Similarly purchase 200 mg flavoxate free shipping spasms on left side of body, an inverse association between the dietary total n-6:n-3 fatty acid ratio and cardiovascular disease 200 mg flavoxate mastercard muscle relaxants yahoo answers, cancer purchase flavoxate 200 mg on-line muscle relaxant 16, and all-cause mortality (Dolecek and Grandits, 1991), as well as between fish intake and coronary heart disease mortality (Kromhout et al. In other studies, however, no differences were found in coronary heart disease risk factors when a diet containing a total n-6:n-3 ratio of 4:1 compared to 1:1 was consumed (Ezaki et al. Hu and coworkers (1999b) observed a weak relationship between the n-6:n-3 ratio and fatal ischemic heart disease since both α-linolenic acid and linoleic acid were inversely related to risk. Desaturation and elongation of trans linoleic and α-linolenic acid isomers containing a double bond at the cis-12 and cis-15 position, respectively, with formation of 20 and 22 carbon chain metabolites that could be incorporated into mem-brane lipids, have also been suggested. In vitro studies and studies with animals fed diets high in trans fatty acids have found evidence of reduced essential n-6 and n-3 fatty acid desaturation (Cook, 1981; Rosenthal and Doloresco, 1984). Studies in term infants found no relation between trans fatty acids and length of gestation, birth weight, or birth length (Elias and Innis, 2001). Similarly, an inverse asso- ciation between plasma phospholipid trans fatty acids and arachidonic acid has been found for children aged 1 to 15 years (Decsi and Koletzko, 1995). The industrial hydrogenation of vegetable oils results in destruction of cis essential n-6 and n-3 fatty acids and the formation of trans fatty acids (Valenzuela and Morgado, 1999). It is not clear if differences in dietary intakes of n-6 and n-3 fatty acids, rather than inhibition of linoleic acid and α-linolenic acid desaturation by trans fatty acids, explains the statistical inverse associations between trans and n-6 and n-3 fatty acids reported in some studies (Craig-Schmidt, 2001). Based on the much greater affinity of the ∆6 desaturase for cis n-6 and n-3 fatty acids than monounsaturated fatty acids (Brenner, 1974; Castuma et al. Fat is the major single source of energy in the diet of infants exclusively fed human milk. The high intake of fat and the energy density that it provides to the diet are important in providing the energy needed for rapid growth during early infancy. Table 8-2 shows the concentration and proportion of energy from fat provided by mature human milk from women delivering at term gestation. The mean energy content of mature human milk is 650 kcal/L (Chapter 5), thus dietary fat represents 55 percent of total energy intake for infants 0 through 6 months of age. Fomon and coworkers (1976) reported that the length and weight of infants were not different when fed formula and strained food providing 29 or 57 percent of energy from fat. Thus, an intake of 55 percent energy most likely exceeds the minimum percent needed for optimal growth of healthy infants. The proportion of energy from dietary fat decreases during the second 6 months of age when complementary foods, specifically infant cereals, vegetables, and fruits, are added to the diet of the infant. The average concentration of fat in milk is approximately 40 g/L during the second 6 months of lactation (Table 8-2). Therefore, the average fat intake from human milk and complementary foods would be 30 g/d ([0. Therefore, for infants 7 though 12 months of age, 40 percent of energy from fat is consumed from human milk and complementary foods. The most common sources of fat in infant formulas are soybean oil, safflower oil, sunflower oil, coconut oil, and palm oil. Children and Adolescents Ages 1 Through 18 Years A number of studies have been conducted to ascertain whether a cer- tain amount of fat is needed in the diet to provide normal growth in children. These data generally conclude that there is no effect of fat intake on growth when consumed at levels as low as 21 percent of energy and provided that the energy intake is adequate (Boulton and Magarey, 1995; Fomon et al. There is insufficient evidence to identify a defined intake level of fat to prevent obesity or chronic diseases. Adults Ages 19 Years and Older The amount of total energy as fat in the diet can vary from 10 to 50 percent without differing effects on short-term health (Jéquier, 1999). When men and women were fed isocaloric diets containing 20, 40, or 60 percent fat, there was no difference in total daily energy expenditure (Hill et al. Similar observations were reported for individuals who consumed diets containing 10, 40, or 70 percent fat (Leibel et al. There are insufficient data, however, to identify a defined intake level for fat based on maintaining fat balance or on the prevention of chronic diseases. Saturated Fatty Acids There is no evidence to indicate that saturated fatty acids are essential in the diet or have a beneficial role in the prevention of chronic diseases. Studies on the essential fatty acid status of older individuals have established that about 2 percent energy from n-6 poly- unsaturated fatty acids (linoleic acid) will prevent abnormal elevation of the triene:tetraene ratio (20:3n-9:20:4n-6) and clinical signs of essential fatty acid deficiency during parenteral nutrition (Barr et al. Inter- pretation, however, is complicated because linoleic acid in the soybean oil emulsion used to provide n-6 fatty acids can also be expected to inhibit synthesis of eicosatrienoic acid (20:3n-9) (Brenner, 1974), and thus reduce the triene:tetraene ratio. Furthermore, children are expected to require higher amounts of n-6 fatty acids than adults in order to support deposi- tion of n-6 fatty acids in cell membranes of growing tissues. The energy content of human milk is approximately 650 kcal/L (Chapter 5) and therefore provides 507 kcal/d (650 kcal/L × 0. Thus, n-6 polyunsaturated fatty acids contribute approximately 8 percent of daily energy intake. The period from 7 through 12 months of age is a time of major transition in the diet, from infants exclusively fed human milk or infant formulas that provide large amounts of dietary fat to a diet containing a variety of foods in addition to milk or formula. Therefore, 6 percent of energy from n-6 poly- unsaturated fat is consumed via human milk and complementary foods.
Hermann Goering generic flavoxate 200mg with mastercard muscle relaxant depression, the Commander-in- Chief of the Luftwaffe cheap flavoxate 200 mg online spasms upper right abdomen, forbade his pilots to smoke in public discount 200 mg flavoxate otc gastrointestinal spasms. In the developed world, we should accept that some people, for whatever reasons, will continue to smoke. While the health hazards of smoking are indisputable, they should be presented truthfully, without exaggeration or moralising. It is dishonest for the state to blame smokers for their addiction, and at the same time to derive fat revenue from tobacco sales. Some paternalism towards children is justified, but the main role in discouraging children from starting to smoke should be left to parents, rather than to the coercive apparatus of the state. The Humean philosopher, Antony Flew, noted that: All persons and organisations campaigning against smok- ing have a compelling reason to establish that environmen- tal tobacco smoke is harmful, and the more extensive and substantial the harm the better. For this is precisely the 134 Lifestylism covery which they need in order to undermine principal 229 libertarian opposition. Luik observed that cor- rupted science has three major characteristics: First, corrupt science is science that moves not from hypothesis and data to conclusion but from mandated or acceptable conclusion to selected data to reach the man- dated or acceptable conclusion. Second, corrupt science is science that misrepresents not just reality, but its own process in arriving at its conclusions. Rather than acknowledging the selectivity of its process and the official necessity of demon- strating the right conclusion, and rather than admitting the complexity of the issue and the limits of its evidence, it invests both its process and its conclusions with a mantle of indubitability. Third, and perhaps most importantly, whereas normal science deals with dissent on the basis of the quality of its evidence and argument and considers ad hominem argument as inappropriate in science, corrupt sci- ence seeks to create formidable institutional barriers to dis- sent through excluding dissenters from the process of review and contriving to silence dissent not by challenging its qual- 230 ity but by questioning its character and motivation. If it is to command academic respect it is crucial that this new epidemiology develops rigor- ous canons of scientific inference and applies scientific criti- cism remorselessly and unselectively even when the results do not please the investigators. The 20th century has already had enough of regimes which tolerate, even encourage, bad or fraudulent science in the name of the good of the nation or society. But not many school leavers have heard of Mill since providers of compulsory state education are careful not to allow his essay On Liberty to fall into the hands of their charges. Until the 18th century, the place of man in the universe and the rules of right conduct were defined by the Church. Right conduct, common decency and even good manners were to be replaced by lifestylism. Lifestyle experts came mainly from the disciplines of epidemiology and statistics. Those on the receiving end were never asked whether their idea of happiness had any resemblance to a correct lifestyle as set down in government publications. As de Jouvenel put it, The handling of public affairs gets entrusted to a class which stands in physical need of certitudes and takes dubi- ous truths to its bosom with the same fanaticism as did in other times the Hussites and Anabaptists. Like Leninism, healthism, with its wonderful promises, attracts dedicated altruists and otherwise intelligent people. Some of them may even acknowledge that people may get hurt in the process, but as Marxist-Leninist activists used to say, when you are clearing a wood, splinters fly around. The glorious visions of Health for All, or of the Smoke-free Planet by the Year 2000 can only be criticised by irresponsible lack- eys on the payroll of industries which thrive on making people sick, or by moral idiots. Their power is, in practice, uncontested because of the legitimacy they have spuriously borrowed from medicine and science and their concerned beneficence. A benign form of paternalism or a puri- tanical zeal to establish behavioral conformity? While the medical profession is not renowned for an exemplary puritanical lifestyle, the control of the lifestyle of others enhances their power. The power of the medical profession is jealously guarded and is vested in their moral, charismatic and scientific authority. The moral authority of doctors has rarely been questioned as doctors are on the side of the angels; they fight evil, suffering and death. The study of human behaviour is not a science in that it discovers no universal laws. It constructs moral stories, meaningful only for a particular society, time and place. This is not to imply that human behaviour is not an important and intriguing subject, but not everything interesting is a science. In medi- cine, blinks correspond to the objective signs of disease, but the concept of disease is in part a wink-construct, and the purpose of medicine is to give blinks meaning. More recently, the urge to normalise has been extended to the behaviour of healthy people, as part of the new policy of health promotion and disease prevention. According to one, the Senior Minister of State for Education announced a new government strategy to combat obesity among schoolchildren - they were to be given marks for their weight in their report books, so that their parents when checking on their academic progress 4 would also see their grade for health and fitness. The Straits Times quoted a cardiologist who called for a tax rebate for those who joined health clubs or purchased sports equip- 5 ment, such as treadmills or exercycles. Health propaganda is disseminated in English, Mandarin, Tamil, and Malay in order to reach as many Singaporeans as possible. Even chew- ing gum is banned in Singapore, though according to the Singapore Ministry of Health, only those who chew in places 6 of food consumption are to be prosecuted. This argument is difficult to refute if those who have power to coerce others to change their ways also have a monopoly of defining what is foolish, stupid or irresponsible.
A Knowledge Network in which diseases are increasingly understood and defined in terms of molecular pathways has the potential to accelerate discovery of underlying disease mechanisms purchase flavoxate 200 mg with amex muscle relaxant tmj. In a molecularly based Knowledge Network discount 200mg flavoxate with visa spasms during sleep, a researcher could readily compare the molecular fingerprint (such as one defined by the transcriptome or proteome) of a disease with an unknown pathogenic mechanism to the information available for better understood diseases trusted 200mg flavoxate xanax muscle relaxer. Similarities between the molecular profiles of diseases with known and unknown pathogenic mechanisms might point directly to shared disease mechanisms, or at least serve as a starting point for directed molecular interrogation of cellular pathways likely to be involved in the pathogenesis of both diseases. A Knowledge Network that integrates data from many different levels of disease determinants collected from individual subjects over time may reveal new opportunities for detection and early diagnosis. The availability of information on a multitude of diverse diseases should facilitate epidemiological research to identify novel diagnostic markers based on correlations among diverse datasets (including clinical, social, economic, environmental, and lifestyle factors) and disease incidence, treatment decisions, and outcomes. In some instances, these advances would follow from the new insights into pathogenic mechanisms discussed above. In other cases, however, molecular profiles may prove sufficiently predictive of a patient’s future health to have substantial clinical utility long before the mechanistic rationale of the correlation is understood. A Knowledge Network of Disease that links information from many levels of disease determinants, from genetic to environment and lifestyle, will improve our ability to predict and survey for diseases. Following outcomes in individual patients over time will allow the prognostic value of molecular-based classifications to be tested and, ideally, verified. Obviously, the clinical utility of identifying disease predispositions depends on the availability of interventions that would either prevent or delay onset of disease or perhaps ameliorate disease severity. The ultimate goal of most clinical research is to improve disease treatments and health outcomes. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 41 Knowledge Network of Disease and its derived taxonomy may be expected to impact disease treatment and to contribute to improved health outcomes for patients. As many of the examples already discussed illustrate, finer grained diagnoses often are the key to choosing optimal treatments. In some instances, a molecularly informed disease classification offers improved options for disease prevention or management even when different disease sub-types are treated identically (see Box 3. A Knowledge Network that integrates data from multiple levels of disease determinants will also facilitate the development of new therapies by identifying new therapeutic targets and may suggest off-label use of existing drugs. In other cases, the identification of links between environmental factors or lifestyle choices and disease incidence may make it possible to reduce disease incidence by lifestyle interventions. Importantly, as discussed below, the Committee believes the Knowledge Network and its underlying Information Commons would enable the discovery of improved treatments by providing a powerful new research resource that would bring together researchers with diverse skills and integrate knowledge about disease processes in an unprecedented way. Indeed, it is quite possible that the transition to a modernized “discovery model” in which disease data generated during the course of normal healthcare and analyzed by a diverse set of researchers would ultimately prove to be a Knowledge Network of Disease’s greatest legacy for biomedical research. Consequently, patients and physicians must currently make decisions about whether to undertake more intensive cancer surveillance (for example, by breast magnetic resonance imaging or vaginal ultrasound) without being able clearly to assess the risks and benefits of such increased screening and the anxiety and potential morbidity that arises from inevitable false positives. Furthermore, some patients elect to undergo prophylactic mastectomies or oophorectomies without definitive information about the extent to which these drastic procedures actually would reduce their cancer risk. Studies attempting to quantify these risks have largely focused on particular ethnic groups in which a limited set of mutations occur at high enough frequencies to allow reliable conclusions from analyses carried out on a practical scale. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 42 individual patients, health-care providers, and payers, by making it possible to avoid unnecessary screening and treatment while reducing cancer incidence and promoting early detection. Molecular similarities amongst seemingly unrelated diseases would also be of direct relevance to drug discovery as it would lead to targeted investigation of disease-relevant pathways that are shared between molecularly related diseases. In addition, ongoing access to molecular profiles and health histories of large numbers of patients taking already-approved drugs would undoubtedly lead to improved drug safety by allowing identification of individuals at higher-than-normal risk of adverse drug reactions. Indeed, our limited understanding of—and lack of a robust system for studying—rare adverse reactions is a major barrier to the introduction of new drugs in our increasingly risk-aversive and litigious society. Major disparities in the health profiles of different “racial”, ethnic, and socio-economic groups within our diverse society have proven discouragingly refractory to amelioration. As discussed above, it is quite likely that key contributors to these disparities can be most effectively addressed through public-health measures and other public policies that have little to do with the molecular basis of disease, at least as we presently understand it. However, the Committee regards the Information Commons and Knowledge Network of Disease, as potentially powerful tools for understanding and addressing health disparities because they would be informed by data on the environmental and social factors that influence the health of individual patients,. For the first time, these resources would bring together, in the same place, molecular profiles, health histories, and data on the many determinants of health and disease, thereby optimizing the ability to decipher the mechanisms through which exogenous factors give rise to endogenous, biological inputs, directly affecting health. Researchers and policy makers would then be better able to sort out the full diversity of possible reasons for observed individual and group differences in health and to devise effective strategies to prevent and combat them. A Hierarchy of Large Datasets Would Be the Foundation of the Knowledge Network of Disease and Its Practical Applications The establishment of a Knowledge Network, and its research and clinical applications, would depend on the availability of a hierarchy of large, well-integrated datasets describing what we know about human disease. These datasets would establish the foundation for the New Taxonomy and many other basic and applied activities throughout the health-care system. The Information Commons would contain the raw information about individual patients from which meaningful links and relationships could be derived.
Ten healthy adults given 5 g of L-tryptophan in a double-blind purchase flavoxate 200 mg fast delivery muscle relaxant end of life, placebo-controlled study reported severe nausea and headache and increased drowsiness soon after ingestion (Greenwood et al cheap 200mg flavoxate with mastercard spasms in lower abdomen. Smith and Prockop (1962) reported sustained nystagmus and drowsiness in seven adults given 70 and 90 mg/kg of body weight of L-tryptophan orally in single doses discount flavoxate 200mg on-line spasms spasticity muscle, but found that these effects were absent at 30 or 50 mg/kg. However, Lieberman and coworkers (1985) reported decreased self-ratings of vigor and alertness and increased subjective fatigue in 20 men treated with a single oral dose of 50 mg/kg of tryptophan. Yuwiler and coworkers (1981) also reported that five individuals given 50 or 100 mg/kg/d of L-tryptophan as a single dose or 50 mg/kg/d for 14 days experienced prolonged lethargy and drowsiness within 30 minutes of inges- tion under all loading conditions. Newborns (2 to 3 days of age) given infant formula supplemented with L-tryptophan (about 20 mg) were found to enter active and then quiet sleep sooner than those newborns given unsupplemented formula (Yogman and Zeisel, 1983). In a later study, these same investigators found that low doses of L-tryptophan have sleep-inducing properties in full-term infants (Yogman and Zeisel, 1985). Blauvelt and Falanga (1991) examined the history of L-tryptophan use in 49 patients with cutaneous fibrosis. Eleven of 17 patients reported using L-tryptophan prior to onset of eosinophilic fasciitis, as did two of ten patients with localized scleroderma, but use of L-tryptophan was not reported in any of 22 patients with systemic sclerosis. L-tryptophan use in individuals with localized scleroderma occurred for 3 or 10 months before onset of symptoms, and intake was 1. Hibbs and coworkers (1992) found that 9 of 45 patients with eosinophilic fasciitis used 0. It is unknown whether or not these results occurred because of impurities in the L-tryptophan supplements. Dose–Response Assessment Taken together, the above studies in humans indicate that relatively short-term (acute and subacute) use of L-tryptophan is associated with appetite suppression, nausea, and drowsiness. Tyrosine L-Tyrosine is considered a conditionally indispensable amino acid because it can be synthesized from L-phenylalanine in the liver. L-Tyrosine is a precursor of several biologically active substances, including catecholamine neurotransmitters, hormones, and melanin skin pigments. Men 31 through 50 years of age had the highest intakes at the 99th percentile of 6. In the mouse with elevated tissue concentra- tions of tyrosine, decarboxylation to tyramine becomes increasingly impor- tant, reducing lethality (David et al. Evidence has been provided that hepatic biotransformation of tyrosine yields a toxic metabolite, possibly an epoxide (David, 1976). In rodents, feeding studies document the toxicity of large supplements of L-tyrosine (Benevenga and Steele, 1984; Harper et al. Effects of tyrosine on weight-gain suppression are a function of the protein content of the diet. For example, feeding rats a low-protein diet, 6 or 9 percent casein, retarded weight gain over a 3-week period. This effect of an inadequate protein intake was exacerbated by the addition of 3 to 8 per- cent L-tyrosine in the diet (Ip and Harper, 1973). With higher protein intakes of 15 or 24 percent, the toxicity of L-tyrosine was reduced, although 8 percent L-tyrosine still resulted in mortality. Subsequently, Rich and coworkers (1973) reported that young adult Simonson albino or Long-Evans pigmented rats fed diets containing 5 or 10 percent L-tyrosine for 15 days developed elevated serum tyrosine levels and experienced reduced weight gain. Corneal disease was the first sign of toxicity; keratopathy was evident by 1 day and progressed in severity. The change began as haziness of the cornea, followed by opacities, and vascularization. The corneal changes were accompanied by elevations of tyrosine concentration in the aqueous humor. Rats were fed the diet for 2 weeks prior to mating and continually for three generations. Brain weight was measured in all three generations and no differences were seen except at days 15 and 20 postpartum in the F2 generation (92 and 95 percent of controls). Serum concentration of tyrosine of F3 generation rats was increased at postnatal day 5. Large single doses of L-tyrosine (500 mg/kg/d) or smaller daily doses (100 mg/kg/d) have not been associated with any adverse affects (Al-Damluji et al. Single oral doses of 100 or 150 mg/kg of L-tyrosine administered to humans lead to a two- to threefold increase in plasma tyrosine concentra- tions (Cuche et al. Similar amounts given over the day in three equal doses result in similar incre- ments in plasma tyrosine (Benedict et al. An increase in the dopamine metabolite, homovanillic acid, has been found in cerebral spinal fluid after L-tyrosine loads (Growdon et al. Loads of L-tyrosine of 100 to 150 mg/kg/d have not been found to have any adverse effects on physiological systems (Benedict et al. No data on blood concentrations in humans predictive of corneal lesions are available. All amino acids had their highest median intake for any life stage and gender group in men aged 19 through 30 years.