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By M. Folleck. United Theological Seminar.

Current standards developed and adopted by federally sponsored genome projects have addressed some of these issues cheap 25mg indocin mastercard, but substantial barriers safe indocin 75 mg, particularly to the sharing of phenotypic and health-outcomes data on individual patients proven 50mg indocin, remain buy cheap indocin 25 mg online. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 6 Commons. Importantly, these standards should provide incentives that motivate data sharing over the establishment of proprietary databases for commercial intent. Resolving these impediments may require legislation and perhaps evolution in the public s expectations with regard to access and privacy of healthcare data. Develop an efficient validation process to incorporate information from the Knowledge Network of Disease into a New Taxonomy. Insights into disease classification that emerge from the Information Commons and the derived Knowledge Network will require validation of their reproducibility and their utility for making clinically relevant distinctions (e. A process should be established by which such information is validated for incorporation into a New Taxonomy to be used by physicians, patients, regulators, and payers. The speed and complexity with which such validated information emerges will undoubtedly accelerate and will require novel decision support systems for use by all stakeholders. The Committee envisions that a New Taxonomy incorporating molecular data could become self-sustaining by accelerating delivery of better health through more accurate diagnosis and more effective and cost-efficient treatments. A major beneficiary of the proposed Knowledge Network of Disease and New Taxonomy would be what has been termed precision medicine. These data are also critical for the development of the Information Commons, the Knowledge Network of Disease, and the development and validation of the New Taxonomy. In general, however, there is a growing shortfall: without better integration of information both within and between research and medicine, an increasing wealth of information is left unused. Twenty five years ago, the patient s mother had breast cancer, when therapeutic options were few: hormonal suppression or broad-spectrum chemotherapy with significant side effects. Today, Patient 1 s physician can suggest a precise regimen of therapeutic options tailored to the molecular characteristics of her cancer, drawn from among multiple therapies that together focus on her particular tumor markers. Moreover, the patient s relatives can undergo testing to assess their individual breast cancer predisposition. The diagnosis gives little insight into the specific molecular pathophysiology of the disease and its complications; similarly there is little basis for tailoring treatment to a patient s pathophysiology. No concrete molecular information is available to customize Patient 2 s therapy to reduce his risk for kidney failure, blindness or other diabetes-related complications. Patient 2 and his family are not yet benefitting from today s explosion of information on the pathophysiology of disease (A. Medical Encyclopedia 2011, Gordon 2011, Kellett 2011) 1 These scenarios are illustrative examples describing typical patients. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 8 What elements of our research and medical enterprise contribute to making the Patient 1 scenario exceptional, and Patient 2 typical? Could it be that something as fundamental as our current system for classifying diseases is actually inhibiting progress? Today s classification system is based largely on measurable signs and symptoms, such as a breast mass or elevated blood sugar, together with descriptions of tissues or cells, and often fail to specify molecular 2 pathways that drive disease or represent targets of treatment. Consider a world where a diagnosis itself routinely provides insight into a specific pathogenic pathway. Consider a world where clinical information, including molecular features, becomes part of a vast Knowledge Network of Disease that would support precise diagnosis and individualized treatment. What if the potential of molecular features shared by seemingly disparate diseases to suggest radically new treatment regimens were fully realized? In such a world, a new, more accurate and precise taxonomy of disease could enable each patient to benefit from and contribute to what is known. The information and opinions conveyed at the workshop informed and influenced an intensive series of Committee deliberations (in person and by teleconference) over a 6 month period. The Committee emphasized that molecular biology was one important base of information for the New Taxonomy, but not a limitation or constraint. Moreover, the Committee did not view its charge as prescribing a specific new disease nomenclature. Rather, the Committee saw its challenge as crafting a framework for integrating the rapidly expanding range and detail of biological, behavioral and experiential information to facilitate basic discovery, and to drive the development of a more accurate and precise classification of disease (i. Preventative or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not. Those who favor the latter term do so in part because it is less likely to be misinterpreted as meaning that each patient will be treated differently from every other patient. The workshop participants will also consider the essential elements of the framework by addressing topics that include, but are not limited to: x piling the huge diversity of extant data from molecular studies of human disease to assess what is known, identify gaps, and recommend priorities to fill these gaps. The ad hoc Committee will use the workshop results in its deliberations as it develops recommendations for a framework in a consensus report. The report may form a basis for government and other research funding organizations regarding molecular studies of human disease. A Brief History of Disease Taxonomies One of the first attempts to establish a scientific classification of disease was undertaken by Carolus Linnaeus, who developed the taxonomic system that is still used to classify living organisms. His 1763 publication Genera Morborum (Linn 1763) classified diseases into such categories as exanthematic (feverish with skin eruptions), phlogistic (feverish with heavy pulse and topical pain), and dolorous (painful). The effort was largely a failure because of the lack of an adequate understanding of the biological basis of disease. For example, without a germ theory of disease, rabies was characterized as a psychiatric disorder because of the brain dysfunction that occurs in advanced cases. This illustrates how a classification system for disease that is divorced from the biological basis of disease can mislead and impede efforts to develop better treatments. Similarly, the health care industry in the United States depends on an accurate disease classification system to track the delivery of medical care and to determine reimbursement rates. Both of these communities rely on highly robust data collection practices to make decisions that can impact millions of individuals. In this context, a formalized nomenclature is essential for clear communication and understanding. This is unfortunate because new insights into human disease emerging from basic research and the explosion of information both in basic biology and medicine have the potential to revolutionize disease taxonomy, diagnosis, therapeutic development, and clinical decisions. However, more integration of the informational resources available to these diverse communities will be required before this potential can be fully realized with the attendant benefits of more individualized treatments and improved outcomes for patients. B) Integration of information and a consolidation of needs could better serve all stakeholders. In 1910 educator Abraham Flexner released a report that revolutionized American medical education by advocating a commitment to professionalization, high academic standards, and close integration with basic science (Flexner 1910). The vast expansion of molecular knowledge currently under way could have benefits comparable to those that accompanied the professionalization of medicine and biomedical research in the early part of the 20th century. The ability of current taxonomic systems to incorporate fundamental knowledge is also limited by their basic structure. Taxonomies historically have relied on a hierarchical structure in which individual diseases are successively subdivided into types and sub-types. This rigid organizational structure precludes description of the complex interrelationships that link diseases to each other, and to the vast array of causative factors. It also can lead to the artificial separation of diseases based on distinct symptoms that have related underlying molecular mechanisms.

It consists of two lobes: Denition r The posterior lobe is a physical and functional exten- Pituitary adenomas are benign slow growing tumours sion of the ventral hypothalamus discount indocin 25mg line. Gene though the anterior lobe is of separate origin to the hy- mutationshavebeencharacterisedinsomepituitaryade- pothalamus buy discount indocin 75 mg,itisunderitsclosecontrol buy 25 mg indocin fast delivery. The hy- Pathophysiology pothalamussecretespolypeptidehormonesthatregulate Seventy per cent of pituitary adenomas are functioning cheap indocin 25mg online, anterior pituitary hormone secretion, mostly by stim- i. Increasingly asymptomatic hormone (10%) pituitary adenomas are found at incidental imag- ing. Continuing growth disrupts other hormone secretion and can result in hypopituitarism. Denition Macroscopy Hypopituitarism is a clinical term referring to under- r Tumours less than 1 cm in diameter without enlarge- function of the pituitary gland. This may imply a de- ment of, or extension outside the pituitary fossa are ciency of single or multiple hormones. The commonest causes are pituitary or hypothalamic r Tumours 1 2 cm may extend outside the fossa to- tumours, or secondary to pituitary surgery or cranial wards the hypothalamus and optic chiasm, laterally radiotherapy (see Table 11. Pathophysiology Hypopituitarism may be primary due to destruction of Investigations the anterior pituitary gland or secondary to a deciency r A mass within the sella turcica (pituitary fossa) may of hypothalamic stimulation (or excess of inhibition). Microadenomas take up less Symptoms and signs are related to the deciency of hor- contrast and macroadenomas take up more contrast. General symptoms of panhy- Ifapituitarymassisidentied,hormoneassaysshould popituitarism include dry, pale skin with sparse body beundertakentoidentifyfunctioningadenomas. On examination postural hypotension and brady- ing also helps identify any associated hypopituitarism, cardia may be found with decreased muscle power and with stimulation or suppression testing where appro- delayed deep tendonreexes. Management Investigations r Forprolactinomas medical treatment with a All functions of the pituitary should be assessed using dopaminergic drug is the treatment of choice (see sec- basal levels, stimulation tests and suppression testing tion on Hyperprolactinaemia, page 424). Progestagen is used to induce bleeding and Type Causes prevent endometrial hyperplasia. In ado- Pituitary apoplexy (haemorrhagic infarction of lescent males testosterone induces epiphyseal closure, pituitary tumour) so replacement therapy should be delayed as long as Inltration Sarcoidosis, haemochromatosis, histiocytosis X possible. Treatment of associated infertility requires Injury Head trauma complex hormone replacement to stimulate ovula- Immunologic Organ-specic autoimmune disease Iatrogenic Surgery, irradiation tion/spermatogenesis. Pituitary haemorrhage causing death of the r Gonadotrophin deciency in women may be treated lactotrophs results in failure of lactation (Sheehan s with cyclical oestrogen replacement to maintain syndrome). The zona deciency glomerulosa and aldosterone secretion usually remains relatively intact, so Addisonian crisis is rare. Clinical features Hyperprolactinaemia In women hyperprolactinaemia causes primary or sec- ondary amenorrhoea, oligomenorrhoea with anovula- Denition tion or infertility. Hyperprolactinaemia is a raised serum prolactin level Oestrogen deciency can cause vaginal dryness and causing galactorrhoea and gondadal dysfunction. In men galactor- Incidence rhoea occurs occasionally, but the most common early Most common endocrine abnormality of the hypothala- features are decreased libido and sexual dysfunction, mic pituitary axis. Complications Acromegaly Headache, visual impairment and hypopituitarism due to local effects of the adenoma. Sex Management M = F Prolactinomasaretreatedwithdopaminergicdrugssuch as cabergoline. The minority of tumours that do not Aetiology respond to medical treatment and hyperprolactinaemia r 95% of cases result from growth-hormone-secreting due to stalk compression are treated surgically. Sleep, exercise, stress Hypoglycaemia Postprandial hyperglycaemia/ free fatty acids Clinical features Glucocorticoids (hence short The course of the disease is slowly progressive. Soft tissue stature in children on overgrowth is the characteristic early feature, causing long-term oral steroids) enlargement of hands and feet, coarse facial features. Acne, sebaceous r Accompanying hypopituitarism is treated as appro- cysts and skin tags are common. Acanthosis nigricans priate with corticosteroids, thyroxine and gonadal of the axillae and neck may occur. Acromegaly causes increased morbidity and r Organomegaly: Thyroid and salivary gland enlarge- mortality mainly due to diabetes and cardiovascular dis- ment, hepatomegaly. Thyroid axis Macroscopy/microscopy The tumour is solid and trabecular, often 1 cm in diame- terbythe time of diagnosis. Oestrogens conversely increase the sensitivity suppress growth hormone production. Large tumours re-absorption of colloid by the cells and the production may be resected by transfrontal craniotomy. The majority of T is converted from the less active 3 r Octreotide or lanreotide, a long-acting somatostatin T4 by peripheral tissues. Disorders of the thyroid axis are analogue, may be used prior to surgery, following in- shown in Table 11. Fur- Age ther classication is based on whether the patient is hy- Increases with age. Irregularmultinodularenlargementofthethyroidgland, which may be hyperthyroid (toxic) or is commonly eu- thyroid (nontoxic). Clinical features Patients may present for cosmetic reasons, with thyro- Incidence/prevalence toxic symptoms, or because of complications. Multin- 25% of cases of thyrotoxicosis are due to multinodular odular goitre can present with a particularly promi- goitre. Causes include the following: r Benign follicular adenoma: Single lesions with well- Macroscopy/microscopy developed brous capsules. Nodules may be cystic, haemorrhagic and - hormones, which may result in hyperthyroidism. Enlargement of the gland can cause tracheal compres- r Thyroid cyst (15 25%): These may be simple cysts sion leading to shortness of breath and choking. About more common with retrosternal goitre, when the nod- 15% are necrotic papillary tumours. Toxic multinodular goitre has a particularly high incidence of cardiac arrhythmias and other cardiac complications. Clinical features Patients may present with a palpable lump or may be diagnosed on incidental imaging. Ultrasound scanning of the thyroid may be useful r History of neck irradiation exposure. Cystsand r Malignancy is more common in children and patients nodules may be aspirated by ne needle aspiration for over 60 years. Investigations Management r Thyroid function tests are used to determine thyroid Subtotal thyroidectomy may be required for cosmetic status. Isotope scans may also be used to demon- reasons or due to compression symptoms or thyrotoxi- strate either a cold nodule, a hyperactive gland (toxic cosis. Patients must be medically treated and euthyroid multinodular goitre) or a cold gland containing a before surgery. A solitary mass within the thyroid gland that may be r Fine needle aspiration for cytology is used to differen- solid or cystic.

Valuable knowledge may include compilations of screens that have been run before and information on past research programs 75 mg indocin with visa. While much of this information is publicly available discount indocin 50mg overnight delivery, what may be most useful is an account of what projects failed order indocin 25mg free shipping, and why order 25mg indocin with amex. The mission of this proposed efort is to efciently and efectively share research fndings with key stakeholders in the antibiotic discovery space. However, creating an environment in which data exchange and knowledge sharing are the status quo will be difcult given proprietary concerns and the variety of information types and formats, which may range from historical data to new fndings produced as part of this research efort. Importantly, the scientifc leadership group leading this initiative should engage early on with technology transfer experts from academia, industry, and government to ensure that fndings are efectively disseminated across the research community. Furthermore, information on screening assays and conditions tested would provide useful information for researchers seeking to fnd new antibiotic starting material. Sharing these fndings with the broader scientifc community in a useful way would be a challenge. In addition, guidelines should ensure that the quality of data and information produced through this efort is standardized and appropriately annotated or analyzed. Considerable resources may be required to build an informatics infrastructure formatted in a way that allows for interoperability across multiple institutions and promotes the sharing of numerous types of data and information among partners. Software could be purchased and modifed to suit research needs through organizations such as Collaborative Drug Discovery, a software company that provides a secure cloud-based platform for sharing and analyzing chemical and biological data. While many experts in industry and academia have published their work, not all of this information is easy to fnd. Some published data would require collation and curation to make them easily accessible to scientists, while unpublished data reside in industry databases, nonindexed notebooks, and internal reports. As research programs have been abandoned, or companies were bought out or downsized over the years, these data have become increasingly difcult to access. A survey of companies working in antibiotic discovery today and in the past would seek to determine what type of unpublished data could be acquired, what incentives might motivate a company to share this information, and what technical hurdles would have to be overcome. Based on survey results, there should be careful consideration of whether the time, manpower, and expense to obtain industry data are a worthwhile investment. In addition, a curated resource of organisms that produce natural products housed at a public institution would help preserve this resource for use by the broader antibiotic discovery community. Goal: Share knowledge and expertise Databases and repositories are not enough to tackle this priority. There must also be shared knowledge on what has been done before and what gaps remain. The long-term viability of the antibiotic pipeline depends on the ability of researchers to share drug discovery know-how across disciplines and sectors, to build on lessons learned rather than repeat mistakes, and to pass down expertise to the next generation of scientists. Such a resource would help provide clarity for researchers on how to better vet compounds for antibiotic discovery, whether they are natural products or synthetic compounds. For example, a stepwise fow chart with links to structural alerts could help researchers eliminate pan-assay interference compounds, which turn up as artifacts in multiple assays and can be mistakenly reported as having promising activity against a wide variety of protein targets. Sharing drug discovery know-how requires hands-on experience and in-person interaction. A mentorship program that brings experienced industry scientists into the academic, startup, and biotech settings, or industry fellowships for postdoctoral students and early-career faculty would provide real-time feedback and consultation opportunities for antibiotic discovery researchers and be one way to efectively share institutional knowledge. Scientists with extensive pharmaceutical experience working alongside young investigators would aford unique opportunities to exchange ideas, share lessons learned, and teach the art of discovery science between sectors and across disciplines. Further input is needed to defne how this program might best serve the discovery community, including opportunities for senior scientists to share knowledge through existing programs. Models for antibiotic discovery Existing mechanisms of publicly and privately funded science have failed to meet the needs of the antibiotic research community in part because of a lack of direction, integration, and focus on key barriers to discovery. Success would require agreement on a common mission, strong scientifc leadership, a willingness to undertake high-risk work and change direction as needed, and an interdisciplinary team of dedicated research scientists working on long-term difcult problems. Pew examined a number of existing organizational structures to better understand how other biomedical areas have supported research eforts (see Appendix C). It is important to note that many existing initiatives focus on discovery, development, and delivery of drugs and other therapies. In contrast, the mission of this efort is focused exclusively on flling key gaps in knowledge to spur discovery. Several potential organizational structures may lend themselves to this efort: A free-standing, self-contained institute under the umbrella of an existing organization that houses a central coordinating entity, multidisciplinary research teams, and the equipment and infrastructure necessary to carry out all research activities. This model would allow for long-term research that is fully integrated across projects but would likely entail high startup costs. A variety of formal and informal mechanisms would be established to ensure accountability and foster scientifc interchange between partners. This model may be easier to establish and would allow more fexibility to adjust research activities as projects evolve, but it would depend on collaboration and commitment from the broader research community. This model incorporates both in-house research teams and the fexibility to work with multiple external partners as needed. The priorities laid out in this roadmap could be addressed concurrently or sequentially. Leading this group would be a director with a strong scientifc background and credibility in the feld, an ability to efectively communicate across private and public sector partners, and an appreciation for the real-world challenges facing antibiotic 20 discovery. Together, this scientifc leadership group would actively manage and guide projects to ensure that project milestones are met, working directly with laboratory heads and research partners. In addition, the leadership group would identify and develop lines of work and make decisions on scientifc direction with input from the scientifc advisory committee. The second phase of this efort (pilot phase) would focus on optimizing collaborative research to advance objectives. Early pilot projects are likely best suited for small research teams, but as general direction is established (e. For example, assay development or methods for determining how molecules move across bacterial membranes may require the building of new tools, engagement of specifc expertise, or the use of specialized equipment. Outputs from the pilot phase may include: assays to measure drug entry independent of drug activity; preliminary conditional rules of entry; and completion of assessment studies for single-target antibacterials used in combination. Once pilot studies on Gram-negative drug entry and efux have been conducted to determine what chemical space to explore, there may be advantages to seeking out a diversity of chemical matter from a variety of institutions that use diferent chemical methods and approaches. Strong scientifc leadership would be required to manage multiple lines of work while maintaining focus on the core mission in order to achieve long-term objectives. The third phase of this efort (implementation phase) would focus on long-term outcomes such as: the elucidation of a robust set of conditional guidelines for Gram-negative drug entry and efux based on chemical class, bacterial species, or drug target; the generation of diverse chemical collections tailored for antibiotic discovery; and in vitro or in vivo pre-clinical models to evaluate specifc alternative therapies to treat bacterial infections. Intellectual property If successfully implemented, the work outlined in this roadmap is expected to produce a range of data, tools, and scientifc knowledge critical for fostering and accelerating antibiotic discovery. As such, a core principle of this efort would be to rapidly promote access to research fndings to the greatest extent possible, so that they may form the basis of future discoveries and maximize benefts to public health. Outputs generated through this efort would be focused on overcoming scientifc barriers impeding the discovery of antibiotics rather than the development of new products or technologies.

This suggests that the initiation of fatty Concentric lipid rich: 28% of plaques streak may not be due to the risk factors for atheroscle- Eccentric lipid rich: 12% of plaques rosis cheap 25mg indocin with visa. They contain varying amounts of free lipid purchase 50mg indocin visa, collagen tains free lipid as well as foam cells with an overlying and foam cells order 25 mg indocin free shipping. A grading system exists based on (dobutamine) may show abnormal ventricular wall the level of activity provoking pain (see Table 2 buy indocin 25mg otc. Risk factor modication is crucial, in particularstoppingsmoking,treatmentofhypertension, Grade I Pain as a result of strenuous physical activity only improving diabetic control and lowering cholesterol. The gure shows a cardiac cycle from each lead taken at rest (left) and during exercise (right). Symptomatic treatment may involve one or a combi- careinconjunctionwith-blockersorinpatientswith nation of the following: heart failure. They are particularly useful after a my- If symptoms cannot be controlled by medication, the ocardial infarction to reduce the risk of a subsequent main choices for coronary intervention are between cardiac event. In patients with triple vessel disease or verapamil also reduce the heart rate and the force of left main stem coronary artery disease, surgery im- ventricular contraction resulting in a decreased my- proves outcome. A bal- plaques with a lipid-rich morphology are at greatest risk loon is inated in the coronary artery to reduce the of ssuring. It includes the follow- or is provoked more easily, persists for longer and often ing: fails to respond to medical treatment. Patients require r Unstable angina describes clinical states between sta- emergency assessment and investigation to allow rapid ble angina and acute myocardial infarction. Pathophysiology As with stable angina, the underlying pathological lesion Clinical features istheatheromatousplaque. There may also be signs of r High-risk patients may benet from a glycoprotein hypertrophy or previous infarction (Q waves). If the level is normal patients venousheparininplaceoflow-molecular-weighthep- are dened as having unstable angina. Artery occluded Pattern of infarction r 24 72 hours: Cellular inammation visible. If the atrioventricu- Acute myocardial infarction is caused by the occlusion lar node is involved bradyarrhythmias are common, of a coronary artery, usually as the result of rupture of although any arrhythmia is possible. The myocardium supplied by that artery eas of infarction, which cause contractile dysfunction. Myocardial infarctions due to extensive myocardial damage, rupture of the occur more commonly in the early morning possibly ventricular septum or papillary muscle leading to mi- due to increased coronary artery tone, increased platelet tral regurgitation. The latter present with worsening aggregatability and decreased brinolytic activity. The refractory heart failure and a loud pansystolic mur- extent and distribution of the infarct is dependent on the mur. If left untreated this has a very poor prognosis, coronary artery affected, but also on individual variation and early surgical correction should be considered. A haemopericardium develops due to exsanguination into the pericardial cavity resulting in tamponade and rapid death. This Clinical features complication tends to affect older hypertensive pa- Patients typically present with central crushing chest tients, females more than males and the left ventricle pain worse than stable angina, radiating to the jaw and more than the right. It may provoke fear of imminent death over the infarction with resulting risk of embolism. It is often associated with restlessness, breath- r Recurrent ischaemia or myocardial infarction may oc- lessness, sweating, nausea and vomiting. Macroscopy/microscopy r Ventricular aneurysms may form as the collagen scar In the infarct-related artery, there is nearly always evi- that replaces the infarcted tissue formation does not dence of plaque rupture/erosion and thrombotic occlu- contract and is non-elastic. In the infarct zone a sequence of changes occurs: frequently complicated by thrombus formation but r 0 12hours:Notvisiblemacroscopically,thereislossof embolism is rare. The development of tion, hypotension or in patients previously exposed persistent Q waves usually denotes a more substantial in- to streptokinase. It is now available as These should be given to all patients without evidence abedside test. They reduce mortality, reduce the number who de- Myoglobin velop cardiac failure and slow progression of the in- farct, by improving the remodelling of myocardium postinfarct. Primary percu- Arrhythmiasmayoccurintheischaemicepisode(usually taneous coronary intervention (i. It is of particular value in patients with contraindica- Investigations tions to thrombolysis. Management Full mobilisation should be achieved after about 3 days r Nitrates and calcium antagonists are useful as pro- and discharge at 5 days, if there are no complications. The patient Prognosis may return to work after 2 3 months, depending on the The prognosis in patients with angina without underly- typeofwork. Rheumatic fever Prognosis Denition 50% 30-day mortality; 25% die before reaching hospital. Recurrent inammatory disease affecting the heart; it Of those who leave hospital alive, 15 25% die within the occurs following a streptococcal infection. Incidence 1in100,000 United Kingdom/United States population peryear; incidence has declined over the last 100 years. Variant/Prinzmetal s angina Denition Age Angina of no obvious provocation not as a direct result First attack usually 5 15 years. Sex Aetiology/pathophysiology M = F Causedbyspasmofacoronaryarterymostoftenwithout atheroma or in association with a mild eccentric lesion. Common in Middle and Far East, South America and Central Africa, declining in the West. Clinical features Pain is usually more severe and more prolonged than Aetiology classical angina occurring at rest particularly in the early Cell-mediated autoimmune reaction following a pha- morning. Risk fac- centre over the trunk and limbs, which appear and tors forstreptococcalinfectionincludepovertyandover- disappear over a matter of hours. Non-specic symptoms include It appears that antistreptococcal antibodies crossre- malaise and loss of appetite. Macroscopy r Pericarditis: Nodules are seen within the pericardium Fibrinous vegetations form on the edges of the valve associated with an inammatory pericardial effusion. Valve leaets may fuse r Myocarditis:Nodulesdevelopwithinthemyocardium and scar, particularly affecting the mitral and aortic associated with inammation. These may result in an acute disturbance thesecellsarereplacedbyhistiocytes,whichmaybemult- of valve function. Complications Clinical features More than 50% of patients with acute rheumatic cardi- There may be a history of pharyngitis in up to 50% of tis will develop chronic rheumatic valve disease 10 20 patients. The diagnosis is made on two or more major years later, particularly mitral and aortic stenosis. These manifestations or one major plus two or more minor may be complicated by atrial brillation, heart failure, manifestations (Duckett Jones criteria).

Contact dermatitis of the face order 25mg indocin with visa, for example best 75mg indocin, is often due to cosmetics directly applied to the area discount indocin 50 mg otc. Therefore purchase indocin 75mg mastercard, it is vital that the physician be familiar with various distribution patterns of contact dermatitis that may occur in association with particular allergens. Frequently, the distribution of the skin lesions may suggest a number of possible sensitizing agents, and patch testing is of special value. Smoke from burning the poison ivy plant may contain the oleoresin as particulate matter, and thus expose the sensitive individual. Another route of acquiring poison ivy contact dermatitis without touching the plant is by indirect contact with clothing or animal fur containing the oleoresin. It should be remembered also that systemic administration of a drug or a related drug that has been previously used topically and to which the patient has been sensitized can elicit a localized or generalized eruption. The oral mucosa also may be the site of a localized allergic contact reaction resulting in contact stomatitis or stomatitis venenata ( 7). The relatively low incidence of contact stomatitis compared with contact dermatitis is attributed to the brief duration of surface contact, the diluting and buffering action of saliva, and the rapid dispersal and absorption because of extensive vascularity. Agents capable of producing contact stomatitis include dentifrices, mouthwashes, dental materials such as acrylic and epoxy resins, and foods. The clinical response is most commonly inflammation of the lips, but cases of burning mouth syndrome have also been attributed to contact allergy. Patch Testing Principle Patch testing or epicutaneous testing is the diagnostic technique of applying a specific substance to the skin with the intention of producing a small area of allergic contact dermatitis. The patch test is generally kept in place for 48 to 96 hours (although reactions may appear after 24 hours in markedly sensitive patients), and then observed for the gross appearance of a localized dermatitis. A positive patch test is not absolute proof that the test substance is the actual cause of dermatitis. It may reflect a previous episode of dermatitis, or it may be without any clinical relevance at all. Allergic Contact Dermatitis and Indications for Patch Testing All unexplained cases of eczema that either do not respond to treatment or recur after treatment may be due to contact allergy and should be considered for patch testing (8). Currently, patch testing is the only accepted scientific proof of contact allergy. If patch testing is successful at identifying a causative allergen, avoidance will often be curative. Alternatively, if the causative agent is not identified, it is likely that the patient will need ongoing treatment and that treatment will be less than optimal. A thorough history and physical examination should be performed with emphasis on the distribution and timing of the clinical lesions. Once this information is obtained, an exhaustive history should be taken to identify all potential allergens that had opportunity to come in contact with the skin of the patient. Most physicians doing patch testing use the True Test, a ready-made series of 23 common allergens that can be easily applied in a busy office setting ( Table 18. Since a recent study reported that less than 26% of contact allergy problems will be fully solved using the True Test, patients often need referral to a physician specializing in patch testing. These specialists will generally have a wide array of allergens relevant to most occupations and exposures and are familiar with where these allergens are found and alternatives to avoid exposure. Testing is usually performed with an expanded standard tray and additional allergens individualized to the patient exposure. Allergens on the true test standard tray listed by function The physician should become familiar with the potent sensitizers and with the various modes of exposure. It is important to keep in mind the possibility of cross-reactivity to other allergens because of chemical similarities. Sensitivity to paraphenylenediamine, for example, also may indicate sensitivity to para-amino-benzoic acid and other chemicals containing a benzene ring with an amino group in the para position. The most common cause of allergic contact dermatitis in the United States is Toxicodendron (poison ivy, poison oak, poison sumac). Latex-induced contact dermatitis affects health-care workers, patients with spina bifida, and manufacturing employees who prepare latex-based products. More detailed information on other sensitizers, environmental exposures, and preparation of testing material is contained in several standard texts ( 10,11 and 12). Allergens are placed into the chambers as a drop of liquid on filter paper or as a 1-cm cylinder of allergen in petrolatum from a syringe. With the patient standing erect, the patch test strips are applied starting at the bottom and pressing each allergen chamber firmly against the skin as it is applied. The skin surrounding the patch test strips is then typically outlined with either fluorescent ink or gentian violet marker. Reinforcing tape, and sometimes a medical adhesive such as Mastisol, is then used to further affix the patches in place. The patch test series is documented in the medical records clearly showing the position of each allergen. It is important that the patient be instructed to keep the patch test sites dry and avoid vigorous physical activity until after patch test reading is completed. The allergens are removed and read 48 hours after application and the patient returns for a second reading of the patch tests at 72 or 96 hours. Some physicians also do readings at 1 week after application to identify more delayed reactions. It is essential that the skin of the back be free of eczema at the time of testing to avoid false-positive reactions due to what has been called the angry back syndrome. Oral steroids should be avoided when possible; however, some strong patch test reactions can be obtained even when a patient is taking up to 30 mg prednisone daily. Photoallergy and Photopatch Testing When an eruption is observed in a sun-exposed distribution, photoallergic contact dermatitis should be considered. Photopatch testing is performed similar to routine patch testing, but a second identical set of allergens is also applied to the back. If both the exposed and unexposed sites show equal reactions, a standard contact allergy is confirmed. Patch Testing Reading and Interpretation The patch tests are read using a template that is aligned inside the marker lines on the back to show the exact position of each allergen. The sites are then graded as 1+ (erythema), 2+ (edema or vesiculation of <50% of the patch test site), 3+ (edema or vesiculation of >50% of the patch test site), or? Strong irritant reactions sometimes result in a sharply demarcated, shiny, eroded patch test site. Some patch test reactions merely indicate an exposure that occurred many years prior. Pustular patch test reactions can occur with metal salts and do not indicate contact allergy. Also, when a test site is strongly positive or if the patient experiences severe irritation from tape, nearby sites may show false-positive reactions due to the angry back syndrome.

The issues arising in the donation of tissue for research purposes are rather different purchase 75 mg indocin with mastercard. While we accept that this evidence derives from just one study (albeit with a large cohort) discount indocin 50 mg fast delivery, we also note other examples of practice where buy 75 mg indocin, if asked indocin 50 mg online, patients have shown themselves very willing to agree to research use (see Box 3. We conclude that the difficulties experienced by researchers in obtaining tissue for their research do not derive from individuals general unwillingness to consent to such use, nor from a lack of interest on the part of patients or the general public in contributing to the communal good of research, but rather to an absence of systems to ensure that this willingness is harnessed. This suggests that the current system is in fact an example of a non-altruist-focused intervention, on rung 6 of our Ladder. There is no evidence to suggest that payments made in this area have in any way served to undermine solidarity with respect to the donation of bodily material more generally. That public interest is not extinguished by the private financial gains that may also accrue as a result of research carried out within the commercial sector. However, where national self-sufficiency cannot be achieved without taking action that would otherwise be regarded as unethical, the fact that people may still choose to travel abroad should not force a change of policy. However, we have also highlighted repeatedly throughout this report our conviction that the focus on individual motivation, as exemplified by the call for incentives, is only one aspect of a much bigger picture when considering the ethical challenges raised by the donation of bodily material. Given the crucial role played by intermediaries in almost all aspects of donation, we acknowledge that this division is not always clear. But we think it is nevertheless very helpful in drawing attention to the many ways in which donation may be facilitated or alternatively the ways in which the need for donation may be reduced by action at professional, organisational, and state level. The key questions here for each form of bodily material are: What barriers are there to making the best possible use of the material that people are willing to donate and how can these barriers be removed? Before we consider these material-specific issues, however, we highlight a number of over-arching questions that we believe policy-makers need to address: What action can be taken at national, or organisational, level to reduce the need for bodily material? We return here to the question of the public health factors that are playing a significant role in increasing demand for bodily material, in particular for organs for transplant and for gametes for fertility treatment (see paragraphs 3. Thus we are not concerned here with the question of whether lifestyle factors should be used in determining who should have priority in receiving an organ or donated gametes. In the context of organs, the challenge is often put to policy- makers that the current shortage constitutes a national emergency, in response to which radical 644 measures would be justified. Notably absent from these public discussions is consideration of how demand could be reduced by preventive public 646 health action. While it is broadly accepted that it is appropriate for the public health agenda to include consideration of sexually transmitted diseases such as chlamydia that may impact on later fertility, there is no such consensus that any state- sponsored organisation should seek to influence childbearing patterns, such as the age at which women have children. The speed at which this may happen, however, should not be over-estimated: what appear to be exciting research results often take many years before developing into routine procedures. It is therefore exceedingly hard to make any meaningful predictions as to whether, and to what extent, demand for any particular form of material might drop in the future. We do, however, make the following observations: These developing areas pinpoint the importance of research within the donation field. Research on the optimisation of organs donated after death, with the aim of improving transplant outcomes, for example, may lead to a good outcome in itself (longer graft life) and at the same time reduce the need for other bodily material (by reducing the need for re- transplantation). Here we consider the wider implications for policy of the various (and interlocking) public and private aspects of donation. We have already suggested that the potential benefits to health to be achieved through the donation of bodily material for treatment and research represent a sufficient ethical justification for taking action, within ethical limits, whether this takes the form of reducing demand or increasing supply. Such conclusions, however, leave open the question of who or what (if anyone) is responsible for ensuring such interventions take place. Many of the specific recommendations in that earlier report, particularly those relating to obesity and excessive alcohol use, are clearly highly relevant to the subject of this report. However, we also conclude that the underpinning concept of the state as steward of public health is equally applicable to the responsibilities of states with respect to the donation of bodily materials. We endorse the views of those respondents to our consultation who saw responsibility as appropriately resting with the state, while noting at the same time the common- sense constraint that, while organisations may have responsibilities, only individuals have the 650 bodies from which bodily material may come. We concluded that it might therefore be more practical to focus organisational efforts on reaching those individuals who are not particularly troubled by these anxieties (see paragraph 6. However, such an approach will only be appropriate where it is irrelevant who donates as long as sufficient material overall is obtained. We therefore suggest that a stewardship state has a direct responsibility to explore the reasons why some populations are hesitant to donate, and if appropriate, to take action to promote donation. We have, however, highlighted very clearly in Part I of this report the central role that bodily materials play in research, and how difficulties in access to the necessary tissue are acting in some cases as the key factor limiting progress in research (see paragraph 3. If we argue (as we do) that the state has an interest in promoting the good health of its citizens, and has a role as a steward in supporting and facilitating environments in which good health may flourish, then such an interest will also include supporting and facilitating environments in which health-related research may flourish. The difficulties that arise relate therefore not so much to encouraging people to consider donating, but rather in the need for much better systems to be in place to ensure that consent is sought and documented appropriately; and that materials are appropriate shared. Any commercial return would be many years after the initial donation, and the particular contribution of any individual would in most circumstances be impossible to measure. We suggest therefore, that although it is clearly just that commercial companies in such circumstances should seek in some way to share the financial benefits of their research more widely, such benefit sharing should take place in a wider context, rather than in response to the financial potential of bodily material from particular individuals. We note also here that the role of consent at the point of donation, including clear information about possible commercial uses, is clearly central in ensuring ethical treatment of donors in this respect. Case law has given conflicting answers, with the Court in Yearworth most recently suggesting that freezing in liquid nitrogen alone might be sufficient. Such lack of clarity adds to the uncertainty around the legal status of materials that are donated for transplantation: for example, the status of an organ that is being treated prior to transplantation. Such a model of custodianship would include rights of possession and use, but only for the purposes envisaged in the original consent. It would also include remedies, for example against misuse or interference by other third parties. The specific treatment of the individual abroad remains the responsibility of 657 the local professional team. Such general standards include factors such as the protocols used to recruit donors (with particular reference to the hazards of using intermediate agencies for such recruitment) and the routine measures taken by the clinic to safeguard the welfare of donors. We make the following observations: Transparency, for example with respect to where material has come from, and the circumstances in which it has been obtained, is essential. Legislation is, of course, only one way of ensuring such standards are met, and we note here 660 the influence of professional standards and practices in this area. However, we also need to consider to what extent there is a public interest in seeking 657 Shenfield F, Pennings G, De Mouzon J et al. However, where this national self- sufficiency cannot be achieved without taking action that would otherwise be regarded as unethical, the fact that people may still choose to travel abroad should not force a change of policy. The Working Party endorses the Organ Donation Taskforces focus on tackling the structural problems that have, in the past, hindered the optimal use of the organs that are potentially available. Given the gradual shift in influence away from hospital trusts, it is likely to become increasingly important that primary care is appropriately represented in these structures.