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Cancer is the second most deadly disease and is expected to surpass heart disease early in the 21st century to top that nefarious list (see Chapter 193) heart attack 34 years old purchase bisoprolol 10mg online. Over the past half century blood pressure low generic bisoprolol 5mg visa, the frequency of most cancers has been stable pulse pressure 90 order cheapest bisoprolol and bisoprolol, but some dramatic changes have taken place blood pressure medication new zealand discount bisoprolol online. Steady declines in stomach and uterine cancer have occurred, the latter undoubtedly due to routine cytologic screening for cervical cancer. The cause of the decline in stomach cancer is unclear but may in part relate to increased use of antibiotics and their effect on chronic Helicobacter pylori infection. The most striking change has been the increases in lung cancer in both men and women, undoubtedly related to smoking. The overall mortality, particularly for those younger than age 65, has declined, primarily due to more effective therapy for cancers of fetal and hematopoietic origin that occur in the younger population. A broad array of agents can cause or directly contribute to a sequence of events or sensitize cells in such a way that cancer develops (see Chapter 190). The final common pathway in virtually every instance is a cellular genetic mutation that converts a well-behaved cellular citizen of the body into a destructive renegade that is unresponsive to the ordinary checks and balances of a normal community of cells. Promoters (oncogenes) and suppressors (like the retinoblastoma or p53 gene) play a central role in many cases (see Chapter 191). Chemicals such as benzene and nitrosamines, physical agents such as gamma and ultraviolet radiation, and biologic agents such as the Epstein-Barr and hepatitis viruses contribute to carcinogenesis under certain circumstances. Evidence exists to link dietary factors to carcinogenesis; although not as clear as one would like, the evidence is strong enough to recommend diets low in fat and high in fiber. A sensible diet is based on grains, vegetables, and fruits, with smaller than the current average proportions of fat. Inherited susceptibilities are becoming more evident and probably play a key role in a significant number of cancers of the breast and colon. Down syndrome and the Li-Fraumeni syndrome are well-known harbingers of a substantial risk for developing cancer. The single most important carcinogen in the United States and Europe is tobacco (see Chapter 13), because it causes or contributes to the development of about one third of all cancers: primarily lung, esophageal, head and neck, and bladder. Less well appreciated is the contribution tobacco may make to causing breast, colon, and gastric cancer. Tobacco-related cancer is also important because it is preventable by the obvious, inexpensive, and 100% effective means of abstention. Although the total number of smokers in the United States has declined, women smoke more than ever, adolescents continue to view smoking as socially chic, and the number of smokers in Asia and developing countries is growing at an alarming rate. When prevention of cancer is not possible because effective means are lacking, early detection is the next best strategy to reduce cancer mortality. As a general rule, the smaller and more confined the tumor, the more likely therapy will result in permanent cure. This approach has been most successful for directly accessible tumors that have an early malignant or premalignant state. Examples include Papanicolaou smears and surgical conization for cancer of the uterine cervix, physical removal of early skin cancer, and colonoscopic removal of colorectal polyps. However, it is not clear that all in situ breast and prostate cancers will become invasive and fatal, so there is some risk of overtreatment, particularly for prostate cancer. An even more exciting development in this effort has been the emergence of genetic screening and counseling of families at high risk for developing cancer. Individuals at risk are identified largely by analysis of family pedigrees, and the increasing availability of the revolutionary tools of molecular biology can identify specific genetic mutations (see Chapter 191). It is certain that many such genes will be identified, focusing the cancer screening and early detection efforts more efficiently and productively on high-risk populations (see Chapter 190). Although it is impossible to know the specific details of early in vivo tumor growth and the efficiency of tumor cell renewal of human cancer, clinical and laboratory observations have provided a reasonable conceptual framework. This framework should be used with caution, however, because it is certain that the intrinsic factors that control tumor growth and propagation are far more complex, episodic, and heterogeneous than currently known, even within a single tumor mass. Furthermore, the stromal environment and neovascularization of tumors have become more central to our understanding of this process than heretofore.
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Nutrition interacts with each step of carcinogenesis (carcinogen activation and tumor initiation blood pressure and exercise order bisoprolol toronto, promotion hypertension frequent urination order bisoprolol with mastercard, and progression) blood pressure medication iso purchase bisoprolol discount. Humans are exposed to countless potential carcinogens blood pressure ranges low normal high bisoprolol 5mg overnight delivery, but to many anticarcinogens as well, each day through dietary and other means. By contrast, antioxidant nutrients scavenge free radicals and other (pre)carcinogens and thereby inhibit their activation and/or their ability to initiate mutations. Obesity, excess dietary fat intake, and excess alcohol appear to promote tumor growth. Much evidence indicates that the number one cancer killer, lung cancer, is strongly influenced by diet. Although the most important causal factor is cigarette smoking, consumption of fruits and vegetables is inversely associated with lung cancer risk in both smokers and non-smokers. It is probable that many nutrients in fruits and vegetables, such as beta-carotene and folic acid, as well as non-nutritive components, are partly responsible for the protective effects. Moreover, in view of the disappointing results of randomized trials of supplementation with beta-carotene, antioxidant supplements should not be relied on to reduce disease risk. Diets should be based on a variety of common foods to provide other nutrients for which human requirements have been less well defined. These allowances have been designed for the maintenance of good nutrition of practically all healthy people in the United States. Because the toxic levels for many trace elements may be only several times the usual intake, the upper levels for the trace elements given in this table should not be habitually exceeded. Department of Agriculture/Department of Health and Human Services Food Guide Pyramid. Oldways Preservation & Exchange Trust and the President and Fellows of Harvard College. Probably caused by oxidants in cigarette smoke and poorer dietary habits in smokers, this difference is an example of an interaction between nutritional factors and environmental exposure that explains more of the variation in cancer incidence than does either factor alone. The 2nd largest cause of cancer deaths in women, breast cancer, is positively associated with dietary fat intake and obesity, especially when the latter predominantly affects the abdomen. Because of the inconsistencies between ecologic and cohort studies noted earlier, however, it is unclear whether dietary fat per se, total calorie intake, or other factors are responsible for the associations. Epidemiologic evidence suggests that alcohol intake may also be a risk factor for this disease. Colorectal cancer is the 2nd leading cause of cancer mortality in men and the 3rd in women. Its risk correlates positively with dietary fat intake in both ecologic and cohort studies and inversely with intake of dietary fiber, calcium, and folic acid. Other malignant diseases for which dietary fat intake appears to increase risk include prostate and ovarian cancer. The interaction of all these influences is powerful enough to indicate that diet contributes to about 35% of cancer deaths in Western countries. Even though the independent influences of potentially protective nutrients such as carotenoids, vitamins C and E, folic acid, and fiber are not known because they are all present in vegetables and fruits, the evidence that liberal intake of fruits and vegetables reduces cancer risk is overwhelming. It is often associated with obesity, especially abdominal obesity, and weight reduction in obese hypertensives usually leads to improvement in blood pressure. A diet rich in fruits, vegetables, and low-fat dairy products and with reduced saturated and total fat content can also decrease blood pressure levels, even when body weight and sodium intake are held constant. Because alcohol intake elevates blood pressure, its use should be minimized in hypertensive patients. This relationship is especially true for abdominal obesity and less so for peripheral obesity. Sugar consumption does not lead to diabetes except to the extent that it may promote weight gain. Alcohol can cause hypoglycemia, hyperglycemia, and increased triglyceride levels in diabetics, and its use should be minimized. In both diabetics and non-diabetics, excess alcohol intake is responsible for many deaths, particularly from accidents and liver disease, and is a factor in some suicidal deaths. Inadequate calcium intake during adolescence may result in suboptimal peak bone mass in early adulthood, and during later life it may lead to more rapid bone loss, thereby increasing the risk for osteoporosis.
Granulosa cells express aromatase heart attack 720p movie download buy cheap bisoprolol online, the enzyme that catalyzes placement of three double bonds in the A ring of estrogens but cannot provide precursor androstenedione arteria iliaca externa bisoprolol 5 mg cheap, which is synthesized in the theca interna cell located adjacent to the granulosa cell blood pressure medication causes nightmares order bisoprolol 5 mg. Granulosa cells efficiently convert precursor androstenedione provided by the theca interna to estrone and estradiol interleukin 6 arrhythmia quality bisoprolol 10mg. Vitamin D3 is formed from 7-dehydrocholesterol by ultraviolet irradiation of skin. In contrast to peptide hormones, steroid hormones have longer circulating half-lives and may be active when administered orally. After secretion into the circulation, steroid hormones are bound to transport glycoproteins made in the liver. The transport proteins, which have a binding but not an activity site, provide a reservoir of hormone, protected from metabolism and renal clearance, that can be released to cells. Free steroid hormone, which is in equilibrium with that bound to transport protein, enters cells to bind intracellular receptors and generate biologic responses. The free fraction is also the active one in feedback regulation, so it is the concentration of free hormone that is altered in homeostatic responses. The free fraction is very small compared with the bound fraction, but total hormone concentrations from both fractions are measured in most clinical assays. Conditions such as pregnancy, which alter binding protein concentrations, alter total measured hormone but not the biologically relevant free hormone concentration. In special clinical situations, measurement of binding protein concentration and of free hormone may be required for accurate assessment. Steroid hormones are metabolized principally in the liver to inactive water-soluble metabolites. Cortisol is inactivated by reduction of the double bond in the A ring and conjugation to glucuronide or sulfate at carbon 3 to make it water soluble for renal excretion. Androstenedione produced in the ovary and the adrenal gland can be converted to testosterone in peripheral tissues. Significant 1186 quantities of estradiol are produced by conversion of circulating precursors. Like their hormonal ligands, receptor synthesis is highly regulated to control cellular responses and sensitivity to hormones. Receptor synthesis is increased in response to environmental or developmental need or is repressed in negative feedback loops and during stages of development. Receptor concentration is as important as hormone concentration in determining cell responses. Regulation of receptor synthesis is therefore central to providing coordinated and appropriate endocrine responses. Multiple hormones cooperate to coordinate development, reproduction, and homeostasis. When a hormone has elicited an appropriate response, the signal must be terminated. In addition to the buffering that occurs in target cells, feedback control is the principal mechanism through which this occurs. Feedback loops are especially important for communication between organs that are spatially separated. The hormonal products of peripheral endocrine glands such as thyroid, adrenal cortex, ovary, and testis exert negative feedback control over the synthesis and secretion of the stimulatory pituitary hormone. Feedback, which occurs at the level of the pituitary cell and in the hypothalamus, operates by control of several essential steps. Feedback principles provide an exquisitely sensitive system for making appropriate changes and then returning to the homeostatic set point. Feedback operates not only through steroid and thyroid hormones but also through peptides and ions. Physiologic responses result from many different cell types and organs acting in concert. The necessary coordination is provided both by a hormone acting at multiple sites and by each hormone eliciting multiple responses, which sum to give the overall effect.
Although a number of epidemiologic studies suggested a link between higher dietary fiber intake and colorectal cancer arrhythmia untreated buy generic bisoprolol on line, a recent large study found no association blood pressure chart and pulse purchase online bisoprolol. Overcoming sedentary or inactive lifestyles benefits the cardiovascular blood pressure chart dr oz order 5 mg bisoprolol overnight delivery, respiratory heart attack vol 1 pt 3 discount bisoprolol online american express, muscular, cognitive, and metabolic systems. Increased physical activity seems to offer significant protection against colon cancer. Physical activity differences may be influential in cross-national and cross-cultural studies and should be carefully monitored in chemoprevention studies. Tobacco smoke is the most prevalent chemical carcinogen, probably followed by charbroiled meat and fish. Ultraviolet radiation is the primary cause of skin cancer, including melanoma and lip cancer. Ionizing radiation (including radiotherapy) increases rates at essentially all exposed sites (see Chapter 19). The Environmental Protection Agency estimates that as many as 21,000 cases of lung cancer (see Chapter 85) per year may be attributed to alpha-particle-emitting radon gas in homes, for which simple testing and venting procedures are available to reduce exposure and risk. Non-ionizing radiation and electromagnetic fields, although previously suspected of increasing leukemia (of any type) and brain cancer, seem not to raise risks based on current data in aggregate. Environmental control of parasites, antibiotic treatment of Helicobacter, interferon treatment of hepatitis, and/or vaccines to protect against exposure to the viruses and Helicobacter should be effective cancer prevention strategies. For example, population-wide neonatal immunization against hepatitis B virus is expected to eliminate the scourge of primary liver cancer in Taiwan. Many candidate agents are natural products, food constituents, or pharmaceuticals already approved for other indications. Various agents block activation of procarcinogens, enhance detoxification of carcinogens, block the carcinogenic action, or make the cells less responsive to carcinogenic effects. Carotenoids and retinoids have been prime candidates based on observational epidemiologic work and animal and cell culture findings suggesting protective effects through antioxidant, tumor suppressor, or immunomodulatory actions. For example, calcium supplementation, aspirin, and other non-steroidal anti-inflammatory agents can reduce colonic cell proliferation in humans; selective inhibitors of cyclooxygenase 2 are particularly promising for preventing colon cancer. The largest studies of the past 15 years involved beta-carotene alone (22,000 male physicians), beta-carotene plus vitamin E (29,000 male smokers in Finland), beta-carotene plus vitamin A (14,000 male and female U. The Alpha-Tocopherol/Beta-Carotene study in Finland found no benefit from vitamin E or from beta-carotene; instead, the men receiving beta-carotene, 20 mg/day, had an 18% higher rate of 1035 lung cancer and 8% higher overall mortality. These adverse effects of beta-carotene have also stimulated a search for other chemopreventive constituents of fruit and vegetables, of which the many candidates include folic acid and calcium D-glucarate. In the United States, cancer of hormone-responsive tissues accounts for 20% of the newly diagnosed cancers in men and more than 40% in women. Although the early sequential oral contraceptives increased endometrial cancer risk, modern estrogen-progesterone combinations are potent chemopreventive agents. Women with 6 or more years of oral contraceptive use have less than one sixth the risk of endometrial cancer when compared with never-users, and the effect lasts at least 15 years after discontinuation of the oral contraceptives. Combination oral contraceptives also suppress gonadotropin levels and ovulation, thereby decreasing the risk for epithelial ovarian cancer by about 40%, independent of parity. The breast responds differently: progesterone increases the rate of cell division beyond that induced by estrogen, so there is a potential increase in breast cancer. Antiestrogenic agents such as tamoxifen reduce the incidence of new primary cancers in the other breast of breast cancer survivors. In a subsequent double-blind, randomized, multiple-end point trial in 13,000 women, tamoxifen halved the rates of invasive and non-invasive breast cancer and fractures, so the trial was halted after 5 years, 2 years ahead of schedule; however, endometrial cancer rates and venous/pulmonary thromboses were significantly increased among those receiving tamoxifen. Among candidate agents, the 2-arylbenzothiophene raloxifene is a target-site selective estrogen receptor modulator that has estrogen agonist effects on bone and serum lipids but estrogen antagonist effects on the breast and uterus. Preliminary findings from randomized double-blind trials in 12,000 postmenopausal women with osteoporosis to reduce the risk of fractures within the first 2 years indicate that raloxifene reduces the incidence of breast and endometrial cancer, with the difference in breast tumors being due to fewer that are positive for estrogen or progesterone receptors. Finasteride, a testosterone 5alpha-reductase inhibitor, is being tested in 18,000 men for primary prevention of prostate cancer. Molecular studies of cancer have revealed numerous oncogenes, tumor suppressor genes, and other genes affecting cell division, cell cycle, and cell proliferation (see Chapter 191). The host of potential molecular targets for cancer prevention include those identified in inherited cancer syndromes, such as retinoblastoma and polyposis coli, and those identified in molecular analyses of sporadic cancers. A study of nearly 90,000 women showing no association of dietary fiber with colorectal cancer.
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