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One might object that our apparent problem is not genuine purchase toprol xl canada pulse pressure is, and that there is nothing strange about intellectuals participating in traditional cul- tic activities such as prayer and sacrifice buy online toprol xl arrhythmia low blood pressure, while at the same time holding ‘advanced’ religious or theological ideas which seem inconsistent with the presuppositions underlying these cultic practices 100 mg toprol xl amex arrhythmia in 6 year old. It is probably this hypothetical character which has led most interpreters to refrain from bringing these statements to bear on the discussion of the writer’s theological ideas (e. Norenberg (¨ 1968) 69 also claims that the sections 41–6 are put into the mouth of the magicians, although later on (74–6) he suddenly takes them seriously as reflecting the author’s own opinion. However, his own ‘hypothetical’ remarks there on the ‘moral significance’ of the divine remain inconclusive and partly contradict his earlier views on the divinity of nature. As will become clear in the course of this chapter, I do not believe that ‘the divine’ (to theion) mentioned in 1. His remarks reflect, indeed, a genuine belief in the Divine, but, as perhaps in the case of a Socrates or a Euripides, it is not simply a belief in the gods as traditionally and popularly conceived. At least three questions are important: (i) To what extent did intellectuals try to harmonise their own theological conceptions with traditional beliefs and, if they did, then for what 48 Hippocratic Corpus and Diocles of Carystus does not concern a discrepancy between religious theory and religious prac- tice or between theology and cult, but a tension between different ideas in one and the same text. For there is a difference between intellectuals simply participating (from habit or under social pressure) in cultic actions, and intellectuals, such as the author of On the Sacred Disease, making explicit statements and definitions about what they believe should be the right way of approaching the gods. Moreover, the author’s assertions not only con- cern cult and ritual, but also characteristics of the divine and the way in which it manifests itself within human experience. Therefore the problem deserves to be considered, and we must try to find out how these two sets of religious opinions are related to each other. I shall first deal with the statements on the divine character of the disease and consider whether these admit of being extrapolated into a ‘theology’. This will for a substantial part consist in an attempt to evaluate and clarify the interpretative debate on the author’s claim that ‘all diseases are divine and all are human’. Then I shall deal with the statements in his chapter 1 and relate these to the assertions about the divine character of the disease. Finally I shall summarise my conclusions concerning the religious notions which can, with some degree of certainty, be attributed to the author of On the Sacred Disease. On the one hand it is often stated that there was no institutionalised orthodoxy in ancient Greece and no sacred books with authorised interpretations and that, consequently, many different religious beliefs were tolerated (see Lloyd (1979) 10–15). On the other hand it cannot be denied that at the end of the fifth century (in Attica at least) a growing intolerance manifests itself, e. In this respect it is significant that it is the author of On the Sacred Disease himself who accuses his opponents of impiety and atheism (1. On all these matters see Bryant (1986); Dover (1975); Fahr (1969); Guthrie (1969) vol. Miller (1953) 9–15), though I shall say something about this in the course of my comments on interpretation (1). On the Sacred Disease 49 intend to offer a new one, but I believe that the debate would benefit from recognising that these interpretations are different and incompatible, and from acknowledging the presuppositions underlying both views. My second a priori remark is that the use of terminological oppositions such as ‘rational versus irrational’ and ‘natural versus supernatural’ in order to define the meaning of theios and anthropinos¯ is confusing rather than illuminating. The two interpretations are as follows: (1) A disease is divine in virtue of being caused by factors ( prophasies;on this term see below) which are themselves divine: the climatic factors heat, cold and winds. These can, on this view, be called divine because they are beyond human control (the author accepting aporos, ‘hopeless’, ‘impossible to resolve’, as a proper associate of theios,cf. These factors can be called human because they (or at least some of them) are capable of being controlled, or in any case influenced, by human agency. The governing connotations of theios 12 This is not to suggest that the oppositions ‘rational–irrational’ and ‘natural–supernatural’ are used by modern scholars as if they were equivalent, but rather to avoid the anachronistic associations these terms conjure up. One of these reasons, he says, may be the ‘hopelessness’ (ˆpor©h) with which the disease confronted them. But he proceeds to show that this only applies to a cognitive ‘hopelessness’ (ˆpor©h toÓ mŸ ginÛskein); as for the therapeutic aspect, he says, these people claim to be ‘well provided’ with means to cure (eÎporoi) rather than ‘hopeless’ (Šporoi). Apparently the author accepts aporos as a justified associate of theios, but he points out that these people are actually not aporoi at all. By showing that the disease is caused by ‘human’ factors as well (which are in their turn influenced by the divine factors mentioned) the author demonstrates that in his account a disease can be both divine and human (i. These connotations, in fact, also led the Presocratic philosophers to apply the word to their ultimate principles. It is rather that just as the other diseases have a nature from which they arise, likewise this one has a nature and a cause. Each of these arguments may be questioned: repetition of this kind is quite frequent in On the Sacred Disease (e. Besides, after the opening sentence (perª t¦v ¬r¦v noÅsou kaleom”nhv æde ›cei) it is more reasonable to expect an exposition of what the author believes than the rejection of what other people believe. On the Sacred Disease 51 kaª ¡l©ou kaª pneum†twn metaballom”nwn te kaª oÉd”pote ˆtremiz»ntwn. This disease which is called sacred arises from the same causes as the others, from the things that come and go away and from cold and sun and winds that change and never rest. These things are divine, so that one ought not to separate this disease and regard it as being more divine than the others; it is rather that all are divine and all are human, and each of them has a nature and a power of its own, and none is hopeless or impossible to deal with. The first interpretation is mainly based upon the remark ‘these things are divine’ (taÓta d’–stª qe±a, 18. The author derives the divinity of the disease from the divinity of its causes, the climatic factors whose influence has been discussed in 10. And since these factors are – as the author claims – the causes of all diseases, all diseases are equally divine, so that none of them should be distinguished from the others as being more divine. It is not stated explicitly in either of these passages in what sense they are human,17 but it has been suggested that diseases are caused (or at least determined in their development) by human factors as well. For these reasons, for instance, the brain (¾ –gk”f- alov) is not mentioned in chapter 18, although the writer had stated ear- lier (3. But in the author’s view all diseases are both divine and human: the explanandum is not that all diseases are human, but in what sense all diseases are divine as well. Among the ‘human’ factors determining the disease we should probably also reckon the individual’s constitution (phlegmatic or choleric: 2. A difficulty of this view is that not all of these factors seem to be accessible to human control or even influence, so that this connotation of anthropinos¯ seems hardly applicable here. Yet perhaps another association of the opposition theios– anthropinos¯ has prompted the author to use it here, namely the contrast ‘universal–particular’, which also seems to govern the use of theios in the Hippocratic treatise On the Nature of the Woman. Firstly, the meaning of the word phusis and the reason for mentioning it in all three passages remains unclear. If, as is generally supposed,20 phusis and prophasis are related to each other in that phusis is the abstract concept and prophasis the concrete causing factor (prophasies being the concrete constituents of the phusis of a disease), then the mention of the word phusis does not suffice to explain the sense in which the disease is to be taken as divine, for the nature of a disease is constituted by human factors as well. It is the fact that some of the constituents of the nature of the disease are themselves divine which determines the divine character of the disease.

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Paromomycin (Humatin) is a broad-spectrum antibiotic related to neomycin and strepto- mycin that is useful as an alternative treatment of mild-to-moderate luminal infections or in asymptomatic carriers in place of iodoquinol generic toprol xl 100mg on-line pulse pressure 90. Stibogluconate sodium (Pentostam) (1) Stibogluconate sodium is a pentavalent antimonial purchase line toprol xl blood pressure chart normal blood pressure range. However buy generic toprol xl blood pressure smoothie, adverse effects are numerous and include severe and dangerous nephrotoxicity and hypoglycemia. It is also the drug of choice when antimonials are ineffective or are contraindicated. Nifurtimox is used to treat South American trypanosomiasis caused by Trypanosoma cruzi (Chagas disease). Suramin is useful for the treatment of end-stage African trypanosomiasis, or sleeping sick- ness, caused by T. Eflornithine (Ornidyl), an alternative for late-stage African trypanosomiasis, is an ornithine decarboxylase inhibitor that is effective in arousing comatose sleeping sickness patients (the ‘‘resurrection drug’’). Melarsoprol (mel B) (1) Melarsoprol is a trivalent arsenical that reacts with sulfhydryl groups in proteins. Toxoplasmosis is treated with a combination of pyrimethamine and sulfadiazine (or clindamycin). Mebendazole (Vermox) and albendazole (Albenza) (1) Mebendazole and albendazole are benzimidazole carbamates that bind with high affin- ity to parasite free B-tubulin to inhibit its polymerization and microtubule assembly. It is also rec- ommended for infections caused by the cestodes Echinococcus granulosus and E. Diethylcarbamazine (Hetrazan) (1) This agent decreases microfilariae muscular activity, causing their dislocation, and it also disrupts their membranes, making them susceptible to host defense mechanisms. Chapter 11 Drugs Used in Treatment of Infectious Diseases 275 (2) Diethylcarbamazine is the drug of choice to treat loiasis, despite host response-induced toxicity, and it is a first-line agent for the treatment of lymphatic filariasis and tropical pulmonary eosinophilia caused by Wucheria bancrofti and Brugia malayi. Ivermectin (Mectizan) (1) Ivermectin causes paralysis of the organism’s musculature by activation of inverte- – brate-specific glutamate-gated Cl channels. Praziquantel (Biltricide) (1) Praziquantel causes muscle contraction, with paralysis of the worm; it also causes teg- mental damage, with host-defense activation and destruction of the worm. It is recommended for Fasciola hepatica (sheep liver fluke infection) and as an alternative to praziquantel for acute paragonimiasis. Acyclovir is a purine analogue that needs to be converted to nucleoside triphosphate for activity. Valacyclovir (Valtrex), a prodrug, is converted rapidly and completely to acyclovir, increas- ing its oral bioavailability to 50%. Chronic oral administration provides suppression and shortening of duration of symptoms in recurrent genital herpes. It is also used in herpes zos- ter in immunocompromised patients; ophthalmic application is used to treat herpes sim- plex dendritic keratitis; and topical application is used for mucocutaneous herpetic infections in immunosuppressed patients. In up to 5% of patients, reversible renal insufficiency due to crystalline nephropathy, or neu- rotoxicity, including tremor, delirium, and seizures, develop. Famciclovir (Famvir) is a prodrug that is well absorbed and then converted by deacetylation to penciclovir, which has activity similar to that of acyclovir except that it does not cause chain termination. It can also be used in combination therapy with Foscarnet, which is shown to be more effective. Resistance is primarily the result of impaired phosphorylation due to a point mutation or a deletion in the viral phosphotransferase. Valganciclovir is an ester prodrug that is converted to ganciclovir by intestinal enzymes. The therapeutic efficacy of foscarnet is limited by nephrotoxicity and hypocalcemia-related symptoms, including paresthesia, arrhythmias, and seizures. Adverse effects of these agents include edema around the eyes or eyelids with pain, pruri- tus, and inflammation. Docosanol (Abrevia), Penciclovir (Denavir)—These drugs are over-the-counter topical agents used to treat herpes labialis. Amantadine and rimantadine are used to treat orthomyxovirus (influenza A) infections when administered within the first 48 hours of symptoms, and as prophylaxis during flu sea- son. This agent may also be beneficial against measles pneumonitis, as well as severe respiratory influenza infections. The adverse effects of zidovudine, a pyrimidine analogue, include headache, diarrhea, and fever; dose-limiting toxicities are granulocytopenia and anemia. Dose-limiting toxicities are pancreatitis, sensory peripheral neuropathy, and optic neuritis. Except for acid lability, stavudine, a thymidine nucleoside analogue, is simi- lar to didanosine in pharmacokinetics, therapeutic use, and adverse effects that typically resolved with discontinuation. Reversible peripheral neuropathy may limit the use of this agent in 30% of patients. Emtricita- bine is a fluorinated analog of lamivudine with a long half-life that allows for once-daily dos- ing. This agent is more convenient than older antiretroviral agents in that it has a once-daily dosing schedule. Severe reactions, including Steven-Johnson syndrome and toxic epidermal necrolysis, have been reported, as has hepatotoxicity. Resistance due to changes in the protease gene has been described; different modifications may be responsible for resistance to some protease inhibitors. Resistance is more common when patients are noncompliant or take drug ‘‘holidays’’ or when inhibitors are used as mono- therapy or are given at subtherapeutic doses. Saquinavir (Invirase) Chapter 11 Drugs Used in Treatment of Infectious Diseases 279 (1) The bioavailability of this agent is reduced by other drugs that increase liver microsomal enzyme activity; it is increased by drugs that inhibit enzyme activity. Therefore, for greater efficacy, it is of- ten co-administered with ritonavir, a protease inhibitor (see below). Ritonavir (Norvir) (1) Ritonavir extensively inhibits many liver cytochrome P-450 enzymes, leading to accumu- lation of many drugs that are metabolized by this system (including saquinavir). It also induces some forms of cytochrome P-450 enzymes, leading to reduced bioavailability of other drugs. Indinavir (Crixivan) (1) Like ritonavir, it interferes with liver microsomal enzyme metabolism, but not to the same extent, and it inhibits the metabolism of some drugs and vice versa. Nelfinavir (Viracept), Amprenavir (Agenerase), Fosamprenavir (Lexiva) (1) These agents exhibit drug interactions similar to those of indinavir. Tipranavir (Aptivus) (1) Tipranavir, whose bioavailability is increased with a high-fat meal, undergoes extensive first-pass metabolism and, therefore, is co-administered with ritonavir. Its use is also associated with development of hepatic dysfunction (black box warning). Enfuvirtide (Fuzeon) blocks entry of virus into the cell by binding to viral gp41 glycoprotein.

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In systemic infections discount 100mg toprol xl free shipping blood pressure goal diabetes, recovered slightly curved septate hyphae may from blood cultures purchase discount toprol xl blood pressure xanax. Pneumocystis jiroveci Atypical interstitial plasma Cysts are 4–12 μm spheres with Can’t be cultured buy generic toprol xl 50 mg online pulse pressure in septic shock. Front is Septate hyphae, branching at Can cause invasive infec- fluffy, granular, or powdery 45°angle. Unbranched conid- Can cause eye, skin, nail, is white & cottony, develop- iophores. Conidiophores Can cause subcutaneous is gray-white & wooly at of variable length, sometimes infection. Dark branching is green-brown or black with conidiophores producing 2 or more velvety nap. Simple or Can cause sinusitis, dark olive green to brown or branched conidiophores, bent keratitis. Penetration Virus enters host cell by direct penetration, endocytosis (entering in a vacuole), or fusion with cell membrane. Direct fluorescent antibody stain Fluorescent-labeled antibody added to patient cells fixed to slide. Useful in evaluating immune status or diagnosing viral infections where culture is difficult or impossible. Lymphs (%) 18–38 42–72 37–73 23–53 18–42 Newborns: A few benign immature B cells may be seen (“baby” or “kiddie” lymphs). Liver & spleen may be reactivated (extramedullary hematopoiesis) if bone marrow fails to keep up with demand. Sickle cells (drepanocytes) Crescent, S or C shaped, boat shaped, Sickle cell anemia. Teardrops (dacryocytes) Teardrop shaped Myelofibrosis, thalassemia & other anemias. Staining Hypochromia Central pallor >1/3 cell diameter Iron deficiency anemia, thalassemia. May be artifact due to delay in spreading drop of blood or smear that’s too thick. Usually accelerated or & megaloblastic only 1 per cell abnormal anemias, sickle cell erythropoiesis anemia Cabot rings Wright’s Reddish purple May be part of mitotic Rapid blood regen- Megaloblastic anemia, rings or figure-8s spindle, remnant of eration, abnormal thalassemia, microtubules, or erythropoiesis postsplenectomy fragment of nuclear membrane Pappenheimer Wright’s (siderotic Small purplish blue Iron particles Faulty iron Sideroblastic anemias, bodies granules with granules. Amino acid sequence of globin sequence of globin chain, not in amount of globin chains is normal, but underproduction of 1 or more globin produced. Note: Some hematologists refer to all qualitative & quantitative hemoglobin abnormalities as hemoglobinopathies. Pappenheimer bodies, basophilic stippling β –thalassemia major ↓β-chain production. More often normocytic normochromic but included here because must be considered in differential Dx of microcytic anemia. May be transient Microcytic, hypochromic (due to iron deficiency) macrocytosis when↑retics reach circulation. Can be 48–72 hr before full extent of hemorrhage is evident (after fluid from extravascular spaces moves into circulation to expand volume). Toxic granulation Dark-staining granules in cytoplasm of neutrophils Infection, inflammation. Vacuolization Phagocytic vacuoles in cytoplasm of neutrophils Septicemia, drugs, toxins, radiation. Hypersegmentation >5 % of segs with 5-lobed nuclei or any with >5 lobes One of 1st signs of pernicious anemia. Pelger-Huët anomaly Most neutrophils have round or bilobed nuclei Inherited disorder. Auer rods Red needles in cytoplasm of leukemic myeloblasts & Rules out lymphocytic leukemia. Variant lymphocytes 1 or more of following: large size, elongated or indented Viral infections (e. Myelodysplastic Premalignant hematopoietic stem Refractory anemia, More common in elderly. Rare in older nous, acute from 1–200 cells, Howell-Jolly bodies, children & teens. Acute lymphoblastic Acute lymphocytic ↑in 50% of Small, homogeneous blasts in Peak incidence 2–5 yr. Waldenström’s macroglobulinemia Malignant lymphocyte–plasma cell proliferative disorder. Microhematocrit Screening for Microhematocrit tubes centrifuged at Values may be slightly higher than calcu- (packed cell anemia 10,000-15,000 rpm for 5 min. Reticulocyte count Assess rate of Blood smear stained with new Miller ocular can be used to facilitate count- erythropoiesis methylene blue. Follow up with hgb elec- Hemoglobin S produces turbid solution that obscures trophoresis. Osmotic fragility Dx of hereditary Blood added to serial dilutions of NaCl & ↑in hereditary spherocytosis. Amount of hemolysis deter- cells, sickle cell anemia, iron deficiency ane- mined by reading absorbance of super- mia, thalassemia. Tube 2 in- biphasic antibody (autoanti-P) that binds hemoglobinuria cubated at 37°C only. Optical light scattering Hydrodynamically focused stream of cells passes through quartz flow cell Cell counting & sizing, (flow cytometry) past light source (tungsten halogen lamp or laser light). Lymphocytes Mononuclear cells Granulocytes 50 100 200 300 400 Femtoliters (From Ciesla B. Electrons of fluorochrome raised to higher energy state; emit light of specific wavelength as they return to ground state. Applications Immunophenotyping: Differentiating cells on basis of surface & cytoplasmic markers. Plt drome, plt storage pool defects, idiopathic aggregation curves generated (time vs. Sees coagulation as 3 overlapping phases that pathways converge on common pathway. Reagent(s) Thromboplastin reagent (thromboplastin, Activated partial thromboplastin reagent (phospholipid, phospholipid, Ca2+). If pt has factor defi- ciency, time will be corrected because normal plasma supplies missing factor. Results obtained from calibration curve prepared from testing dilutions of a fibrinogen standard.

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Sinai Medical Center’s Personalized Medicine Research Program In 2007, the Mount Sinai Medical Center in New York received a $12. The research center is studying personalized medicine, and the medical center will use the funds to start “an institution-wide biobank” and a “translational biomedical informatics center. The Institute will bridge the gap between genom- ics research and clinical patient care in the area of personalized medicine. Access and training in these resources will be critical to overcoming current research infrastructure bar- riers that limit our disease-oriented research centers in deciphering the genetic underpinnings of, and developing personalized approaches to, complex diseases. It is comprised of 11 collaborators, mostly from New York City but also from institutions in other states. Through the unique collaboration, scientists and physicians will share clinical and genomic data on a large scale in studies aimed at identifying and validating biomarkers, understanding the molecular basis of diseases, and speeding up the development of new diagnostic and therapeutic technologies. It is using an initial $125 million investment to build the 120,000 square-foot center in Manhattan to begin operations. The partner institutions serve >5 million patients and offer scientists a broad and diverse range of genetic variation that would be difficult to find in any other single region. New York City is the largest concentration of medical and academic research anywhere in the world. It provides a place where new products and tests can be developed for a variety of ethnic groups and age groups for which different drugs and approaches might be appropriate. P4Mi was co-founded in 2010 by the Institute for Systems Biology and the Ohio State University Medical Center, which is develop- ing more specific, cost-effective treatments for patients, creating new technologies and tools that will define wellness at a deep molecular level, and empowering indi- viduals to take an active role in their health care. P4Mi is now joined by PeaceHealth, a Washington-based not-for-profit Catholic health care system, with major medical centers and laboratories in Alaska, Washington and Oregon with approximately 15,000 employees. The partnership will engage Sanford-Burnham’s research exper- tise and genomics and metabolomics technologies, Moffitt’s biospecimen bank, data warehouse, and genome mapping capabilities, and Florida Hospital’s patient population and clinical research capacities. Partners Personalized Medicine at Massachusetts General Hospital Since its founding in 2001, the mission of Partners Personalized Medicine has been to promote genetics and genomics in research and medicine and to help realize the promise of personalized genetic medicine by accelerating the integration of genetic knowledge into clinical care. Personalized Oncology In 2009, oncologists at the Massachusetts General Hospital started to personalize cancer therapy. They read the genetic fingerprints of nearly all the new patients’ tumors in a strategy designed to customize treatment. They will search for abnor- malities carried on major cancer genes that can predict whether drugs already avail- able or in development might be effective against a particular patient’s cancer. High throughput techniques are being used for sequencing 5,000–6,000 patients a year, replacing labor-intensive techniques that had been used only selectively for a hand- ful of cancers. The focus is more on the genetic profile of a tumor and less on Universal Free E-Book Store 624 20 Development of Personalized Medicine whether it is in the lung, breast, or prostate. The genes inside the malignancy are considered to be more important than the location of the cancer. The testing could be especially useful for patients with rare cancers, usually neglected by cancer researchers or pharmaceutical companies, as they may share genetic signatures with more common tumors already being successfully treated. One limitation is the cost as the hospital charges $2,000 for the test and it may not be covered by the health insurance companies. It manages >1,000 research projects, and conducts ~400 clinical trials every year. Through these efforts, the institute will develop a new model for patient care designed to tailor treatment plans toward the tumor biology of each individual patient. The institute envisions genotyping tumors so patients can be linked to new therapies or, if deemed appropriate, clinical trials. The Institute is also promising to overhaul its clinical molecular lab operations, which can map the genomes of patients to determine the appropriate treatment for their cancers. The main set of tools and technologies to be acquired will be for next-generation sequencing. Southeast Nebraska Cancer Center’s Personalized Medicine Network In 2005, the Southeast Nebraska Cancer Center (Lincoln, Neb) was awarded $1. The center, will be part of the DoD’s National Functional Genomics Center, and will use the funding to create a network to collect cancer tissue samples and to follow the patients’ progress through therapy, which would be merged into a national database. This large-scale effort combines government, academic and private-sector resources. 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The center l promotes personalized medicine by building on research from the sequencing of the genome of Stephen Quake, by using Heliscope single molecule sequencer and showing the potential for use of the information obtained in assessing personalized disease sus- ceptibility and responsiveness to drugs. The center blends highly efficient, rapid sequencing technology with the research and clinical efforts of experts in genomics, bioinformatics, molecular genetic pathology and even ethics and genetic counseling to bring advances from the laboratory to the patient. The center’s sequencing facil- ity is already operating with new equipment estimated to increase its sequencing capacity by about fivefold while significantly reducing the cost. This is an integrated resource about how variation in human genes leads to variation in our response to drugs. 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