungicides, while the herbicide glyphosate was introduced in the mid-1970s. Pesticides play a major role in the control of vector-borne diseases, which represent a major threat to the health of large human populations. Pesticides of various types are used in the control of insects, rodents, and other pests that are involved in the life cycle of vector-borne diseases such as malaria, filariasis, yellow fever, viral encephalitis, typhus, and many others (Novak and Lampman, 2001). There are still hundreds of millions of people in the world who are at risk from schistosomiasis, filariasis, and intestinal worm infestations, particularly in Africa and some Asian countries, and these major health problems require a continuous judicious use of pesticides (Novak and Lampman, 2001). In many parts of the world, excessive loss of food crops to insects or other pests may contribute to possible starvation, and use of pesticides seems to have a favorable cost-benefit relationship (Murphy, 1986). In developed countries, pesticides allow production of abundant, inexpensive, and attractive fruits and vegetables, as well as grains. In this case, cost-benefit considerations are based on economic considerations, particularly with regard to labor costs.