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Besides mechanically obstructing blood flow erectile dysfunction causes in young men cheap malegra dxt plus online american express, atherosclerotic plaques can rupture leading to catastrophic obstructive vascular thrombosis impotence in men over 50 safe 160 mg malegra dxt plus. Atherosclerotic plaques can also increase the diffusion distance from the lumen to the media erectile dysfunction causes in early 20s buy cheapest malegra dxt plus and malegra dxt plus, leading to ischemic injury and weakening of the vessel wall impotence specialists cheap malegra dxt plus 160 mg overnight delivery, changes that can result in aneurysm formation. The well-established familial predisposition to atherosclerosis and ischemic heart disease is usually polygenic, relating to small effects of many shared alleles common to a family or population. The development of atherosclerotic plaque is a progressive process that usually becomes clinically manifest in middle age or later (see later). Thus between ages 40 and 60, the incidence of myocardial infarction increases fivefold. Death rates from ischemic heart disease rise with each decade even into advanced age. Increasingly, however, this age association is being recognized as perhaps more than just the accumulated slings and arrows of vascular injury over the years. Indeed, with aging, there is a tendency for the outgrowth of hematopoietic clones (so-called clonal hematopoiesis of indeterminate potential [CHIP]) carrying mutations that confer a proliferative advantage. Perhaps more remarkable, however, is that such clonal hematopoiesis is even more Table 11. Although atherosclerosis-associated ischemic heart disease is ubiquitous among most developed nations, risk reduction and improved therapies have combined to moderate the associated mortality. At the same time, reduced mortality from infectious diseases and the adoption of Western lifestyles has led to the increased prevalence of ischemic heart disease in low income nations. As a result, the death rate for coronary artery disease in Africa, India, and Southeast Asia now exceeds that in the United States; eastern European countries have rates 3 to 5 times higher than the United States and 7 to 12 times higher than Japan. Risk Factors the prevalence and severity of atherosclerosis and ischemic heart disease among individuals and groups are related to a number of risk factors identified through several prospective analyses. These risk factors typically have greater than additive effects, but treatment (even less than optimal) can mitigate some of the risk. Nonmodifiable (Constitutional) Genetic abnormalities Family history Increasing age Male gender Modifiable Hyperlipidemia Hypertension Cigarette smoking Diabetes Inflammation Atherosclerosis 495 60 50 Estimated 10 yr rate (%) 40 30 20 10 5. BP, Blood pressure; ECG, electrocardiogram; HDL-C, high-density lipoprotein cholesterol; LVH, left ventricular hypertrophy. In women (B) and men (C), one or more risk factors of blood pressure, cholesterol, diabetes, and cigarettes significantly increases the lifetime risk of a cardiovascular event. An explanation is beginning to emerge that the same CHIP mutations that affect cellular proliferation. Premenopausal women are relatively protected against atherosclerosis and its consequences compared with age-matched men. Thus myocardial infarction and other complications of atherosclerosis are uncommon in premenopausal women unless they are otherwise predisposed by diabetes, hyperlipidemia, or severe hypertension. After menopause, however, the incidence of atherosclerosis-related diseases increases and at older ages exceeds that of men. Although a favorable influence of estrogen has been proposed to explain this effect, clinical trials of estrogen replacement did not show any benefit; indeed, postmenopausal estrogen therapy actually increased cardiovascular risk in some older women. Modifiable Major Risk Factors Hyperlipidemia-and more specifically hypercholesterolemia- is a major risk factor for atherosclerosis; even in the absence of other risk factors, hypercholesterolemia is sufficient to initiate lesion development. The major component of serum cholesterol associated with increased risk is LDL cholesterol 496 C H A P T E R 11 Blood Vessels ("bad cholesterol"). LDL is the lipid-cholesterol-protein complex that delivers cholesterol to peripheral tissues; in contrast, high-density lipoprotein (HDL) is the complex that mobilizes cholesterol from the periphery (including atheromas) and transports it to the liver for catabolism and biliary excretion. Understandably, dietary and pharmacologic interventions that lower LDL or total serum cholesterol are of considerable interest. Although previously considered important, the contribution of most dietary fats to atherosclerosis is now viewed as minimal. Nevertheless, omega-3 fatty acids (abundant in fish oils) are considered beneficial, whereas trans unsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) can adversely affect cholesterol profiles. Statins are a class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis (Chapter 5). Statins are widely used to lower serum cholesterol levels, lowering rates of myocardial infarctions, arguably one of the most significant success stories of translational research. Interestingly, some of the benefit of the statins may be due to "off-target" effects on reducing inflammation (see also later). Chronic hypertension is the most common cause of left ventricular hypertrophy, and hence the latter is also a surrogate marker for cardiovascular risk. Other factors being equal, the incidence of myocardial infarction is twice as high in diabetics relative to normoglycemic individuals. There is also an increased risk of strokes and a 100-fold increased risk of atherosclerosisinduced gangrene of the lower extremities. The x-axis is the 10-year risk of a cardiovascular event derived from the traditional risk factors identified in the Framingham study. Indeed, more than 75% of cardiovascular events in previously healthy women occur with LDL cholesterol levels below 160 mg/dL (levels generally considered to connote low risk). Inflammation is present during all stages of atherogenesis and is intimately linked with atherosclerotic plaque formation and rupture (see later). With the increasing recognition that inflammation plays a significant causal role in ischemic heart disease, assessment of systemic inflammation has become important in overall risk stratification. A number of circulating markers of inflammation correlate with ischemic heart disease, and C-reactive protein (CRP) has emerged as one of the most stable and simplest to measure. Although CRP does not appear to be causally related to the development of atherosclerosis or its sequelae, it is well established that plasma CRP is a strong, independent marker of risk for myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death, even among apparently healthy individuals. Interestingly, CRP levels are also typically lowered in concert with other risk reduction measures including smoking cessation, weight loss, exercise, and statin administration. Serum homocysteine levels correlate with coronary atherosclerosis, peripheral vascular disease, stroke, and venous thrombosis.
IgA antibodies erectile dysfunction vasectomy best buy malegra dxt plus, produced in mucosal lymphoid tissues such as Peyer patches and secreted into the gut lumen (Chapter 17) erectile dysfunction doctors in sri lanka order 160mg malegra dxt plus overnight delivery, can neutralize potential pathogens erectile dysfunction alcohol purchase malegra dxt plus 160 mg on-line. Finally treatment for erectile dysfunction before viagra generic malegra dxt plus 160mg fast delivery, the normal gut microbiota competitively inhibits colonization and overgrowth by potential pathogens, such as Clostridioides difficile. Norovirus (the scourge of the cruise ship industry) is a nonenveloped virus that is resistant to inactivation by acid, bile, and pancreatic enzymes and hence easily spreads in places where people are crowded together. Intestinal protozoa and helminths transmitted as cysts or eggs, respectively, have acid-resistant outer coats. Pathogens may establish symptomatic gastrointestinal disease through several distinct mechanisms: Toxin production. Some organisms contaminating food can produce gastrointestinal disease without necessarily establishing an infection in the host. An example is Staphylococcus aureus, which elaborates a powerful exotoxin during its growth in contaminated food that is responsible for acute food poisoning. These organisms elaborate potent exotoxins that are responsible for symptomatic disease. Candida albicans invades superficially into oral and esophageal squamous mucosa in immunocompromised patients to cause thrush. The damage to respiratory mucociliary clearance by influenza, mechanical ventilation, smoking or cystic fibrosis sets the stage for superinfection by bacteria. Many other infectious agents cause respiratory infections primarily in the setting of systemic immunodeficiency. Examples include fungal infections by Pneumocystis jirovecii in acquired immunodeficiency syndrome (AIDS) patients and by Aspergillus spp. The urinary tract is protected from infection by regular emptying during micturition. Women have more than 10 times as many urinary tract infections as men because the length of the urethra is 5 cm in women versus 20 cm in men, making women more susceptible to entry of bacteria from the rectum. Predictably, obstruction of urinary flow or reflux of urine is a major factor in susceptibility to urinary tract infections. From puberty until menopause the vagina is protected from pathogens by lactobacilli, which ferment glucose to lactic acid, producing a low pH environment that suppresses the growth of pathogens. Antibiotics can kill the lactobacilli and allow overgrowth of yeast, causing vaginal candidiasis. Vertical Transmission Vertical transmission of infectious agents from mother to fetus or newborn child is a common mode of transmission of certain pathogens and may occur through several different routes. Some resulting infections interfere with fetal development, and the degree and type of damage depend on the age of the fetus at the time of infection. Rubella virus infection during the first trimester can lead to heart malformations, intellectual disability, cataracts, or deafness, but rubella virus infection during the third trimester has little effect. Respiratory Tract A plethora of microorganisms, including viruses, bacteria, and fungi, are inhaled daily, mainly in dust or aerosol particles. Microorganisms in large particles are trapped in the mucociliary blanket that lines the nose and the upper respiratory tract and transported by ciliary action to the back of the throat, where they are swallowed and cleared. Particles smaller than 5 microns are carried into the alveoli, where they are phagocytosed by leukocytes. The microorganisms that infect the healthy respiratory tract evade local defenses through several different mechanisms. Some respiratory viruses attach to and enter epithelial cells in the lower respiratory tract and pharynx. For example, influenza viruses have envelope proteins called hemagglutinins that bind to sialic acid on the surface of epithelial cells. Attachment induces the host cell to endocytose the virus, leading to viral entry and replication. Certain bacterial respiratory pathogens, including Mycoplasma pneumoniae and Bordetella pertussis, release toxins that enhance their ability to establish an infection by impairing ciliary activity. Another important mechanism of establishing respiratory infection is resistance to killing following phagocytosis. Mycobacterium tuberculosis gains a foothold Spread and Dissemination of Microbes Within the Body Although some disease-causing microorganisms remain localized to the initial site of infection, others have the capacity to invade tissues and spread to distant sites via the lymphatics, the blood, or the nerves. Some pathogens secrete enzymes that break down tissues, allowing the organisms to spread contiguously in tissue. Release may be accomplished by skin shedding, coughing, sneezing, voiding of urine or feces, during sexual contact, or through insect vectors. Some pathogens are released for only brief periods of time or periodically during disease flares, but others may be shed for long periods by asymptomatic carrier hosts. Fragile pathogens persist outside of the body for only short periods of time and must be passed quickly from person to person, often by direct contact. Most pathogens are transmitted from person to person by respiratory, fecal-oral, or sexual routes. Some respiratory pathogens, including influenza viruses, are spread in large droplets that travel no more than 3 feet from the source, but others, including M. Water-borne pathogens involved in epidemic outbreaks that are spread in this fashion include hepatitis A and E viruses (HAV and HEV), poliovirus, rotavirus, V. Saliva is responsible for transmitting viruses that replicate in the salivary glands or the oropharynx, including Epstein-Barr virus (EBV).
PAF (Chapter 3) is a lipid mediator produced by some mast cell populations that is not derived from arachidonic acid erectile dysfunction symptoms treatment discount malegra dxt plus 160mg on-line. It causes platelet aggregation jack3d impotence order malegra dxt plus 160mg with amex, histamine release erectile dysfunction injection purchase malegra dxt plus 160mg, bronchospasm erectile dysfunction pump amazon buy 160mg malegra dxt plus visa, increased vascular permeability, and vasodilation. On activation, mast cells release various classes of mediators that are responsible for the immediate and late-phase reactions. Mediators contained within mast cell granules are the first to be released and can be divided into three categories: Vasoactive amines. Histamine causes intense smooth muscle contraction, increases vascular permeability, and stimulates mucus secretion by nasal, bronchial, and gastric glands. These are contained in the granule matrix and include neutral proteases (chymase, tryptase) and several acid hydrolases. The enzymes cause tissue damage and lead to the generation of kinins and activated components of complement. Mast cell activation is associated with activation of phospholipase A2, an enzyme that converts membrane phospholipids to arachidonic acid. Mast cells are sources of many cytokines, which may play an important role at several stages of immediate hypersensitivity reactions. The cytokines include: TNF, IL-1, and chemokines, which promote leukocyte recruitment (typical of the late-phase reaction); IL-4, which amplifies the Th2 response; and numerous others. The mediators produced by mast cells are responsible for most of the manifestations of immediate hypersensitivity reactions. Some, such as histamine and leukotrienes, are released rapidly from sensitized mast cells and trigger the intense immediate reactions characterized by edema, mucus secretion, and smooth muscle spasm; others, exemplified by cytokines, including chemokines, set the stage for the late-phase response by recruiting additional leukocytes. Not only do these inflammatory cells release additional waves of mediators (including cytokines), but they also cause epithelial cell damage. Epithelial cells themselves are not passive bystanders in this reaction; they can also produce soluble mediators, such as chemokines. Late-Phase Reaction In the late-phase reaction, leukocytes are recruited that amplify and sustain the inflammatory response without additional exposure to the triggering antigen. Eosinophils are often an abundant leukocyte population in these reactions. They are recruited to sites of immediate hypersensitivity by chemokines, such as eotaxin, and others that may be produced by epithelial cells, Th2 cells, and mast cells. Upon activation, eosinophils liberate proteolytic enzymes as well as two unique proteins called major basic protein and eosinophil cationic protein, which damage tissues. Eosniophils contain crystals called Charcot-Leyden crystals composed of the protein galectin-10, which are sometimes released into the extracellular space and can be detected in the sputum of patients with asthma. These crystals promote inflammation and enhance Th2 responses, so they may contribute to allergic reactions. It is now believed that the late-phase reaction is a major cause of symptoms in some type I hypersensitivity disorders, such as allergic asthma. Clinical Syndrome Anaphylaxis (may be caused by drugs, bee sting, food) Bronchial asthma Clinical and Pathologic Manifestations Fall in blood pressure (shock) caused by vascular dilation; airway obstruction due to laryngeal edema Airway obstruction caused by bronchial smooth muscle hyperactivity; inflammation and tissue injury caused by late-phase reaction Increased mucus secretion; inflammation of upper airways, sinuses Increased peristalsis due to contraction of intestinal muscles Development of Allergies Susceptibility to immediate hypersensitivity reactions is genetically determined. The basis of familial predisposition is not clear, but studies in patients with asthma reveal linkage to polymorphisms in several genes encoding cytokines with important roles in allergic reaction, including the genes for the cytokines IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF. How the diseaseassociated polymorphisms influence the development of allergies is not known. Linkage has also been noted to polymorphisms lying within the HLA genes located on chromosome 6, suggesting that the inheritance of certain HLA alleles permits reactivity to certain allergens. Exposure to environmental pollutants, which is common in industrialized societies, is an important predisposing factor for allergy. For example, dogs and cats diverged from humans about 95 million years ago and are genetically distant from humans compared with chimpanzees, which diverged only about 4 to 5 million years ago and are >95% identical to humans genetically; yet dogs and cats, who live in the same environment as humans, develop allergies, and chimps do not. This observation suggests that environmental factors may be more important in the development of allergic disease than genetics. Viral infections of the airways are triggers for bronchial asthma, an allergic disease affecting the lungs (Chapter 15). It is estimated that 20% to 30% of immediate hypersensitivity reactions are triggered by non-antigenic stimuli such as temperature extremes and exercise, and do not involve Th2 cells or IgE; such reactions are sometimes called nonatopic allergy. It is believed that in these cases mast cells are abnormally sensitive to activation by various nonimmune stimuli. The incidence of many allergic diseases has increased in high income countries, as populations have urbanized and exposure to the natural environment has diminished. These observations have led to an idea, sometimes called the hygiene hypothesis, that early childhood and even prenatal exposure to microbial antigens "educates" the immune system in such a way that subsequent pathologic responses against common environmental allergens are prevented. Thus, paradoxically, improved hygiene in early childhood may increase allergies later in life. This hypothesis, however, is difficult to prove, and the underlying mechanisms are not defined. With this consideration of the basic mechanisms of type I hypersensitivity, we turn to some clinically important examples of IgE-mediated disease. These reactions can lead to a wide spectrum of injury and clinical manifestations (Table 6. Allergic rhinitis, sinusitis (hay fever) Food allergies occur in sensitized individuals in hospital settings after administration of foreign proteins.
Syndromes
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Chemicals may be excreted in urine or feces; eliminated in expired air; or accumulate in bone erectile dysfunction hormonal causes purchase discount malegra dxt plus, fat impotence cure discount malegra dxt plus 160mg amex, brain erectile dysfunction and injections purchase discount malegra dxt plus online, or other tissues impotence quotes the sun also rises buy malegra dxt plus 160mg fast delivery. Chemicals may act at the site of entry or at other sites following transport through the blood. Most solvents and drugs are lipophilic, which facilitates their transport in the blood by lipoproteins and their penetration through the plasma membrane into cells. Most solvents, drugs, and xenobiotics are metabolized to form inactive water-soluble products (detoxification) or are activated to form toxic metabolites. More broadly, it also includes the study of the effects of physical agents such as radiation and heat. Of the approximately 100,000 chemicals in commercial use in the United States, only a small proportion has been tested experimentally for health effects. Several agencies in the United States set permissible levels of exposure to known environmental hazards. Factors such as the complex interaction between various pollutants and the age, genetic predisposition, and different tissue sensitivities of exposed persons create wide variations in individual sensitivity to toxic agents, limiting the value of establishing "safe levels" for entire populations. Nevertheless, such cutoffs are useful for comparative studies of the effects of agents between specific populations and for estimating risk of disease in heavily exposed individuals. We now consider some basic principles relevant to the effects of toxic chemicals and drugs. The quote from Paracelsus in the 16th century that "all substances are poisons; the right dosage differentiates a poison from a remedy" is still valid today, given the number of pharmaceutical drugs with potentially harmful effects. Pollutants in the air, water, and soil are absorbed through the lungs, gastrointestinal (GI) tract, and skin. In the body they may act at the site of absorption, but are generally transported through the bloodstream to various organs where they may be stored or metabolized. Xenobiotics may be metabolized to watersoluble compounds that are excreted or to toxic metabolites, a process referred to as activation. Products of phase I reactions are often metabolized into water-soluble compounds through phase II reactions, which include glucuronidation, sulfation, methylation, and conjugation with glutathione (GSH). Cytochrome P-450 enzymes (CYPs) are a large family of heme-containing enzymes, each with preferred substrate specificities. These enzymes are primarily expressed in hepatocytes, in which they localize to the endoplasmic reticulum, but can also be found in skin, lungs, gastrointestinal mucosa, and other organs. The P-450 system catalyzes reactions that either detoxify xenobiotics or, less commonly, convert xenobiotics into active compounds that cause cellular injury. Both types of reactions may produce, as a by-product, reactive oxygen species (ROS), which can cause cellular damage (Chapter 2). Examples of metabolic activation of chemicals through CYPs are the production of the toxic trichloromethyl free radical from carbon tetrachloride in the liver and the generation of a DNAbinding metabolite from benzo[a]pyrene, a carcinogen present in cigarette smoke, in the lung. CYPs participate in the metabolism of alcohol (discussed later) and a large number of common therapeutic drugs, such as acetaminophen, barbiturates, warfarin, and anticonvulsants. The variation may be a consequence of genetic polymorphisms in specific CYPs, but more commonly it is due to exposure to drugs or chemicals that induce or diminish CYP activity. Known CYP inducers include environmental chemicals, drugs, smoking, alcohol, and hormones. Inducers of CYP act by binding to specific nuclear receptors, which then heterodimerize with the retinoic X receptor (RXR) to form a transcriptional activation complex that associates with promoter elements located in the 5-flanking region of CYP genes. Nuclear receptors participating in CYP induction include the aryl hydrocarbon receptor, the peroxisome proliferator-activated receptors (PPARs), and two orphan nuclear receptors, constitutive androstane receptor (CAR) and pregnane X receptor (PXR). This brief overview of the general mechanisms of toxicity provides the background for the discussion of environmental diseases presented in this chapter. Airborne microorganisms have long been major causes of morbidity and mortality, especially in low income countries. More widespread are airborne chemical and particulate pollutants, especially in high income nations. Outdoor Air Pollution the ambient air in industrialized nations is contaminated with an unsavory mixture of gaseous and particulate pollutants, more heavily in cities and in proximity to heavy industry. In the United States, the Environmental Protection Agency monitors and sets allowable upper limits for six Environmental pollution pollutants: sulfur dioxide, CO, ozone, nitrogen dioxide, lead, and particulate matter. It may seem that air pollution is a modern phenomenon, but this is hardly the case. John Evelyn wrote in 1661 that inhabitants of London suffered from "Catharrs, Phthisicks and Consumptions" (bronchitis, pneumonia, and tuberculosis) and breathed "nothing but an impure and thick mist, accompanied by a fuliginous and filthy vapour, which renders them obnoxious to a thousand inconveniences, corrupting the lungs, and disordering the entire habit of their bodies. Although the lungs bear the brunt of the adverse consequences, air pollutants can affect many organ systems. Except for some comments on smoking, pollutant-caused lung diseases are discussed in Chapter 15. Ozone (O3) is produced by interaction of ultraviolet (UV) radiation and oxygen (O2) in the stratosphere and naturally Table 9. This layer protects life on earth by absorbing the most dangerous UV radiation emitted by the sun. In 1985, it was discovered that ozone was nearly completely depleted over Antarctica and was thinned elsewhere, a dire effect stemming from the widespread use of chlorofluorocarbon gases in air conditioners and refrigerators and as aerosol propellants. When released into the atmosphere, these gases drift up into the stratosphere and participate in chemical reactions that destroy ozone. Due to prevailing stratospheric air currents, the resulting depletion is most profound in polar regions, particularly over Antarctica during the winter months. Recognition of the problem led in 1987 to the Montreal Protocol, international agreements that call for a complete phase-out of chlorofluorocarbon use by 2020 in higher income countries and by 2040 in lower income countries.
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