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A pilot study provided preliminary evidence of reduced functional B vitamin status buy 100 mg zenegra mastercard, particularly of pyridoxine purchase zenegra 100 mg with amex, in these patients 100 mg zenegra with amex. Supplementation with vita- min B12 in doses ranging from 3000 μg four times weekly to 9000 μg daily induces well-being zenegra 100mg mastercard,10 even in a substantial proportion of individuals with normal serum levels. Fatigue and depression are prominent symptoms in patients with folate and/or vitamin C deficiency. Furthermore, fatigue, las- situde, and depression may respond to vitamin C supplementation. On the Chapter 19 / Chronic Fatigue Syndrome 273 other hand, treatment with some deficient nutrients, for example, essential fatty acids, has more unpredictable results. Herbs that are tonics help to revitalize the patient and correct immune function (e. No stud- ies to support the use of ginseng, astragalus, licorice, echinacea, or St. Graham J: Chronic fatigue syndrome—a review, J Aust Coll Nutr Env Med 20: 19-28, 2001. Diefendorf D, Healey J, Kalyn W, editors: The healing power of vitamins, minerals and herbs, Surry Hills, Australia, 2000, Readers Digest. Developed Western nations have a higher incidence of colon cancer than Eastern and underdeveloped countries. The Western diet is associated with higher levels of fecal cholesterol, bile acids, and peroxidized fats. In colon cancer, constipation predominates, pain is colicky in nature, and patients often have anemia caused by occult blood loss. In rectal cancer, diarrhea is more common, tenesmus is prevalent, and the stool is often blood-stained. Consumption of fiber may reduce the risk of colon can- cer because it has all of these effects. Although no increased risk has been identified for the cis-form of the fatty acids, results of a case-control study confirmed that trans-fatty acids are car- cinogenic. The level of trans-fatty acids consumed had no influence on the risk of colon cancer in women who were estrogen-positive. Laboratory studies suggest that the enhancement of colon cell proliferation and carcinogenesis by a high-fat diet may be mediated through elevated serum leptin levels. Although this may be linked to an intake of animal fat, it may also be explained by the fact that red meat is a rich source of heme. Animal experiments showed that dietary heme increased colonic mucosal exposure to luminal irritants and enhanced proliferation of colonic epithelium. Although high levels of physical activity had the strongest inverse relationship, in a study that confirmed different lifestyle patterns have age-specific and tumor site–specific associations, a high intake of calcium was found to reduce the risk of colon cancer. A randomized study of patients with stage 1 or stage 2 colon cancer or adenomatous polyps suggested that 9 g of ω-3 fatty acid daily may be a useful chemopreventive agent in some cases. La Vecchia C: Mediterranean epidemiological evidence on tomatoes and the prevention of digestive-tract cancers. Liu Z, Uesaka T, Watanabe H, et al: High fat diet enhances colonic cell proliferation and carcinogenesis in rats by elevating serum leptin, Int J Oncol 19:1009-14, 2001. Schatzkin A, Lanza E, Corle D, et al: Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas, N Engl J Med 342:1149-55, 2000. Prinz-Langenohl R, Fohr I, Pietrzik K: Beneficial role for folate in the prevention of colorectal and breast cancer, Eur J Nutr 40:98-105, 2001. Pappalardo G, Guadalaxara A, Maiani G, et al: Antioxidant agents and colorectal carcinogenesis: role of beta-carotene, vitamin E and vitamin C, Tumori 82:6-11, 1996. Fukuda K, Hibiya Y, Mutoh M, et al: Inhibition by berberine of cyclooxygenase- 2 transcriptional activity in human colon cancer cells, J Ethnopharmacol 66: 227-33, 1999. Analysis of a cohort of smokers from the Alpha-Tocopherol Beta- Carotene Cancer Prevention Study showed that neither administration of dietary vitamins C and E and beta-carotene nor supplementation with vita- min E (50 mg/day) and beta-carotene (20 mg/day) had any meaningful association with the incidence of the common cold. Analysis of 23 studies suggested that vitamin C in daily doses of two or more grams was effective in managing the common cold. A randomized, double- blind, placebo-controlled trial demonstrated that zinc lozenges reduced the duration and severity of cold symptoms, especially cough. However, another randomized, double-blind, placebo-controlled clinical trial suggested that zinc gluconate lozenges reduced the duration of symp- toms by 42%. Successful therapy seemed most likely when the intervention was started within 48 hours and lozenges were sucked every 2 hours while subjects were awake. Perhaps the situation is best summarized by the Cochrane Project systematic review in which it was concluded that evidence of the effect of zinc lozenges for treating the common cold remains inconclusive. Furthermore, existing literature suggests that echinacea should be used as a treatment for illness, not as a means of prevention. A randomized, controlled trial showed that volunteers taking an allicin-containing garlic supplement (one capsule daily) were less likely to contract a cold and recovered faster if they were infected. For a sore throat, topical kava for its anesthetic effect and licorice for its soothing anti-inflammatory effect are useful. Hemila H, Kaprio J, Albanes D, et al: Vitamin C, vitamin E, and beta-carotene in relation to common cold incidence in male smokers, Epidemiology 13:32-7, 2002. Hemila H: Vitamin C supplementation and common cold symptoms: factors affecting the magnitude of the benefit, Med Hypotheses 52:171-8, 1999. A randomized, double-blind, placebo-controlled trial, Ann Intern Med 133:245-52, 2000. Zinc lozenges reduce the duration of common cold symptoms, Nutr Rev 55:82-5, 1997. Linde K, ter Riet G, Hondras M, et al: Systematic reviews of complementary therapies—an annotated bibliography. Henneicke-von Zepelin H, Hentschel C, Schnitker J, et al: Efficacy and safety of a fixed combination phytomedicine in the treatment of the common cold (acute viral respiratory tract infection): results of a randomised, double blind, placebo controlled, multicentre study, Curr Med Res Opin 15:214-27, 1999. Josling P: Preventing the common cold with a garlic supplement: a double- blind, placebo-controlled survey, Adv Ther 18:189-93, 2001. Mills S, Bone K: Principles and practice of phytotherapy, Edinburgh, 2000, Churchill Livingstone. It is character- ized by despondency, a lack of motivation, poor self-esteem, sleep distur- bance, and mental and physical slowness. Masked depression presents as flatness of mood, loss of interest, avoidance of people, lethargy, an inabil- ity to cope with stress, and pervasive anxiety. Increasing the cerebral level of serotonin and/or norepinephrine has an antidepressant effect. Effective antidepressants, such as the tricyclics and monoamine oxidase inhibitors, raise the concentration of the amines at the postsynaptic level. A frequent finding in endogenous depression is suppression of the normal hypothalamic-pituitary-adrenal axis characterized by hypersecretion of 285 286 Part Two / Disease Management corticotropin-releasing hormone, hypersensitivity of the adrenal cortex to corticotropin, and increased cortisol levels. Excess cortisol activates the enzyme tryptophan pyrrolase, shunting tryptophan away from the sero- tonin pathway into niacin production. Turkey, salmon, and milk are rich sources of tryptophan and may lighten depression. Some people who have started a caffeine-free and sugar-free diet report feeling less depressed, moody, and tired. In fact, depression may be one of the earliest signs of an incipient min- eral deficiency. Depression is also associated with iron deficiency anemia and may take months to resolve after the anemia has been corrected. Depression is the first symptom of experimental scurvy, and deficiency of vitamin B5 results in depression accompanied by fatigue and “burning feet. Correction of deficiency of vitamin C (500 mg daily), selenium (200 μg daily), iron (300 mg ferrous sul- fate three times daily), or folic acid (800 μg daily) has also been shown to be effective in clinical trials. In another reasonably large study of outpatients with mild or moderate depression, investigators found that L-tryptophan was associated with a sig- nificantly better outcome than placebo. The production and transport of L-tryptophan from the blood stream into the central nervous system can be compromised by several factors, includ- ing vitamin B6 deficiency. Vitamin B6, 40 mg daily, helps to alleviate depres- sion in women taking oral contraceptives. It has also been suggested that chromium may have an antidepressant effect by enhancing insulin utiliza- tion and increasing tryptophan availability in the central nervous system. Side effects were rare and mild, and most commonly included enhanced dreaming and mild psychomotor activation. In addition to the findings on tryptophan, there is intriguing preliminary evidence that folate and phenylalanine may enhance the effectiveness of con- ventional antidepressants, that S-adenosylmethionine may have antidepres- sant effects, and that ω-3 polyunsaturated fatty acids, particularly docosahexaenoic acid, may have mood elevating and stabilising effects. However, of the natural remedies for depression, it is an herb that enjoys greatest scientific support. John’s wort is 23% to 55% more effective than placebo but is 6% to 18% less effective than tri- cyclic antidepressants in the treatment of mild to moderate depression. John’s wort is an effective antidepressant for mild to moderate depression and causes fewer side effects, although further trials are needed to establish long-term efficacy and safety. In a randomized, double-blind, placebo- controlled clinical trial of 900 mg given daily for 4 to 8 weeks, with increases to 1200 mg daily in the absence of an adequate response, Shelton et al22 con- cluded that St. This may be cause for concern because an American study indicated that complementary and alternative therapies were used more than conven- tional therapies by people with self-defined severe depression. It should be noted that although many of the herbal agents said to bene- fit depressed patients appear to be safe, serious neuropsychiatric side effects and interactions have been reported for several over-the-counter “antide- pressants. His symptoms included lowered mood, reduced energy and motivation, poor sleep (initial insomnia and early morning wak- ening), poor appetite, and weight loss of 6 kg. He was still able to work and found that his spirits would rally if he were involved in an interesting proj- ect. His general health was good except for a several-year history of chronic nasal congestion and poor digestion (recurrent bloating, pain, and erratic bowel habits). His mother, to whom he was close, had died 6 months after the divorce, and it was at that time that he had felt his energy and mood slipping. Don’s brother lives abroad, and his father had died several years earlier, leaving few other close relationships or social supports in Don’s life. The family history revealed that a paternal uncle had had bipolar disorder and that a maternal great- aunt had been treated for a thyroid condition. On the dietary front, he had no breakfast and usually had a salad sandwich for lunch. Dinner, formerly a cooked meal at home, had now become an erratic affair with take-away fried rice and dim sums as staples. He found that coffee tended to pick him up, as did alcohol, which he was now consuming at a level exceeding 30 standard drinks per week. In his youth he had been a competitive swimmer, but he had not engaged in regular exercise for years. Don presented himself as a moderately depressed intelligent man with little to say for himself. Closer questioning revealed that he had always felt on the low energy side and that eating fatty foods made this worse. Skipping breakfast and even lunch had 290 Part Two / Disease Management been a lifelong habit, and he seldom felt very hungry before evening. He was aware that desserts or light meals such as fish and salad tended to improve his mental clarity, but he had never undertaken systematic dietary change.

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Next discount zenegra 100mg visa, EndNote software was used to create a database of the selected articles and duplicates were excluded buy 100 mg zenegra otc. Duplicates proven 100mg zenegra, as well as articles whose titles and summaries did not conform to the search criteria zenegra 100mg with visa, were eliminated. After a close reading of the full result, a total of eight articles were selected for inclusion. Several sources were used to identify the countries that could be used as case studies: the previous literature review, previous studies made by the authors and personal recommendations from experts. Finally, the following countries were selected: Brazil, Colombia, Czech Republic, Hungary, Indonesia, Iran, Jordan, Lebanon, Mexico, Oman, South Africa, United Arab Emirates and Yemen. A survey of 27 questions was designeda with 11 multiple choice questions and 16 open questions. A pilot test was done in July 2009 to a subgroup of 3 countries (Brazil, Czech Republic and Hungary) to assess the appropriateness and comprehensibility of the questionnaire, and two of them provided comments and suggestions that were incorporated in the final version. The questionnaire was designed in English and translated into Spanish for Mexico and Colombia. The next step was to contact those in charge of determining/negotiating the prices of medicines in the countries selectedc. After explaining the objectives of the survey, the countries were invited to participate. In order to ensure a high response rate, several contacts were made (email and/or telephone call) with the officers in charge of answering the questionnaire. The completed questionnaires were reviewed by two people in order to check that that the questions had been correctly understood and answered. In some cases the questionnaire was sent back to the respondents for clarification or doubts were cleared on a telephone call. Finally, a descriptive analysis of the results as well as a qualitative summary of the answers was carried out. The review revealed that European countries tend to select as reference countries those that share economic similarities or geographic proximity (1, 2, 12, 13). However, many differences were found between countries regarding the methodology used. For instance, the number of countries or sources utilized varies considerably (6-10). It is worth noting that a majority of countries used either the average or the minimum price taken from the set of reference countries. As a result, Japan’s prices can vary between 150% above or 75% below the reference countries’ prices (14). Mexico uses the weighted average of the ex-factory prices with respect to the previous quarter in the six countries with bigger sales. This method can result in high prices in Slovakia because prices in the country of origin (e. Working Paper 1: External Reference Pricing decision while waiting for information about the prices in the neighbour countries (Czech Republic, Hungary and Poland), but delay rules are not explicit (16). Latvia and Lithuania were chosen because these are the closest neighbouring countries to Estonia with a similar economic situation, population structure and epidemiological status. Hungary was chosen because it has a similar pricing procedure (negotiations with manufacturers) to Estonia (17). By employing different analytical models this study concluded that countries should use a variety of instruments to set their prices. It suggests that other countries’ prices should only be used to set maximum prices when the medicine has been included in the reference country’s positive list. They conclude that countries with lower prices or lower market volume had fewer medicines available and also suffered from longer delays in medicine launches (once adjusted for other b c, ,d variables ). The alleged reason is that pharmaceutical companies have an interest in delaying product launches in low-price countries until the medicine has been approved for use in high- price countries, thus enabling them to keep prices high in the former. Companies knew that prices in these countries would later become references for other countries, and that those prices, in turn, would be used in other countries as a reference in the future (18-21). By a The delay of a product’s launch is defined here as the number of months that elapse between the product’s global launch and its launch in a specific country (with no distinction made between delays in obtaining the marketing authorization, delays in price setting/reimbursement decisions and the manufacturer’s decision on when to launch). Using an analytical model they estimated that a €1 reduction in German medicine prices would lead to a reduction of between €0. This was made evident in a recent European Commission report that asked companies to indicate which countries they preferred to use for launching new medicines. Companies preferred to initiate their product launches in countries with free prices (United Kingdom, Germany, and Sweden). In contrast, countries with smaller markets, such as Cyprus or Malta, or with lower disposable income, such as Poland, Bulgaria, Lithuania, Latvia, Estonia, Hungary and Romania (23), are mentioned last. Considering the relatively small number of new medicines that actually make any substantial therapeutic contribution over existing ones, such delays in marketing might not necessarily be a bad thing. The countries stated that they combine between two and five criteria to set prices. The second most used method is the cost of existing treatment for the same condition or disease within the same country (8 countries). Some countries use as the comparator the manufacturer’s country of origin (as in the case of Iran and Jordan). However, there are some countries that are commonly used as reference despite not necessarily being in the same region. Then because of its apparent ineffectiveness in containing pharmaceutical expenditure, the system was abandoned. Working Paper 1: External Reference Pricing the United Kingdom, which are chosen due to their low prices, transparency and accessibility of price information. In all of the case study countries, a manufacturer submitting a new product for pricing is obliged to provide the price of the product in the reference countries. Failure to do so or to provide false information could lead to fines and penalties. Regarding the methodology for arriving at the reference price, the most widespread criterion was the minimum price of the set of reference countries (6 countries), followed by the average price (2 countries). The reasons given are either relatively low prices or availability of information. The case studies indicate that it is also becoming popular among developing and transitional countries. Countries differ, as well, in how they enforce the calculated price: some present suppliers with a “take it or leave it” decision, meaning that if they do not accept the price offered, the product will not be approved or reimbursed. At the other extreme are some countries that use the calculated price as a relatively flexible benchmark for negotiating the price. As has been extensively mentioned in the literature, some evidence points to market launch delays in low-price countries. Consequently, countries that in the past were able to obtain relatively lower prices might not be able to do so in the future. Answers to the questionnaires and previous experience of the authors suggest that the reference price does not often become the actual national price, especially in the case of medicines that enjoy a monopolistic position. On the other hand, countries seldom consider potential long-term effects, such as delays in new product launches. However, it must be acknowledgeda that certain countries’ actual objectives may diverge from these. A country might only regulate prices to reduce their pharmaceutical expenditure or to protect domestic industry. This can be interpreted as recognizing investment in research and development in their pricing process. It should also be feasible and affordable in relation to the technical capacities and resources of the country. Another aspect to be considered is whether the mechanism is objective – non discretional – predictable and transparent, as this reduces unnecessary uncertainty to the suppliers. This potentially leads to lower supply prices and fewer delays in marketing a product. Objectivity and transparency are also requisites for ensuring regulators’ accountability and for reducing the risk of corruption and discrimination against certain suppliers. Finally, price regulation mechanisms should take into account the unexpected, long-term effects on the country itself as well as on other countries. It needs to be considered by countries as one of a variety of pricing tools that can be implemented to attain the objectives of universal availability, affordable medicines, equitable access and rational use. For example, price control based on the cost-plus (or cost of production) criterion seeks to determine a price that allows producers to recover production costs and obtain a fair/acceptable profit. Pharmacoeconomic analysis assumes that the price of a medicine should reflect its therapeutic or welfare-added value in relation to existing therapies. It also assumes that new products that do not bring any added value should not get a higher price than existing treatments. To obtain prices similar to – in fact, not higher than - those of a set of countries. To obtain differential - usually lower - prices in relation to those of a set of countries. All the method tries to ensure is that the country does not pay more than other countries do or that it pays less, because the country is not that wealthy. It is, however, difficult to assess whether the resulting prices will be appropriate, efficient or optimal in accordance with any objective criterion. At least one country in the world should use a different method otherwise new products would never be priced and marketed. Medicine regulatory policies are usually a national responsibility, although there are clear trends towards globalisation of some aspects, particularly on efficacy and safety standards for market authorisation and intellectual property rights. Working Paper 1: External Reference Pricing spreads the effects of national price and reimbursement regulations well beyond the regulating country’s own national boundaries. Delaying the launch of new products in countries that try to attain lowest prices, or even not market, especially in small markets where the opportunity cost of the strategy is lower, and countries that are referenced by other countries with larger markets. This pricing strategy, known as discriminant monopolist, can be used only when there is one sole supplier of a medicine. But as companies seek to maximise global profits, wherever possible they could charge a higher single price for the same product in all countries. However, this single price might mean consumers in lower-income countries could not afford to buy the medicine. Imposing a single international price is not a profit-maximising option compared to price discrimination and might not be feasible, anyway. Companies may, therefore, try to apply a second strategy: initially marketing a new product in countries where prices are not regulated or where high prices are common. Launches in lower-price countries may be delayed so as not to influence other countries.

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Smooth-muscle relaxants buy zenegra 100mg low price, bulking agents purchase zenegra 100 mg online, and prokinetic agents target the bowel; and psychotropic agents are used to treat any asso- ciated anxiety or depression trusted 100mg zenegra. Patients with grain sensitivities may benefit from an increase in pectin-based fiber found in citrus fruits generic 100mg zenegra free shipping, apples, and other fruits and vegetables. Gas symptoms may be relieved by reducing the intake of beans, cabbage, lentils, legumes, apples, grapes, and raisins. Fiber may help to overcome colonic motor dysfunction; however, doses of at least 12 g per day may be required for patients with constipation-predominant disease. Therefore when bulking approaches are used, a com- bination of soluble and insoluble fiber-containing foods and supplements should be added gradually. Psyllium seed and ispaghula are more readily tolerated bulking agents than wheat bran. Asparagus and Jerusalem artichokes, apple and citrus pectins, guar gum, and legumes are particularly good sources of soluble fiber and short-chain fatty acids. Enteric-coated capsules allow menthol, the active anti- spasmodic, to be delivered directly to the large intestine and prevent its absorption by the stomach. One in five patients experienced a side effect such as heartburn, nausea, vomiting, blurred vision, or a burning sensation in the anal area. Sedative herbs such as valerian (Valeriana officinalis) and scullcap (Scutellaria lateriflora) have both relaxing and antispasmodic properties and are therefore particularly useful for patients who also have insomnia and/or anxiety. Thea can be prepared by pouring boiling water (125 mL) over one to two tea- spoons of dried basil and brewing for 15 minutes. Starbuck J: Irritable bowel syndrome: a gut reaction, Nutr Sci News 5:127-32, 2000. Gaby A: The role of hidden food allergy/intolerance in chronic disease, Altern Med Rev 3:90-100, 1998. Camilleri M: Therapeutic approach to the patient with irritable bowel syndrome, Am J Med 107:27S-32S, 1999. Schrezenmeir J, de Vrese M: Probiotics, prebiotics and synbiotics—approaching a definition, Am J Clin Nutr 73:361S-364S, 2001. Olesen M, Gudmand-Hoyer E: Efficacy, safety, and tolerability of fructooligosaccharides in the treatment of irritable bowel syndrome, Am J Clin Nutr 72:1570-5, 2000. Mills S, Bone K: Principles and practice of phytotherapy, Edinburgh, 2000, Churchill Livingstone. Diefendorf D, Healey J, Kalyn W, editors: The healing power of vitamins, minerals and herbs, Surry Hills, Australia, 2000, Readers Digest. Castleman M: Herbal healthwatch: minty relief for irritable bowel syndrome, Herb Q 86:8-9, 2000. Pittler M, Ernst E: Peppermint of for irritable bowel syndrome: a critical review and meta-analysis, Am J Gastroenterol 93:1131-5, 1998. Khosh F: A natural approach to irritable bowel syndrome, Townsend Lett Doc Pat 204:62-4, 2000. Extraintestinal manifestations include arthritis, skin rashes, ocular disorders, and anemia. In an attempt to avoid side effects from prescribed medicines, as a result of unsat- isfactory outcomes, or in search of a cure, patients may try complementary medicine alternatives. Studies suggest that around four in 10 patients have tried alternative health therapies for their gastrointestinal problems. One possible explanation is an immune-based inflammatory response of bowel mucosa to neurotransmit- ters and neurohumoral peptides. Because inflammation is fundamental to the pathogenesis of both ulcerative colitis and Crohn’s disease, the aims of intervention are to dampen the inflammatory response and improve nutri- tion of the epithelial lining. Plasma levels of antioxidant vitamins (ascorbic acid, alpha-and beta-carotene, lycopene, and β- cryptoxanthin) are all significantly lower in patients with Crohn’s disease than in control subjects. Supplementation with ω-3 fatty acids and antioxi- dants may dampen the inflammatory response, and dietary choice and bowel microflora can affect production of butyrate, the preferred fuel for colonic epithelium. Short-chain fatty acids, produced by colonic bacterial fermentation of dietary fiber, play a pivotal role in the integrity and metabolism of colonic mucosa. Butyric acid, the preferred fuel for colonic epithelial cells, has a trophic effect on colonic epithelium. Because oxidation of ω-butyrate gov- erns the epithelial barrier function of colonocytes, the functional activity of short-chain acyl-CoA dehydrogenase may be critical in maintaining colonic mucosal integrity. Sulfur is essential for ω-butyrate formation, and its production aids in the disposal of hydrogen produced by colonic bacteria. Patients with ulcerative colitis have enhanced sulfate metabolism, and removal of foods rich in sulfur amino acids—such as milk, eggs, and cheese—has therapeutic benefits. In controlled clinical trials, butyric acid enemas have been found to be beneficial in the treatment of ulcerative colitis. Supplementation with ω-3 fatty acids plus antioxidants significantly changes the eicosanoid precursor profile and may lead to the production of eicosanoids with attenuated proinflammatory activity. Results of a 12-month study suggested that 8 weeks of zinc supplementation (110 mg of zinc sul- fate three times daily) could resolve altered bowel permeability in patients with Crohn’s disease in remission. Chamomile and meadowsweet may be useful in patients with mucus in the stool, which suggests underlying inflammation. Small nonrandomized studies suggest that Boswellia serrata may be effec- tive in the treatment of ulcerative colitis. Heuschkel R, Afzal N, Wuerth A, et al: Complementary medicine use in children and young adults with inflammatory bowel disease, Am J Gastroenterol 97:382-8, 2002. Babidge W, Millard S, Roediger W: Sulfides impair short chain fatty acid beta- oxidation at acyl-CoA dehydrogenase level in colonocytes: implications for ulcerative colitis, Mol Cell Biochem 181:117-24, 1998. A novel neutraceutical therapeutic strategy for ulcerative colitis, Digestion 63:S60- S677, 2001. Belluzzi A, Boschi S, Brignola C, et al: Polyunsaturated fatty acids and inflammatory bowel disease, Am J Clin Nutr 71:339S-342S, 2000. Langmead L, Dawson C, Hawkins C, et al: Antioxidant effects of herbal therapies used by patients with inflammatory bowel disease: an in vitro study, Aliment Pharmacol Ther 16:197-205, 2002. Mills S, Bone K: Principles and practice of phytotherapy, Edinburgh, 2000, Churchill Livingstone. Pinn G: The herbal basis of some gastroenterology therapies, Aust Fam Physician 30:254-8, 2001. Treatment can be problematic because the recommended duration for hyp- notic drug use is 4 weeks. The time limitation advocated for hypnotic drug use has been set to prevent habituation and the withdrawal symptoms after long-term use. Persons with insomnia have difficulty getting to sleep and staying asleep, and they wake unrefreshed. Acute stress and environmen- tal disturbances are the most common causes of transient and short-term insomnia. Chronic insomnia is often associated with medical conditions, psychiatric problems such as depression, or persistent psychophysiologic disorders such as inadequate sleep hygiene. This involves creating external and internal environments that are conducive to sleep. Except for a physiologic mid-afternoon dip in alertness, the circadian rhythm of sleepiness and alertness promotes a daily cycle of nighttime sleep and daytime alertness. Normal sleep consists of four to six behaviorally and electroencephalo- graphically defined cycles. It initially reduces sleep latency and decreases arousals but then causes increased waking in the second half of the night. Caffeine may reduce sleep latency, but it fragments sleep, causing sleep disruption in the latter part of the night. Milk is a rich source of tryptophan and nicotinic acid, one of the B group of vitamins that influences the conversion of tryptophan to serotonin. The belief that drinking a warm glass of milk before going to bed will help one sleep is biochemically plausible. Single low doses of melatonin, provided that they mimic the nocturnal phys- iologic concentration of this hormone, exert immediate sleep-inducing effects. L-Tryptophan is the amino acid precursor to serotonin, the neurotrans- mitter thought to induce sleep. A dose of 1 to 2 g of L-tryptophan has been reported to halve sleep latency and decrease waking time. The sleep patterns of insomniacs taking tryptophan more closely Chapter 32 / Insomnia 341 resemble those of normal sleepers than those of untreated insomniacs or per- sons taking sleeping tablets. In fact, the only change noted in the architecture of tryptophan-assisted sleep is an increase in duration of the third and fourth stages of slow-wave sleep. The immediate precursor of sero- tonin, 5-hydroxytryptophan (10 mg), is currently being used as a sleep aid, a treatment for depression, and a weight loss aid. When tryptophan is taken with vitamin B6 (50 mg) and niacinamide (500 mg), the conversion of tryptophan to serotonin is favored. Controlled clinical trials suggest that deficiency of potassium or thiamine may contribute to insomnia. A lignan, hydroxypinoresinol, with the ability to bind to benzodiazepine receptors is also present. The considerable variation in the composition and content of valerian and the instability of some of its constituents pose serious problems for standardization, but the range of components that contribute to its over- all activity suggest that it may correct a variety of underlying conditions that benefit from a general sedative or tranquilizing effect. Results of clinical trials indicate that 400 to 900 mg of valerian extract taken at bedtime improves sleep quality, decreases sleep latency, and reduces the number of night awakenings. A randomized, double-blind, placebo-controlled, crossover study with multiple dosages of valerian demonstrated that slow-wave sleep latency was reduced after administration of valerian over several days. The researchers concluded that valerian could be recom- mended for the treatment of patients with mild psychophysiologic insomnia. Another randomized, controlled, double-blind trial indicated that neither single nor repeated evening administration of 600 mg of native valerian root extract had any relevant adverse effect on reaction time, alertness, and con- centration the morning after. Johns wort, valerian is particularly useful for insomniacs with depression or anxiety. In a pilot study that included 24 patients with stress-induced insomnia treated for 6 weeks, valerian and kava were compared for efficacy. Most patients have no side effects, and the most common effects are vivid dreams with valerian (16%) and dizziness with kava (12%). Several relatively short-term clinical studies have provided favorable evidence that kava is effective in treating anxiety and insomnia. The recommended daily dosage is 1 to 2 g of the crude root, or 200 to 600 mg of extract. Although current data suggest that the use of some herbal treatments in insomnia may be efficacious, further laboratory and clinical studies are required to validate their safety and efficacy. National Center on Sleep Disorders Research Working Group, Am Fam Physician 59:937-44, 1999.

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Farr initially disagreed with Snow’s hypothesis that cholera was transmitted by water order 100 mg zenegra with visa. However zenegra 100mg on-line, he was eventually convinced order 100 mg zenegra mastercard, and his book based on the 1866 epidemic demonstrated that contaminated water was a risk for cholera cheap zenegra 100 mg amex. Anton van Leeuwenhoek (1632–1723) invented the microscope, and in 1683 he described how materials such as rainwater and human excretions had cocci, bacilli, and spirochetes. Because they were often present in decaying or fermenting materials, some people maintained that they were spontaneously generated from inanimate material. Further, he could pass the disease from one mouse to another by inoculating them with these microorganisms. In the subsequent 50 years, numerous microorganisms were identifed as the causative agents of important human diseases (Table 1-1) and their epidemiology elucidated. Among these was the causative agent of plague, identifed in 1894 by Alexander Yersin (1863–1943) and Shibasa- buro Kitasato (1852–1931). They discovered the organism in both rats and humans who had died of plague during an epidemic in Hong Kong. Once a rat fea becomes infected with Yersinia pestis, the plague bacillus, it cannot digest its food—rat blood. Starving, it looks aggressively for another animal to feed on and, in so doing, passes the organism on to humans. After it is infected, the rat fea can hibernate for up to 50 days in grain, cloth, or other items and spread the disease to humans coming into contact with these items of commerce. The frst specifc published account of human hookworm disease was in 1843 by Angelo Dubini (1813–1902) from Milan. However, the means of spread was commonly believed to be by the fecal–oral route until the observation of Arthur Looss in Cairo, Egypt, in 1898. Then he recalled that he had accidentally spilled a fecal inoculum on his hands that caused a transitory itchy red rash. He then intentionally exposed his skin to another hookworm inoculum and, after a few minutes, was unable to fnd the organisms on his exposed skin. After several additional careful experiments, he reported the entrance of hookworms into humans by skin penetration of the parasites, rather than by ingestion. One self-experimenter who suc- cumbed was Daniel Carrion (1858–1885), a medical student in Lima, Peru. Carrion injected himself with the material from a chronic skin lesion called Verraga peruana. This self-experiment was designed to determine whether the same organism (later identifed to be Bartonella bacilliformis) could also cause another disease, known as Oroya fever. When Carrion developed Oroya fever, he proved that the two diseases were caused by the same infectious organism but the experiment cost him his life. The explosive epidemic nature of yellow fever and malaria when they occurred in Europe and the United States, not to mention the military and commercial interests in their control, spurred researchers and their governments to support studies. The frst proof that an animal disease was spread by an arthropod was the report in 1893 by Smith and Kilbourne on the transmission of Thexas cattle fever by a Borrelia sp. However, Stubbins Firth (1784–1820) in 1804 observed that secondary cases among nurses or doctors caring for patients with the disease were unheard of. To prove that person-to-person transmission wasn’t a risk, he undertook a remarkable series of self-experiments, in which he exposed himself orally and parenterally to the hemorrhagic vomitus, other excretions, and blood of patients dying of yellow fever. He was unable to transmit the infection in these experiments, and he concluded that yellow fever wasn’t directly trans- mitted from person to person. The commission studied the transmission of yellow fever © Jones and Bartlett Publishers. In the course of the investigation, one of the volunteers, who was a member of the committee, Jesse H. Lazear (1866–1900), contracted yellow fever following a mosquito bite and succumbed to the disease. After several defnitive experiments, the commission was able to report that yellow fever was transmitted to humans by the bite of an infected mosquito. Furthermore, their studies showed that yellow fever had an obligate insect cycle and was not transmitted directly from person to person. Mosquitoes were also suspected in malaria, although early researchers were unsure as to whether it was a marker of poor sanitation or a neces- sary part of the malaria life cycle. In De Noxiis Palodum Efforiis (On the Noxious Emanations of Swamps), published in 1717, Giovanni Maria Lancisi (1654–1720) speculated on the manner in which swamps produced malaria epidemics. The animate emanations were mosquitoes, and these, he thought, could carry animalcules. Over 150 years later, the microscope was the tool used to wage an intense scientifc competition to identify the malaria life cycle. The malaria parasite, Plasmodium falciparum, was originally discovered by Alphonse Laveran (1845–1922), a French army surgeon working in Algeria. On November 5, 1880, he “was astonished to observe, [in a soldier’s blood specimen]. The Italian research team took a wrong turn and concluded that the parasite might be an amoeba or other spore outside of the human and concentrated on collecting materials from malari- ous locations, including but not limited to mosquitoes. It was the tireless work of Ronald Ross (1857–1932) in India that fnally uncovered the life cycle of avian malaria. Painstakingly dissecting mosquitoes he searched for malaria parasites and fnally found the salivary glands packed with the germinal rods of malaria. He described the excitement of his discovery in a letter to Sir 77 Patrick Manson (1844–1922) on July 6, 1898. I think that this, after further elaboration, will close at least one cycle of proteosoma, and I feel that I am almost entitled to lay down the law by direct observation and tracking the parasite step by step—Malaria is conveyed from a diseased person or bird to a healthy one by the proper species of mosquito and is inoculated by its bite. Even when the microscope has done its utmost, healthy birds must be infected with all due precaution. In all probability it is these glands which secrete the stinging fuid which the mosquito injects into the bite. Arrived there, numbers of them are probably instantly swept away by the circulation of the blood, in which they immediately begin to develop into malaria parasites, thus completing the cycle. In fact, when the Nobel com- mittee considered splitting the 1902 Nobel Prize in medicine between Ross and Grassi,49 Koch’s vehement opposition prevented it, allowing Ross the honor alone. Also, many other human diseases caused by viruses were defned in the ensuing decades. The means of transmission and the fact that dengue was a flterable virus were discovered by the Australian Thomas Bancroft et al. The 0th Century The identifcation of the causative microorganisms of specifc infections allowed for a much better understanding of their epidemiology, which in turn informed prevention strategies. The disciplines of microbiology, virology, and immunology paralleled and complemented the disciplines of epidemiol- ogy, statistics, and public health in the prevention of infectious diseases. Despite advances, epidemic diseases continued to occur in the United States, particularly in the nation’s port cities. Cholera, frst seen in the Western Hemisphere in 1832,27 yellow fever, malaria, and plague were constant con- cerns. Although public health authorities had a better understanding of the diseases, treatments lagged behind, and quarantine remained the staple tool of prevention. Kinyoun who promoted the science of health and introduced laboratory diagnostics for the confrmation of cholera cases. The Public Health Service was instrumental in addressing sanitation issues during the First World War and also during the infuenza epidemic of 1918. Treatments for diphtheria with antitoxin and the develop- ment of vaccines for rabies, anthrax, diphtheria, and tetanus were devel- oped. However, many of the antisera that were developed and antiseptics that were tried for the therapy of infectious diseases were of only limited effectiveness. Complicating their use was the risk of contamination in the production of these medications. In 1924, investigators at the Bayer pharmaceutical company in Germany synthesized a new antimalarial drug, pamaquine (Plasmoquine). Shortly thereafter, they synthesized other antimalarial compounds, includ- 52 R1 ing quinacrine (Atabrine). In 1932, Gerhardt Domagk, experimenting with syn- thetic dyes, discovered that Prontosil could cure mice challenged with lethal doses of hemolytic streptococci. In the 1930s and 1940s, Alexander Fleming, Howard Florey, and Ernst Chain at Oxford University conducted experiments that led to the demonstration that penicillin, a mold product, was effective against many pathogenic organisms. For the frst time, it was possible to effectively treat a wide range of infections, and this gave birth to the search for new antibiotics produced by organisms in nature or synthesized in the laboratory. Alexander Langmuir, grew dramatically to include surveillance of infectious and noninfectious diseases, the provision of expert scientifc advice on health issues to policy makers in the United States, serve as a reference laboratory to the states and inform the public about health issues through the Morbid- ity and Mortality Weekly Report. Although some vaccines were developed earlier, the number and impact of vaccines developed in the 1900s century was monumental. The renamed Centers for Disease Control and Prevention in 1999 published a review of the 10 great public health achievements in the United States during the 1900s. The vaccines developed and licensed to prevent vaccine-preventable diseases are shown in Table 1-3, and an estimate of their effect on reported infectious disease morbidity is shown in Table 1-4. During the previous century, the average life span of persons in the United States lengthened by about 30 years, and 25 years of this gain has been attributed to advances in public health. During the 1900s, infectious R1 disease mortality declined from about 800/100,000 population to under © Jones and Bartlett Publishers. The effectiveness of treatments and vaccines coupled with increased fnancial support fueled spectacular advances as the underlying science of diseases was unraveled. Since that time gradual progress in deciphering and manipulating the genetic code of animals and plants had occurred. Dolly the sheep, born July 5, 1996, was the frst higher animal to be cloned, and several other animals have followed. The project was completed ahead of schedule and in April 2003 the human genome was published in several articles in Nature and Science. The felds of genomics and proteomics, the study of protein expression, are rapidly evolving felds that hold great promise for understanding the interaction of humans with infec- tious pathogens. This genome will be informative for all grains, as rice, corn and wheat diverged from a common grass ancestor only 50,000 years ago. Earlier researchers manipulated the rice genome to insert a daffodil gene which added vitamin A to rice. Unfortunately, although genetically modifed foods hold great promise, they are also highly controversial. Hardier plants, enhanced with insect repel- lant genes or drought resistance, threaten to drive out native plants, which could ultimately reduce global genetic diversity. Highly successful seeds are patented, and this elevates the cost of seed beyond the reach of subsistence farmers. The concentration of ownership of seeds is severe, and only a handful of companies own the rights to most of the food seed sold in the world. The Infectious Diseases Challenge In the previous century, such spectacular progress was made in infectious disease control that many health professionals felt that antibiotics and vac- cines would soon eliminate infectious disease threats from most developed nations.

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