By Q. Vandorn. Monterey Institute of International Studies. 2018.
This effort is proceed- ing in tandem with progress toward development of an effective vaccine cheap penegra 100mg mastercard. Immunotherapy for Infectious Diseases is intended to review the state-of-the-art developments of this rapidly emerging and evolving field penegra 100 mg cheap. Much of the work in this area is only beginning to be appreciated by clinicians and medical scientists. We hope Immunotherapy for Infectious Diseases will not only serve as a useful guide to current knowledge of the field, but will also stimulate readers to contribute to its further devel- opment. The first sec- tion provides an overview of the basic principles of immune defense, as seen in the context of developing strategies of immunotherapy. Because many infectious agents enter and exit through mucosal surfaces, there has been growing appreciation of the role of mucosal immunity in protection against infection and immunopathogenesis. The second section discusses the principles of immunotherapy on a molecular level. The fourth section reviews immunotherapy for additional infections and virus-asso- ciated malignancies. They repre- sent some of the finest minds working in this area, and did superb jobs in reviewing the latest information in their areas of expertise. Thanks also to the secretaries and copy editors who diligently worked to put together the elements of the book. Finally, I wish to thank the readers, who I hope will use the knowledge gained from this book to advance our ability to treat infectious diseases. In 1888 Emile Roux and Alexandre Yersin isolated a soluble toxin from cultures of diphtheria. The bacterium itself is only found in the throat, but its destructive effects are found throughout the body. Clearly, the bacteria must be sending out an invisible factor, most likely chemical in nature, to cause the body-wide destruction. They filtered diphtheria cultures to remove the bacteria and then injected the remaining fluid filtrate (which we call the supernatant) into healthy animals. As expected, the animals showed diphtheria lesions but without any obvious presence of bacteria. They then took serum from animals infected with diphtheria and injected it into healthy animals. When these animals were later inoculated with diphtheria, they were found to be resistant to infection. This first demonstration of defense against infection was described as mediated by antitoxin. It was clear to von Behring and Kitasato (2) that the antitoxin was specific only for diphtheria; it did not confer any defense against other forms of infection. We now know that this antitoxin is composed of anti- bodies produced specifically against the diphtheria microbe. In 1897, Rudolf Kraus first visualized the reaction of antitoxins to bacteria by simply adding serum from infected animals to a culture of the bacteria and seeing a cloudy precipitate develop as the antibodies bound the bacteria together. Other scientists took different approaches and revealed serum-based responses toward bacteria and their products. Initially these serum properties were given a range of different names, such as precipitins, bacteriolysins, and agglutinins. Immunologic research would have to wait until 1930 before these subtly different properties were unified and recognized as a single entity. Long before antibodies were actually isolated and identified in serum, Paul Erlich had put forward his hypothesis for the formation of antibodies. The words antigen and antibody (intentionally loose umbrella terms) were first used in 1900. It was clear to Erlich and others that a specific antigen elicited production of a specific antibody that apparently did not react to other antigens. He hypoth- esized that antibodies were distinct molecular structures with specialized receptor areas. He believed that specialized cells encountered antigens and bound to them via receptors on the cell surface. This binding of antigen then triggered a response and pro- duction of antibodies to be released from the cell to attack the antigen. First, he suggested that the cells that produced antibody could make any type of antibody. He saw the cell as capable of reading the structure of the antigen bound to its surface and then making an antibody receptor to it in whatever shape was required to bind the antigen. He also suggested that the antigen-antibody interaction took place by chemical bonding rather than physically, like pieces of a jigsaw puzzle. Thus, by 1900, the medical world was aware that the body had a comprehensive defense system against infection based on the production of antibodies.
Finally generic penegra 100mg free shipping, we examine our current understanding of the biology of frailty as a basis for generating hypotheses about the biological mechanisms that link aging and chronic diseases purchase 100 mg penegra mastercard. This approach led to the development of a number of classication systems, some relatively simple (such as Etiological Role of Aging in Chronic Diseases: From Epidemiological Evidence 41 the now disproven distinction between inammatory and degenerative diseases) and some extremely precise and sophisticated (such as classication of lymphomas based on histological characteristics). While the ability to recognize specic dis- eases and to treat them successfully has increased tremendously, the limitations of these approaches have also become apparent. Biomarker studies perhaps better than any other scientic approaches have offered evidence that, in many cases, diseases that are driven by different mecha- nisms converge into the same pathological and clinical manifestations. For example, it is now widely accepted that under the label of Alzheimer s disease exist a num- ber of conditions with different underlying mechanisms . Conversely, diseases that appear quite different from the perspective of phenotypic and end-organ mani- festations are now known to have shared etiologic biomarkers (e. Interestingly, such biomarkers are often also related to aging itself and predict the development of frailty, a major adverse health outcome associated with aging. This is consistent with evidence that the biology of aging is associated with chronic dis- ease development through mechanisms beyond the length of time for exposure and cumulative risk from external risk factors; rather, the evidence actually points to aging as playing a powerful causal role in development of chronic diseases. With the increase in longevity due to the demographic transition, chronic diseases have become the dominant causes of morbidity and mortality in the devel- oped world, and are rapidly reaching that dominance globally. However, we should not assume that the relationship between aging and disease is monotonic; in fact, it is quite complex. Some chronic diseases, such as those due to genetic defects, exposures during gestation, or environmental perturbation may become clinically evi- dent early in life and are unlikely to emerge after a certain age. Some other diseases have a typical age of emergence and only rarely occur outside a certain time window (e. Ferrucci Given the extreme variability of human pathology, making a generalization is difcult. However, it is plausible that biological aging plays an important patho- physiologic role in diseases whose incidence and prevalence increase with aging. To offer the counterarguments rst, there are basically two objections to this theory. In both cases, objections can be easily overcome by hypothesizing that the clinical emergence of disease results from a tradeoff between organ or tissue-specic susceptibility, the rate of progression by which subclinical processes become clinical, and the overall dys- regulation induced by the aging process. As an example of the latter, aging can facilitate an imbalance in cholesterol metabolism, but such imbalance may never emerge clinically in individuals who do not have a certain genetic susceptibility and maintain a healthy diet and weight. Further, the clinical presentation of disease may be delayed by behavioral compensations, such as walking more slowly in patients with pulmonary diseases so as not to experience the symptoms or increased walking to improve muscle efciency in utilizing oxygen in patients with peripheral artery disease and thus decreasing the symptoms. Unfortunately, modern medicine, public health and much of science has focused almost exclusively on mechanisms that create susceptibility to a single disease, and have substantially ignored the clues as to the potential direct contribution of aging and related biology to health as well as to chronic diseases. In this context, it is understandable why age has been considered merely a confounder. In surveying the literature on chronic disease, the attributable fraction of the burden of chronic diseases to the health burden of aging appears quite high across diseases, even when the effect of powerful risk factors such as hypertension or smoking are factored out. However, such analyses have rarely been conducted comprehensively, because most studies have focused on one disease outcome and ignored the effect of competing risk or aggregate impact. Future studies are needed to estimate in large, representa- tive cohorts the population-attributable fraction to aging and health of multiple chronic diseases after adjusting for known risk factors and using a multivariate approach that addresses competing risk and selective mortality. Such studies would help to estimate the extent to which the burden of morbidity in older persons is attributable to aging per se. An interpretation of the epidemiologic literature strongly suggests that aging con- tributes independently to the pathogenesis of many chronic diseases, and there are truly very few exceptions, largely in the form of rare diseases. Almost counterintui- tively, the only diseases that have been interrogated to reveal aging effects are the Etiological Role of Aging in Chronic Diseases: From Epidemiological Evidence 43 differential mechanisms for congestive heart failure by age , and the progeroid syndromes. Whether progeroid syndromes truly recapitulate the effect of aging in their early emergence of the aging phenotypes is unclear . In general, very few of the ndings of these studies have been translated into better understanding of the interface between aging and disease in people who have an average lifespan. To go beyond age as a confounder or aging as a process independent of and unrelated to chronic diseases in the study of human pathology requires a shift in perspective. Technology is currently available or in an advanced stage of development that should allow the testing of some of these theories in humans. Fully developing and testing such technology and then the theories themselves is clearly an important priority in aging research. Criteria for disease diagnosis and multimorbidity classication should be devel- oped that are not exclusively based on clinical manifestations and that do not ignore the role of the aging process or novel insights about causal pathways [9 ]. A list of potential biomarkers that change with aging and may be modied by chronic diseases or that themselves modify disease should be developed, and their ability to predict the decline in physical and cognitive function that occurs with aging should be evaluated. Ideally, these biomarkers should belong to path- ways that have been demonstrated to be altered in animal models of aging and frailty. In fact, the condition of multi-morbidity is the most frequent medical condition that affects individuals 65 years and older. Ferrucci present in a person increases exponentially with aging, and the longitudinal rise in multi-morbidity is even higher than what can be estimated from a cross-sectional survey because of selective mortality . Of course, the scenario of morbidity is more complex than just the counts of specic chronic diseases or considerations about their individual etiology.
Echocardiography can also demonstrate other important findings in patients with anomalous coronary arteries quality penegra 100mg, including ventricular size and function generic penegra 100 mg otc, the presence of atrioventricular valve insufficiency, and the presence of other congenital heart disease. Cardiac Catheterization Cardiac catheterization is typically only used in the diagnosis of anomalous coro- nary artery when other imaging modalities are inconclusive. Coronary angiography may help in demonstrating the anomalous origin of a coronary artery, but proving 310 R. Hemodynamic evaluation performed at cardiac catheterization can be useful in the management of certain patients with anomalous coronary arteries to evaluate cardiac output, filling pres- sures, and measurement of shunts, but in most cases these measurement are not necessary. Treatment/Management The treatment of an anomalous coronary passing between the great vessels or of anomalous origin of the left coronary from the pulmonary artery is predominately surgical. In the case of an anomalous coronary passing between the great vessels, surgical reimplantation of the abnormal coronary into the correct sinus can some- times be performed if the anomalous coronary artery arises as a separate origin from the abnormal sinus. In cases where a portion of the anomalous coronary courses in the wall of the aorta, the coronary may be unroofed such that the intra- mural portion of the coronary is opened to the lumen of the aorta so as to widen the origin and minimize tension or compression effects that may result from the coro- nary passing between the two great vessels. In the case of anomalous left coronary from the pulmonary artery, several surgical approaches have been used historically. If adequate collaterals have formed, one straightforward approach is to ligate the anomalous origin from the pulmonary artery to eliminate the pulmonary coronary steal. This procedure has also been performed in association with a bypass graft to augment coronary flow if collaterals were not sufficient. Currently, however, the most accepted approach is direct excision and reim- plantation of the anomalous coronary from the pulmonary artery into the aorta. In these cases, an aortopulmonary window can be created and a baffle placed in the pulmonary artery to tunnel coronary flow from the aorta (Takeuchi procedure). It is generally accepted that surgical intervention should be undertaken in these patients at the time of presentation. Patients with significant cardiac dysfunction or heart failure may require acute medical management of these symptoms before proceeding to surgery. Long-Term Follow-Up and Prognosis It remains unclear as to what extent surgical intervention in cases of anomalous coronary passing between the great vessels minimizes the risk of sudden death. It is widely felt, though, that surgical intervention should be undertaken in any patient with the finding of an anomalous left coronary between the great vessels. The finding of an anomalous right coronary passing between the great vessels is more controversial, but surgical intervention is frequently undertaken, particularly in patients who are symptomatic in any way. Patients with a coronary arising from the pulmonary artery generally have significant improvement in their ventricular 26 Congenital Abnormalities of Coronary Arteries 311 function following coronary reimplantation, with some eventually returning to normal myocardial function. However, patients with significant myocardial injury at presentation often continue to have cardiac dysfunction and remain at increased risk for cardiac issues, including sudden death. Following surgical intervention for anomalous coronary arteries, some may benefit from medical therapy to improve cardiac function, such as diuretics and afterload-reducing agents. Patients undergoing surgical intervention should have long-term follow-up to evaluate cardiac function and rhythm, and potential myocardial perfusion abnor- malities. They typically undergo stress testing when old enough, and may have coronary angiography performed in the first decade to evaluate for coronary steno- sis. Patients who experience myocardial infarction are at increased risk for lethal arrhythmias and may be candidates for automatic implanted cardiac defibrillators. The coach and the team trainer immediately evaluate the teenager and find him to be unresponsive and with short gasping breaths. On arrival to the field, paramedics find that the young man is in ventricular fibrillation. He is successfully defibrillated and following resumption of normal sinus rhythm, the patient is intubated and is then transported to the local emergency room. When the young man s father arrives at the hospital, he tells the doctors that his son has commented on a couple of episodes of chest pain and dizziness while playing soccer in the past, but that the symptoms had always gone away after he stopped playing. Intubated, on mechanical ventilation as well as inotropic and extracorporeal support, but is well perfused. On auscultation, a 3/6 systolic regurgitant murmur is heard at the apex and a gallop rhythm is present. There are also inverted T-waves in the left precordial leads, but ventricular voltages are normal. Sudden collapse in an otherwise healthy teenager is most likely due to a primary cardiac arrest. If there were history of trauma immediately preceding the arrest, commotio cordis would also be considered. The finding on history that the patient had episodes of chest pain and dizziness suggests some sort of an ischemic process, which makes an anomalous coro- nary artery more likely in this case. Basic labs would rule out an electrolyte abnormality, and the negative toxicology screen is helpful to rule out drugs of abuse (e. However, if there were serious concern for substance abuse, specific test would have to be done. Regardless, an echocardiogram is indicated to assess the coronaries and to evaluate for any other congenital defect. Detailed echocardiogram demonstrates a mildly dilated left ventricle that has moderately decreased function, most notably in the anterior left ventricular free wall and anterior ventricular septum.
Studies dier considerably in the methods used to identify the amino acid sites dening an epitope generic penegra 50 mg otc, the choice of sites to mutate generic penegra 50 mg mastercard, the amino acids used for substitution, and the calculation of changes in equilibrium binding constants or the free- energy of binding. Benjamin and Perdue (1996) discuss these general issues and summarize analyses of epitopes on four proteins. First, approximately 5 of the 15 amino acids in each epitope strongly inuence binding. Certain substitutions at each of these strong sites can reduce the relative binding constant by two or three orders of magnitude. These strong sites may contribute about one-half of the total free-energy of the reaction (Dougan et al. Second, the other 10 or so amino acids in contact with the antibody may each inuence the binding constant by up to one order of magni- tude. Third, the consequences of mutation at a particular site depend, not surprisingly, on the original aminoacidandtheamino acid used for substitution. Fourth, theoretical predictions about the free-energy consequences of substitutions based on physical structure and charge can sometimes be highly misleading. This problem often occurs when the binding location between the antibody and a particular amino acid is highly accessible to solvent, a factor that theoretical calculations have had diculty incor- porating accurately. Fifth, antibodies raised against a particular epitope might not bind optimally to that epitope the antibodies sometimes bind more strongly to mutated epitopes. In addition, antibodies with low anity for an antigen can have higher anity for related antigens (van Regenmortel 1998). Each antibody binding site denes a paratope, composed of the particular amino acids of that antibody that physically bind to a specic epitope. Approximately 50 variable amino acids make up the potential binding area of an antibody (van Regenmortel 1998). However, in both epitope and paratope, substitutions both in and away from the binding site can change the spatial conformation of the binding region and aect the binding reaction (Wedemayer et al. The antibody s 50 or so variable amino acids in its binding region dene many overlapping groups of 15 amino acids. A paratope does not dene asinglecomplementary epitope; rather it presents certain molecular characteristics that bind antigenic sites with varying anity. First, an antibody can have two completely independent binding sites (paratopes) for unrelated epitopes (Richards et al. Bhattachar- jee and Glaudemans (1978) showed that two puried mouse antibodies (M384 and M870) each bind methyl D-galactopyranoside and phos- phorylcholine at two dierent sites in the antigen-binding region of the antibody. Second, an antibody presumably has many overlapping paratopes that can potentially bind to a variety of related or unrelated epitopes. I did not, however, nd any studies that dened for a particular antibody the paratope map relative to a set of variable epitopes. The potential distribution of paratopes may change as a B cell clone matures in re- sponse to challenge by a matching antigen I take this up in the next section (4. Third, a single paratope can bind two unrelated epitopes (mimotopes, Pinilla et al. X-ray diraction of three competing peptides showed that they all bound to the same site on the antibody (Keitel et al. Fourth, a particular epitope can be recognized by two dierent par- atopes with no sequence similarity. The two antibodies also have dierent patterns of cross- reactivity with other antigens. Experimental studies of specicity frequently compare pairwise ani- ties between an epitope and various paratopes or between a paratope and various epitopes. In these pairwise measures, one rst raises anti- body to a monomorphic (nonvarying) antigenic molecule and then iso- lates a single epitope-paratope binding in other words, one raises a monoclonal antibody that binds to a single antigenic site. Variations in anity are then measured for dierent epitopes holding the paratope constant or for dierent paratopesholding the epitope constant. Alternatively, one can challengeahost with a polymorphic popula- tion of antigens. One controlled approach varies the antigens only in asmall region that denes a few epitopes (Gras-Masse et al. If exact replicas of each epitope occur rarely, then antibodies will be se- lected according to their binding anity for the aggregate set of varying epitopes (mixotopes) to which they match. This method may be a good approach for nding antibodies with high cross-reactivity to antigenic variants of a particular epitope. An antibody is a secreted form of a receptor that occurs on the surfaces of B cells. Each B cell clone makes IgM with dierent binding characteristics that is, the variable binding regions of the IgMs dier. The host has a large repertoire of naive B cells that produce a diverse array of IgM specicities.