By Z. Shakyor. Lambuth University. 2018.
The Dutch ethologist Nikolaas Tinbergen (1963) pointed out that traits have two distinct proximate causes and two ultimate causes buy 100 ml mentat ds syrup. The proximate causes of a trait include its development during an organism’s ontogeny and the physiological or molecular mechanisms that produce it quality mentat ds syrup 100 ml; the ultimate causes are its phylogenetic origin and its adaptive significance cheap 100 ml mentat ds syrup visa. Physicians have traditionally been concerned with proximate causes of disease because these are the causal pathways that are amenable to medical intervention. In contrast, evolutionists want to understand ultimate causes of biological phenomena. Recent advances in evolutionary development biology, or “evo-devo,” have called attention to the relationship between evolution and development and have led to a blurring of the distinction between proximate and ultimate causes (Laland et al. As discussed below, there is currently great interest in understanding the ways in which our evolved mechanisms of development may predispose us to disease in adult life. To a great extent, medicine has tried to separate humans from the rest of nature and protect us from species that might cause disease. Evolutionists, on the other hand, view populations as embedded in ecological communities that comprise a myriad of interrelated and interacting species, all of which are subject to natural selection and are therefore coevolving. Physicians certainly recognize environmental causes of disease, espe- cially infectious diseases and diseases due to environmental toxins. Nonetheless, medical research has focused on the inner workings of human beings, on the physiological and pathophysiological mechanisms that promote health or lead to disease. Medicine is concerned with what Claude Bernard (1957) termed the “internal environment,” the blood and extracellular fluids that provide the immediate environment in which our cells and organs function. In this view, health involves the maintenance of constant, or nearly constant, conditions in the internal environment—conditions that enable cells and organs to function prop- spring 2013 • volume 56, number 2 177 Robert L. Perlman erly—while diseases are manifest by deviations from these “normal” conditions. Evolutionary biologists appreciate that the physiological mechanisms that main- tain homeostasis are adaptations that enhance fitness, but they are more inter- ested in studying the interactions of organisms with their external environments, because it is these ecological interactions that shape the struggle for existence and natural selection. Appreciation of the physiological functions and patho- physiological effects of the human microbiome, the communities of microor- ganisms that inhabit our skin, intestines, and other body cavities, has led to the recognition that humans are ecological communities. Indeed, study of the microbiome is a growing area of research in which the interests of physicians and evolutionists are converging (Turnbaugh et al. Finally, medicine and evolutionary biology have different ways of thinking about variation. Physicians distinguish between “normal” values of traits, values that are associ- ated with good health or that are common in the population, and “abnormal” values, values that are associated with an increased risk of disease. In a medical context, this distinction between normal and abnormal often makes good sense. Many deviations from normal values—elevated blood pressure, blood choles- terol, and body mass index, for example—are risk factors for diseases that may be prevented or postponed by medical interventions. Occasionally, however, extreme values of a trait—short stature, for example—may be labeled abnormal even if they do not have implications for health. Since the rise of the Human Genome Project, physicians are certainly aware of and concerned about genetic variations among their patients. But medicine is still influenced by an essential- ist view of biology that tends to view phenotypic variations as deviations from a normal, healthy, or ideal state. This medical understanding of variation differs from that of evolutionary biologists, who view variation as a fundamental prop- erty of biological populations. Not only is variation abundant in nature, it pro- vides the substrate for evolution by natural selection; if there weren’t heritable variations among individuals, populations couldn’t evolve. The values of specific traits among individuals typically exhibit a distribution, frequently a normal or lognormal distribution, that is associated with variations in fitness. Often, but not always, the median or mean value of a trait is maintained by natural selection be- cause it is associated with maximal fitness. Only rarely if ever are there sharp cut- offs that separate health from disease or distinguish different levels of fitness. Historically, then, medicine and evolutionary biology have been concerned with different biological problems and have developed different approaches to study their areas of interest. It is not surprising that they have developed as sep- arate, unrelated disciplines. But physicians and nonmedical biologists have begun to realize that there is much to be gained by integrating these disciplines. Evo- lutionary medicine recognizes that these different perspectives are complemen- tary, and that integrating them will give a richer understanding of health and disease. Understanding evolutionary processes helps to explain our evolved vul- 178 Perspectives in Biology and Medicine Evolution and Medicine nerabilities or susceptibilities to disease and our current burden of disease. Con- versely, since disease has served as an important selection factor in evolution (Haldane 1949a), knowledge of the present patterns of disease gives insights into our evolutionary history. Analysis of the evolutionary causes of diseases may lead to novel strategies to prevent, postpone, or ameliorate them. Understanding both the proximate and ultimate causes of diseases will provide a richer understand- ing of disease. Finally, evolutionary explanations of disease are important because patients often want to know why they have the diseases they have. In the absence of evolutionary explanations, they may fall back on unhelpful folk beliefs, such as the idea that their diseases are punishment for sinful behavior (Bynum 2008). Why Our Evolutionary Heritage Has Left Us Vulnerable to Disease Many diseases cause premature death (death before the end of the reproductive and child-raising periods) or reduced fertility. But most diseases do not affect all members of a population or do not affect everyone to the same degree. Rather, individuals exhibit variation in resistance or response to diseases, just as they exhibit variation in virtually all other traits. At least some of this variation is due to genetic or heritable variation in the population. Heritable variations in resis- tance to these diseases represent variations in fitness; individuals who survive and remain fertile in the face of a disease will on average produce and raise more children than will people who die from or become infertile as a result of the dis- ease. As a disease spreads through a population, natural selection will increase the frequency of alleles that are associated with resistance to it. The alleles associated with resistance to malaria are classic examples of this process. Despite selection for disease resistance throughout our evolutionary history, however, natural selection has clearly not eliminated disease. Evolutionary med- icine helps us understand the limits as well as the power of natural selection in shaping human biology and the reasons—the ultimate causes—for our contin- ued vulnerability or susceptibility to disease. Broadly speaking, there are several important limits to natural selection that contribute to the persistence of disease (Nesse 2005; Perlman 2005). First, there are limitations intrinsic to the process of evolution by natural selection itself.
At the same time buy mentat ds syrup 100 ml overnight delivery, Florence Nightingale was using statistical graphs to show the need to improve sanitation and hygiene in general for the British troops during the Crimean War buy cheap mentat ds syrup 100 ml on line. Speciﬁcs include the discovery of modern medicines by Paul Erlich discount mentat ds syrup 100 ml visa, antibiotics (specif- ically sulfanilamide by Domagk and penicillin by Fleming), and modern A brief history of medicine and statistics 7 chemotherapeutic agents to treat ancient scourges such as diabetes (speciﬁcally the discovery of insulin by Banting, Best, and McLeod), cancer, and hyperten- sion. The modern era of surgery has led to open-heart surgery, joint replacement, and organ transplantation. Before the middle of the twentieth century, advances in medicine and conclusions about human illness occurred mainly through the study of anatomy and physiology. The case study or case series was a common way to prove that a treatment was beneﬁcial or that a certain etiology was the cause of an illness. There were intense battles between those physicians who wanted to use statistical sampling and those who believed in the power of inductive reasoning from physiological experiments. This argument between inductive reasoning and statistical sampling contin- ued into the nineteenth century. Pierre Simon Laplace (1814) put forward the idea that essentially all knowledge was uncertain and, therefore, probabilistic in nature. The work of Pierre Charles Alexandre Louis on typhoid and diphtheria (1838) debunking the theory of bleeding used probabilistic principles. On the other side was Francois Double, who felt that treatment of the individual was more important than knowing what happens to groups of patients. The art of medicine was deﬁned as deductions from experience and induction from phys- iologic mechanisms. The rise of modern biomedical research Most research done before the twentieth century was more anecdotal than sys- tematic, consisting of descriptions of patients or pathological ﬁndings. James Lind, a Royal Navy surgeon, carried out the ﬁrst recorded clinical trial in 1747. In looking for a cure for scurvy, he fed sailors afﬂicted with scurvy six different treatments and determined that a factor in limes and oranges cured the disease while other foods did not. His study was not blinded, but as a result, 40 years later limes were stocked on all ships of the Royal Navy, and scurvy among sailors became a problem of the past. Research studies of physiology and other basic science research topics began to appear in large numbers in the nineteenth century. By the start of the twenti- eth century, medicine had moved from the empirical observation of cases to the scientiﬁc application of basic sciences to determine the best therapies and cat- alog diagnoses. Although there were some epidemiological studies that looked at populations, it was uncommon to have any kind of longitudinal study of large 8 Essential Evidence-Based Medicine groups of patients. There was a 200-year gap from Lind’s studies before the con- trolled clinical trial became the standard study for new medical innovations. It was only in the 1950s that the randomized clinical trial became the standard for excellent research. Beginning in the early 1900s, he developed the basis for most the- ories of modern statistical testing. Austin Bradford Hill was another statistician, who, in 1937, published a series of articles in the Lancet on the use of statisti- cal methodology in medical research. In 1947, he published a simple commen- tary in the British Medical Journal calling for the introduction of statistics in the medical curriculum. He showed that streptomycin therapy was superior to standard therapy for the treatment of pulmonary tuberculosis. Finally, Archie Cochrane was particularly important in the development of the current movement to perform systematic reviews of medical topics. He was a British general practitioner who did a lot of epidemiological work on respira- tory diseases. In the late 1970s, he published an epic work on the evidence for medical therapies in perinatal care. This was the ﬁrst quality-rated systematic review of the literature on a particular topic in medicine. As Santayana said, it is important to learn from history so as not to repeat the mistakes that civilization has made in the past. The improper application of tainted evidence has resulted in poor medicine and increased cost without improving on human suffering. This book will give physicians the tools to evalu- ate the medical literature and pave the way for improved health for all. In the next chapter, we will begin where we left off in our history of medicine and statistics and enter the current era of evidence-based medicine. The most savage controversies are those about matters as to which there is no good evidence either way. Bertrand Russell (1872–1970) Learning objectives In this chapter, you will learn: r why you need to study evidence-based medicine r the elements of evidence-based medicine r how a good clinical question is constructed The importance of evidence In the 1980s, there were several studies looking at the utilization of various surg- eries in the northeastern United States. These studies showed that there were large variations in the amount of care delivered to similar populations. They found variations in rates of prostate surgery and hysterectomy of up to 300% between similar counties. The researchers concluded that physicians were using very different standards to decide which patients required surgery. Both clinicians and policy makers need to know whether the 9 10 Essential Evidence-Based Medicine Fig. Patient values conclusions of a systematic review are valid, and whether recommendations in practice guidelines are sound. This is a paradigm shift that represents both a breakdown of the traditional hierarchical system of medical practice and the acceptance of the scientiﬁc method as the governing force in advancing the ﬁeld of medicine. Evidence-based medicine can be seen as a combination of three skills by which practitioners become aware of, critically analyze, and then apply the best avail- able evidence from the medical research literature for the care of individual patients. This set of skills will help you to develop critical thinking about the content of the medical literature. The application of research results is a blend of the available evidence, the patient’s preferences, the clinical situation, and the practitioner’s clinical experience (Fig. In response to the high variability of medical practice and increasing costs and complexity of medical care, systems were needed to deﬁne the best and, if pos- sible, the cheapest treatments. Individuals trained in both clinical medicine and epidemiology collaborated to develop strategies to assist in the critical appraisal of clinical data from the biomedical journals. In the past, a physician faced with a clinical predicament would turn to an expert physician for the deﬁnitive answer to the problem. This could take the form of an informal discussion on rounds with the senior attending (or consul- tant) physician, or the referral of a patient to a specialist. The answer would come from the more experienced and usually older physician, and would be taken at face value by the younger and more inexperienced physician. That clinical answer was usually based upon the many years of experience of the older physi- cian, but was not necessarily ever empirically tested.
The global goal of saving 36 million lives by the year 2015 can be achieved with urgent buy 100 ml mentat ds syrup visa, coordinated action buy mentat ds syrup 100 ml line. A range of effective interventions for chronic disease prevention and control exist buy mentat ds syrup 100 ml with mastercard, and many countries have already made major reductions in chronic disease death rates through their implementation. In low income countries, it is vital that supportive poli- cies are put in place now to reduce risks and curb the epidemics before they take hold. In countries with estab- lished chronic disease problems, additional measures are needed not only to prevent the diseases through popula- tion wide and individual risk reduction but also to manage illness and prevent complications. Taking up the challenge for chronic disease prevention and control, especially in the context of competing priori- ties, requires courage and ambition. On the other hand, the failure to use available knowledge about chronic dis- ease prevention and control is unjustiﬁed, and recklessly endangers future generations. There is simply no excuse for allowing chronic diseases to continue taking millions of lives each year when the scientiﬁc understanding of how to prevent these deaths is available now. Journal of the Pakistan Medical Association, Control Noncommunicable Diseases in Tonga. Geneva, World Health nutrition-related chronic diseases and obesity: examples from 14 Organization, 2004 (http://www. A set of relatively These socioeconomic variables show clear historical simple models was used to project future health trends relationships with mortality rates, and may be regarded under various scenarios, based largely on projections of as indirect, or distal, determinants of health. In addition, a economic and social development, and using the histori- fourth variable, tobacco use, was included in the projec- cally observed relationships of these to cause-speciﬁc tions for cancers, cardiovascular diseases and chronic mortality rates. The data inputs for the projection mod- respiratory diseases, because of its overwhelming impor- els have been updated to take account of the greater tance in determining trends for these causes. This latter vari- changes to current transmission rates due to increased able captures the effects of accumulating knowledge and prevention efforts. Similarly, projections of sent to Member States for comment in 2003, and com- mortality for chronic respiratory diseases were adjusted ments or additional information incorporated where for projected changes in smoking intensity. The new projections for low income By their very nature, projections of the future are highly countries were based on the observed relationships for a uncertain and need to be interpreted with caution. The projected Surveys, and from the use of cause-speciﬁc mortality global population in 2015 was 7. Projections were carried out at country level, but aggre- The projections of burden are not intended as forecasts gated into regional or income groups for presentation of what will happen in the future but as projections of results, apart from the projections for nine selected of current and past trends, based on certain explicit countries included in this report. Mortality estimates were based on analysis of lat- largely on broad mortality projections driven to a large est available national information on levels of mortal- extent by World Bank projections of future growth in ity and cause distributions as at late 2003. Alternative projections of mortality and of pessimistic and optimistic projections under alternate disability by cause 1990-2020: Global Burden of Disease Study. Alternative visions of the future: projecting The results depend strongly on the assumption that future mortality and disability, 1990-2020. The global burden of disease: a comprehensive assessment mortality trends in poor countries will have the same of mortality and disability from diseases, injuries and risk factors relationship to economic and social development as has in 1990 and projected to 2020. Mortality from rate of decline of communicable and noncommunicable tobacco in developed countries: indirect estimation from national diseases. Overweight and obesity (high body countries, then again the projections for low and middle mass index). Comparative quantiﬁcation of health risks: global and regional burden of disease attributable to selected major risk factors. Global burden of disease in 2002: data sources, methods and then adjusted by subtraction of an additional 2% per results. Death rates for the years 2006 to 2015 were then recomputed using the adjusted annual trends for age/sex-speciﬁc rates. Note that the ﬁnal death rates for chronic diseases in 2015 under the bold goal scenario will be substantially lower than the base projections, since the additional 2% annual declines are cumulative. Netherlands Saudi Arabia Netherlands Antilles Seychelles New Caledonia Slovakia New Zealand Trinidad and Tobago Northern Mariana Islands Uruguay Norway Venezuela (Bolivarian Republic of) Portugal Qatar Republic of Korea San Marino Singapore Slovenia Spain Sweden Switzerland United Arab Emirates United Kingdom United States of America United States Virgin Islands 168 Annex 3. Three main approaches were initially considered: (1) Estimation of the economic impact was based on projec- econometric estimation and projections; (2) economet- tions to 2015 for nine countries: Brazil, Canada, China, ric estimation and calibration; and (3) straightforward India, Nigeria, Pakistan, the Russian Federation, the calibration using information on variables from various United Kingdom and the United Republic of Tanzania. The third approach was adopted for this phase The focus was on heart disease, stroke and diabetes. K = capital accumulation Historical savings rates, depreciation, were obtained from L = labour inputs the World Bank Development Index database. There was difﬁculty in obtaining data for capital accumulation in the Russian Federation; this was then set to the average of countries. World Bank Economic Review, changes in population health in the assessment of 2001, 15:177–219. Sources of economic growth: an extensive accounting or changes in life expectancy from disease, estimated exercise. This would correspond to a rate of decrease in economic welfare due to mortality increase of 2% per annum. This approach, which may seem more complete than the previous approaches, does not account for the total value of the changes in health. It is, however, useful in that it demonstrates fuller returns to investment in health compared to the above approaches. Estimation should be of interest to country development strategists and policy-makers in the health and ﬁnance sectors, and also useful for international comparison. The model was programmed to compute output if there were no deaths due to chronic disease (the counterfactual) against out- put given the projected deaths from chronic disease on an annual basis. This procedure was then repeated for estimating the global goal of an additional 2% annual reduction in chronic disease death rates over and above baseline projections, over 10 years from 2006 to 2015. All the variables in the Cobb-Douglas model were sub- jected to univariate and multivariate analysis (Monte Carlo) using Crystal Ball software. These contributions have been vital to the project, both in creating and enriching the report. The production of this publication was made possible through the generous ﬁnancial support of the Government of Canada, the Government of Norway and the Government of the United Kingdom. Expert and Tropical Medicine, United Stéfanie Durivage reviewers do not necessarily endorse Kingdom Amanda Marlin the full contents of the ﬁnal version. Klumbiene, Kaunas University of Auckland, New Zealand Ofﬁce for Europe Medicine, Lithuania I. Sklodowska-Curie Josie d’Avernas, Health Promotion Health Institute, Finland Memorial Cancer Center and Institute Consulting, Canada Otaliba Libânio de Morais, Ministry of of Oncology, Poland Jarbas Barbosa da Silva Júnior, Health, Brazil Ministry of Health, Brazil V. Mohan, Madras Diabetes Research Ashley Bloomﬁeld, Ministry of Health, Foundation, India New Zealand A. Nissinen, National Public Health Antonio Carlos Cezário, Ministry of Institute, Finland Health, Brazil C. Shanthirani, Madras Diabetes Deborah Carvalho Malta, Ministry of Research Foundation, India Health, Brazil Sania Nishtar, Heartﬁle, Pakistan Rhona Hanning, University of Waterloo, Rafael Oganov, State Research Centre Canada for Preventive Medicine, Russian Lenildo de Moura, Ministry of Health, Federation Brazil J. Dzerve, National Institute of for Preventive Medicine, Russian Cardiology, Latvia Federation Brodie Ferguson, Stanford University, R. Overall, this set of photographs Steve Ewart and stories from ﬁve diverse countries demonstrates that chronic diseases are Maryvonne Grisetti widespread in low and middle income countries and are an underappreciated Peter McCarey source of poverty, requiring comprehensive and coordinated responses.
For the thrombolytic-therapy arm order 100 ml mentat ds syrup fast delivery, the clot can be dissolved successfully cheap 100 ml mentat ds syrup, there can be residual deﬁcit buy cheap mentat ds syrup 100 ml on line, or the patient may have an intracranial bleed resulting in death, or have partial improvement but be left with a residual deﬁcit. The degree of deﬁcit can also be divided into different categories, for example using the Modi- ﬁed Rankin Scale to create six criteria for outcomes. Resolution U = 1 (cure) Pc Standard medical therapy Death U = 0 Pdm Residual damage U = Ux 1 − Pc − Pdm E = Pc(1) + (1 − Pc − Pdm) Ux + Pdm × 0 Fig. The probability of death due to hem- orrhage is Pdt and for residual damage due to hemorrhage is 1 – Pdt. Here Pc is the probability of complete resolution and Pdm the probability of death. The reason that a decision tree is needed at all is because while there is an increase in complete cures with thrombolytic therapy there is also an increase in intracranial hemorrhage leading to residual damage or death. This is especially true when one or both of the alternative outcomes can lead to a lifetime of disability. Sensitivity analysis is a way to deal with imprecision in the data used to create the decision tree. We have discussed that this is true of almost all data obtained from the medical literature and insist that the results of any kind of study have appro- priate conﬁdence intervals to give the uncertainty of the result. A sensitivity anal- ysis tests the “robustness” of the conclusions over a range of different values of probabilities for each branch of the decision tree. Sensitivity analysis asks what would happen to the expected value of thrombolytics against standard medical management if we varied the probability or utility of any of the outcomes. One simple way of doing this it to take the 95% conﬁdence intervals of the probabili- ties and use them as the extreme used in the sensitivity analysis. If there is very little difference between the expected values of the two treat- ments being compared, then a slight change in the probabilities assigned to each arm could easily alter the direction of the decision. In that case, if the values of the probabilities are off by just a little bit, the entire result will change and the patient and physician will have little useful information regarding the relative merits of the two treatments, or which one is superior. Multi-way sensitivity analysis looks for the variable that causes the biggest change in the value of the overall model. Then the analysis changes all those assumptions that are “very sensitive” to see what happens to the model. Finally, a curve is drawn to show what happens to the expected values when the two most “sensitive” vari- ables are changed (Fig. The results of a sensitivity analysis can be graphed, showing the effect on the ﬁnal outcomes with a change in each of these values. The ultimate decision should still be based on whichever strategy gives the highest ﬁnal expected utility. It can be used to create health policy or to determine the best strategy for a practice guideline. In actu- ality, physicians have trouble applying decision analysis to individual patients even when there is a clearly superior treatment. Also, the model requires that the outcomes be put into a few discrete categories when in fact there are many outcomes that are not as clear-cut as in the model. In this example, thrombolytic therapy complications can vary from serious to mild in severity. Chronic disability can also vary from a mild to a constant dis- abling deﬁcit, which can be very severe and last for only a brief period of time and then spontaneously resolve. Standard medical treatment may actually result in more patients having only a small amount of residual deﬁcit. This can occur even if a “cure” is The probabilities have been omitted for clarity. You must include all of these outcomes to make this a more realistic model of the situation. Finally, any decision analysis must include a reasonable “time horizon” over which the outcomes should be assessed. Computers can be used to show patients how their personal values for each outcome will change the expected value of each treatment. There are computer programs that have been developed to assist patients in making difﬁcult deci- sions about whether or not to have prostate cancer screening and what options to take if the screening test is positive, but they are not yet commercially avail- able and are currently used only in research programs. The development of user-friendly computerized interfaces will help improve the quality of patient decisions. The doctor must continue to be able to edu- cate his or her patient about the consequences of each action and describe the objective reality of each disease state and treatment options for them so that the Decision analysis and quantifying patient values 343 patient can make appropriate decisions on the utility they want to assign to each outcome. In short, the role of the health-care provider is to give their patients the facts and probability of the outcomes and help the patient decide on their utility for each outcome. Threshold approach to decision making Earlier, in Chapter 26, we talked about the treatment and testing thresholds. The threshold approach to testing and treatment can use decision trees to determine when diagnostic testing should be done. Consider the situation of a patient com- plaining of shortness of breath in whom you suspect a pulmonary embolism or blood clot in the lungs. Should you order a pulmonary angiogram test in which dye is injected into the pulmonary arteries? The test itself is very uncomfortable, causes some complications, and can rarely cause death. There are basically three options: (1) Treat based on clinical examination and give the patient an anticoagulant without doing the test. The treatment threshold is the probability of disease above which a physician should initiate treatment for the disease without ﬁrst doing the test for the dis- ease. This is the level above which, testing will produce an unacceptable number of false negatives and the patient would then be denied the beneﬁts of treatment. This is the prob- ability below which, there are an unacceptable number of false positives and patients would then be unnecessarily exposed to the side effects of treatment. If the post-test probability after a negative test, the false reassurance rate, falls below the test- ing threshold, it was a worthwhile test and the patient does not need treatment. It took the probability of disease from a value of probability at which testing should precede treating, to one at which neither treatment nor further testing is beneﬁcial. If the post-test probability of a bleed is high, standard treatment is likely to be better, since thrombolytic therapy is more likely to lead to increased bleeding in the brain. An exam- ple would be a person with known atrial ﬁbrillation, not on anticoagulants, who had a sudden onset of severe left hemiparesis without a headache. Changing one fact of this pattern would change the probability of a bleed and the ﬁnal decision. At a high pretest probability the clinical picture is so strong that the test shouldn’t be done at all since a false negative is much more likely than a true negative leading to treatment of someone with a potential bleed.
The front part of the cortex discount mentat ds syrup 100 ml mastercard, the frontal cortex or forebrain buy mentat ds syrup 100 ml otc, is the thinking center of the brain purchase mentat ds syrup 100 ml with amex; it powers our ability to think, plan, solve problems, and make decisions. It links together a number of brain structures that control and regulate our ability to feel pleasure. Feeling pleasure motivates us to repeat behaviors that are critical to our existence. The limbic system is activated by healthy, life-sustaining activities such as eating and socializing— but it is also activated by drugs of abuse. In addition, the limbic system is responsible for our perception of other emotions, both positive and negative, which explains the mood-altering properties of many drugs. Networks of neurons pass messages back z Receptors—The Brain’s Chemical Receivers and forth among different structures within the brain, the spinal cord, The neurotransmitter attaches to a specialized site on the receiving and nerves in the rest of the body (the peripheral nervous system). A neurotransmitter and its receptor oper- These nerve networks coordinate and regulate everything we feel, ate like a “key and lock,” an exquisitely specific mechanism that think, and do. Once a cell receives and porters recycle these neurotransmitters (that is, bring them back processes a message, it sends it on to other neurons. The neurotransmitter crosses the synapse and attaches to proteins (recep- tors) on the receiving brain cell. This causes changes in the receiving cell—the Transmitter Receptor Neurotransmitter Receptor message is delivered. Madras Most drugs of abuse target the brain’s reward system by flooding it with dopamine. Drugs are chemicals that affect the brain by tapping into its communication system and interfering with the way neurons normally send, receive, and process information. Some drugs, such as marijuana and heroin, can activate neurons because their chemical structure mimics that of a natural neurotransmitter. This similarity in structure “fools” receptors and allows the drugs to attach onto and activate the neurons. Although these drugs mimic the brain’s own chemicals, they don’t activate neurons in the same way as a natural neurotransmitter, and they lead to abnormal messages being transmitted through the network. Other drugs, such as amphetamine or cocaine, can cause the neurons to release abnormally large amounts of natural neuro- transmitters or prevent the normal recycling of these brain chemicals. This disruption produces a greatly amplified message, ultimately disrupting communication channels. Most drugs of abuse directly or indirectly target the brain’s reward system by flooding the circuit with dopamine. Dopamine is a neurotransmitter present in regions of the brain that regulate movement, emotion, motivation, and feelings of pleasure. Overstimulating the system with drugs, however, produces euphoric effects, which strongly reinforce the behavior of drug use—teaching the user to repeat it. When some drugs of abuse are taken, they can release 2 to 10 times Our brains are wired to ensure that we will repeat life-sustaining activ- the amount of dopamine that natural rewards such as eating and sex 15 ities by associating those activities with pleasure or reward. In some cases, this occurs almost immediately (as when drugs this reward circuit is activated, the brain notes that something impor- are smoked or injected), and the effects can last much longer than tant is happening that needs to be remembered, and teaches us to do it those produced by natural rewards. Because drugs of abuse pleasure circuit dwarf those produced by naturally rewarding behav- 16,17 stimulate the same circuit, we learn to abuse drugs in the same way. The effect of such a powerful reward strongly motivates peo- ple to take drugs again and again. When cocaine is taken, dopamine increases are exaggerated, and communication is altered. As a result, dopamine’s For the brain, the difference between normal rewards and impact on the reward circuit of the brain of someone who drug rewards can be described as the difference between abuses drugs can become abnormally low, and that per- someone whispering into your ear and someone shouting son’s ability to experience any pleasure is reduced. Just as we turn down the volume on a This is why a person who abuses drugs eventually feels flat, radio that is too loud, the brain adjusts to the overwhelm- lifeless, and depressed, and is unable to enjoy things that were previously pleasurable. Also, the person will often need to take larger amounts of the drug to produce the familiar dopamine high—an effect known as tolerance. We know that the same sort of mechanisms involved in the development of tolerance can eventually lead to profound Healthy Control Drug Abuser changes in neurons and brain circuits, with the potential to severely compromise the long-term health of the brain. For 20 example, glutamate is another neurotransmitter that influences the W hat other brain changes reward circuit and the ability to learn. Chronic exposure to drugs of abuse disrupts the way critical brain Similarly, long-term drug abuse can trigger adaptations in habit or structures interact to control and inhibit behaviors related to drug use. Conditioning is one example of this Just as continued abuse may lead to tolerance or the need for higher type of learning, in which cues in a person’s daily routine or environ- drug dosages to produce an effect, it may also lead to addiction, which ment become associated with the drug experience and can trigger can drive a user to seek out and take drugs compulsively. Drug addic- uncontrollable cravings whenever the person is exposed to these cues, tion erodes a person’s self-control and ability to make sound deci- even if the drug itself is not available. This learned “reflex” is extreme- sions, while producing intense impulses to take drugs. Imaging scans, chest X-rays, and blood tests show the damaging effects of long-term drug Pabuse throughout the body. For example, research has shown that tobacco smoke causes cancer of the mouth, throat, larynx, blood, 19 lungs, stomach, pancreas, kidney, bladder, and cervix. In addition, some drugs of abuse, such as inhalants, are toxic to nerve cells and may damage or destroy them either in the brain or the peripheral nervous system. Three of the Injection drug use is also a major factor in the spread of hepatitis more devastating and troubling consequences of addiction are: C, a serious, potentially fatal liver disease. Injection drug use is not z Negative effects of prenatal drug exposure on infants the only way that drug abuse contributes to the spread of infectious and children diseases. It is also likely that some drug- hepatitis B and C, and other sexually transmitted diseases. According to the Surgeon General’s 2006 Report, The Health Consequences of Involuntary Exposure to Tobacco Smoke, involuntary exposure to secondhand smoke increases the risks of heart disease and lung cancer in people who have never 20 smoked by 25–30 percent and 20–30 percent, respectively. Tobacco use is responsible for an estimated 23 5 million deaths worldwide each year. Tobacco smoke increases a user’s risk Throat of cancer, emphysema, bronchial disorders, and cardiovascu- Larynx (voice box) Mouth Esophagus lar disease. Tobacco use killed approximately 100 mil- Lung Blood (leukemia) lion people during the 20th century, and, if current smoking Stomach Kidney Pancreas trends continue, the cumulative death toll for this century has Bladder Cervix 24 been projected to reach 1 billion. However, misuse or abuse of these drugs (that is, taking impairs short-term memory and learning, the ability to focus attention, them other than exactly as instructed by a doctor and for the purposes and coordination. It also increases heart rate, can harm the lungs, prescribed) can lead to addiction and even, in some cases, death. Unfortunately, there is a common misperception that because medications are prescribed by physicians, they are safe even when used illegally or by another person than they were prescribed for. Users also may have traumatic experiences and ucts, such as oven cleaners, gasoline, spray paints, and other emotions that can last for many hours. It slows respiration, and its use is linked to an toxic and can damage the heart, kidneys, lungs, and brain.
Tonry (2011) and Provine (2007) summarize studies on the effects of racial attributions and stereotypes on people’s perceptions generic 100 ml mentat ds syrup amex, attitudes mentat ds syrup 100 ml lowest price, and beliefs and the ways race correlates with policy choices mentat ds syrup 100 ml with amex. Whites may no longer consciously believe in the inherent racial inferiority of blacks, but they nonetheless harbor unconscious racial biases (Rachlinski et al. In one typical study, police officers shown black and white photographs of male university students and employees thought more of the black than white faces looked criminal; the more stereotypically black the face was, the more likely the officers thought the person looked criminal (Eberhardt et al. Unconscious notions and attitudes are most likely to influence criminal justice decisions that have to be made in the face of uncertainty and inadequate information or in ambiguous or borderline cases. To recognize the influence of race on social psychology, unconscious cognitive habits, and “perceptual shorthand” (Hawkins 1981, p. Race helps explain the development and persistence of harsh drug laws and policies. White Americans tend to support harsher punishments more than do blacks, a predilection that has strong roots in racial hostilities, tensions, and resentments (Tonry 2011, p. Researchers have found that whites with racial resentments toward blacks are far more likely to support punitive anticrime policies and that whites are twice as likely as blacks to prefer punishment over social welfare programs to reduce crime (Unnever, Cullen, and Johnson 2008). Even assuming public officials who championed the war on drugs decades ago operated from the best of motives or were simply remarkably ignorant about the likely effects of their decisions, good intentions or ignorance can be no excuse today. No reasonable public official can believe it is a good thing for black America to have in its midst a large caste of second-class citizens—banished into prisons and then branded for life with a criminal record. The persistence of drug policies that disproportionately burden black Americans reflects factors similar to those that led to the adoption of harsh penal policies initially: punitive attitudes toward crime, fear of “the other,” misinformation about drugs and their effects, the belief that using drugs is immoral and wrong, and the lack of instinctive sympathy for members of poor minority communities. At a structural level, the drug war—as part of the criminal justice system—retains its historic function of perpetuating and reinforcing racial inequalities in the distribution of political, social, and economic power and privileges in the United States. White Americans have long used the criminal justice system to advance their interests over those of blacks; the difference today is that they may no longer be doing so consciously. Over a decade ago, observers of drug criminalization in the United States began labeling its impact on black Americans as the “new Jim Crow,” recognizing that drug law enforcement has the effect of maintaining racial hierarchies that benefit whites and disadvantage blacks. In her best-selling book, The New Jim Crow: Mass Incarceration in the Age of Colorblindness, Alexander (2010) contends that criminal justice policies and the collateral consequences to a criminal conviction today are—like slavery and Jim Crow in earlier times—a system of legalized discrimination that maintains a racial caste system in America: “today it is perfectly legal to discriminate against criminals in nearly all the ways that it was once legal to discriminate against African Americans…. As a criminal, you have scarcely more rights and arguably less respect, than a black man living in Alabama at the height of Jim Crow. She argues convincingly that drug policies have been and remain inextricably connected to white efforts to maintain their dominant position in the country’s social hierarchy. As Tonry says, “the argument is not that a self-perpetuating cabal of racist whites consciously acts to favor white interests, but that deeper social forces collude, almost as if directed by an invisible hand, to formulate laws, politics, and social practices that serve the interests of white Americans” (Tonry 2011, p. What will it take to change a quarter of a century of drug policies and practices that disproportionately and unjustifiably harm blacks? What will it take for Americans to condemn racial disparities in the war on drugs with the same fervor and moral outrage that they came to condemn the “old” Jim Crow? One part of the answer has to be public recognition that racial discrimination can exist absent from “racist” actors. The norm of racial equality has become descriptive and injunctive, endorsed by nearly every American. Subscriber: Univ of Minnesota - Twin Cities; date: 23 October 2013 Race and Drugs loathe to recognize or acknowledge structural racism because that would raise questions about their commitment to racial equality—and their willingness to give up the privileges of being white. White discomfort with even the very notion of structural inequality no doubt also is strengthened by conservative American political and moral cultures that stress individual responsibility. Implicit racial bias, racial self- interest, and conservative values combine to make it easy for whites to believe that black incarceration is a reflection of choices blacks have made and penal consequences they have merited. Whites rationalize or avoid seeing the inequities inherent in the war on drugs, assuming or persuading themselves “that the problem is not in the policies they and people like them set and enforce, but in social forces over which they have no control or in the irresponsibility of individual offenders” (Tonry 2011, p. The “myth of a colorblind criminal justice system” is widely influential in the United States because the language of police, judges, prosecutors, and public officials has been wiped clean of explicit racial bias (Roberts 1997, p. United States courts, unfortunately, have made it easier for white Americans to ignore racial disparities in twenty-first century America. Under current constitutional jurisprudence, facially race-neutral governmental policies do not violate the constitutional guarantee of equal protection unless there is both discriminatory impact and discriminatory intent. Supreme Court has decided that every lawsuit involving claims of racial discrimination directed at facially race-neutral rules would be conducted as a search for a “bigoted decision-maker”…. If such actors cannot be found—and the standards for finding them are tough indeed—then there has been no violation of the equal protection clause. In contrast, international human rights law prohibits racial discrimination unaccompanied by racist intent (Fellner 2009). Obviously, laws that make explicit distinctions on the basis of race (other than affirmative action policies) constitute prohibited discrimination. But so do race-neutral laws or law enforcement6 practices that create unwarranted racial disparities, even if they were not enacted or implemented by culpable actors who intentionally sought to harm members of a particular race (United Nations Committee on the Elimination of Racial Discrimination 2005; Zerrougui 2005). It has recommended that the United States “take all necessary steps to guarantee the right of everyone to equal treatment before tribunals and all other organs administering justice, including further studies to determine the nature and scope of the problem, and the implementation of national strategies or plans of action aimed at the elimination of structural racial discrimination” (United Nations Committee on Elimination of Racial Discrimination 2008, paragraph 20). Laws or practices that harm particular racial groups must be eliminated unless they “are objectively justified by a legitimate aim and the means of achieving that aim are appropriate and necessary” (United Nations Committee on the Elimination of Racial Discrimination 2008, paragraph 10). The operational and political convenience of making arrests in low-income minority neighborhoods rather than white middle-class ones may be an explanation but certainly not a justification. Even assuming the legitimacy of the goal of protecting minority neighborhoods from addiction and drug gang violence, the means chosen to achieve that goal—massive arrests of low-level offenders and high rates of incarceration—are hardly a proportionate or necessary response. No independent and objective observer believes the United States can arrest and incarcerate its way out of its “drug problem. Subscriber: Univ of Minnesota - Twin Cities; date: 23 October 2013 Race and Drugs Criminology 44:105–37. National Corrections Reporting Program: Most Serious Offense of State Prisoners, by Offense, Admission Type, Age, Sex, Race, and Hispanic Origin, 2009. Imprisoning Communities: How Mass Incarceration Makes Disadvantaged Neighborhoods Worse. The Rest of their Lives: Life Without Parole for Child Offenders in the United States. Subscriber: Univ of Minnesota - Twin Cities; date: 23 October 2013 Race and Drugs Husak, Douglas N. Marijuana Arrest Crusade: Racial Bias and Police Policy in New York City 1997-2007. Racial Disparity in Criminal Court Processing in the United States: Submitted to the United Nations Committee on the Elimination of Racial Discrimination. Black Arrests for Drug Abuse Violations, 1980 to 2009, generated using the Arrest Data Analysis Tool. Subscriber: Univ of Minnesota - Twin Cities; date: 23 October 2013 Race and Drugs Spohn, Cassia, and Jeffrey Spears. Substance Abuse in States and Metropolitan Areas: Model Based Estimates from the 1991-1993 National Household Survey on Drug Abuse. Administration of Justice, Rule of Law, and Democracy: Discrimination in the Criminal Justice System. Notes: (*) Includes some persons of Hispanic origin; however, there are additional persons of Hispanic origin who are new court commitments who were not categorized as to race and who are not included in these figures.
Overall the Drainage of pus and arthroscopic joint washout under knee is the most commonly affected joint order 100 ml mentat ds syrup visa, but hips are anaesthesia can be performed purchase 100 ml mentat ds syrup with amex. There may be evidence of the r Surgical drainage may be indicated if the infection source of infection such as a urinary tract infection generic mentat ds syrup 100 ml with visa, skin does not resolve with appropriate antibiotics or if per- orrespiratoryinfection. Arthroscopic pro- immobilised in the position that maximises the intra- cedures allow visualisation of the interior of the joint, articular volume (e. Movement of the joint r Surgerymayalsoberequiredfortheremovalofforeign is very painful and often prevented by pain and muscle bodies or infected prosthetic material. Complications r If treatmentisdelayedthereisseverearticulardestruc- Prognosis tion, which may heal by ﬁbrosis with permanent re- Outcome is related to immune status of the host, viru- striction of movement, deformity or bony union. In Staphylococcal infections r In children extensive destruction of the epiphysis may involvement of multiple joints carries a signiﬁcant mor- occur causing growth disturbance and deformity. Investigations r X-ray of the affected joint may show widening of joint Osteoarthritis spaceandsofttissueswellingbutareoflittlediagnostic value. Blood cultures should be taken and may be pos- of ageing, osteoarthritis is now considered to be a joint itive in a third of cases. Stiffness occurs after a period of Structural change Intra-articular fracture, joint malalignment, joint hypermobility, rest, but is less severe than rheumatoid arthritis and lasts congenital dysplastic hips, 5–15 minutes in morning. On examination there may be Perthes’ disease joint line tenderness, joint effusion, crepitus and bony Inﬂammatory joint Septic arthritis, rheumatoid arthritis, enlargement due to osteophyte development. The damage seen in osteoarthritis is initiated by trauma, which may be a single event or repeated microtrauma. There is resultant increased The ﬁrst radiological ﬁnding is narrowing of the joint proliferation and activity of chondrocytes under the in- space. In weight-bearing joints narrowing is maximal ﬂuence of monocyte-derived growth peptides. As the process of osteoarthritis has begun a number of factors cartilage is worn away, friction causes the exposed sub- are involved in the continued disease process: chondral bone to become sclerotic (subarticular bony r Mechanical forces can be causative, preventative or sclerosis). Later ﬁndings include bony collapse and r Proteases that are involved with cartilage degradation. Chapter 8: Seropositive arthritis 359 3 Surgical: The aim of surgery is to relieve pain not Geography treated by medical management and to increase useful Prevalence varies across the world from 0. Itallowsalterationof tors occur in a genetically susceptible individual setting the muscle use, the contact areas and the blood dy- up a sustained inﬂammatory response. It is of most use in younger r Twin studies demonstrate a signiﬁcantly higher con- patients with a good range of movement and rela- cordance in monozygotic compared with dizygotic tive preservation of the intra-articular cartilage. Hip and knee replace- difference diminishes after the menopause reinforcing ments are the most successful; however, there is a the possibility of a role for sex hormones. Sixty per mal range of movement is difﬁcult to achieve and centofpatientswhodeveloprheumatoidarthritishave the prostheses are prone to failure. There are some genetically inherited disorders with early onset os- Pathophysiology r Tcells: Antibody-mediated activation of T cells trig- teoarthritis, which have a much worse prognosis. Cytokine cascades result in a com- Rheumatoid arthritis bination of angiogenesis and cellular inﬂux, leading to transformation of the synovium with the ability to in- Deﬁnition vade cartilage and connective tissue. The transformed Rheumatoid arthritis is a chronic multisystem, inﬂam- synovium may also activate osteoclast-mediated bone matory disorder with a characteristic symmetrical pol- erosion. Age r Rheumatoid factors are autoantibodies to the Fc por- Peak age of onset 30–55 years. These factors undergo a maturation of afﬁnity 2–3 F : 1 M for Fc and tend to form lattice-like complexes found 360 Chapter 8: Musculoskeletal system throughout the tissues of the rheumatoid joint. It is r There is often associated muscle weakness and gen- thought that they provoke further inﬂammation and eralised osteopenia due to immobility, which may be activate the complement system. Clinical features (extra-articular) r Long-standing inﬂammation and effusion distends See Fig. The overall result is joint instability and continued use leads to joint deformity. Investigations r r Blood: Anaemia (usually normochromic normo- Afteravariableperiod,synovialinﬂammationmaybe- come quiescent. Later there is progressive loss of joint space, more ex- Clinical features (articular) tensive erosive changes and bone destruction, joint Classically, rheumatoid arthritis presents as an insidious, subluxation and secondary degenerative changes. Tender swelling inﬂammatory drugs, which reduce pain and stiff- of the ulnar styloid, subluxation and deviation of the ness(ibuprofen,indomethacin,diclofenac,etc. Degradation of scleral collagen (blue Lung: appearance) which rarely may Pleural involvement is common and progress to perforation (scleromalacia may result in pain and effusions. Skin: Haematology: Rheumatoid nodules are found in 20% Splenomegaly and neutropenia in of patients. Anaemia may occur due to fibroblasts with an outer coat of chronic disease iron deficiency, or lymphocytes. Methotrex- r Because of immobility and steroid therapy patients ate is normally used as ﬁrst line, other agents include with rheumatoid arthritis are at high risk for develop- sulphasalazine, gold and hydroxychloroquine. Bis- is slow, 10–20 weeks, and all have some degree of phosphonate therapy should be considered in high- toxicity. Synovitis of the spine and large arthrodesis (joint fusion) may be performed for in- joints may occur, and there is both synovitis and enthe- tractable pain at the elbow or wrist; however, there sopathy at the sacroiliac joints. Atlantoaxial sub- intervertebral disc becomes calciﬁed and forms a bony luxation may require surgical stabilisation. As 4 Joint replacement has signiﬁcant postoperative these extend up the spine, calciﬁcation causes rigidity morbidity but can be an effective longer term treat- and a typical ‘bamboo’ appearance on X-ray. Clinical features Prognosis Patients develop a gradual onset of episodic low-back The disease generally progresses insidiously in the ma- painandmorningstiffness. Thereisalossofnormallum- jority of cases although most patients experience periods barlordosisduetomusclespasmandsacroiliacjointten- of exacerbation and quiescence. Movement of the spine is restricted in all planes and a limitation of chest expansion may occur. Acute anterior uveitis, aortic regurgitation and (spondyloarthropathies) apical lung ﬁbrosis are known extra-articular features. Ankylosing spondylitis Deﬁnition Ankylosing spondylitis is a chronic inﬂammatory arthri- tis predominantly affecting the axial skeleton, causing pain and progressive stiffness. Chapter 8: Seronegative arthritides (spondyloarthropathies) 363 Complications Age Spinal fractures may occur with minimal trauma due to Peak incidence age: 30–50 years. Pathophysiology r Patients should be encouraged to remain active, avoid Synovitis is histologically the same as that of rheumatoid prolonged bed rest and avoid lumbar supports. Phys- arthritis, although bone resorption is sometimes promi- iotherapy involvement is important. Itislikelythatboththeskinlesionsandthearthritis r Pain and morning stiffness are treated with non- are immunologically mediated. Fivepatternsofarthritis osteotomy may be helpful in patients with severe cur- are seen: vature.
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