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Nutritional epidemiology ences between the two sets that occurred thereafter provides scienti c evidence to understand the role of would be causally attributed to the single factor that nutrition in the cause and prevention of disease. The comparison and choice of different epidemio Experimental epidemiological designs are those in logical study designs depends on exposure measures, which the investigator assigns the exposure to each outcome measures, costs, and expected length of subject. The selection of a study method is often is assigned with the aim of attaining maximum com in uenced by pragmatic issues such as feasibility, parability between treated and untreated groups as well as by ethical questions. Observa sets of circumstances is to assign subjects randomly tional studies can be further divided into descriptive to exposure (treatment) or control groups. All randomized is a set of observations, conducted under controlled studies are experimental designs. Exposure, from an epidemiological point of view, describes lifestyle or environmental factors that may Experimental Clinical trial be relevant to health. Outcome is another generic term used to describe the health-related events or Yes Field trial variables that are being studied in relation to the Community trial effect of an exposure. In nutritional epidemiology, the Yes Randomization primary exposure of interest is dietary intake, whereas Intervention trial outcome measures usually involve disease occurrence No (quasi-experiment) or nutritional status indicators (anthropometry, Assignment of exposure by clinical signs of disease/health status, biological or investigator physiological measures or dietary habits). Cross-sectional Descriptive For example, if a whole town is assigned to receive (prevalence) Nonexperimental an educational program about healthy eating and Ecological another neighboring town is assigned to control (no (observational) (correlation) educational program), this would be a community Figure 13. Therefore, random be large, there would be no guarantee that the groups ized experiments with humans can only be conducted to be compared would be identical. It is not permissible to carry out experimental and the whole sample is large enough, a random studies where the exposure is potentially harmful. The tially homogeneous in all measured and unmeasured design options in nutritional epidemiology must take factors. This balance makes groups directly compa into account the setting, uses, advantages, and limita rable and ensures the validity of causal inferences tions (Table 13. Experimental designs in epidemiology In general, experimental studies with individual Experimental epidemiologists try to conduct con randomization provide the strongest evidence for the trolled studies, and in these studies it is the investiga effect of an exposure on an outcome. Human studies, however, studies are the inferentially strongest designs to unlike animal studies, involve aspects that the inves demonstrate causality, but they may raise substantial tigator cannot control. This is particularly so when ethical problems because the scheme of random they are carried out on a free-living population. Two assignment is used to help not the subject, but the study designs dominate this area of epidemiology: experiment. Subjects are exposed only to meet the randomized controlled trials and crossover studies. Also, all research data partners this form will cover the following aspects: will obtain national authorization from an ethical committee or I. Without further explanations pregnant women No Yes Therefore, I freely con rm my availability to be involved in the healthy volunteers No Yes trial Use of nonhuman primates No Yes Use of transgenic animals No Yes Date Use of other animals No Yes Signature Genetic modi cation of animals No Yes In addition, all the partners agree with the following statement Genetic modi cation of plants No Yes Other speci cations: In implementing the proposed research I shall adhere most the regulations, concerning human and medical research, strictly to all national and international ethical and safety will be respected with precise reference to the recommenda provisions applicable in the countries where the research is tions of the Helsinki (1964), Tokyo (1975), Venice (1983) and carried out. Crossover designs in epidemiology operate on the They are sometimes called intervention trials (Figure same principles as the repeated-measures designs 13. All study subjects Some randomized trials are referred to as primary receive the treatment and the placebo for equal prevention trials and others as secondary prevention periods, with a washout period in between, and the trials. Primary prevention trials are those conducted order of treatment or placebo administration is among healthy individuals with the aim of preventing selected at random for each study subject. All participants were free of this disease at relationships between speci c exposures and indica the start of the study and they were followed up for tors of health or disease status. This is an example of associated with population-based intervention trials a primary prevention trial. For this approach has been increasingly selected from the example, to study the bene ts of a Mediterranean 1990s to assess the effects of speci c micronutrients style diet, in the Lyon Diet Heart Study, patients were (-carotene, -tocopherol, folic acid, and other randomized to two different dietary patterns after minerals and vitamins) using large-scale randomized suffering a myocardial infarction (de Lorgeril et al. The outcome was not the onset of disease but When only one micronutrient is compared with a the incidence of reinfarction or cardiac death during placebo, the study is called a single trial, whereas mul the follow-up period. In a Nonexperimental (observational) 2 2 factorial design, two treatments are evaluated epidemiological studies simultaneously by forming four groups (treatment A, When experiments are not feasible or are unethical, treatment B, both treatments, and placebo). In nonex Experimental studies keep the highest internal perimental (observational) studies the investigator validity among epidemiological designs. However, has no control over the exposure, because the they may lack generalization. Match cohort studies ing eliminates variability between cases and controls ecological studies. Nevertheless, between study designs relate to the time when expo matching does not control for the confounding effects sure and outcome are measured. Cross-sectional surveys provide a snap this limitation by measuring past diet using food fre shot of descriptive epidemiological data on nutrition, quency or diet history methods. One concern is that identifying nutritional needs in the population and recall of past diet by cases may be in uenced by their forming a basis for health promotion and disease pre present disease status. Several had a heart attack may attach an unfair level of impor countries conduct regular cross-sectional surveys on tance to their intake of speci c foods, based on representative samples of their populations focusing misinformation. A random sample or a matched sample of Subjects are identi ed and recruited on the basis of non-cases is also selected from the cohort to make up the presence or absence of the disease or the health the control series as the comparison group. Ideally, the controls are randomly selected from the same study base as the Cohort studies cases, and identical inclusion and exclusion criteria In cohort studies exposure is evaluated in the present are applied to each group. Nutrition Research Methodology 321 Cohort studies are most commonly longitudinal or Studies considering the individual (instead of the prospective, with subjects being followed forward in population) as the unit of observation are always time over some prede ned period to assess disease preferable because in an individually based study it is onset. They may also be retrospective (historical possible to relate exposure and outcome measures cohorts), with groups identi ed on the basis of expo more directly, preventing many aws that are likely to sure sometime in the past and then followed from that invalidate the ndings of ecological studies. The feasibility of retrospective cohorts is the bias resulting because an association observed depends on the availability of good-quality data from between variables on an aggregated level does not pre-existing les. The research costs associated with necessarily represent the association that exists at an cohort study designs mean that such studies are less individual level. Nevertheless, a sub based studies over aggregated studies is that they stantial effort to develop large cohort studies in nutri allow the direct estimation of the risk of disease in tional epidemiology has been made since the early relation to exposure. Ecological comparisons have been start with a roster of healthy individuals whose base important in hypothesizing diet and disease associa line diet would be recorded. Nevertheless, they are not able to establish lowed up over several years to compare the occurrence causal relationships. Two main investigations in which the unit of observation and measures of the frequency for an outcome are used in analysis is not the individual but a whole community epidemiology: prevalence and incidence. In ecologi cal studies, measures of exposure routinely collected Prevalence and aggregated at the household, local, district, the prevalence of an outcome is the proportion of regional, national, or international level are compared subjects in a population who have that outcome at a with outcome measures aggregated at the same level. The numerator of prevalence is An example of an ecological study would be plotting the number of existing cases and the denominator is the mortality rates for colon cancer in several coun the whole population: tries against the average intakes of saturated fat in Existing cases these same countries and calculating the correlation Prevalence = between the two variables. Total population 322 Introduction to Human Nutrition Incidence by the combination of data may be misleading because the incidence of an outcome is the proportion of new the ndings may still be invalid.

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Tyrosine, tryptophan, glycine and thiyl Essential to catalytic activity of several enzymes radicals such as ribonucleoside diphosphate reductase and pyruvate dehydrogenase. Vitamin K hydroquinone and Required for carboxylation of glutamate to semiquinone carboxylglutamic acid by microsomal glutamic acid carboxylase. During evolution one option would have been to prevent the formation of pro oxidant species. This, however, would be virtually impossible to achieve in an oxygen-enriched environment as pro-oxidants are unavoidable side reactions of other important biochemical processes. Instead nature accepted that pro oxidants would be produced so protective mechanisms evolved to repair and replace damaged molecules. Interestingly, aerobes also make good use of pro-oxidants as messengers, signals and defense molecules (Table 1. Under normal conditions the production of pro-oxidants is presumed to be in balance with antioxidant defenses. However, the overproduction of pro-oxidants and/or decreased antioxidant protection can lead to tissue damage and disease. Thus, in individuals with a genetic predisposition or for those exposed to environmental stressors such as cigarette smoke, sunlight and pollution, the pro oxidant/antioxidant balance can be upset (Figure 1. The overproduction of pro oxidant species or the failure of antioxidant defenses results in a condition called oxidative stress, a causal, or at least ancillary, factor in the pathology of many diseases (Sies (1985, 1997)). Under Some Circumstances Oxidant Production Can Overwhelm these Defenses Resulting In Oxidative Stress, Cellular Damage And Disease. A continuously growing list of diseases and conditions, especially those involving inflammation, are reported to be associated with oxidative stress (Table 1. It is interesting to note that a number of these diseases are being treated by manipulation of antioxidant levels or by the use of drugs with antioxidant activity (Sies (1991)). Oxidation can be defined as a gain in oxygen, a loss of hydrogen, a loss of protons or the loss of electrons. The theory behind it has been extensively reviewed elsewhere (Acworth and Bowers (1997) and references therein; Acworth et al. The CoulArray is the only electrochemical detector that can work with even the most aggressive gradients. Practical examples using these detectors will be presented throughout this handbook. Oxygen is toxic and exerts its toxicity through the production of a variety of pro oxidant species. During evolution living organisms either remained anaerobic surviving in oxygen poor conditions or became aerobic, adapting to the increased atmospheric levels of oxygen. Aerobic organisms tolerate continued production of pro-oxidants and have evolved mechanisms to repair or remove damaged molecules or to prevent the formation and to intercept and deactivate the pro oxidant species. Normally there is a balance between production of pro-oxidant species and destruction by the antioxidant defenses. However, under certain conditions this balance is upset in favor of overproduction of the pro-oxidants leading to oxidative stress and disease. Phenotypic heterogeneity in motor neuron disease patients with CuZn superoxide dismutase mutations in Scandinavia. Plasma 3-nitrotyrosine is elevated in premature infants who develop bronchopulmonary dysplasia. The role of oxidative stress in disease progression in individuals infected by the human immunodeficiency virus. Increased nitric oxide production accompanied by the up-regulation of inducible nitric oxide synthase in vascular endothelium from patients with systemic lupus erythematosus. Increased mucosal antioxidant enzyme activities in chronic gastritis and benign gastric polyps. The activity of Cu/Zn-superoxide dismutase and catalase of gastric mucosa in chronic gastritis, and the effect of alpha-tocopherol. Oxidative stress in the development of human ischemic hepatitis during circulatory shock. Free radicals and oxidative stress challenge dialysis patients: effects of two different membranes. Tetrahydrobiopterin loading test in xanthine dehydrogenase and molybdenum cofactor deficiencies. Enhanced monocyte generation of reactive oxygen species in primary systemic vasculitis. Altered ascorbic acid status in the mucosa from inflammatory bowel disease patients. Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function [see comments]. Superoxide dismutases, glutathione peroxidase, and catalase in neuromuscular disease. Changes in cerebrospinal fluid levels of malondialdehyde and glutathione reductase activity in multiple sclerosis. Enhanced reactive oxygen species metabolism of air space cells in hypersensitivity pneumonitis. Increased alveolar macrophage chemiluminescence and airspace cell superoxide production in active pulmonary sarcoidosis. Plasma levels of antioxidant vitamins, selenium, total sulfhydryl groups and oxidative products in ischemic-stroke patients as compared to matched controls in Taiwan. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Neuropathology of amyotrophic lateral sclerosis: new perspectives on an old disease. Extracellular and intracellular phospholipase A2, inducible and constitutive cyclooxygenase, and inducible nitric oxide synthase. The role of nitric oxide and other endothelium-derived vasoactive substances in vascular disease. Structural and biochemical changes in rat lungs occurring during exposures to lethal and adaptive doses of oxygen. Enhancement of reactive oxygen species production and cell surface markers expression due to haemodialysis. Oxidants and respiratory tract epithelial injury: pathogenesis and strategies for therapeutic intervention. Antioxidant activity and other mechanisms of thiols involved in chemoprevention of mutation and cancer. Relationship between red blood cell antioxidant enzymatic system status and lipoperoxidation during the acute phase of malaria. Association between reactive oxygen species and disease activity in chronic hepatitis C. Lipid peroxidation and superoxide dismutase activity in muscle and erythrocytes in adult muscular dystrophies and neurogenic atrophies. The spin trap N-tert-phenyl -butylnitrone prolongs the life span of the senescence-accelerated mouse. Reactive oxygen species, chromosome mutation, and cancer: Possible role of clastogenic factors in carcinogenesis. Further evolution toward effective therapy for acute ischemic stroke [see comments]. N-tert-butyl -phenylnitrone improves recovery of brain energy state in rats following transient focal ischemia. Responses of baboons to prolonged hyperoxia: Physiology and qualitative pathology. Oxidized low density lipoprotein, antioxidants and coronary atherosclerosis [editorial]. Studies in neuronal ceroid lipofuscinosis: enzymes of liver and brain tissues involved in the defense against oxidative damage.

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Humans are infected by ingestion of raw or undercooked beef Specific serological tests are available to infected with cysticerci bovis, the larval support the clinical diagnosis of stage of T. Meat should be routinely inspected for Additional sources of information evidence of taeniasis at slaughter. Consult the current version of Therapeutic guidelines: antibiotic (Therapeutic Guidelines Limited). The blue book: Guidelines forthe control of infectious diseases 225 Tetanus Victorian statutory requirement Laryngeal spasm is a very serious Tetanus is still common in developing Tetanus (Group B disease) must be complication which may occur at any countries with low immunisation rates notified in writing within five days of stage and can cause sudden asphyxia. Intravenous drug use is an independent Clostridium tetani, the tetanus bacillus is risk factor for tetanus in the absence of Method of diagnosis the causative agent. Clinical features Laboratory confirmation of tetanus Reservoir Tetanus is an acute, potentially fatal infection is often difficult. Spores can usually be found detectable in serum samples but may produce an exotoxin that reaches the wherever there is contamination with result from waning past immunisation. Depending on the incubation period is usually three to Spores may be introduced through severity, muscle rigidity usually affects 21 days although it may range from one contaminated puncture wounds, most parts of the body and is associated day to several months depending upon lacerations, burns or contaminated with hyperreflexia. Tetanus rarely follows surgical and occurrence involve most body muscles procedures today. Infection is most Spores may remain viable for many years the back muscles causing the head and likely in older people who have never in the environment. For further information on tetanus Control of environment vaccination, particularly with respect to Not required. The use of tetanus toxoid in the management of wounds, with or without tetanus immunoglobulin, is determined by considering the vaccination history of the person and the nature of the wound. For further information on the management of bites and other tetanus prone wounds, consult the current edition of Therapeutic guidelines: antibiotic (Therapeutic Guidelines Limited). The blue book: Guidelines forthe control of infectious diseases 227 Toxoplasmosis Victorian statutory requirement Serological results require careful Reservoir Notification and school exclusion are not interpretation and should preferably be the main host in Australia is the required. In general, mainly through eating small infected Infectious agent toxoplasma-specific IgG antibody mammals including rodents and birds, Toxoplasma gondii is a protozoal disease. They sheep, goats, rodents, cattle, swine, with other symptoms of muscle pain, are common in autoimmune disease. This occurs more commonly in Dormant infection persists for life and muscle and brain. Tissue cysts remain can reactivate in the immunosuppressed Testing paired sera taken two weeks viable for long periods. Children may become infected by Public health significance ingestion of oocysts in dirt or sandpit Acute toxoplasmosis in pregnant women and occurrence sand after faecal contamination by cats, can affect the unborn child. In early Toxoplasmosis occurs worldwide in particularly kittens, or other animals. Infection in humans the infection may also be transmitted Infection in late pregnancy may result in is common. Transplacental Toxoplasmosis acquired after birth severe complications for the foetus. Period of communicability Infection may be diagnosed by Toxoplasmosis is not transmitted from visualisation of the protozoa in biopsy person to person spread except in-utero. Infection in the They may remain infective in water or water to dispose of the oocysts before first trimester results in a low foetal moist soil for over a year. Infection later in Tissue cysts in meat remain infective for Cats should only be fed with dry, canned pregnancy results in a higher infection as long as the meat is edible and under or boiled food and should be discouraged rate but generally less severe disease. However, direct contact with cats is rarely the Diagnosis and treatment during Susceptibility and resistance cause of infection. Cats are generally pregnancy appears to reduce the effects Everyone is susceptible to infection. About 75% of women of childbearing age oocysts for two weeks after their original False positive IgM antibody test (and less are susceptible. Where infection of the immunosuppressive therapy, in particular mother is confirmed, treatment is Control of case for haematological malignancies, or indicated. Immunosuppressed persons may also infection during pregnancy or active Pregnant women and require prophylactic treatment for the infection, and immunosuppressed immunosuppressed people should be duration of their immunosuppression. It is communicable as long as typhoid or School exclusion: exclude until approved Incubation period paratyphoid bacilli are present in excreta. Public health significance recognised serovars A, B and C are the and occurrence Control measures infectious agents. Typhoid and paratyphoid infections occur Preventive measures Identification worldwide. Outbreaks occur in areas with Vaccination is not routinely Clinical features poor sanitation and inadequate sewerage recommended, except for travellers who Typhoid fever (enteric fever) is a systems. Vaccination should be considered for Reservoir Complications such as intestinal laboratory workers in potential contact Reservoirs for typhoid and paratyphoid haemorrhage or perforation can develop with Salmonella typhi. A combination hepatitis A and typhoid Method of diagnosis Mode of transmission injectable vaccine is also available. All Diagnosis is made by culture of typhoid or Salmonella is transmitted by formulations are equally effective. Serology in the form of the water used), raw vegetables, salads and advised to exercise care in selecting food Widal test is no longer routinely used. A history of travel to an about personal hygiene, especially they should be advised to cease work until endemic area is usually found. If there is no history of travel, local the Department arranges the collection sources of infection are investigated to Control of case and testing of weekly faecal specimens identify further cases, asymptomatic Hospitalisation is usually required for for S. Food preparation, the Department will ciprofloxacin, ceftriaxone, handlers and workers in high risk determine the appropriate management chloramphenicol, amoxycillin or co professions are generally excluded from of the workplace on an individual basis. However, strains resistant to high risk work or patient care until they chloramphenicol, amoxycillin and co have had three consecutive negative Outbreak measures trimoxazole are common in south Asia. All cases are intensively investigated, Failure to respond to ciprofloxacin has Control of contacts whether sporadic or part of a cluster. Education should be given to the patient food-handlers or in a high risk Widespread use of typhoid vaccine is not regarding the importance of completing profession. Follow-up of all patients is conducted by Use of typhoid vaccine for contacts is the Department of Human Services to Additional sources of information not generally recommended. The blue book: Guidelines forthe control of infectious diseases 231 Verotoxin producing E. Humans serve as dysenteriae type 1 are the causative in the presence of the following: reservoirs for person to person agents. Fever is usually the incubation period is two to eight meat or mince, is a source of infection. Asymptomatic infection days, with an average of three to four Other known food sources have included can occur.

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The "rush to empire" of this period intensified the political, military, and economic rivalry between England and Ger 25 many that culminated in the First World War. For Polanyi the imperialist impulse cannot be found somewhere in the genetic code of nations; rather, it materializes as nations strug gle to find some way to protect themselves from the relentless pres sures of the gold standard system. The flow of resources from a lucra tive colony might save the nation from a wrenching crisis caused by a sudden outflow of gold, and the exploitation of the overseas popula tions might help keep domestic class relations from becoming even more explosive. Polanyi argues that the utopianism of the market liberals led them to invent the gold standard as a mechanism that would bring a bor derless world of growing prosperity. Instead, the relentless shocks of the gold standard forced nations to consolidate themselves around heightened national and then imperial boundaries. The gold standard continued to exert disciplinary pressure on nations, but its function ing was effectively undermined by the rise of various forms of protec 24. Peter Gourevitch, Politics in Hard Times: Comparative Responses to Interna tional Economic Crises (Ithaca, N. Polanyi takes pains to argue that financial capitalists can be a major force for preventing war. And yet even when this entire contradictory system came crashing down with the First World War, the gold standard was so taken for granted that statesmen mobilized to restore it. The whole drama was tragically played out again in the 1920s and 1930s, as nations were forced to choose between protecting the ex change rate and protecting their citizens. Since the end of the Cold War, they have insisted that the integration of the global economy is mak ing national boundaries obsolete and is laying the basis for a new era of global peace. Once nations recognize the logic of the global market place and open their economies to free movement of goods and capi tal, international conflict will be replaced by benign competition to produce ever more exciting goods and services. As did their predeces sors, neoliberals insist that all nations have to do is trust in the effec tiveness of self-regulating markets. To be sure, the current global financial system is quite different from the gold standard. Exchange rates and national currencies are no longer fixed in relation to gold; most currencies are allowed to fluctu ate in value on the foreign exchange markets. There are also powerful international financial institutions, such as the International Mone tary Fund and the World Bank, that play a major role in managing the global system. This fundamental belief lies behind the systematic efforts of neo liberals to dismantle restraints on trade and capital flows and to re duce governmental "interference" in the organization of economic life. Thomas Friedman, an influential defender of globalization, writes: "When your country recognizes. Moreover, he cheerfully describe how the constraints of this garment are en forced by the "electronic herd" of international traders on foreign ex change and financial markets. Just as national economies depend on an active governmental role, so too does the global economy need strong regulatory institutions, including a lender of last resort. But the more fundamental point learned from Polanyi is that mar ket liberalism makes demands on ordinary people that are simply not sustainable. Workers, farmers, and small business people will not tol erate for any length of time a pattern of economic organization in which they are subject to periodic dramatic fluctuations in their daily economic circumstances. Polanyi believes that to expect that kind of flexibility is both morally wrong and deeply unrealistic. To him it is inevitable that people will mobilize to protect themselves from these economic shocks. Moreover, the recent period of ascendant neoliberalism has al ready witnessed widespread protests occurring around the world where people attempt to resist the economic disruptions of globaliza 27 tion. As such dissatisfactions intensify, social order becomes more problematic and the danger increases that political leaders will seek to 26. Thomas Friedman, the Lexus and the Olive Tree (New York: Farrar, Strauss, 1999), p. John Walton and David Seddon, Free Markets and Food Riots: the Politics of Global Adjustment (Cambridge, Mass. This is how the Utopian vision of neoliberals leads not to peace but to intensi fied conflict. In many parts of Africa, for example, the devastating effects of structural adjustment policies have disintegrated societies and produced famine and civil war. Elsewhere, the post-Cold War period has seen the emergence of militantly nationalist regimes with aggressive intentions toward neighbors and their own ethnic 28 minorities. If Polanyi is right, these signs of disorder are harbingers of even more dangerous circumstances in the future. The key step was to overturn the belief that social life should be subordinated to the market mecha nism. Once free of this "obsolete market mentality," the path would be open to subordinate both national economies and the global economy 29 to democratic politics. Through democratic politics, people decided that the elderly should be protected from the need to earn income through Social Se curity. Similarly, democratic politics expanded the rights of working people to form effective unions through the National Labor Relations Act. At the global level Polanyi anticipated an international economic order with high levels of international trade and cooperation. He did not lay out a set of blueprints, but he was clear on the principles: However, with the disappearance of the automatic mechanism of the gold standard, governments will find it possible to drop the most obstructive features of absolute sovereignty, the refusal to collaborate in interna tional economics. At the same time it will become possible to tolerate willingly that other nations shape their domestic institutions accord ing to their inclinations, thus transcending the pernicious nineteenth century dogma of the necessary uniformity of domestic regimes within the orbit of world economy. In other words collaboration among governments would produce a set of agreements to facilitate high levels of international trade, but societies would have multiple means to buffer themselves from the pressures of the global economy. Moreover, with an end to a single economic model, developing nations would have expanded oppor tunities to improve the welfare of their people. This vision also as sumes a set of global regulatory structures that would place limits on 31 the play of market forces. He challenges the now fashion able view that more government will inevitably lead to both bad eco nomic results and excessive state control of social life. For him a sub stantial governmental role is indispensable for managing the fictitious commodities, so there is no reason to take seriously the market liberal axiom that governments are by definition ineffectual. But he also ex plicitly refutes the claim that the expansion of government would nec essarily take an oppressive form. Polanyi argues instead that "the pass ing of market economy can become the beginning of an era of unprecedented freedom. Juridical and actual freedom can be made wider and more general than ever before; regulation and control can achieve freedom not only for the few, but for all. For a recent effort to concretize this vision, see John Eatwell and Lance Taylor, Global Finance at Risk: the Case for International Regulation (New York: New Press, 2000). Introduction [ xxxvii ] cial injustice; he also calls for an expansion of civil liberties, stressing that "in an established society, the right to nonconformity must be in stitutionally protected. The individual must be free to follow his con science without fear of the powers that happen to be entrusted with administrative tasks in some of the fields of social life. This is the meaning of freedom in a complex society; it gives us all the certainty 32 that we need. The coming of the Cold War meant that the New Deal was the end of reform in the United States, not the beginning. Planned global eco nomic cooperation gave way relatively quickly to new initiatives to ex pand the global role of markets. There is a possible alternative to the sce nario in which the unsustainability of market liberalism produces economic crises and the reemergence of authoritarian and aggressive regimes. The alternative is that ordinary people in nations around the globe engage in a common effort to subordinate the economy to dem ocratic politics and rebuild the global economy on the basis of inter national cooperation. Indeed, there were clear signs in the last years of the 1990s that such a transnational social movement to reshape the 33 global economy is now more than a theoretical possibility.

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There is a large variety in fatty acids, with the saturated fatty stearic acid, the monounsaturated oleic acid, and the polyunsaturated linoleic acid being the most abundant fatty acids. The fatty acid profle, which is typical for certain oils, determines to a great extent the characteristics of an oil with respect to stability, skin feel, and effects on the skin. The most important feature of a fatty acid is the number of double bonds and their distribution over the carbon chain. The essential fatty acids infuence skin physiology via their effects on the skin barrier function, eicosanoid production, membrane fuidity, and cell signaling. Fatty acids with the frst double bond at the 6th C atom counting from the end of the carbon tail is called omega-6, whereas those with the frst double bond at the 3rd C atom are called omega-3 fatty acids. Omega-6 and omega-3 fatty Moisturizers 237 acids are derived from linoleic and -linoleic acid, respectively. Long-chain fatty acids are one group of commonly used anionic emulsifers, for example, stearic acid and palmitic acid. Cholesterol is another component of the lipid bilayer, which also is used as an nonionic emulsifer in moisturizers. Nonionic emulsifers depend cheify upon hydroxyl groups and ether linkages to create the hydrophilic action. Lanolin is an animal type of wax (from the Latin lana for wool and oleum for oil) secreted by the sebaceous glands of the sheep. Lanolin is a complex mixture of esters, disesters, and hydroxy esters of high molecular weight lanolin alcohols and lanolin acids. A typical example of a vegetable-derived wax is carnauba, which is obtained from the leaves of the carnauba palm tree. Mineral oils are derived from petroleum and the most important materials are liquid paraffn (paraf fnum liquidum), solid paraffn, and petrolatum (vaseline). The materials used for topical products are highly purifed and consist of complex combinations of oxidation-resistant hydrocarbons. Depending on the distribution of the molecular weight, materials with different viscosity are obtained. The most conventional one is occlusion, which implies a simple reduction of the loss of water from the outside of the skin. Common occlusive substances in moisturizers are petrolatum, beeswax, lanolin, and various oils. Activation of certain receptors regulates keratinocyte proliferation and differentiation. Lactic acid has been used in topical preparations for several decades because of its buffering properties and water binding capacity. Propylene glycol is also used as a solvent, penetration enhancer, and as a vehicle for substances unstable or insoluble in water. Hyaluronic acid is a member of the class of amino-sugars containing polysaccharides known as the gly cosaminoglycans. The polymer is widely distributed in body tissues and provides the turgor for the vitre ous humor of the eye and functions also as a lubricant between the collagen and the elastic ber networks in dermis. The name hyaluronic acid derives from the Greek hyalos (glossy, vitreous) and uronic acid. Swelling of corneocytes is noted after treatment with humectants, such as glycerin. A recent study also found that urea affects cutaneous arterial sympathetic nerve activity and elevates blood fow via histaminergic H3-receptor. The polymer may be injected to obtain a smoother surface and reduce the depth of wrinkles. Preservatives and Antioxidants the entire composition of the moisturizer is believed to be important for the outcome of the moisturizer treatment, that is, ingredients supposed to constitute the vehicle may also contribute to the effect on the skin. For example, preservatives may be positive or negative to the skin not only due to risks for adverse skin reactions to the preservatives, but also due to potential infuences of the preservatives on skin microfora. Preservatives are used in moisturizing creams to kill or inhibit the growth of microor ganisms inadvertently introduced to the cream during manufacturing or use. Badly preserved moistur izers allow contamination and growth of microorganisms in the products. The presence of certain microorganisms on the surface has been linked to infammation, as microorganisms may release, for example, exotoxins, superanti gens, and enzymes which can break down the barrier. Furthermore, ingredients in moisturizers may change the frst line of defense in the skin by up or down-regulation of antimicrobial peptides, as these are key elements in the innate immune response. Certain substances, such as ethanol and propylene glycol, may enhance the effect of the preservatives. In addition, alcohols may on their own prevent contamination of the product when they are used at high concentrations. The ingredients infuence the initial feel of the product, its spreading behavior on the skin, whether and how fast it is absorbed, and how the skin feels after its use. Smoothing of the skin surface is observed immediately after application as a result of the flling of spaces between partially desquamated skin fakes. After eight hours, 50% of applied cream has been reported to remain on the surface. Low compliance can therefore be a problem with topical treatments of diseases and the process of treating the skin can often itself add to the burden of having the disease. The patients can also receive conficting treatment advice, leading to frustration, non-compliance, and diffculty in following an effective regimen. Hyperkeratosis thus indicates a failure of epidermis to produce a competent barrier with normal thickness, but may also refect an undesired inhibition of the desquamation process. The improvements are reported to be signifcant when compared to an untreated control foot or when compared to the degree of xerosis at baseline (start of treatment). More rapid effect from (LacHydrin) urea158 Randomized, bilateral, double-blind (43/57, 12% ammonium lactate vs. Furthermore, no differ ence in effcacy between once and twice-daily applications was found. No signifcant dif ference in the occlusive effect between the 5% urea-cream and a barrier-deteriorating cream containing lactic-acid and propylene glycol (Locobase) has been detected. The probability of not having a relapse during the 26-week period was 68% in the moisturizer group and 32% for those not using the moisturizer, which resulted in a 53% relative risk reduction. The results from the barrier-strengthening urea-cream study can be compared to results from similar studies focusing on long-term disease control using anti-infammatory agents. Although these studies have slightly different designs, the results suggest that a barrier-strengthening moisturizer may prevent relapse of eczema to a comparable extent as intermittent treatment with anti-infammatory medicinals on controlled atopic eczema. Whether a similar delay in the fare-up of eczema would be observed with a moisturizer without barrier-improving properties has yet to be studied. Moisturizers in Pediatric Skin Care In general pediatric skin care guidelines, it is recommended to use emollient/moisturizer treatment to reduce the need for more complicated treatments and associated consultations. However, the use of skin care products have also been questioned due to the risks of inducing eczema and asthma. In one of the frst steroid-sparing studies, the effectiveness of hydrocortisone cream plus an emollient (Eucerin), was compared with a regimen of hydrocortisone cream applied twice daily (Table 19. However, the emollient did not decrease the consump tion of moderate potency topical corticosteroid. Reduction in pruritus was also signifcantly higher with the glycerol cream compared to placebo. Superior with emollient and improvement was 2 + 4 week weeks and then 4 weeks without corticosteroid maintained during the 4 weeks of follow up175 Neonatal, prospective. Superior treatment or as-needed with a water-in-oil skin condition, less skin bacterial colonization, etc. The types of problems covered by the term dry skin may not always be diminished by an increase in skin hydration.

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Further characterization of delivered, no on-target disruption was observed with either half-site of-target insertion revealed that repetitive elements, when included reagent alone. Capable of knocking out specifc genes with high efciency for on-target editing and is accompanied by rare of target integration in resting T cells, it can be applied to the manufacture of allogeneic events. Utilizing Human Whole Blood to Predict In Vivo Immune Responses in Human Setup 172. Henderson, Dongwon Shin, Alexandre Knowlton, Hillard Rubin, Meghan Scarpitti, Laura 2 2 2 Lebedev, Richard I. However, the development of efective and Genomics and Gene Terapy in Pediatrics, University of Tubingen, Tubingen, safe therapeutic editing technologies will require highly sensitive Germany assays to identify and quantitate the accuracy of genome editing. However materials using microfluidic technology at scales for screening no attempts were made to improve designer nuclease treatment for applications, in vitro experiments and research in animals. The localized injections into the cortex Recombination and the striatum are well tolerated and have extensive distribution. Genome-Wide Analysis of Talen Activity fanking a ribosomal-skipping P2A and therapeutic coding sequence to in Primary Cells integrate sequences just upstream of the stop codon of an endogenous gene. Klein7, Tomas Jans1, Jaitip Tipanee1, Sara Seneca8, Warut Tulalamba1, Hui Figure 1. Therapeutics Suggested Reading: Salvatore Botta1, Elena Marrocco1, Nicola de Prisco1, 1. Mol Cell 1 2 3 Mariangela Lupo, Maria Laura Bacci, Carlo Gesualdo, Pediatr 2015, 2(1):11. Surgical and Dental Sciences, Eye Clinic, Second University of Naples, Naples, Italy Transcriptional regulation represents the key frst functional expression of genetic programs. Overall, prior to transplant to eliminate alloreactive T-cells that could mediate our data support the consideration of 0. T-cells could be cultured with the stem cell graf prior to infusion to eliminate donor alloreactive T-cells that could attack host tissues. In conclusion, we show here a proof of concept that primary Human T-Cells human T-cells can be engineered to recognize and target mismatched David H. Defcient Chronic Granulomatous Disease Immunosuppressive drugs can mitigate these outcomes, but due to Andrea Shejtman1, Walmir Cutrim Aragao Filho2, their broadly inhibitory action against immune cells, they increase 1 1 1,3 Maren Weisser, Marta Zinicola, Claire Booth, the risk of opportunistic infections. As expected, the expression of the p47phox protein was mainly confned to myeloid cells in blood, bone marrow 188. The percentage of functional neutrophils remained stable A Non-Human Primate Model over time up to six months, suggesting that the vector is not prone Citra Mattar1, Arijit Biswas1, Nuryanti Johana2, to epigenetic inactivation. The presence of corrected granulocytes in secondary transplanted animals also indicates that we can successfully Yvonne Tan2, Lay Geok Tan3, Sonia Bakkour4, Mahesh transduce haematopoietic stem cells. Additionally, fetuses are thought to be relatively pre-immune, minimising the risk of adverse reactions. Ofspring key vectors for gene therapy, it is imperative to understand the factors were serially monitored for transgene and immune expression, and that regulate their pharmacokinetics and bio-distribution in the intact interval biopsies of liver and peripheral tissues were performed to animal. Of note, hepatic vector copy numbers sera was also included to test concordance between the two laboratories. Integration analyses sample whereas Nab titers of positive samples were assessed using a indicate random, non-repeating, low-level integration. Concordance of no abnormality, neither visually nor histologically, and transaminase Nab levels measured in the two cell assays was 100%. No signifcant change in humoral immune response and neutralization falling equally into four groups: less than or equal to transgene expression was observed. Moreover, we also showed a its impact on the biological and functional activities of transduced cells. Our results represent a signifcant step forward for gene editing-based therapies in support of translational application. Marco Zahn, Diana Schenkwein, Stefan Wilkening, Ning Wu1, Saira Afzal1, Rafaele Fronza1,2, Susanne 3 3 4 192. Kootstra, Christof 1 1 1,2 Treatment of Wiskott-Aldrich Syndrome von Kalle, Stephanie Laufs, Manfred Schmidt, Wei 1 1 1 1,2 Alessia Cavazza, Rajeev Rai, Marta Zinicola, Wang 1 1 1,2 1 Elizabeth Rivers, Giorgia Santilli, Adrian J. The virus integrates cellular and humoral immunity, recurrent infections and development into the genome of host cells and replicates. Integrated cell lineages, for proper platelet production and lymphoid cell function. Although efective, viral cells over time, before therapy (1-7 time points) and afer therapy (1-4 vectors carry a potential risk of genotoxicity and non-physiological time points). Around the half of those integration sites were located within haematopoietic cell lines. Clonal persistence over time was observed in nearly all with Cas9 protein, we were able to achieve high levels of gene editing, patients, but mostly before therapy start. Notarangelo4, Anna Villa1,5 Transplantation of genetically-modifed stem cells is becoming a new paradigm for treatment of rare genetic disorders. However, this method chromosomal translocation or development of autoimmune reactions. Chemotherapeutic alkylating agents are profoundly bone also result in a broad spectrum of clinical phenotypes with immune marrow ablative and used clinically as a preparative regimen for stem dysregulation and autoimmunity. Gene therapy has been proposed as an alternative among the most important obstacles to overcome as the feld pushes -/ treatment, however preclinical studies in Rag1 mice highlight the to expand this therapy to other less severe monogenic diseases. Tese sequences were sub-cloned into expression plasmids and bone marrow, respectively. Resistance of Mouse Hematopoietic Immunological Aspects of Gene Therapy Stem and Progenitor Cells to the Genome and Vaccines I Editing with Cas9 Suvd Byambaa1, Hideki Uosaki1, Hiromasa Hara1, 196. Second Generation Anti-Cocaine Vaccine Tomoyuki Abe1, Yasumitsu Nagao1, Osamu Nureki2, Based on Modifed Adenovirus Capsid Tsukasa Ohmori1, Yutaka Hanazono1 Proteins 1Jichi Medical University, Tochigi, Japan, 2The University of Tokyo, Tokyo, Japan Vasiliki P. However, viral vectors used in gene therapy may cause random transgene integration and might result in Cocaine addiction remains a signifcant public health issue, accounting dysregulated gene expression. Tereby, targeted repair of mutations for approximately 40% of drug related emergency department visits and causing disease is highly desired. Currently, the only treatment option for cocaine the mutation with a correct sequence in site-specifc manner by addicts is behavioral intervention. We used Staphylococcus aureus Cas9 (SaCas9, 1053 serotype 5 E1 E3 adenovirus (Ad). In experimental animals, this amino acids) that is smaller than widely-used Streptococcus pneumoniae vaccine generates high-titer anti-cocaine antibodies that successfully Cas9 (SpCas9, 1368 amino acids) with expectation of easier delivery to sequesters cocaine in the blood, preventing the drug-induced reward. B cell diferentiation requires both cytokines, we are currently further investigating this phenomenon. We are currently undertaking studies indicate a cytotoxic lymphocyte-mediated clearance of transduced to determine whether observed levels of palivizumab are protective cells. AutoAg stimulation of splenocytes isolated still enabling therapeutic levels of antibody expression. InsB: Ag-specific FoxP3+ Tregs specifc T cell responses against transduced muscle fbers. By histological analyses expression and secretion of therapeutic quantities of antibodies from of pancreas and transplant site we are investigating whether Ag-specifc passive vaccines. In addition, that there will be approximately 70 approved therapeutic antibodies on many combination therapies are expected to be studied due to the the market by 2020, with combined worldwide sales of $125 billion. To this end, we compared the efcacy of the heavy chain light chain pairing and tissue penetration. Trough these changes we are able to increase the in vivo confrmed the presence of a strong anti-viral adaptive immunity in expression levels, but not sacrifce the biology of the original mAb mice. F10 mouse melanomas Background: Prostate cancer is a major cause of death in men around demonstrated that electrotransfer of vector plasmid induced the the world. Despite a variety of treatments, disease progression and production of several proinfammatory cytokines and chemokines metastases still occur in most cases. Histologically, tumor necrosis independent of of an immunocompetent mouse model for simultaneous monitoring caspase-3 was observed. The cells were inoculated into immunocompetent mice study was to fnd out whether the efects observed in B16. The intensity of bioluminescence imaging in to cancer-targeted gene therapies delivered by electroporation.

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In the absence of antibiotic treatment, bowel perforation can ensue afer three Estimated burden Limitations to four weeks of illness. Fortunately, the case fatality We estimated annual averages of 0 deaths and 133 Tese estimates for the burden of typhoid/ ratio is less than 1% among travelers returning to incident cases attributable to typhoid/paratyphoid paratyphoid fever are limited by the sources of industrialized countries. Disease burden was relatively equal between to consider a diagnosis of typhoid/paratyphoid fever Since typhoid and paratyphoid fever are reportable males and females and afected mostly individuals or failing to collect specimens for laboratory testing diseases in Ontario, we used an agent-based approach from one to 44 years of age. We used epidemiologic studies to determine the duration of typhoid/paratyphoid fever. Although the use of health care utilization data to Static nature of burden supplement reportable disease data in burden of Use of the pathogen-based approach of disease methodology disease studies is not novel, we are not aware of any One advance from previous burden of disease One important assumption common across all previous studies that were able to link individuals studies is that we used the pathogen-based approach studies based on the Global Burden of Disease across datasets. While we also methodology is that the natural history of a disease linkable health care utilization data to defne episodes provided estimates of the burden of selected non and the relationship between incident cases and of care across health care settings for each case of a specifc syndromes. This approach would be further strengthened The burden of infectious diseases may be afected interventions, the pathogen-based approach allows with the anticipated capacity to link health care by: 1) long-term changes. To our knowledge, this is the greatest number emergence of new pathogens or antibiotic resistance numerous experts who contributed wide-ranging of pathogens ever included in a burden of disease among current pathogens. In comparison, a pilot study estimating the to a static assessment of the burden of infectious burden of infectious diseases in Europe included only investigative team brought tremendous clinical and diseases by: using the available Ontario data and seven infectious agents. The limitations of this study are We included a greater range of health states mortality, and the full impact of real and potential presented in three sections: those that afected the representing longer-term sequelae of infectious outbreaks. Ontario Burden of Infectious Disease Study Chapter 5 / Strengths and Limitations Institute for Clinical Evaluative Sciences Ontario Agency for Health Protection and Promotion a burden of disease study. In an ideal world, valid, timely premature mortality and year-equivalents of disease burden. Co-infection with more than one and locally-derived data would be available for reduced functioning from living with the disease, infectious agent can impact both morbidity and all required parameters (disease incidence, health and we did not take into account other important mortality. Not accounting for other comorbidities state distribution and duration, severity weights, burdens. For example, there are tremendous may have led to overestimating the disease burden and mortality; all disaggregated by age and sex). In direct (health care costs) and indirect economic if individuals with comorbidities are also those practice, however, burden of disease studies have burdens (work/school absenteeism, industry costs) who sufer from infectious diseases, because people to use existing data. Ofen, we were able to identify this Herein lies one of the major fndings of this deserves further study. We made the simplifying assumptions that and timeliness of Ontario vital statistics and the impacts of co-morbid the distributions do not vary by age or sex, and the infectious disease reporting data would permit infections and other co-morbidities distribution for fatal cases was similar to that for non improved assessments of disease burden. The issue of comorbidity is likely tends to have a worse outcome than septicaemia experts, but the reader needs to be aware that these of greater consequence for chronic diseases, where 176 caused by other gram-positive bacteria, and Ontario Burden of Infectious Disease Study Chapter 5 / Strengths and Limitations Institute for Clinical Evaluative Sciences Ontario Agency for Health Protection and Promotion S. We were through our syndrome-based approach to estimate Use of different time frames for also ofen unable to distinguish between infectious disease burdens of various infectious agents. This was necessary because the acquired in these settings, and the interventions morbidity and mortality for certain non-traditional availability of the data varied by source. Tese and health states generated outbreaks in Ontario either before data codes are assigned to deaths or hospitalizations Due largely to lack of readily available data. Teir burden purposes of billing the Ontario Health Insurance using health administrative data), as well as the would have been signifcantly higher had another Plan (for ofce visits), but their accuracy for timescale of the project, we did not include certain time frame been used. However, our methodology provides a The results here may be limited in the future for procedures) matched in 94%. Most responsible useful framework for the addition of these pathogens, interpretation of disease burden. Some infectious agents could be the mortality data were compiled, the most recently cases is acceptable because they do not contribute considered under more than one disease grouping available data were from 2005. Unfortunately, we were able to adjust for Bacterial Infections group and hepatitis B was is anticipated in the near future. Most infectious diseases so could have reasonably been included under the comparisons, it was a deliberate decision by the are of short duration, so most instances of reportable Common Bacterial Infections group. Despite subset of infectious diseases with chronic courses Mortality data quality and availability the methodological diferences, it was reassuring to. Consequently, many deaths are attributed to non-infectious causes even if some of cases of blood-borne viruses underestimates the Burden of undiagnosed/ those deaths may have been precipitated or hastened underreported cases impact of prevalent cases diferentially in some by an infectious agent. Our estimates generally do not include cases that to consider an infectious etiology, incomplete had symptoms but did not seek medical attention Health care utilization data quality investigation for diagnosing infectious diseases or and/or were not diagnosed and reported, although Health care utilization data in Ontario are collected misattribution of the cause of death. Although it we attempted to adjust for underreporting and primarily for the purposes of administering the is fair in some cases to attribute the death to the underdiagnosis when possible. While this limitation health care system, and are used secondarily for underlying illness. For example, For the physician claims data, only a single diagnostic severe infections. Second, microbiological testing is 127 sometimes a diagnostic code for a certain disease code is associated with each visit; this may lead to conducted across a range of laboratories. However, laboratory data were indirectly were coded for the diferent encounters that actually not been fully assessed. Other limitations include: the incorporated in this report, as the estimation of comprised the same illness, then these instances possibility of duplicates; the symptom onset date may the burden of some diseases. In the future, the and then a subsequent diagnosis of pneumonia for reported date; and missing data. Lastly, due to the Ontario Laboratory Information System may the same instance of a lower respiratory tract illness). First, many infections are agent (when using the syndrome-based approach multiple infections occur sequentially in that diagnosed on clinical grounds. Ontario Burden of Infectious Disease Study Chapter 5 / Strengths and Limitations Institute for Clinical Evaluative Sciences Ontario Agency for Health Protection and Promotion Reliance on epidemiologic studies Differential burden in population 128 and expert opinion subgroups Many of the parameters used in this study are not We were unable to take into account the diferential based on empirical Ontario data, which would have burden that would be expected for certain population been more ideal than relying on: 1) epidemiologic subgroups, such as more severe infections among studies that may not be representative of present people with impaired immune function or diferent day Ontario; and 2) expert opinion, which may infectious disease risks among new immigrants to be susceptible to referral/spectrum bias. Terefore, we may have underestimated epidemiologic studies may or may not have been the burden of diseases that commonly occur among conducted within Ontario or even Canada, their such subpopulations. This may be especially true if the studies were carried out in countries with diferent health care systems. The Ontario Burden of Infectious Disease and the Population Health Impact of Disease in To our knowledge, this represents the most Study sought to estimate the burden Canada methodologies and used a range of local thorough examination of the burden of infectious of a wide range of infectious diseases data sources and epidemiologic studies to estimate, diseases to date. Ontario Burden of Infectious Disease Study Chapter 6 / Conclusions and Recommendations Institute for Clinical Evaluative Sciences Ontario Agency for Health Protection and Promotion 130 Some of the major fndings included the following. Although the limitations burden of infectious diseases could be attributed health care settings; addressing this burden will related to the data sources and parameters required to the top fve pathogens. The results of this of the efectiveness of available interventions is report indicate that hepatitis B and C are among another important component that will infuence the 10 most burdensome infectious diseases priority setting, and economic, political and ethical in Ontario. Eforts to making, identify areas of future research and action, identify individuals with hepatitis B and C prior to and highlight gaps in data availability and quality. We entry, and to support them and their contacts afer hope that planners, decision-makers, practitioners arrival, would facilitate prevention of a substantial and researchers will use these fndings in their eforts portion of the burden of viral hepatitis. Ontario Burden of Infectious Disease Study Chapter 6 / Conclusions and Recommendations Institute for Clinical Evaluative Sciences Ontario Agency for Health Protection and Promotion 133 References Ontario Burden of Infectious Disease Study References Institute for Clinical Evaluative Sciences Ontario Agency for Health Protection and Promotion 134 1. New York: Oxford University Press and Accessed on September 12, 2010 at dsp-psd. The Burden of Disease and Injury in Melbourne, Australia: Victorian Government Department of Human Australia. Ontario Burden of Infectious Disease Study References Institute for Clinical Evaluative Sciences Ontario Agency for Health Protection and Promotion 22.

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Tese diferences are summarized in Table 4:3 and can be used as a guide to evaluate patients when considering these two diagnoses. The experienced clinician knows that the diagnosis in all patients must be periodically reconsidered and reserve the right to change their minds about a diagnosis when new data or test results become available. Neuromyelitis optica: a demyelinating disease characterized by acute destruction and regeneration of perivascular astrocytes. She has now presented in clinic again with another transverse myelitis attack and optic neuritis. Tese individuals can present with numbness, weakness, walking difculties, and/or bladder and bowel dysfunction. When infammation of the spinal cord is identifed patients must be aggressively treated to limit the scope of damage. Subsequently patients must be carefully and systematically evaluated in an attempt to understand the underlying cause of the myelitis so that an appropriate treatment and prevention plan can be formulated. This is sometimes referred to as a forme fruste, French for the partial presentation of a disease. Yet at the time of the myelitis there is clinical evidence of only one lesion and only one event in time. If identifed early it can make a signifcant diference because the clinical treatments are so diferent. Both of these conditions can cause attacks and corresponding symptoms that are separated in time and space. Sarcoid, while more common in African American women, can also occur in Caucasians and men. Five percent of patients with sarcoidosis present with neu rologic symptoms, but without the pulmonary symptoms typical of sarcoidosis. Activated lymph nodes could be targeted for biopsy in order to look for evidence of granulomatous (non-caseating) infammation that is diagnostic of sarcoidosis. Tese patients present with severe and recurrent loss of vision from optic neuritis and change in sensations of the body from spinal cord infammation and demyelination (transverse myelitis). Tese patients can have brain lesions in addition to the well known spinal and optic abnormalities. Brainstem tegmentum events can be associated with vomiting, vestibular or ocular motor abnormalities, and the more classic syndromes of optic neuritis or transverse myelitis. Analyses of cerebrospinal fuid in the diagnosis and monitoring of multiple sclerosis. Its mechanism of action involves modulation of the sphingosine-1-phosphate receptor. This drug promotes the redistribution of lymphocytes from the circulation to the lymphoid organs and inhibits the egress of lymphocytes back into circulation. Over the course of the morning, these sensations moved up to her chest on the right side in conjunction with a squeezing sensation around her mid thorax. She denied any weakness, alteration in gait, or change in bowel or bladder function. She had no antecedent fever, infection, trauma, or known exposures to explain the symptoms. On neurological exam, she had reduced sensation to soft touch in a circumferential distribution with a sensory level at approximately T5. In addition, she had evidence of mild optic disc pallor in the left eye that was suggestive of a subclinical optic neuropathy. The patient denied having an episode of visual disturbance that would correlate with optic neuritis. One of the white matter lesions was ovoid in shape, and another was oriented perpendicularly to the long axis of the ventricles. Cerebrospinal fuid showed ten lymphocytes, normal protein and glucose, two oligoclonal bands and an elevated IgG index of 1. The patient was treated with intravenous methylprednisolone at 1gm daily for three days without a taper. Optic disc pallor is a manifestation of both infammatory optic neuritis and subclinical optic neuropathy. In es sence, what could be ofered to this patient to reduce the risk of future clinical events of the disease process. This also means a reduction in the corresponding compromise or loss of functional capabilities including physical, emotional, and intellectual capacities. Tree of the interferons (Betaseron, Rebif, and Extavia ) are administered by subcutaneous injection and taken either every other day (Betaseron and Extavia) or three times weekly (Rebif). Tese medications are available in preflled syringes that can be used with an autoinjector device. This makes the process of taking treatment substantially convenient and highly practical. A once weekly formulation of interferon (Avonex ) is available and administered through intramuscular injection. The side efects of interferons are well recognized and include fu-like symptoms, headache, and arthralgias. In most patients, pre-treatment with a nonste roidal anti-infammatory agent is sufcient to abolish these side efects. A combined preparation called Treximet includes naproxyn (500mg) and sumitriptan (85mg). Injection site reactions are more common with subcutaneous interferon treatment when compared to weekly intramuscular interferon. Careful counseling and attention to injection technique and site rotation typically limits the impact of this frustrating side efect. Tese studies are performed at baseline, then again at three months after the initiation of treatment and every six months afterward. This therapy consists of a random polymer of the four principle amino acids contained in myelin basic protein. This polymer is administered by subcutaneous injection daily and appears to have potent immunomodulatory properties including the ability to increase the number of immune regulatory cells. Tese cells modulate by decreasing the immune responses and thereby reduce excessive infammation. Unlike the interferons, glatiramer acetate has fewer adverse side efects with the exception of site reactions. Over time, and with repetitive injection, lipoatrophy can develop in patients treated with glatiramer acetate. Once remission is achieved, the use of mitoxantrone is discontinued and a safer agent is utilized indefnitely for disease modifcation. A heightened risk of a vacuolar cardiomyopathy is associated with doses of mitoxantrone greater than 140mg/m2. Ejection fraction studies should be determined before each dose of mitoxantrone, and then yearly, following cessation of therapy. This antigen is a cell-surface integrin receptor that is expressed on the surface of T lymphocytes, B lymphocytes and macrophages. Integrins are transmembrane glycoprotiens that mediate cellular adhesion to substrates. The migration of lymphocytes and macro 63 phages is necessary for immune surveillance as they move from the blood into the brain. Even more impressive, natalizumab will reduce new gadolinium enhancing lesions by over 90%.

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This should not mislead the student who has taken a careful history of the time course of the events. Test for spasticity in the upper limbs by asking the patient to relax and rapidly extending the elbow. Test the lower limbs with the patient supine and relaxed; attempt to lift the leg off the bed by support it slightly rostral to the knee. Often, chronic spasticity coexist with contractures that make the clasp-knife aspect of spasticity difficult to discern. Like a lead pipe or mechanical rachet, the resistance to passive motion is uniform across the range tested. Cog-wheel rigidity can often also be appreciated at the elbow, but less readily in the lower extremities. Paratonia, also called gegenhalten, is increased tone from variable resistance to movement. Individuals with defuse cerebral disturbances or frontal lobe disorders may be unable to relax their muscles, producing paratonia. It can be distinguished from spasticity or lead pipe rigidity by the variable nature of the increased tone and a tendency for it to be worse when the arm is moved faster or when the patient is alarmed by a sudden examiner movement. Hypotonia, occurs acutely following injury to the pyramidal tracts (as in cord transection) and chronically with injury to the lower motor neuron, neuromuscular junction or muscle. Hypotonia is often difficult to demonstrate, but an asymmetry of tone can be demonstrate by asking the patient to rest their elbows on a bedside tables, with the wrists flexed; the arm with reduced tone shows greater flexion of the wrist. Test cerebellar function during the examination of eye movements (see above), looking for saccadic dysmetria, impaired ability to hold eccentric gaze (gaze-evoked nystagmus), and downbeat nystagmus. In the limbs, observe coordination during finger-to-nose and heel-to-knee-to shin testing. During rapid repetitive movements, such as tapping each side of the hand in turn against the thigh, note irregularity of the movement, which is called dysdiachokokinesis. During gait testing, observe whether the base is broadened, whether the patient can perform rapid turns without losing balance, and whether they can walk in tandem. In patients with no sensory symptoms, it is essential only to screen sensation in the toes; vibration and joint position sense are most sensitive. In addition, all patients should be tested for sensory extinction with double-simultaneous stimulation to identify any neglect. The single most useful maneuver is to ask a patient, presuming that they are competent to respond, whether they have numbness or unusual sensations anywhere over their head or body. Sometimes even putting temporary pin marks on the borders can be helpful to guide the examination. Always note whether the patient is attentive to testing; be prepared to take a break if they are tired. Modalities tested in the screening neurological examination include pain and temperature, joint position sense, vibration, discriminative sensation such as graphesthesia, and occasionally other specialized testing. It may be assayed by pin sensation (asking whether sharp or dull), or temperature sensation (warm or cool). Remember not to reuse a pin on different patients, in order to avoid the potential of spreading disease, and there is never need to draw blood in the testing of pain. Only the recognition of sharp sensation gives information to the examiner, since sharp will be perceived as dull and dull will be perceived as dull in most areas or relative anesthesia. Therefore, the examiner should make most of the test sensations with a sharp point, and only throw in a few dull sensations as control stimuli. Deep pain can be ascertained by squeezing a tendon, but this is not usually done in the alert patient. Temperature sensation can most easily be assayed by holding the usually cool tuning fork up against the skin of the distal extremities and asking if it feels cool. Decrease of cool sense or of pain sense should be drawn on a sketch or described in terms clear enough to allow a reader to transfer the words to a drawing of his or her own. A distribution of numbness in a stocking-glove pattern suggests a diffuse polyneuropathy, such as might occur with some forms of diabetes mellitus. If the patient is numb in the little finger and half of the adjacent ring finger and the corresponding part of the palm of the hand, then an ulnar neuropathy should be considered. Numbness on the anterior and lateral thigh may indicate a problem with the lateral cutaneous branch of the femoral nerve. Hemibody numbness below a certain level, for example mid thoracic or cervical, would suggest spinal cord lesion. Numbness involving the face cranial nerve problems, and numbness involving face and body on one side would point to problems in the somatosensory system of the brain, including thalamus, hemispheric white matter or parietal cortex on the side contralateral to the numbness. Position and vibration sense travel together in the dorsal column of the spinal cord through the brainstem, to cross at the medial lemniscus, to ascend to ventral posterior thalamus, and from there to parietal cortex. Test vibration sense by applying a large (128Hz) tuning fork against the toenail or the bone of the large toe on each side. If vibration cannot be perceived at the toes, the examiner should test vibration at the malleolus of the ankle, and then the knee, and then the iliac bone at the hip. If there are symptoms referable to the arms or hands, or vibrations senses abnormal in the feet, then testing vibration on the bones of the fingers or wrist should be performed. Vibration testing on the forehead or on the sternum is useful in suspected cases of functional (hysterical) numbness. A sharp division of vibration perception at the midline of these bones is unphysiological, since the vibration carries through the bone for a considerable distance. Position sense may be impaired with peripheral nerve injuries, rude or posterior spinal cord processes, brainstem, white matter or parietal cortical diseases. The toe should be held at the side when moving it in order to eliminate cues from pressure on the top or bottom of the toe. If position sense is absent in the toes, then it should be assayed in the ankles and knees. Position sense may also be tested by moving the distal knuckle of the finger joints up and down. An indirect measure of position sense is the finger to nose test with the eyes closed and the attempt to maintain palms upward without drift, with the eyes closed. Patients with position sense abnormality may find their finger missing their nose, but with no difficulty powering the finger to the nose, or may find their hand drifting out in to space. Complete anesthesia to any form of touch is a rarity in the neurological examination, but sometimes does occur with complete nerve or root lesions. These areas should be assayed with a light touch with a wisp of cotton, heavy touch with a finger as well as pin sensation. Be careful to not overlook a spinal sensory level with anesthesia from one point on the body downward. This may be an indication of a serious condition such as spinal cord compression by metastatic tumor. Hypesthesia indicates partial reduction of a sensory modality and anesthesia absence of the sensory modality, not to be confused with surgical anesthesia which can mean loss of consciousness as well as loss of pain sensation. Sensitivity of skin from irritation such as sunburn, a partial peripheral nerve injury or a central process, usually at the level of the thalamus can all cause dysesthesia. Pain clinics invest a great deal of effort in diagnosis and therapy of syndromes of dysesthesia. The student should refer to textbooks for discussion of causalgia, or reflex sympathetic dystrophy. The muscle contains fibers called intrafusal fibers, which provide a reflex loop signal via the spinal cord when they are stretched.

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Antioxidant Properties the skin is the largest organ in the body and is the outermost barrier. Resveratrol itself is able to directly scavenge free radicals such as hydroxyl, superoxide, and metal/enzymatic-induced and cellular generate radicals. These genes encode enzymes such as glutathione peroxi dase, catalase, superoxide dismutase, and hemoxygenase-1. Utilizing autoradiography, a signifcant amount of specifc [3H]-resveratrol binding sites within the HaCaT cell epidermis as compared to the dermis, with a majority of sites found within the granular layer. These proteins aggregate between collagen bundles in the aging dermis, causing the characteristic sallow appearance of photoaged skin. The loss of collagen and accumulation of end-glycation products cause the skin to become thin and wrinkled. Resveratrol also activated the transcription of estrogen-responsive reporter genes. Therefore, resveratrol can function as a phytoestrogen and estrogen beta-receptor agonist. Further studies should be performed to investigate the use of resveratrol as a topical anti-aging cosmeceutical with similar collagen-boosting effects of estrogen, which can decrease the associated risk factors of oral estrogen use. Facial hyperpigmentation can also contribute to an aged appearance and can be distressing. Post-infammatory hyperpigmentation can result after an infammatory dermatosis or irritation, in which increased melanin production or transfer of melanin to keratinocytes is induced by skin injury. Causative factors include increased amounts of melanin in response to sun exposure, oral contraceptives, and pregnancy. Cultured human melanocytes were treated with resveratrol 20 g/mL for 24 h, which signifcantly decreased in situ tyrosinase activity without adversely affecting cell viability or numbers. Additionally, resveratrol caused a signifcant reduction of tyrosinase protein levels that correlated with the decrease in tyrosinase activity. Hypertrophic and keloid scars are an abnormal form of wound healing characterized by excessive fbroblast proliferation and collagen production after injury. Keloids extend upwards and beyond the original site of the scar onto normal adjacent skin, while hypertrophic scars are within the margins of the original site of injury. Hypertrophic scars present as erythematous, itchy, raised lesions on the site of the skin injury. First and second-line treatments include intralesional corticosteroids, exci sion, skin grafting, and pressure therapy, among others. Resveratrol was shown to markedly alter cell morphology after incubation with 150 M resveratrol. Cell proliferation was signif cantly inhibited in a dose and time-dependent manner. Specifcally, treatment with resveratrol caused fbroblast cell cycle arrest at the G1/S phase and induced apoptosis in a dose and time-dependent manner. The investigators also investigated whether resveratrol would also reduce collagen. Production of the collagen precursor hydroxyproline was signifcantly decreased in a time-dependent manner when fbroblasts were treated with 150 M resveratrol for 24, 48, and 72 hours. Most importantly, resveratrol suppressed the proliferation of keloid fbroblasts and induced apoptosis of these fbroblasts. These results suggested resveratrol as a possible compound for the treatment of hypertrophic scars. Wound Healing Wound healing is a dynamic, complex, restorative process in response to skin injury. There are three phases involved in wound healing: infammation, proliferation, and maturation and remodeling. The immediate infammatory phase is characterized by activation of the local innate immune system, which leads to an infux of neutrophils and macrophages. A 4-cm midline laparotomy was performed, and then treatment was maintained until the rats were sacrifced at post-operative day 7 or 14. Tensile strength and histology of the wounds were measured, along with hydroxyproline levels, which would be indicative of collagen deposition. It was found that oral resveratrol signifcantly increased tensile strength of the abdominal fascia and increased hydroxyproline levels by postoperative day 14. Additionally, neovascularization on postoperative days 7 and 14 were signifcantly higher in the resveratrol treatment group compared with control. Granulation tissue and fbroblast maturation scores were also signifcantly higher for the resveratrol treatment group when compared with control. These fndings showed that resveratrol might be a useful adjunct for wound healing. It is known that resveratrol is naturally produced by several plants, including peanuts, mulberries, and skins of certain grapes, when under attack by bacte rial or fungal pathogens. At each time interval, the cultures were plated on blood agar plates and colony growth was observed. Resveratrol signifcantly decreased viable counts at 1 hour of incubation, and continued being reduced in a time-dependent manner, and at 24 hours, no colonies were able to grow. Resveratrol activity against Lactobacillus strains was also investigated to determine any negative effects on natural fora. Acne As mentioned earlier, resveratrol is a natural phytoalexin exhibiting natural antimicrobial and anti infammatory properties. Acne vulgaris is one of the most common skin disorders seen by dermatolo gists, affecting patients from infancy into adulthood. There are many different causes of acne, most commonly beginning with hormonal changes in puberty, which leads to stimulation of sebaceous glands within an obstructed pilosebaceous unit; this creates a favorable environment for bacteria to play a pathogenic role in infammatory acne. The causative bacterium, Propionibacterium acnes, induces infammation in the comedo by inducing the release of neutrophils and pro-infammatory cytokines, which causes the characteristic infamed lesions of acne. First-line treatments for acne include oral and topical antibiotics, which are often combined with comedolytic treatments such as topical retinoids and salicylic acid. The plates were washed and then incubated with 118 other various plant extracts, including resveratrol, for 24 hours. Only fve compounds were capable of signifcantly reducing more than 50% of bioflms when tested at a concentration of 0. The use of resveratrol for the treatment of clinical infammatory acne was investigated by Fabbrocini et al. Resveratrol was incorporated into a carboxymeth ylcellulose-based gel at a concentration of 0. Twenty patients were treated with the formula applied to one side of the face once daily for 60 days. Clinical evaluation utilizing a standardized Global Acne Grading System showed a signifcant mean reduction of 53. All 20 patients were satisfed with the active treated size and tolerated the resveratrol gel very well without side effects. Conclusion Resveratrol, a powerful antioxidant polyphenol naturally found in the skin and seeds of red grapes, offers a wide range of skincare benefts. These include antioxidant and chemopreventive properties, anti infammatory properties, improvement of wound healing and hyperpigmentation, and anti-microbial properties. These qualities have brought resveratrol to the forefront as a highly effective ingredient in topical cosmeceuticals. Delivery of resveratrol, a red wine polyphenol, from solutions and hydrogels via the skin. Monitoring caffeine and resveratrol cutaneous per meation by confocal Raman microspectroscopy.

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