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By X. Trano. George Washington University.

Skin changes are seen in 5090% of patients: difuse hyperpigmentation discount levitra 20mg visa impotence pumps, hypertricho- sis discount levitra 10 mg line impotence young men, skin thickening and formation of glomeruloid hemangiomas a type of capillary an- gioma which clinically resembles senile angiomas discount levitra 20 mg fast delivery erectile dysfunction therapy treatment, but difers histologically with vascular channels resembling renal glomeruli generic levitra 20mg fast delivery erectile dysfunction treatment natural medicine. Presenting signs are most ofen a periph- eral sensory / motor polyneuropathy and endocrine dysfunction (diabetes, hypothyroid- ism, erectile dysfunction). Main causes of death are cardiorespiratory failure, infection, capillary leak syndrome and inanition, but interestingly not progression to multiple myeloma. Treat- ment focuses on radiation therapy to eliminate Castleman disease and osteosclerotic my- eloma; medical treatment rests on chemotherapy (cyclophosphamide, melphalan, corti- costeroids). Schnitzler syndrome (SchS) is a relatively new acquisition (Schnitzler L, 1972) to the realm of paraneoplasias which appears to be fairly rare with around 100 published cases. The urticarial lesions do not difer much from those of plain urti- caria (though they may persist somewhat longer, are mainly located on the trunk and are not accompanied by angioedema); histopathology is non-contributory. Immunofuores- cence revealed paraprotein deposits at the dermoepidermal junction zone and in dermal capillaries in a subset of cases (but such deposits are found in Waldenstrm disease as well where no wheals are formed). Although various autoantibodies were discovered, an autoimmune basis for the disease is not evident. The pathogenesis of SchS was enigmatic for long time and is still not fully elucidated. Some features, however, are parallel to some of the hereditary periodic fever syndromes, now included in the so called autoinfammatory diseases group (Masters et al. Tey are thus considered not a dysregulation of the adaptive but of the innate immune sys- tem, caused by mutations in various relevant genes, e. SchS is a disease of advanced age, getting manifest at average at 50 years, whereas the fever syndromes are of neonatal onset. It is a slowly progressive incapacitating disorder which is associated with a monoclonal gammopathy (IgG light chain) in up to 80%. Myeloma (or much more rarely other lymphoproliferative diseases) develop in less than 10%. Normolipemic difuse plane xanthoma is a rare non-Langerhans cell histiocytosis char- acterized by fat yellow plaques predominantly of the face. It is frequently (but not always) associated with monoclonal gammopathies (IgG) and has been reported in myeloma and other lymphoproliferative disorders. It is believed that paraproteins and lipoproteins form complexes which are taken up by the histiocytes. Necrobiotic xanthogranuloma is likewise a rare instance of a non-Langerhans cell histi- ocytosis which is characterized by papulonodular lesions predominantly of the face (espe- 532 Peter Fritsch Fig. Scleromyxedema: pearl-like arrangement of indurated opaque papules retroauricularly and on the abdomen. Histopa- thology shows a granulomatous infltration of infammatory cells, foam cells and Touton giant cells, with sharply delineated necrotic areas. Cryoglobulinemia type I is characterized by the presence of a single monoclonal immu- noglobulin (IgM or IgG) with the properties of cryoglobulins, i. It is almost always associated with hematologic malignancies, in particular with multiple myeloma or B-cell lymphomas. Miscellaneous Acquired C1 esterase inhibitor dysfunction has been described in a few instances of sys- temic lymphoproliferative disease, monoclonal gammopathy and lupus erythematosus. Presenting sign is ofen severe polyarthritis, accompanied by systemic symptoms (fever, weight loss, weakness). It is also associated in up to 30% with internal malignancies of various kinds (ofen pulmonary and breast carcino- mas). Unfortunately, there is some blurring of terminology (Varki, 2007): clinical hallmark of the syndrome is the recurring nature of superfcial and deep phlebothrombosis (ofen complicated by pulmonary embo- lism), which leads to the impression of a migratory process. Today, the term is ofen used as a synonym for malignancy-associated hypercoagulability in general. The risk is markedly increased around the time of detection of the neoplasm and in metastatic disease, and it is additionally considerably higher in patients undergoing surgery, chemotherapy, antiangiogenetic and hormonal therapy. Multiple mechanisms may be (and usually are) involved in creating a thrombophilic milieu in cancer patients, and many of them are operative well before the neoplasm is de- tected, as e. The mechanisms overlap and may specifcally shape the risk profle and clinical course in individual neoplasms. Other relevant cancer cell activities are: the expression of the tumor coagulant a cysteine protease only expressed in malignant tissue which directly activates factor X; defcient activity of von Willebrand factor cleaving pro- teases; down-regulation of thrombomodulin and thrombospondin. For the former, anticoagulation therapy with unfractionated heparin is recom- mended (Varki, 2007) in view of its broad biological activities which may be more suited in dealing with a multifaceted coagulation disturbance than low molecular weight heparins. Not surprisingly, the likelihood to detect undiagnosed malignancies is higher the more extensive the screening is (Carrier et al. Summary Cutaneous paraneoplasias include a number of dermatoses which are associated in a vari- able degree with internal malignancies. Tey are a very heterogenous group of diseases, difering greatly in their clinical appearance and pathogenesis (which is not well under- stood in most of them). Some of the more re- cently described entities promise a better insight in the mechanisms of cancer pathophysi- ology. Dermatology has taken a keen interest in the paraneoplasias, particularly because of the expectation that they may lead to earlier detection of malignancies at a time when they are more likely to be curable. A case studied with immunofuorescence, immunoelectron microscopy and immunohistochemistry. E Medicine Dermatology, Internal Medicine Noble S, Pasi J (2010) Epidemiology and pathophysiology of cancer-associated thrombosis. J Dermatol Science 47:17 Schnitzler L (1972): Lsions urticarienne chroniques permanentes (rythme ptaloide? Richard L, Sturtz F, Couratier P (2008) Contribution of electron microscopy to the study of neuropathies associated with an IgG monoclonal paraproteinemia. Micron 39:6170 Varki A (2007) Trousseaus syndrome: multiple defnitions and multiple mechanisms. Blood 110:17231729 18 Targeted Therapies in Autoimmune 19 and Inflammatory Skin Disorders Rdiger Eming and Ingo H. Tarner Introduction Autoimmune diseases represent the clinical manifestation of a complex dysregulation of im- mune mechanisms and regulatory networks fnally resulting in loss of self-tolerance. In re- cent years the principal insight into underlying immune processes has greatly advanced. Novel therapeutic strategies in autoimmunity aim at specifcally targeting defned cellular and humoral components of the immune system, thus trying to reduce severe side efects and comorbidity which currently arise from broad unspecifc high-dose immunosuppres- sive therapies. Due to a more defned understanding of basic immune mechanisms shap- ing the complex network of chronic infammation and autoimmunity, these diseases have at- tracted a plethora of promising therapies targeting a variety of cell surface molecules, soluble mediators and intracellular proteins that are of importance for the function of immune cells. Monoclonal antibodies directed against defned receptors on the surface mostly of B-lym- phocytes and to a lesser extent of T-lymphocytes as well as soluble receptor fusion proteins interfering with important infammatory mediators, such as tumor necrosis factor alpha, have been the dominant tools recently applied in various autoimmune and chronic infam- matory disorders. Moreover, stem cell therapy and small molecule inhibitors are being vali- dated in clinical trials for the treatment of diferent autoimmune disease. This chapter aims at providing a concise review of the most recent developments and their corresponding clinical translation in dermatological diseases and closely related rheumatic autoimmune disorders. Antigen Specific Approaches for the Therapy of Autoimmune Diseases The majority of therapies approved for autoimmune diseases involve global immunosup- pressive and immunoregulatory strategies, respectively, inhibiting infammatory (auto)im- mune processes. Although partly efective in controlling autoimmune dysregulation, these drugs harbour numerous side efects leading to severe comorbidity and thus continous im- munosuppressive therapy is mostly not feasible. Tarner pies in autoimmunity has been able to induce long-term, drug-free remission in any auto- immune disease.

For those still unresponsive purchase 20mg levitra erectile dysfunction vacuum pump price, there are other optional therapies that have been effective in series of cases purchase levitra 20mg protein shakes erectile dysfunction. Prob- ably generic levitra 10mg with visa erectile dysfunction caused by obesity, the most accepted one would be to administer pulsed Differential Diagnosis intravenous methylprednisolone (30 mg/Kg for 13 days) cheap levitra 20mg on line erectile dysfunction oil treatment. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fin- Although the exact mechanism of action is not clear, effec- gers and toes in children [in Japanese]. Kawasaki syndrome Fever, Endocarditis, and Kawasaki Disease, Council on Car- and the eye. High-dose gammaglobulin therapy for Kawa- composition in patients with Kawasaki disease. Curr Treat health professionals from the Committee on Rheumatic Options Cardiovasc Med 2007; 9(2):148158. The time interval between ocular and audiovestibular involvement may be as long as 2 years. Another group includes patients with more than 2 years between the onset of the ophthalmogic symptoms and the audiovestibular manifestations. A third group includes patients with typical ocular manifestations associated, within 2 years, with audiovestibular symptoms different from Meniere-like episodes. Keywords Autoimmunity progressive hearing loss interstitial keratitis when both eye and ear findings were noted) was 38 years Introduction (range 970 years) (6). The earliest description of nonsyphilitic keratitis coexisting with vestibuloauditory disturbances was published by Morgan and Baumgarther in 1934 (1). This opinion and Williams called attention to the systemic manifesta- has been supported by the findings of antibodies against tions of this syndrome (3). Interestingly, tinnitus, vertigo and hearing loss, which is usually bilateral only 5% of the patients were initially presented with both (4). Hearing loss may initially fluctuate with repeated vestibuloauditory and ophthalmologic symptoms. In this attacks but generally develops progresses to irreversible series, 47% of patients presented initially with only vestibu- bilateral deafness in 5285% of patients (6, 12). In their loauditory signs and 33% had only ophthalmologic symp- review, Gluth et al. In most patients (85%), both vertigo (90%), tinnitus (80%), ataxia (53%) and oscillopsia vestibuloauditory and ophthalmologic symptoms developed (25%). Additionally, physical examination Ophthalmic Manifestations revealed spontaneous and/or gaze-induced nystagmus at some point of their disease in 20% of the patients. In most cases, both eyes are affected during the disease Systemic Manifestations course, with great variability in symptoms from one eye to the other, and from day to day. Cardiovascular involvement is present in 10% of tapered slowly and continued for 26 months. Recent reports suggested that, in cases of relapse tis and Wageners granulomatosis (11). Patients with profound hearing loss after unsuccess- Laboratory and Radiological Data ful treatment with anti-inflammatory drugs are candidates for cochlear implantation. Low titers of rheu- Unlike other systemic collagen or autoimmune diseases, matoid factor, antinuclear antibodies and cryoglobulins it is not associated with a specific autoantibody. The other difficulty in gathering diag- Treatment nostic criteria arises from the low incidence of reported cases of the disease. The time interval between ocular and rapid initiation of high-dose corticosteroids (11. Cogan Infectious syndrome: studies in Thirteen patients, long-term follow-up, Congenital and acquired syphilis and a review of the literature. Cogan Immune-mediated diseases syndrome: a retrospective review of 60 patients throughout a Polyarthritis nodosa half century. Serum antibodies against corneal Rheumatoid arthritis and internal ear tissues in Cogans syndrome. Laryngol Relapsing polychondritis Temporal arteritis Rhinol Otol 1984; 63: 42832. Autoantibodies to Behc ets syndrome innear ear and endothelial antigens in cogans syndrome. Clinical rele- between the onset of the ophthalmogic symptoms and the vance of magnetic resonance imaging and computed tomo- audiovestibular manifestations. Acta Otolaryngol 1993; 113: patients with typical ocular manifestations associated, 62531. Cor- patients could benefit from early referral to specialized onary involvement in cogans syndrome. Am Heart J 1992; centers, where early initiation of immunosuppressive 123(2): 52830. Syndrome of nonsyphilitic interstitial keratitis and festations of cogans syndrome. The natural history of the disease is cure in most cases, although recurrence and end-stage kidney disease are described. However, Schonlein first described the combi- This is a variant of acute leukocytoclastic vasculitis nation of acute purpura and arthritis in children in 1837, of the immunoglobulin A (IgA)mediated type. This and Henoch reported the manifestations of abdominal disorder is characterized by a purpuric rash occurring pain and nephritis in 1874. Some have specu- Endothelial 65% 30% proliferation lated that an antigen stimulates the production of IgA, Thin basement- 6% 0% which, in turn, causes the vasculitis. IgA and immunoglobulin M (IgM) and/or C3 deposit Clinical Manifestations Capillary wall 70% 43% staining for IgA The signs and symptoms are listed in Table 26. Palpable purpura usually occurs first on the lower limbs and then spreads to the buttocks. Hives, angioedema, and Both occur in the same family target lesions can also occur. Vesicular eruptions and swel- Same prevalence in certain ling and tenderness of an entire limb have been noted. In 80% of patients, Arthralgia 50% 0 renal involvement becomes apparent within the first Renal pathology (Table 3) Long-term remission 73% 20% 4 weeks of illness. Abdominal pain and bloody diarrhea may precede the Hematemesis occurs less frequently. The occur in approximately 50% of cases and usually consist of pain most commonly affects the knees and ankles and less frequently the wrists and fingers. Less frequent Prevalence manifestations occur in other organs, mostly by vasculitis. The results show effectiveness formation of pathogenic immune complexes were recently in both reducing proteinuria and improving the histologi- identified. Serum levels of IgA anticardiolipin antibody all patients who received a follow-up kidney biopsy (18). Early were: age <20 years at onset, palpable purpura, bowel tonsillectomy was correlated with better outcome. The new (revised) pathological changes on biopsy, including crescentic criteria, from 2006 are listed in Table 26. Long term renal criteria) in addition to at least one of the following four criteria prognosis of Henoch-Shoenleine purpura in an unselected 1. The American College of Rheumatology IgA1-containing immune complexes, and activation of 1990 criteria for the classification of Henoch-Schonlein pur- mesangial cells. Scand J Rheumatol gical study comparing Henoch-Schonlein purpura nephritis 2005; 34(5): 3925. Pediatr of urinary podocytes reflects disease progression in IgA Nephrol 2005; 20(8): 108792.

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A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis 20 mg levitra otc erectile dysfunction treatment at gnc. Effect of diet and smoking intervention on the incidence of coronary heart disease purchase levitra 20 mg food that causes erectile dysfunction. An interventional controlled trial in the multifactorial prevention of coronary heart disease purchase 20 mg levitra free shipping erectile dysfunction protocol amino acids. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease levitra 10mg without a prescription treatment for erectile dysfunction before viagra. A statement for physicians and health professionals by the Nutrition Committee, American Heart Association. Canadian Consensus Conference on the Prevention of Heart and Vascular Disease by Altering Serum Cholesterol and Lipoprotein Risk Factors. Systematic review of dietary intervention trials to lower blood cholesterol in free-living subjects. The Norwegian diet during the last hundred years in relation to coronary heart disease. The efficacy of intensive dietary therapy alone or combined with lovastatin in outpatients with hypercholesterolemia. Individual variability in lipoprotein cholesterol response to National Cholesterol Education Program Step 2 diets. Long-term cholesterol-lowering effects of 4 fat-restricted diets in hypercholesterolemic and combined hyperlipidemic men: The Dietary Alternatives Study. A prospective study of moderate alcohol consumption and the risk of coronary heart disease and stroke in women. Demonstration of deductive, meta-analysis: ethanol intake and risk of myocardial infarction. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Serum total cholesterol and long- term coronary heart disease mortality in different cultures. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. Randomised trial of alpha-tocopherol and beta- carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Anti-Oxidant Study. Vegetable, fruit and cereal fiber intake and risk of coronary heart disease among men. Intake of dietary fiber and risk of coronary heart disease in a cohort of Finnish men. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control at Health Canada, Heart and Stroke Foundation of Canada. The concept of habitual physical activity is an integrator of the daily amount of energy expended for activity. Leisure time physical activity is of particular interest because the adult has typically about 3 to 4 h of discretionary time/day after completion of work, travelling, domestic chores and personal hygiene. Anumber of surveys conducted over the past two decades have shown that the profile of the participation in leisure-time physical activity among Canadians is characterized by several rather consistent features (1-4). Briefly, the level of participation in various types of activities decreases during the school years, more so in girls than in boys, with the lowest levels being reached during the last years of high school. Among young adults and middle-aged individuals, about one-third are totally sedentary, one third are occasionally engaging in some forms of physical activity and only about one-third are physically active regularly or fairly regularly. Participation rates are highest in Western Canada and lowest in the Atlantic Provinces. There is a strong seasonal effect on the participation rates of Canadians, with peak rates being attained in the summer months and the highest levels of sedentarism being observed during winter. In one of these studies, data were available on men and women, and the same relationship was observed in each sex (6). A substantial decrease in the risk is observed at moderate levels of physical activity or cardiorespiratory fitness, but more benefits appear to be derived from higher levels of physical activity or fitness (5,7). The effect is graded in the sense that the risk decreases progressively with the increase in the level of habitual physical activity or in cardiorespiratory fitness (5). The volume of activity necessary to induce some of these apparent benefits is not overwhelmingly high because the risk diminishes rapidly when comparing low with moderate weekly energy expended in physical activity (7-10). Even though moderate levels of habitual physical activity have an important effect, higher levels reduce the risk even more. Evidence also suggests that regular physical activity may be helpful in preventing recurrent events in patients with myocardial infarction (12,13). There is some epidemiological evidence suggesting that the risk of cerebrovascular accidents is less in active individuals (14), but other studies are negative (5). Cardiac muscle: Favourable changes in the heart muscle, cardiac blood vessels, coronary blood flow and myocardial metabolic characteristics have been described (20-23). Animal research and some observations in human subjects show that with regular exercise the size of existing cardiac vessels can be increased, that capillary density is augmented even in the presence of cardiac hypertrophy, that coronary blood flow capacity can be improved and that neurohumoral control over the myocardial vascular bed is improved (20-23). Regular endurance exercise leads to an increase in maximal oxygen uptake due to an enhanced ability to increase stroke volume and to widen the total body arteriovenous oxygen difference. Blood pressure: Many epidemiological studies have reported an inverse relationship between level of habitual physical activity and resting blood pressure. Intervention studies have shown that regular physical activity in patients with essential hypertension can reduce systolic and diastolic blood pressures by a mean of approximately 10 mmHg (29). Regular physical activity is associated with a mean reduction of systolic and diastolic blood pressure of 3 mmHg in subjects with a normal pressure and of about 6 mmHg in borderline hypertensives. Data suggest that being regularly active at moderate intensity is sufficient to induce these effects. A review of the prospective studies relating level of physical activity or cardiorespiratory fitness to the future risk of hypertension concluded that physical inactivity and low fitness level are associated with a 30% to 52% risk of developing hypertension over the years compared with more active or fit men and women (5. In acute response to physical activity, fat is oxidized in progressively increasing amounts as the total energy expenditure increases, so that lipids may contribute to as much as 90% of the oxidative metabolism in prolonged bouts of moderate intensity exercise. Regular exercise increases the activity of both skeletal muscle and adipose tissue lipo-protein lipase, thereby facilitating the use of circulating triglycerides as a fuel source in trained muscles and promoting the clearance of circulating triglycerides, even at rest. A number of studies suggest that regular physical activity has small but favourable influences on hemostatic factors: it decreases plasma fibrinogen concentration, increases fibrinolytic activity, diminishes antifibrinolytic activity and inhibits platelet aggregability (32). Important and favourable metabolic changes are observed with programs of walking and other low to moderate intensity, long duration exercise sessions that do not necessarily cause an increase in maximal oxygen intake. Health benefits are also likely to be accrued by daily, low intensity physical activity of longer duration (eg, 45 to 60 mins). Higher energy expenditure from leisure-time physical activity or from exercise at higher intensities are, however, likely to generate even more health benefits. For a middle-aged man, 30 mins of daily physical activity at moderate intensity translates into an additional weekly energy expenditure of about 1000 to 1200 kcal. This is a level of habitual physical activity associated with substantial health benefits. Lower levels of weekly energy expenditure associated with added physical activity carry lesser but nonetheless important health benefits. Because physical inactivity is so prevalent in the Canadian population, a sedentary lifestyle thus constitutes a very important risk factor. All children and adolescents should be physically active at moderate to high intensity levels on most days, preferably every day, for a minimum of 20 mins/day. Develop and evaluate innovative methods to promote regular physical activity in the Canadian population, particularly among hard to reach subgroups such as low socioeconomic status populations and ethnic minorities.

Immunology and Evolution of Infectious Disease Introduction 1 Multidisciplinary has become the watchword of modern biology buy levitra 20 mg amex drugs for erectile dysfunction philippines. Surely buy levitra 10 mg low price impotence at 37, the argument goes cheap levitra 20 mg erectile dysfunction first time, a biologist interested in the biochemical pathways by which genetic variants cause disease would also want to understand the population processes that determine the distribution of genetic vari- ants cheap 10mg levitra with mastercard best erectile dysfunction pills at gnc. And how can one expect to understand the interacting parts of complex immune responses without knowing something of the histori- cal and adaptive processes that built the immune system? Working in the other direction, evolutionary biologists have often treated amino acid substitutions within a parasite lineage as simply statistical marks to be counted and analyzed by the latest mathemat- ical techniques. Synthesis between the details of molecular biology and the lives of organisms in populations will proceed slowly. It is now hard enough to keep up in ones own eld, and more dicult to follow the foreign concepts and language of other subjects. The typical approach to syn- thesis uses an academic discipline to focus a biological subject. I use the biological problem of parasite variation to tie togethermanydierent approaches and levels of analysis. Why should parasitevariationbethe touchstone for the integration of disciplines in modern biology? On the practical side, infectious dis- ease remains a major cause of morbidity and mortality. Consequently, great research eort has been devoted to parasites and to host immune responses that ght parasites. This has led to rapid progress in under- standing the biology of parasites, including the molecular details about how parasites invade hosts and escape host immune defenses. But many parasites escape host defense by varying their antigenic molecules recognized by host immunity. The challenge has been to link molecular understanding of parasite molecules to their evolutionary change and to the antigenic variation in populations of parasites. On the academic side, the growth of information about antigenic vari- ation provides a special opportunity. For example, one can nd in the literature details about how single amino acid changes in parasite mol- ecules allow escape from antibody binding, and how that escape pro- motes the spread of variant parasites. Evolutionary studies no longer depend on abstractionsone can pinpoint the physical basis for success or failure and the consequences for change in populations. Molecular understanding of host-parasite recognition leads to a com- parative question about the forces that shape variability. Why do some viruses escape host immunity by varying so rapidly over a few years, whereas other viruses hardly changetheirantigens? The answer leads to the processes that shape genetic variability and evolutionary change. The causes of variability and change provide the basis for understanding why simple vaccines work well against some viruses, whereas complex vaccine strategies achieve only limited success against other viruses. Rather, I have long been interested in how the molecular basis of rec- ognition between attackers and defenders sets the temporal and spatial scale of the battle. The battle often comes down to the rates at which attacker and defender molecules bind or evade each other. The bio- chemical details of binding and recognition set the rules of engagement that shape the pacing, scale, and pattern of diversity and the nature of evolutionary change. Of the many cases of attack and defense across all of biology, the major parasites of humans and their domestic animals provide the most information ranging from the molecular to the population levels. New advances in the conceptual understanding of attack and defense will likely rise from the facts and the puzzles of this subject. From that foundation, I describe new puzzles and dene the key problems for the future study of parasite variation and escape from host recognition. I summarize the many dierent ways in which parasites generate new variants in order to escape molec- ular recognition. Next, I build up the individual molecular interactions into the dynam- ics of a single infection within a host. Theparasites spread in the host, triggering immune attack against dominant antigens. The battle within the host develops through changes in population numbersthe num- bers of parasites with particular antigens and the numbers of immune cells that specically bind to particular antigens. Ithendiscusshow the successes and failures of dierent parasite antigens within each host determine the rise and fall of parasite vari- ants over space and time. The distribution of parasite variants sets the immune memory proles of dierenthosts,whichinturn shape the landscape in which parasite variants succeed or fail. These coevolution- ary processes determine the natural selection of antigenic variants and the course of evolution in the parasite population. Experimental evolution of parasites under controlled condi- tions provides one way to study the relations between molecular rec- ognition, the dynamics of infections within hosts, and the evolution- ary changes in parasite antigens. Sampling of parasites from evolving populations provides another way to test ideas about what shapes the distribution of parasite variants. How do the molecular details of recognition and specicity shape the changing patterns of variants in populations? How does the epidemio- logical spread of parasites between hosts shape the kinds and amounts of molecular variation in parasite antigens? Icompare dierent types of parasites because comparative biology provides insight into evolutionary process. For example, parasites that spread rapidly and widely in host populations create a higher density of immune memory in their hosts than do parasites that spread slowly and sporadically. Host species that quickly replace their populations with ospring decay their population-wide memory of antigens faster than do host species that reproduce more slowly. How do these epidemiological and demographic processes inuence molecular variation of parasite antigens? At the molecular level, new technologies provide structural data on the three- dimensional shape of host antibody molecules bound to parasite anti- gens. At the population level, genomic sequencing methods provide detailed data on the variations in parasite antigens. One can now map the nucleotide variations of antigens and their associated amino acid substitutions with regard to the three-dimensional location of antibody binding. Thus, the spread of nucleotide variations in populations can be directly associated with the changes in molecular binding that allow escape from antibody recognition. No other subject provides such opportunity for integrating the re- cent progress in structural and molecular analysis with the conceptual andmethodological advances in population dynamics and evolutionary biology. My problems for future research at the end of each chapter emphasize the new kinds of questions that one can ask by integrating dierent levels of biological analysis. I present enough about the key cells and molecules so that one can understand how immune recog- nition shapes the diversity of parasites. For example, antigenic variation can help to escape host immunity dur- ing a single infection, extending the time a parasite can live within a particular host. Or antigenic variation may avoid the immunological memory of hosts, allowing the variant to spread in a population that previously encountered a dierent variant of that parasite. The nature of recognition depends on specicity, the degree to which the immune system distinguishes between dierent antigens. Sometimes two dierent antigens bind to the same immune receptors, perhaps with dierent binding strength. Cross- reactivity may also interfere with immune recognition when immune receptors bind a variant sucientlytopreventanewresponse but not strongly enough to clear the variant. Many parasites generate variants by the stan- dard process of rare mutations during replication. Although mutations occur rarely at any particular site during replication, large populations generatesignicant numbers of mutations in each generation. Other parasites store within each genome many genetic variants for an antigenic molecule.

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