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They include: • An increase in total meat consumption13 • A dramatic increase in added fats and oils14 • Increases in calorie sweeteners (sugar from beet or cane and high fructose corn sweeteners)15 • A dramatic increase in cheese consumption16 • A decrease in total cereal grains and increase in refined grains17 • Reduced physical activity18 We simply reverse these diet and lifestyle patterns and we dra- matically improve America’s health (and prosperity! At the same time we make these changes order raloxifene 60 mg without a prescription menstruation 3 times in a month, we will create real healthcare reform and this current political debate regarding healthcare becomes non-existent cheap raloxifene 60mg mastercard 45 menstrual cycle. Inflammation is a natural response to stress, infec- tion, injury, and trauma and is a needed response. If inflammation - 20 - the american lifestyle is chronically activated, it leads to a continued release of chemical compounds by the body originally meant to be of short duration that can cause chronic tissue damage and the aforementioned dis- eases. We need to reverse these conditions on a daily basis to reverse or slow chronic disease problems. Change the types of foods you eat and you can reverse inflam- mation and chronic diseases individually, locally, nationally, and worldwide. When I collectively look at medical studies, success- fully aging cultures, and years of experiencing diseases improved by diet change, it is easy for me to say that “food is the most power- ful medicine there is! Before we get to the “how” of changing this negative health di- rection, I think it is important to address this next question: Is it just crazy, stressed-out Americans who are struggling with these health issues of chronic disease, or is the rest of the world strug- gling with these issues as well? The more I learned about the state of health and chronic dis- ease in North America and developed countries, the clearer it be- came that over-consumption and lack of physical activity are no longer confined to the wealthiest countries. As these popu- lations move from their agrarian rural lifestyle, which was more physically active and predominantly plant based, with whole foods and small amounts of free-range animal foods, their per capita calorie consumption increases. With this increase in calories and reduction in nutrient dense foods and physical activity, come the overweight issues and subsequent chronic diseases of the indus- trialized countries. Just as in the United States, the typical diets of developing na- tions are now characterized by a significant increase in total calo- ries, animal foods (meats), added fats, oils, caloric sweeteners, and a mild increase in grains (but a reduction in the percent of calories from grains compared to other food stuffs), in conjunction with - 23 - staying healthy in the fast lane a more sedentary lifestyle. In fact, the similarities between the unhealthy trends in Western and developing societies are startling but make sense. Why is it important for us to consider the global scope of this problem even before embarking upon our own journey of person- al wellness and change? Because everything we do has a ripple effect; every choice we make has ramifications that we may not have ever imagined. If we realize that the patterns of how we, as individuals and societies, live and eat really do affect the rest of - 24 - global health: where are we going? At the same time, these healthy choices can pre- serve the ecological balance of other species on the planet, which eventually effects our survival. Initially this appeared to be only a problem in high-income countries, but now being overweight and obese are dramatically occurring in low- and middle-income countries, par- ticularly in urban settings. Furthermore, childhood obesity is associated with a higher chance of premature death and disability in adulthood. Many low-income countries are now facing a double burden of risk: They continue to deal with problems of infectious disease and under-nutrition - 25 - staying healthy in the fast lane at the same time that they are experiencing a rapid upsurge in chronic diseases related to excess calories from more processed and animal-based foods. It is now common for under-nutrition and obesity to exist side by side within the same country. Heart Disease Heart disease, which is still the number one cause of death worldwide (cancer may overtake heart disease this year), is be- coming a terrible problem in countries with rapidly developing economies such as India and China, and in Japan, where they con- tinue to develop a more urban lifestyle similar to that of the United States. The Asia Pacific Cohort Studies Collaboration analyzed data from six hundred thousand people involved in forty-three studies in nine places: China, Hong Kong, Thailand, Singapore, Australia, Japan, South Korea, Taiwan, and New Zealand. Findings from this exhaustive body of research show conclusively that “Asia is facing a cardiovascular disease epidemic as a result of increases in obesity, high blood pressure, and smoking. In fact, India now carries 60 percent of the world’s heart disease burden, with the same risk factors as elsewhere. Nearly 72 percent of these cancer deaths occurred in low- and middle-income coun- tries, where leading risk factors include low fruit and vegetable intake in addition to tobacco and alcohol use and infections from hepatitis B and C and the human papilloma virus. There are three primary types of diabetes: type 1, type 2, and gestational diabetes. It is estimated that 5 to 10 percent of the world’s diabetics have type 1 diabetes.

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Scores Computing Cumulative Frequency and Percentile 51 In fact order raloxifene 60mg visa pregnancy stages, whatever the variable might be order raloxifene 60 mg with visa women's health clinic ballarat, whatever the N might be, and whatever the ac- tual frequency of each score is, we know that the area these scores occupy is 33% of the total area, and that’s all we need to know to determine their relative frequency. This is especially useful because, as you’ll see in Chapter 6, statisticians have created a system for easily finding the area under any part of the normal curve. Therefore, we can easily determine the relative frequency for scores in any part of a normal distribu- tion. If a score occurs 23% of the time, its relative fre- ■ The area under the normal curve corresponds to quency is. They make up of the 15% of people in the parking lot are standing at these area under the normal curve. For example, it may be most informative to know that 30 people scored above 80 or that 60 people scored below 80. When we seek such information, the convention in statistics is to count the number of scores below the score, computing either cumulative frequency or percentile. To compute a score’s cumulative frequency, we fies the scores, the center col- add the simple frequencies for all scores below the score to the frequency for the score, umn contains the simple to get the frequency of scores at or below the score. We add this f to the previous cf for 10, so the cf for 11 is 3 (three people scored at 11 or below 11). Next, no one Score f cf scored at 12, but three people scored below 12, so the cf for 12 is also 3. And so on, each time adding the frequency for a score to the cumulative frequency for the score 17 1 20 16 2 19 immediately below it. Computing Percentiles We’ve seen that the proportion of time a score occurs provides a frame of reference that is easier to interpret than the number of times a score occurs. Therefore, our final procedure is to transform cumulative frequency into a percent of the total. A score’s percentile is the percent of all scores in the data that are at or below the score. Thus, for example, if the score of 80 is at the 75th percentile, this means that 75% of the sample scored at or below 80. Score f cf Percentile This says to first divide the score’s cf by N, which transforms the cf into a proportion of the total sample. Then we multiply this times 100, which converts it into a percent of 17 1 20 100 the total. Thus, if a score has a cf of 5 and N is 10, then 15>10211002 5 50, so the score 16 2 19 95 15 4 17 85 is at the 50th percentile. With one person scoring 10 or below, (1/20)(100) equals 5, so 10 12 0 3 15 is at the 5th percentile. The three people scoring 11 or below are at the 15th percentile 11 2 3 15 and so on. The highest score is, within rounding error, the 100th percentile, because 10 1 1 5 100% of the sample has the highest score or below. However, a quick way to find an approximate per- centile is to use the area under the normal curve. Finding Percentile Using the Area Under the Normal Curve Percentile describes the scores that are lower than a particular score, and on the normal curve, lower scores are to the left of a particular score. Therefore, the percentile for a given score corresponds to the percent of the total area under the curve that is to the left of the score. Because scores to the left of 30 are below it, 50% of the distribution is below 30 (in the parking lot, 50% of the people are standing to the left of the line and all of their scores are less than 30). Say that we find that 15% of the curve is to the left of 20; then 20 is at the 15th percentile. We would measure over until 85% of the area under the curve is to the left of a certain point. Notice that we make a slight change in our definition of percentile when we use the normal curve. This is acceptable if we are describing a large sam- ple or a population because those participants at the score are a negligible portion of the total (remember that we ignored those relatively few people who were straddling the line). However, if we are describing a small sample, we should not ignore those at the score, because those participants may actually constitute a sizable portion of the sam- ple.

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Gender Differences in Pharmacogenetics There are gender-related differences in pharmacokinetics purchase 60mg raloxifene with mastercard women's health center colonial park, which may be related to pharmacogenetic differences in to drug-metabolizing enzymes 60mg raloxifene menstrual cycle age 7. Other gender differences in pharmacokinetics may be due to fluctuations in hormone levels in women with menstruation and pregnancy. Moreover, development of diseases such as heart disease and cancer may affect women differently from men. There is no data to support the efficacy of statins in preventing heart attacks and stroke in women with hypercholesterolemia, partly because there have not been adequate representation of women in clinical Universal Free E-Book Store Role of Pharmacogenetics in Pharmaceutical Industry 115 trials as compared to men. Use of statins in women is associated with a higher rate of complications such as myositis and cognitive impairment. Statin therapy in women without cardiovascular disease is controversial, given the insufficient evidence of benefit. Participants included 6,800 women and 11, 000 men with high- sensitivity C-reactive protein and low-density lipoprotein cholesterol randomized to rosuvastatin versus placebo. Meta-analysis studies were randomized placebo- controlled statin trials with predominantly or exclusively primary prevention in women and sex-specific outcomes. This study demonstrated that in primary preven- tion rosuvastatin reduced cardiovascular disease events in women with a relative risk reduction similar to that in men, a finding supported by meta-analysis of pri- mary prevention statin trials. Role of Pharmacogenetics in Drug Safety Variability in drug response among patients is multifactorial, including environmen- tal, genetic, and disease determinants that affect the disposition of the drug. Children may be exposed to these drugs through in utero exposure during preg- nancy, through breast feeding, and through exposure during adolescence. Adverse Drug Reactions Related to Toxicity of Chemotherapy Neurotoxicity and myelotoxicity are well known adverse reactions of chemother- apy in cancer patients. Additionally, patients who were homozygous variant at the 2677 and 3435 loci had a significantly greater percent decrease in absolute neutrophil count at nadir. Polymorphisms in the genes that code for drug-metabolizing enzymes, drug transporters, drug receptors, and ion channels can affect an individual’s risk of having an adverse drug reaction, or can alter the effi- cacy of drug treatment in that individual. Mutant alleles at a single gene locus are the best studied individual risk factors for adverse drug reactions, and include many genes coding for drug-metabolizing enzymes. These genetic polymorphisms of drug metabolism produce the phenotypes of “poor metabolizers” or “ultrarapid metabolizers” of numerous drugs. The vast majority arise from classical polymorphism in which the abnormal gene has a prevalence of more than 1 % in the general population. Toxicity is likely to be related to blood drug concentration and, by implication, to target organ concentration as a result of impaired metabolism. The other type is rare and only 1 in 10,000 to 1 in 100,000 persons may be affected. Mutant alleles at a single gene locus are the best studied individual risk factors for adverse drug reactions, including the genes for N-acetyltransferases, thiopurine methyltransferase, dihydropyrimidine dehydro- genase, and cytochrome P450. However, pharmacogenetic factors rarely act alone; rather they produce a phenotype in concert with other variant genes such as those for receptors and with environmental factors such as cigarette smoking. Most idiosyncratic drug reactions are unpredictable and because of their rarity my not show up in patients during clinical trials with a few thousand patients. They may first surface when the drug has been taken by hundreds of thousands of patients in the post-marketing phase. Pharmacogenetics, by individualizing treatment to patients for whom it is safe, provides a rational framework to minimize the uncer- tainty in outcome of drug therapy and clinical trials and thereby should significantly reduce the risk of drug toxicity. Topiramate, an anticonvulsant medication, is an efficacious treatment for alcohol dependence. Future studies in larger samples are needed to more fully establish these preliminary findings. In other situations, it may help in the adjustment of dose of the drug such as in warfarin therapy. Clinical signs include unexplained elevation of end-tidal Universal Free E-Book Store Role of Pharmacogenetics in Pharmaceutical Industry 119 carbon dioxide, muscle rigidity, acidosis, tachycardia, tachypnea, hyperthermia, and evidence of rhabdomyolysis. However, it is invasive, requiring skeletal muscle biopsy and is not widely available. Researchers have begun to map mutations within the ryanodine receptor gene (chromosome 19q13. Pharmacogenetics of Clozapine-Induced Agranulocytosis Clozapine has long been accepted as one of the most effective medications for treat- ing schizophrenia but has had limited utilization due to the risk of inducing agranu- locytosis, a life-threatening decrease of white blood cells that requires frequent blood testing of patients.

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