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Kapferer in the 1930s on the question whether the Hippocratic writers were familiar with the process of blood circulation; for a review of this debate see Duminil (1998) 169–74 purchase eriacta 100 mg on line. Postmodernism discount 100 mg eriacta with amex, pluralism purchase eriacta 100 mg with amex, cultural relativism and comparativism purchase 100 mg eriacta amex, as in so many other areas generic eriacta 100 mg online, have had their impact also on the study of Greek medicine and science. Questions have been asked about the uniqueness of Greek medical thought, and it has been suggested that its debt to earlier, Near Eastern and Egyptian thinking may have been much greater than was commonly assumed. Questions have also been raised about the rationality of Greek medical thought, about the assumption that Greek medicine developed ‘from myth to reason’,4 and Greek medicine has been shown to have been much more open and receptive to superstition, folklore, religion and magic than was generally believed. Furthermore, in the academic study of medical history – and to a certain extent also in the historiography of science – significant changes have oc- curred over the past decades, especially in the area of medical anthropology, the social, cultural and institutional history of medicine and science, the history of medical ethics, deontology and value systems, and the linguistic study and ‘discourse analysis’ of medical texts. There has been an increasing realisation of the social and cultural situatedness of medicine, healthcare and knowledge systems: individuals, groups of individuals and societies at large understand and respond differently to the perennial phenomena of sickness and suffering, health and disease, pain and death; and these reac- tions are reflected in different medical ideas, different ‘healthcare systems’, different value systems, each of which has its own social, economic and cultural ramifications. This appreciation of the variety of healthcare (and knowledge) systems – and indeed of the variety within one system – is no doubt related to the increasing acceptance of ‘alternative’ or ‘comple- mentary’ medicine in the Western world and the corresponding changes in medical practice, doctor–patient relationship and the public perception of the medical profession. And the traditional assumption of a superiority of Western, scientific medicine over non-Western, ‘primitive’, ‘folklore’ or ‘al- ternative’ medicine has virtually reached the state of political incorrectness. This shift in attitude has had rather paradoxical implications for the study of ancient medicine. In short, one could say that attention has widened from texts to contexts, and from ‘intellectual history’ to the history of ‘dis- courses’ – beliefs, attitudes, perceptions, expectations, practices and rituals, their underlying sets of norms and values, and their social and cultural ramifications. At the same time, the need to perceive continuity between 4 For a more extended discussion of this development see the Introduction to Horstmanshoff and Stol (2004). Introduction 5 Greek medicine and our contemporary biomedical paradigm has given way to a more historicising approach that primarily seeks to understand med- ical ideas and practices as products of culture during a particular period in time and place. As a result, there has been a greater appreciation of the diversity of Greek medicine, even within what used to be perceived as ‘Hippocratic medicine’. For example, when it comes to the alleged ‘ratio- nality’ of Greek medicine and its attitude to the supernatural, there has first of all been a greater awareness of the fact that much more went on in Greece under the aegis of ‘healing’ than just the elite intellectualist writing of doctors such as Hippocrates, Diocles and Galen. Thus, as I argue in chapter 1 of this volume, the author of On the Sacred Disease, in his criticism of magic, focuses on a rather narrowly defined group rather than on religious healing as such, and his insistence on what he regards as a truly pious way of approaching the gods suggests that he does not intend to do away with any divine intervention; and the author of the Hippocratic work On Regimen even positively advocates prayer to specific gods in combination with dietetic measures for the prevention of disease. Questions have further been asked about the historical context and representativeness of the Hippocratic Oath and about the extent to which Hippocratic deontology was driven by considerations of status and reputa- tion rather than moral integrity. And the belief in the superiority of Greek medicine, its perceived greater relevance to modern medical science – not to mention its perceived greater efficacy – compared with other traditional healthcare systems such as Chinese or Indian medicine, has come under attack. As a result, at many history of medicine departments in universi- ties in Europe and the United States, it is considered naıve¨ and a relic of old-fashioned Hellenocentrism to start a course in the history of medicine with Hippocrates. This change of attitude could, perhaps with some exaggeration, be described in terms of a move from ‘appropriation’ to ‘alienation’. Greek, in particular Hippocratic medicine, is no longer the reassuring mirror in which we can recognise the principles of our own ideas and experiences of health and sickness and the body: it no longer provides the context with which we can identify ourselves. Nevertheless, this alienation has brought about a very interesting, healthy change in approach to Greek and Roman medicine, a change that has made the subject much more interesting and 5 For an example see the case study into experiences of health and disease by ‘ordinary people’ in second- and third-century ce Lydia and Phrygia by Chaniotis (1995). An almost exclusive focus on medical ideas and theories has given way to a consideration of the relation between medical ‘science’ and its environment – be it social, political, economic, or cultural and religious. Indeed ‘science’ itself is now understood as just one of a variety of human cultural expressions, and the distinction between ‘science’ and ‘pseudo-science’ has been abandoned as historically unfruitful. And medicine – or ‘healing’, or ‘attitudes and ac- tions with regard to health and sickness’, or whatever name one prefers in order to define the subject – is no longer regarded as the intellectual property of a small elite of Greek doctors and scientists. There is now a much wider definition of what ‘ancient medicine’ actually involves, partly inspired by the social and cultural history of medicine, the study of medical anthropology and the study of healthcare systems in a variety of cultures and societies. The focus of medical history is on the question of how a soci- ety and its individuals respond to pathological phenomena such as disease, pain, death, how it ‘constructs’ these phenomena and how it contextualises them, what it recognises as pathological in the first place, what it labels as a disease or aberration, as an epidemic disease, as mental illness, and so on. How do such responses translate in social, cultural and institutional terms: how is a ‘healthcare system’ organised? How do they communicate these to their colleagues and wider audiences, and what rhetorical and argumentative techniques do they use in order to persuade their colleagues and their customers of the preferability of their own approach as opposed to that of their rivals? How is authority established and maintained, and how are claims to competence justified? The answers to these questions tell us something about the wider system of moral, social and cultural values of a society, and as such they are of interest also to those whose motivation to engage in the subject is not primarily medical. As the comparative history of medicine and science has shown, societies react to these phenomena in different ways, and it is interesting and illuminating to compare similarities and differences in these reactions, since they often reflect deeper differences in social and cultural values.

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Evidence from family studies suggests that at least 100 mutations eriacta 100mg visa, can be predicted with greater confidence eriacta 100mg low price. To date order 100 mg eriacta with mastercard, mutations in Once the cause of hearing loss has been identified generic 100mg eriacta with mastercard, genetic some 50 different genes have been identified as causes of some counselling can be more specific cheap 100 mg eriacta. Some companies claim to be developing methods two general solutions to this: that would allow a person’s entire genome to be sequenced in a few days for a few thousand dollars. Optimists and pessimists ■ Selectively amplify the sequence of interest to such an extent alike dream of the day when everybody’s complete genome that the sample consists largely of copies of that sequence. The to avoid the royalty payments required of users of the patented problem is the great heterogeneity of genetic hearing loss. Some forms of is cooled, each Watson strand will try to find a matching Crick syndromal hearing impairment fall into this category. As will stick to the probe, and by using the label, it can be isolated, mentioned above, our ability to answer questions about a followed, or characterised. Genes can have any number ask such a specific question is if somebody is being tested to see of exons, from 1 to over 100. The nearest approximation to this in hearing pathology laboratory investigation a sample from the patient is impairment is a specific mutation (g. Many of these are tests for specific muta- Occasionally, careful examination can provide a pointer to tions, but multiplexed so that a number of different mutations a candidate gene: are checked in a single operation. Due to recessive ing of this gene should be considered in unresolved cases, inheritance, two pathogenic mutations are expected in order to especially in conjunction with imaging studies. This is not a rare occurrence, especially for the common muta- Other screening methods such as, for example, denaturing high tions, which have a high carrier frequency in the general popu- performance liquid chromatography can be used to provide a lation. Before reaching this uncertain conclusion, however, it is quick initial screen and reduce the sequencing load. These new “active” devices will further improve the use of micro devices in diagnostics and help in screening large numbers of individuals at a low cost and with New approaches for great accuracy. Finally, another example of an array-based hearing impair- Genetics and molecular medicine have an expanding need for ment assay is a gene chip capable of holding 28,000 anchored technologies that allow rapid genotyping, mutation analysis, oligonucleotide probes. The keys to high throughput screening genes and is being developed on the Affymetrix platform lie in miniaturisation, parallelisation and automation. Although it is gradient gel electrophoresis, or chemical cleavage are labour hard to predict exactly which technologies will emerge as domi- intensive (7) and handle only one or a few samples at a time. Microarray assays are based on nucleic acid hybridisation become less of an obstacle and will allow the benefits of genetic (8–10) or hybridisation coupled with an enzyme-mediated testing to be much more widely disseminated. The modified nucleotides are dideoxynucleotides, ensuring that the polymerase reaction can add only a single nucleotide to each primer, and the four dideoxynucleotides each carry a different fluorescent label. After the primer extension reaction, a muta- tion is detected by a change in the colour code of the primer sites. Universal newborn hearing screening: fine-tuning hundreds of mutations underlying sensorineural (largely the process. Curr Opin Otolaryngol Head Neck Surg 2003; 11: nonsyndromal) hearing impairment in a series of genes includ- 424–427. Cystic fibrosis mutation detection by hybridization to light- sensorineural hearing loss earlier. Nested genetic bit analysis is freely available as full searchable text at http://www. For example, in the mammalian The auditory system seems better equipped to deal with injuries vestibular system, hair cell regeneration has been shown to occur in lower species than in mammals. The situation in the auditory inner ear will produce new sensory cells (hair cells) throughout system is less clear. There is evidence of hair cell regeneration in their life and, consequently, injured cells can be replaced contin- newborn mice given explants of cochlear duct (7) and in replac- uously. Birds lose this ability during embryonic development, but ing the damaged hair cells by converting the supporting cells (8). In contrast, mam- homologue of the drosophila gene atonal that encodes a basic malian hair cell loss has always been considered irreversible. Overexpression of The mechanism of cell death in the cochlea is produced in Atoh1 in nonsensory cells of the normal cochlea generates new two ways: through “necrotic cell death” mediated by very loud hair cells, both in vitro and in vivo. Atoh1 has been shown to act noise, or “apoptosis,” mediated by the activation of cysteine as a “prohair cell gene” and is required for the differentiation of protease family within the cells, the caspases [very loud noise can hair cells from multipotent progenitors.

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Preclinical Prediction of Drug Efficacy Assays of drug action typically evaluate biochemical activity order 100 mg eriacta. However cheap 100 mg eriacta free shipping, accurately matching therapeutic efficacy with biochemical activity is a challenge generic eriacta 100mg with visa. High-content cellular assays seek to bridge this gap by capturing broad information about the cel- lular physiology of drug action generic eriacta 100 mg mastercard. Detailed information contained in genomic expres- sion data is usually sufficient to match the physiological effect of a novel drug at the cellular level with its clinical relevance buy eriacta 100 mg. This capacity to identify therapeutic effi- cacy on the basis of gene expression signatures in vitro has potential utility in drug discovery and drug target validation relevant to personalized medicine. Knowledge of genetic variation in a target enables early assessment of the clinical significance of polymorphism through the appropriate design of preclinical studies and use of relevant animal models. A focused pharmacogenomic strategy at the pre- clinical phase of drug development can contribute to the decision-making process for Universal Free E-Book Store 154 5 Pharmacogenomics full development of compounds. Pharmacogenomics and Clinical Trials Examples of role of pharmacogenomics in clinical trials are listed in Table 5. Current applications of pharmacogenomics include development by prospective genotyping in phase I tri- als, to ensure that a subject population is representative with respect to drug metabo- lism phenotypes. The banking of genetic material from later stage trials for retrospective studies on drug response is becoming more frequent, but is not yet standard in the industry. Some examples of use of pharmacogenomics in clinical studies are shown in Table 5. In case of a genotype-specific drug, test groups should contain only the targeted phenotypes. Molecular genetic methods may be applied both for genetic profiling(polymorphisms, mutations, etc. Genotype/ phenotype correlations based on identification of mutations and polymorphisms are used for population segmentation. Pharmacogenomic tests used by the pharmaceutical companies themselves can be used to help identify suitable subjects for clinical trials, aid in interpretation of clinical trial results, find new markets for current products and speed up the devel- opment of new treatments and therapies. Universal Free E-Book Store 156 5 Pharmacogenomics It is anticipated that genotyping at different stages of clinical trials would change the approach to drug development. Currently there are four phases of clinical trials followed by postmarketing studies. Suggestions to shorten the clinical drug devel- opment process by reducing the number of phases are as follows: • Phase I. Detection of rare events and development of diagnostic tests tied in with the drug therapeutics. Some drawbacks of pharmacogenomics-based clinical trials are: • Exclusion of certain subjects from trials on the basis of genotype is interpreted s discrimination similar to exclusion of women and minorities • Stratification into smaller subgroups might confound statistical analysis and interpretation of results • Statistical differences may not be clinically significant • Misuse of the good results in a subgroup to portray the drug as a whole • Need to do separate clinical trials in different countries Limitations of the Pharmacogenomic-Based Clinical Trials Large prospective trials to demonstrate the value of genotyping in patient manage- ment will be required to support the introduction of pharmacogenomics into clinical practice. Some of the limitations to be considered are: • Such studies are costly and can be justified only if there is a reproducible association between genotype and a clinically relevant phenotype. It may reflect real population differences but multiple comparisons, biases and other design limitations suggest that many initial positive associations represent Type I errors. In selected situations, pharmacogenomic studies in healthy volunteers may sup- port a decision to perform such prospective association studies. If the results of these studies are significant and potential health or economic benefits of therapy are considerable, a major clinical trial can be considered to assess the usefulness of a pharmacogenomics-based therapy. Universal Free E-Book Store Current Status and Future Prospects of Pharmacogenomics 157 An alternative to prospective controlled clinical trials is simple examination of a treated population in a clinic by retrospective genotyping. This would reveal indi- viduals that had received treatment by chance from those where it would have been recommended on basis of genotype as well as individuals that received inappropri- ate treatment. This approach could produce valuable data to support the value of pharmacogenomic testing. The authors of this proof-of-concept study propose a shift in the current paradigm to consider the gene as the genomic feature of interest in pharmacoge- nomics discovery. Even, the full potential of currently available data about pharmacogenomics is largely unrealized because of the logistic challenges in obtaining suitable genomic information in a timely manner to guide prescribing. Placing genomic information in the electronic medical record would facilitate personalized medicine. Although this scenario holds great promise, the utility of genomic information for drug prescribing must be documented with rigorous evidence.

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