Telly A. Meadows, MD

• Cardiology Fellow
• Department of Cardiovascular Medicine
• Cleveland Clinic Foundation
• Cleveland, Ohio

The balance between platelet thromboxane A hiv infection by saliva order discount famvir on-line, and endothelial prostacyclin can be shifted by the administration of low doses of aspirin hiv infection rates wiki famvir 250 mg discount. Thromboxane Az and prostacyclin are both produced from arachidonic acid by the cyclooxygenase pathway hiv infection new york generic famvir 250 mg amex. However hiv infection rate in uganda quality famvir 250 mg, endothelial cells make more cyclooxygenase within a few hours antivirus windows order famvir with amex, whereas circulating platelets do not hiv infection through blood transfusion order generic famvir, and new platelet cyclom:ygenase appears only as new platelets enter the circulation over a period of days. Therefore, the chronic administration of small doses of aspirin reduces intravascular clotting for prolonged periods and is of value in preventing myocardial infarctions, unstable angina, transient ischemic attacks, and stroke. Nitric Oxide the production ofa potent vasodilator by endothelial cells was:first suspected when it was noted that removal of the endothelium from rings of arterial tissue converted the normal dilator response to acetylcholine into a constrictor response. One factor is the myogenic response to stretch of the smooth muscle in arterioles; as pressure inside a vessel rises, its smooth muscle is stretched, and its response is to contract. Another factor may be the accumulation of vasodilator metabolites; when flow to a tissue is reduced, the metabolites are not washed away. Substances Secreted by the Endothelium the blood vessels are lined by a continuous layer ofendothelial cells, and these cells play a vital role in the regulation of vascular function. They respond to flow changes (shear stress), stretch, a variety of circulating substances, and inflammatory mediators. In response to these stimuli, they secrete growth regulators and vasoactive substances. The growth factors regulate vascular development and are important in a number of diseases. All are polypeptides related to the sarafotoxins, polypeptides found in snake venoms. All are cleaved from larger prohonnones (big endothelins) by endothelin-converting enzymes. Two G protein-coupled receptors-A and B-that mediate endothelin effects have been identified. The decapeptide lysyl-bradykinin can be converted to the nonapeptide bradykinin by aminopeptidase. These kinin precursor proteins are products of a single gene produced by alternative splicing. The proteases responsible for the cleavage ofkininogens are the kallikreim, a family of enzymes encoded in humans by three genes situated on chromosome 19. Lysyl-bradykinin and bradykinin are primarily tissue hormones produced, for example, by the kidneys and actively secreting glands, but small amounts are also found in the circulating blood. Kinins increase blood flow to actively secreting glands by producing vasodilation, and. This leads to the urinary excretion of sodium and water, a reduction of intravascular volume, and a decreased stretch of the atrial myocytes. As all three natriuretic peptides have cardio- and reno-protective properties, their therapeutic potential in chronic heart failure treatment is currently under study. There is substantial evidence that this hormone is actually ouabain and that it is secreted by the adrenal glands in response to increased dietary sodiwn intake. Neural Control Via the Sympathetic Vasomotor System Table 11-1 summarizes the factors affecting the caliber of the arterioles in the body, and hence peripheral resistance and tissue blood flow. It also includes the control of blood pressure by noradrenergic and, in some instances, cholinergic sympathetic vasomotor nerves to the arterioles. In addition to the extensive nerve supply to these resistance vessels, there is a moderate innervation of the capacitance vessels. Discharge of the noradrenergic vasomotor nerves causes constriction of the arterioles innervated by the nerves, and if the discharge is general rather than local. In addition, the discharge of sympathetic noradrenergic nerves innervating the heart increases blood pressure by increasing the force and rate ofcardiac contraction (inotropic and chronotropic effects), increasing stroke volume and cardiac output Noradrenergic stimulation also inhibits the effect of vagal stimulation, which nonnally slows the heart and decreases cardiac output. McGraw-Hiii, 2016J Neural control Increased discharge of noradrenergic vasomotor nerves Dl. The baroreceptors are stretch-sensitive nerve endings located in the carotid sinuses and aortic arch on the arterial side and in the walls of the great veins and the cardiac atria on the venous side. From the nucleus, second-order neurons pass to the caudal portion of the ventrolateral medulla and environs. From there, third-order inhibitory neurons pass to the rostral ventrolateral medulla, the location of the cell bodies of the neurons that control blood pressure. The axons of these neurons descend into the spinal cord and innervate the cell bodies of the blood pressure-regulating preganglionic sympathetic neurons in the intennediolateral gray column of the spinal cord. The axons of the preganglionic neurons leave the spinal cord and synapse on the postganglionic neurons in the ganglionic chain and collateral ganglia, as well as on the catecholamine-secreting cells in the adrenal medulla. This is brought about by the inhibitory y-aminobutyric acid-secreting neuron link between the caudal portion of the ventrolateral medulla and the rostral ventrolateral medulla. In addition, an increased barore<:eptor discharge stimulates afferents from the nucleus tractus solitarius to the dorsal motor nucleus of the vagus and the nucleus ambiguus. Adrenal medullary seaetion is increased by the discharge of the sympathetic nervous system, although the contributions of circulating catecholamines to the increase in blood pressure are relatively small. Moreover, activation of the lower affinity V1 vasopressin receptor on vascular smooth muscle results in a marked increase in vascular tone. Why does the velocity of blood flow decrease greatly ln the capillaries and then increase in the veins However, it is accelerated by a wide variety of genetic and environmental factors (see later discussion). It is characterized by localized fibrous thickenings of the arterial wall associated with lipid-infiltrated plaques that may eventually calcify. Old plaques are also prone to ulceration and rupture, triggering the formation of thrombi that obstruct flow. It also leads to common severe and life-threatening diseases of the heart and brain because of the formation of intravascular clots at the site of the plaques. In the United States and most other developed countries, it has been calculated that atherosclerosis is the underlying cause of about 50% of all deaths. Almost all patients with myocardial infarction-and most of those with stroke resulting from cerebral thrombosis-have atherosclerosis. The incidence of ischemic heart disease and strokes has been declining in the United States since 1963, but atherosclerosis is still very common. Thus, atherosclerosis underlies and is fundamentally responsible for a large portion of the clinical problems seen by physicians caring for adult patient!. The endothelium is subject to shear 1tre11, the tendency to be pulled along or deformed by flowing blood this is most marked at points where the arteries branch, which is also where the lipids accumulate to the greatest degree. The streaks appear in the aorta in the first decade of life, in the coronary arteries in the second decade, and in the cerebral arteries in the third and fourth decades. Vascular smooth muscle cells in the vicinity of foam cells are stimulated and move from the media to the intima. After vascular Injury, monocytes bind to the endothellum, then cross It to the subendothellal space, and become activated tissue mlaophages. In addition, the "loading" of macrophages with cholesterol can be lipotoxic to the endoplasmic reticulum, resulting in macrophage apoptosis and plaque necrosis. The lesions alone may distort vessels to the point that they are occluded, but it is usually the rupture or ulceration of plaques that triggers thrombosis, blocking blood fiow. Atherosclerotic lesions have been shown to have many of the characteristics of a low-grade infeGtion. A substantial number of studies support an association of various infections, including Chlamydophila ptUumoniae (an organism usually associated with respiratory infection), with the development of atherosclerosis. However, only C pneumoniae (and no other bacteria) has actually been isolated in the atherosclerotic plaque. Clinical trials have been conducted to assess the effects of antibiotics in the secondary prevention of composite cardiovascular events, but results have been disappointing. In the exogenous system, chylomicrons rich in triglycerides of dietary origin are converted to chylomicron remnants rich in cholesteryl esters by the action of lipoprotein lipase. Ifacetykholine is infused via catheter into normal coronary arteries, the vessels dilate; however, if it is infused when atherosclerosis is present, the vessels constrict. It has been speculated that the disrupted signaling via this receptor can be an additional contributing factor in the pathophysiology of atherosclerosis. Monocytes are stimulated to produce these receptors by the action of macrophage colony. Obviously, lipid accumulation in foam cells is a key event in the progression of atherosclerotic lesions, and it is well established that lowering plasma cholesterol slows the progress of atherosclerosis. Dietary cholesterol and triglycerides are packaged in the protein-coated chylomicrons in intestinal epithelial cells. Under the influence of lipoprotein lipase, these particles release triglycerides to fat depots and muscles, and the resulting chylomicron remnants are taken up by the liver. These lipoprotein particles enter the circulation, and, under the influence of lipoprotein lipase, donate triglycerides to tissues. They provide all cells with cholesterol for the production of cell membranes and other uses. They also provide most of the cholesterol that is the precursor for all steroid hormones. In general, however, atherosclerosis is asymptomatic until one ofits complications develops. In coronary arteries, atherosclerotic narrowing that reduces the lumen of a coronary artery more than 75% causes angina pectoris, the chest pain that results when pain-producing substances accumulate in the myocardium. When atherosclerotic lesions cause clotting and occlusion of a coronary artery, the myocardium supplied by the artery dies (myocardial infarction). In the circulation to the legs, vascular insufficiency causes intermittent dandic:ation (fatigue and usually pain on walking that is relieved by rest). Obviously, treating the accelerating conditions that are treatable and avoiding those that are avoidable should reduce the incidence of myocardial infarctions, strokes, and other complications of atherosclerosis. Estrogen increases cholesterol removal by the liver, and the progression of atherosclerosis is less rapid in premenopausal women than in men. In addition, epidemiologic evidence suggests that estrogen replacement therapy may protect the cardiovascular system in postmenopausal women. In addition, in several studies, estrogen treatment of postmenopausal women failed to prevent second heart attaclc. The reason for the discrepancies between the epidemiologic and experimental data is currently unsettled. Increased clrculatlng trlglyterldes produced by diuretics, jHdrenerglc blocking drugs. These increases are associated with accelerated atherosclerosis, and the magnitude of the plasma elevation is positively correlated with the severity of the atherosclerosis. Markedly elevated levels resulting from documented mutations of relevant genes are rare, but mild elevations occur in 7% of the general population. It is metabolized by enzymes dependent on vitamin B6, vitamin B12, and folic acid. Supplementing the diet with these vitamins reduces plasma homocysteine, usually to normal. Determining whether such supplements also reduce the incidence of accelerated atherosclerosis will require prolonged, careful clinical trials, and the results of such studies to date are inconclusive. The desired decrease in lipids can sometimes be achieved with the dietary restriction of cholesterol and saturated and trans fat alone, even though dietary restriction initiates a compensatory increase in cholesterol synthesis in the body. Other molecular biologic approaches to slowing or preventing the development of atherosclerosis are under development. However, the results of antioxidant treatment in humans have generally been disappointing or negative. Men who smoke a pack of cigarettes a day have a 70% increase in death rate from ischemic heart disease compared with nonsmokers, and there is also an increase in women. Lowering blood pressure has its greatest effect in reducing the incidence of stroke, but there are beneficial effects on ischemic heart disease as well. With modern methods of treatment, blood pressure in people with hypertension can generally be reduced to normal or near-normal values, and the decrease in strokes, myocardial infarctions, and renal failure produced by such treatment is clear testimony to the value of reducing or eliminating this risk factor. In people with diabetes, there are both microvascular and macrovascular complications (see Table 18-6). People with diabetes face a twofold increase in the incidence of myocardial infarction compared with those without diabetes; severe circulatory deficiency in the legs with gangrene is relatively common; people with diabetes experience more thrombotic strokes; and renal failure is a serious problem (Chapter 18). While chronic hyperglycemia itself can induce vascular damage, it is becoming more apparent that insulin resistance, such as occurs in type 2 diabetes mellitus, contributes markedly to the development of atherosclerosis. Importantly, however, the rigorous control of blood pressure in people with diabetes is more efficacious in reducing cardiovascular complications than is the rigorous control of blood glucose. Obesity has long been appreciated as an independent risk factor for atherosclerosis. However, the mechanism(s) through which obesity promotes atherosclerosis has remained enigmatic until recently. Despite the overproduction of the satiety-inducing adipose-derived adipokines (eg, leptin and adiponectin) in obese subjects, they exhibit marked resistance to the effects of these adipokines. In addition to the enhanced production of adipokines, perivascular fat also produces pro-inflammatory molecules. Taken together, these findings indicate that perivascular adipose tissue may be a major contributor to obesity-induced atherosclerosis. Nephrotic syndrome and hypothyroidism also accelerate the progression of atherosclerosis and are treatable conditions.

Gutrin is a peptide honnone of 17 or 34 amino acids seaeted from G cells in the gastric antrum during feeding fiebig stages hiv infection purchase famvir american express. Because both acetylcholine and gamin act through similar intracellular pathways hsv-zero antiviral herpes treatment purchase famvir 250mg on-line, the combined effects ofgastrin and acetykb antiviral valacyclovir side effects 250 mg famvir fast delivery. Recent studies indicate that the endocrine cells in the stomach sense luminal nutrient and acid via primary cilia on their apical surfaces hiv infection detection buy famvir 250mg. The combination of histamine and acetylcholine or gastrin can increase the rate of acid production by up to 10-fold over basal levels acute hiv infection stories famvir 250mg lowest price, a much greater effect than simple addition of the effects of the agonists would predict hiv infection rates among youth famvir 250 mg online. Potentiation requires that two different signal molecules bind to receptors that act through different intracellular mechanisms. This hyperpolarizes the cell (more negative inside) to promote Cl- ion secretion across the apical membrane. Excess gastrin aberrantly produced by certain tumors causes the hyperproliferation of gastric glands and parietal cells and an excess secretion of gastric acid the excess acid in the small intestine can lead to ulceration of the mucosa, steatorrhea as a result of the inactivation of pancreatic lipases (which are inhibited by low pH), and diarrhea. Termination of drug treatment then results in an acid production rebound because of the increased content of parietal cells and gastrin-secreting G cells. The importance of histamine to H+ ion secretion is illustrated by studies with histamine H 1 receptor antagonists, such as cimetidine. These drugs not only inhibit histamine-stimulated H+ ion secretion but also block the effects of acetylcholine and gastrin. By preventing such potentiation, these agents can be used to effectively treat the hypersecretion of gastric acid. Somatostatln, a peptide of 14 or 28 amino acids, is an important inhibitor of gastric acid secretion. Somatostatin also inhibits gastrin and histamine secretion, which indirectly inhibits proton secretion. D cells in the gastric antrum have direct contact with the stomach lumen (open endocrine cells), allowing them to sense the lwninal contents. Protons in the antrum stimulate somatostatin secretion, which acts as a paracrine agent to inhibit gastrin secretion from neighboring G cells and to thereby indirectly reduce gastric acid secretion. D cells in the corpus do not have contact with the lumen (closed cells) and thus cannot sense luminal protons. Integrated Regulation of Gastric Acid Secretion the secretion of gastric acid between meals is low. These stimuli activate the dorsal motor nucleus of the vagal nerve in the medulla, resulting in activation/discharge of the vagus nerve and tributary parasympathetic motor nerves. In the corpus, postganglionic nerves release acetylcholine, which directly activates parietal cells by M3 receptors. Acetylcholine also induces histamine release from enterochromaffin cells, which stimulates H+ ion secretion by parietal cells. In the antrum, vagal stimulation induces the release of gastrinreleasing peptide from postganglionic fibers, which stimulates gastrin release and thus indirectly stimulates H+ ion secretion. The gastric phase (-70% of response) of secretion is induced by stimuli within the stomach. Vagal sensory nerves detect gastric distension with food and trigger a vagovagal reflex during which vagal motor nerves release acetylcholine in the stomach to promote acid secretion. Partially digested proteins and amino acids stimulate gastrin release from G cells in the pylorus. G cells, like D cells, are open-type endocrine cells that directly sense the contents of the stomach. Acidification of the pylorus stimulates the release of somatostatin, which inhibits acid secretion by a negative-feedback loop as described. During the intestinal phase, the products of protein digestion, on entering the small intestine, can stimulate gastrin release from G cells in the duodenum. Many substances, most notably fat and acid, stimulate the secretion of hormones from the small intestine that inhibit gastric acid secretion. Helicobacter pylon is a bacterium that lives in the mucous layer of the stomach where the enzyme urease is active, converting urea to col and ammonia. H pylori also secretes proteins, such as CagA and VacA, that modulate immune responses and directly aher mucosa! In most cases, the infection, though chronic, is mild and does not cause symptoms. In some individuals, however, the infection remains confined to the antrum but leads to increased acid secretion and symptomatic inflammation that causes ulceration of the stomach or duodenum. During the gastric phase of digestion, rood in the stomach triggers vagovagal reflexes and stimulates gastTin secretion. Acidification of the gastTic antrum stimulates the release of somatostatin, which inhibits gastrin release and thus acid secretion; vagal acetyk:holine (Ach) inhibits somatostatin release. In some patients, chronic H pylori infection can spread to the corpus and lead to chronic inflammation that triggers the death (atrophy) of parietal cells and altered mucosa! In certain geographical regions (eg, East Asia and parts of Central and South America). Other Gastric Secretions Chief cells in the glands of the gastric corpus secrete pepslno- gen, an inactive pre<:Ursor (zymogen) of the active protease pepsin. Acetylcholine is the main stimulant of pepsinogen secretion, although other factors (eg, gastrin) also stimulate secretion. Once released into the lumen of the stomach, gastric acid and pre-existing pepsin convert pepsinogen to pepsin. It is an endopeptidase that begins the degradation of dietary proteins into peptides. Mudns are high-molecular-weight glycoproteins secreted by mucous cells of gastric glands in the corpus and annum. The peptide backbone of mucins is densely populated with carbohydrate side chains enriched with sulfate groups. Mucins combine with phospholipids, bicarbonate, and water to form the mucous gel layer that adheres to the surface of stomach epithelial cells. Feeding disrupts the migrating myoelectric complex, and now the antrum contracts frequently at a rate of about three contractions per minute. These slow waves of peristaltic contraction originate from spontaneously active interstitial cells of Cajal in the pacemaker zone in the middle of the body of the stomach, and they sweep toward the antrum. When the membrane potential of muscle cells depolarizes to reach threshold, action potentials frre. Gastrin and acetylcholine stimulate contraction by increasing the magnitude and duration of the action potentials. Intrinsic factor is a glycoprotein secreted by parietal cells required for vitamin B12 absorption. Vitamin B12 (cobalamin) is not made in mammalian cells, and the only source is the diet: meat, fish, and dairy products, but not vegetables or fruit. The acidic environment permits the binding of B12 to haptocorrin (R factor), a glycoprotein produced by salivary and gastric glands. The B12-haptocorrin complex enters the duodenum, where pancreatic proteases digest the haptocorrin. Intrinsic factor combines with B12 in the less acidic environment of the small intestine, forming a degradation-resistant complex for transport to the ileum. Specific receptors on epithelial cells lining the ileum bind the vitamin B12-intrinsic factor complex, which is taken into cells by endocytosis. In autoimmune gastritis, parietal cells are destroyed, leading to a loss of intrinsic factor secretion, which can result in vitamin B12 deficiency and pernicious anemia. This anemia is caused by the impaired synthesis of purines and thymine for which vitamin B12 is required. Gastric Emptying Immediately after a meal, the stomach may contain up to 1 L of material, which empties slowly into the small intestine. Regulation of gastric emptying occurs by alterations in the motility of the proximal and distal stomach, pylorus, and duodenum. Gastric emptying is brought about by an increase in tone (intraluminal pressure) in the proximal stomach, an increase in the strength of antral contractions, the opening of the pylorus, and the inhibition of duodenal segmental contractions. The rate of gastric emptying depends on the chemical and physical composition of chyme that enters the duodenum through the stimulation of both neural and hormonal pathways. Solids and liquids empty at different rates: Liquids empty rapidly, and solids empty only after a lag phase. Acid, fat, and hyperosmolar solutions entering the duodenum slow gastric emptying through the stimulation of neuronal and hormonal mechanisms. Sensory neurons in the duodenum, both vagal and spinal, respond to nutrients, H+ ions, and the hyperosmolar content of chyme. Vagal motor nerves decrease antral contractions, contract the pylorus, and decrease proximal gastric motility. Many hormones released by endocrine cells in the small intestine have been implicated in the feedback inhibition of gastric emptying. Secretin, the release of which is stimulated by acid, inhibits antral contractions and stimulates pyloric sphincter contraction to slow emptying. Cholecystokinin, the release of which is stimulated by fat, acts on vagal sensory nerve receptors to produce a vagovagal reflex that decreases gastric emptying. The importance of nervous system control over gastric motility is reflected in the high incidence of dumping syndrome (nausea, bloating, flushing, and explosive diarrhea) that occurs as a consequence of stomach dysmotility in some patients who have undergone surgical procedures such as partial gastrectomy or nonselective vagotomy. Patterns of Gastric Motility In terms of motility, the proximal and distal regions of the stomach are distinct. During each swallow, the stretch of the esophagus induces a vagovagal reflex that causes the gastric corpus to relax in preparation to receive the food, a phenomenon known as receptive relaxation. The antrum of the stomach is highly muscular, and here contractions serve to break food into smaller pieces, thereby facilitating digestion. The pyloric sphincter controls the rate at which the antral contractions propel partially digested food, or chyme, into the duodenum. During fasting, the antrum is relatively quiescent, with occasional forceful contractions occurring every 75-90 min. Describe the cell types found in the mucosa of the gastric corpus and antrum, and indicate the products of each cell type. Name a neurotransmitter, hormone, and paracrine agent that stimulates acid seaetion from parietal cells. Describe the mechanisms of the cephalic, gastric, and intestinal phases of gastric acid secretion. Name two types of drug with distinct mechanisms of action that can be used to treat the hyperseaetlon of gastrTc acid. Describe two processes by which the gastric mucosa Is protected from acid In the lumen. How does the composition of the dlgesta In the lumen of the small Intestine affect the rate of gastric emptying The most prominent disorders of the gallbladder involve gallstone formation (see later discussion). The pyloric sphincter marks the beginning of the duodenum, which is largely retroperitoneal, fi. In the duodenum, gastric contents are mixed with the secretions of the common bile duct and pancreatic duct. Beyond the duodenum, the small intestine is mobile and suspended in the peritoneal cavity by a mesentery. The most striking gross structural features of the small intestine are the numerous v. Eacll villus contains a single terminal branch of the arterial, venous, and lymphatic b:ees. Villi increase the absorptive capacity 5-fold and allow efficient transfer to the circulatory system ofsubstances absorbed from the gut lumen by enteroc:ytes (surface epithelial cells). Many digestive enzymes expressed by intestinal epithelial cells are located at the tips of these microvilli. Each small intestinal crypt contains tetrapotential stem cells at or near the crypt base that produces the four mature epithelial cell types: absorptive enterocyt. Enterocytes, goblet cells, and enteroendocrine cells migrate out of crypts and onto adjacent villi these cells then die by apoptosis at the tips of villi and are extruded into the lumen of the intestine; the average life span of these cells is about 4-6 days. On the other hand, Paneth cells are much longer lived (-60 days), and they migrate to the crypt base where they are in close contact with epithelial stem cells. It is connected to the hepatic biliary system by the cystic duct, which leads to the common bile duct whose opening into the proximal duodenum is controlled by the sphincter of Oddi. The common bile duct and the pancreatic duct usually join just proximal to this sphincter. Biie Secretion Bile, which is produced by the liver, flows down the hepatic duct and into the gallbladder through the cystic duct It is stored there until gallbladder contraction is stimulated to expel the contents of the gallbladder back through the cystic duct into the common bile duct and through the sphincter of Oddi into the duodenum. Stimuli for gallbladder contraction and sphincter ofOddi relaxation necessary for proper bile flow include both hormones and neural inputs. In the adult small intestine, a large and diverse population of commensal microbes inhabits the lumen. Most of these microbes are bacteria, and the major phyla represented are Bacteroides and Firmicutu. The density increases dramatically in the lumen of the intestine (from hundreds per milliliter in the duodenum to trillions per milliliter in the colon). Based on studies in germ-free organisms, it is estimated that these intestinal microbiota increase our ability to extract nutrients from food by as much as 30%.

Because a significant number of platelets normally reside in the spleen xl 3 vr antiviral trusted famvir 250mg, any increase in spleen size or activity (hypenplenism) leads to lower platelet counts stages of hiv infection and treatment cheap famvir 250 mg overnight delivery. Elevations in the platelet count above normal (thromboc:ytoais) are relatively common and are especially apt to occur in recovery from iron deficiency anemia upon iron repletion hiv symptoms two weeks after infection cheap 250mg famvir overnight delivery. Females with the trait have 50% of the normal amount of either factor and tend not to have any bleeding problems; in general symptoms of hiv infection mayo clinic generic 250 mg famvir fast delivery, one needs only half of the normal quantities of most coagulation factors to clot normally antiviral y antibiotico juntos discount famvir 250mg free shipping. This condition is generally a result of overwhelming infection the hiv infection process buy famvir 250mg with visa, specific leukemias or lymphomas, or massive hemorrhage. Often the fibrinolytic system is simultaneously activated, and uncontrolled bleeding may occur throughout the entire circulatory system. Define anemia, and suggest three causes each for mac- rocytic and microcytic anemia. What are some categories of explanations for a white blood cell count that is substantially increased or decreased compared with the normal range Iron Deficiency Anemia Etlology Iron deficiency anemia is the most common form of anemia. Because of recurrent menstrual blood loss, premenopausal women represent the population with the highest incidence of iron deficiency. Blood loss in this case may result from relatively benign disorders, such as peptic ulcer, arteriovenou. Endoscopic investigation to exclude malignancy is mandatory in patients without a known cause ofiron deficiency. There are other less common causes of iron deficiency, but most are related to blood loss: Bleeding disorders and hemoptysis are the chief possibilities. Such malabsorption occurs in patients with celiac disease, He&obacter pylori infection, partial gastrectomy, or gastric bypass surgery. Other mechanisms ofiron deficiency anemia include intravascular hemolysis (paroxysmal nocturnal hemogl. Absorption is increased in the setting of anemia, hypoxia, and systemic iron deficiency. Iron is also recycled from senescent erythrocytes via macrophage phagocytosis and lysis. The export of iron to plasma from these cellular sites is regulated by hepddln, a 25-amino acid peptide produced by the liver. Hepcidin binds to ferroportin, a transmembrane protein, inducing its internalization and lysosomal degradation. Conversely, when iron stores are adequate or elevated, hepcidin production is increased, resulting in the internalization of ferroportin and reduced export ofiron into plasma. In inflammatory states, hepcidin production is increased, leading to the internalization of ferroportln on macrophages and the trapping of recycled iron within macrophage stores. Iron is stored in most body cells as fenitin, a combination of iron and the protein apoferritin. It is also stored as hemosiderin, which is ferritin partly stripped of the apoferritin protein shell. Because of the complex interactions between these molecules, a simple measurement of serum iron rarely retlects body iron stores (see later discussion). Iron is found predominantly in hemoglobin and is also present in myoglobin, the oxygen-storing protein of skeletal muscle. Held stably in the ferrous form by the other atoms in heme, iron reversibly binds oxygen. Hepcldln (middle and right) binds to ferroportln resulting In Its lntemallzatlon and degradatton, thereby decreasing Iron export from Intracellular stores. This directly causes anemia, a decrease in the hemoglobin concentration of the blood. As noted, heme is also the oxygen acceptor in myoglobin; therefore, iron deficiency will also lead to decreased myoglobin production. Other hormones are presumably also stimulated, however, and the resulting "revved-up" marrow usually causes an elevated blood platelet count An elevated white cell count is less common. There is also substantial anisocytosis and poikilocytosis, seen on the peripheral smear, and target "111 may be seen. The target shape occurs because there is a relative excess of red cell membrane compared with the amount ofhemoglobin within the cell, so that the membrane bunches up in the center. A low serum ferritin level is diagnostic of iron deficiency, but even in obvious cases, levels can be normal; ferritin levels rise in acute or chronic inflammation or significant illnesses, which can themselves be the cause of iron (blood) loss. Serum iron levels fall in many illnesses, and levels of its serum carrier, transferrin, fluctuate as well, so neither is a consistent indicator of iron deficiency, nor is their ratio, the transferrin saturation. Nevertheless, serum ferritin is the most sensitive and specific Pathology As iron stores are depleted, the peripheral blood smear pattern evolves. In early iron deficiency, the hemoglobin level of the blood falls, but individual erythrocytes appear normal. TtRs are membrane glycoproteins that facilitate iron transport from plasma transferrin into body cells. Erythroid precursors increase their expression of membrane TtR in the setting of iron deficiency but not anemia ofchronic disease. A high ratio of sTtR to ferritin predicts iron deficiency when ferritin is not diagnostically low. Other than observing a hematologic response to empiric iron supplementation, bone marrow biopsy can confirm a diagnosis of iron deficiency. Iron is normally found in the macrophages of the marrow, where it supplies erythrocyte precursors; intracellular hemosiderin is easily visualized with Prussian blue stain. Decreased oxygen-carrying capacity leads to decreased oxygen delivery to metabolically active tissues, which nonetheless must have oxygen; this leads directly to fatigue. The compensatory mecllanisms of the body lead to additional symptoms and signs of anemia. Some patients appear pale not only be<:ause there is Jess hemoglobin per unit of blood (oxygenated hemoglobin is red and gives color to the skin), but also beause superficial skin blood vessels constrict, diverting blood to more vital structures. This increased cardiac output is appropriate because one way to increase oxygen delivery to the tissues is to increase the number of times each he:moglobin molecule is oxygenated in the lungs every hour. This tachycardia may cause benign cardiac: murmurs due to the increased blood flow. Glossitis, in which the normal tongue papillae are absent, can occur, as can gastric: atrophy with acblorhydria (absence of stomach acid). The achlorhydria may compowid the iron deftdency because iron is best absorbed in an acidic environment, but this complication is quite unusual. Iron-deficient children, mostly in developing regions, perform poorly on tests of cognition compared with iron-replete children. Another unexplained but often observed phenomenon in severe iron deficiency is pica, a craving for nonnutritive substances such as clay or dirt. Many patients have no specific symptoms or findings at all, and their iron deficiency is discovered because of anemia noted on a blood count obtained for another purpose. In addition to the physiologic compensatory mechanisms discussed previously (increased cardiac output. The ability to transfer oxygen from hemoglobin to cells depends partly on a small molecule in erythrocytes called. Other patients who do not present with symptoms directly related to the anemia present instead with symptoms or signs related directly to blood loss. What Is the most common form of anemla and Its most likely cause in a premenopausal woman In what situations might the serum ferritin level be nor- mal or elevated in a patient with iron deficiency What are the physiologic adaptations to slowly developing Iron deficiency anemla7 2. Pernicious Anemia Etiology Pernicious anemia is a megaloblastic anemia in which there is abnormal erythrocyte nuclear maturation. Unlike in many other types of anemia, such as that resulting from iron deficiency, hemoglobin synthesis is normal. Pernicious anemia is the end result of a cascade of events that are autoimmune in origin. The nervous system is also affected, demonstrating that this is a systemic disease. In addition, 90% or more of patients have antibodies in their serum directed against parietal cell membrane proteins. More than half of patients also have antibodies to intrinsic factor itselfor the intrinsic factor-cobalamin complex. Furthermore, patients with pernicious anemia have a higher incidence of other autoimmune diseases, such as Graves disease. Lastly, corticosteroid therapy, used as first-line therapy for many autoimmune disorders, may reverse the pathologic findings in pernicious anemia. Complete vitamin 8 12 deficiency develops slowly, even after total aclllorhydria and loss of intrinsic factor occur. Pernicious anemia accounts for only a small percentage of patients with anemia, however. The gastric parietal cells are initially affected by an autoimmune phenomenon that leads to two discrete effects: loss of gastric acid (adllorhydria) and loss of intrinsic factor. Pernicious anemia interferes with both the initial availability and the absorption of vitamin B12: Stomach acid is required for the release of cobalamin from foodstuffs, and intrinsic factor is a glycoprotein that binds cobalamin and is required for the effective absorption ofcobalamin in the terminal ileum. Lack of cobalamln also leads to abnormal myelln synthesis, probably via a deftdency In methionine production (8). Cobalamin accepts a methyl group from methyltetrahydrofolate, which leads to the formation of two important intracellular compounds. The first is methylcobalamin, which is required for the production of the amino acid methionine from homocysteine. The second is reduced tetrahydrofolate, which is required as the singlecarbon donor in purine synthesis. In cobalamin deficiency, other reduced folates may substitute for tetrahydrofolate (and may explain why pharmacologic doses of folic acid can partially reverse the megaloblastic blood cell changes, but not the neurologic changes, seen in pernicious anemia). However, methyltetrahydrofolate, normally the methyl donor to cobalamin, accumulates. This folate cannot be retained intracellularly because it cannot be polyglutamated; the addition of multiple glutamate residues leads to a charged compound that does not freely diffuse out of the cell. In addition, methionine may serve as a principal donor of methyl groups to these other "substituting" reduced folates; because methionine cannot be produced in cobalamin deficiency, this compounds the problems in purine synthesis. The exact mechanism of the neurologic consequences of pernicious anemia, with demyelination (loss of the myelin sheaths around nerves), is unknown. Defects in the methionine synthase pathway have been suggested but not proven experimentally. In full-blown megaloblastic anemia, however, there are abnormalities in all cell lines. Bone marrow aspiration and biopsy are not necessary in the diagnosis and results from them may be misleading because the marrow pathology can be confused with acute leukemia. J98 byThe McGraw-Hiii megaloblastic changes-nuclei that are too large and immature in cells with mature. These cells are not seen in the peripheral blood because the abnormal erythrocytes generally are destroyed in the marrow (intramed. Megaloblastic changes can be seen in the marrow even in the absence ofobvious changes on the peripheral blood smear. Spinal cord abnormalities consist of demyelination of the posterolateral spinal columns, called mbaarte combined degeneration. Demyelination eventually results in neuronal cell death, which ill also obvious on pathologic examination. Yet there remain high rates of both false positive and false negative test results because only 20% of total measured serum B12 is bound to the cellular delivery protein, transcobalamin; the rest is bound to haptocorrin, which is not available for cells to use. Are changes in the peripheral blood smear necessary for neurologic effects of vitamin 812 deflclency1 Cllnlcal Manifestations the clinical presentation consists of one or more symptoms related to the underlying deficiency. Anemia is the most commonly encountered abnormality and is often very severe; hemoglobin levels of 4 g/dL (less than a third of normal) can be seen. High-output heart failure is relatively common, with tachycardia and signs of left ventricular failure (see Chapter 10). Because oxygen demands are constant (or rise with exercise) and oxygen-carrying capacity is falling, the only way to maintain tissue oxygenation in anemia is to increase cardiac output (ie, the number of tbnes per minute each red cell is fully oxygenated by the lungs). Neurologic symptoms are least likely to improve with cobalamin replacement therapy. As with other neuropathies involving loss of myelin from large peripheral sensory nerves, numbness and tingling (paresthesias) occur frequently and are the most common symptoms. Importantly, but somewhat unexpectedly, neurologic symptoms may occur in the absence of any changes in the peripheral blood smear suggestive of pernicious anemia. Less commonly, vitamin B12 deficiency can manifest: with thrombosis and possibly at unusual sites such as cerebral venous sinuses. The prothrombotic state may be secondary to hyperhomocysteinemia seen in severe vitamin B12 deficiency. Malignant Disorders the most important leukocyte abnormalities are the malignant disorders leukemia and lymphoma. Cyclic Neutropenia Absolute neutropenia, characterized by neutrophil counts less than 1500-2000/. It is of interest because it provides insight into normal neutrophil production and function. It is characterized by a lifetime history of neutrophil counts that decrease to zero or near zero for 3-5 days at a time every 3 weeks and then rebound. There are approximately 100 cases of childhood cyclic neutropenia in the literature.

Testicular causes may be chromosomal (Klinefelter syndrome) or developmental (cryptorchidism) or may result from varicocele hiv infection rates africa purchase discount famvir, trauma examples of antiviral drugs purchase discount famvir online, infection (mumps) hiv yeast infection in mouth buy famvir 250 mg, or drugs and toxins hiv infection lawsuit order famvir overnight. Post-testicular causes include ductal obstruction and scarring hiv infection dendritic cells buy famvir 250 mg with mastercard, retrograde ejaculation hiv infection rate in costa rica order famvir with a mastercard, antibodies to sperm or seminal plasma, developmental abnormalities (penile anatomic defects), androgen insensitivity, poor coital technique, and sexual dysfunction. Despite evaluation, many cases of male infertility are idiopathic in nature, without a currently identifiable cause. Considering the history of sexually transmitted infections and the physical examination findings of epididymal irregularity, the most likely diagnosis is bilateral obstruction to sperm outflow. Predisposing factors for the development of preeclampsia include first pregnancy, multiple previous pregnancies, preexisting diabetes mellitus or hypertension, hydatidiform mole, malnutrition, and a family history of preeclampsia. For unclear (perhaps immune-mediated) reasons, changes that normally occur in the blood vessels ofthe uterine wall early in implantation do not occur in patients with preeclampsiaeclampsia. Endothelial damage alters the balance between vasodilation and vasoconstriction, with increased vasoconstriction of small blood vessels and resultant hypoperfusion and ischemia of downstream tissues and systemic hypertension. The endothelial cell barrier between platelets and the collagen of basement membranes is breached. As a result of these changes, platelet aggregation increases, the clotting cascade is activated, and vasoactive substances are produced, causing capillary leak. These processes all cause further endothelial damage, thus establishing a vicious circle. The risks to the fetus of preeclampsia-eclampsia are the consequence of placental deterioration and insufficiency and include intrauterine growth retardation and hypoxia. Semen analysis should reveal oligospermia (<15 million sperm/mL semen) or, more likely, azoospermia (the absence of sperm). These abnormalities would be expected because the epididymal abnormalities on examination suggest bilateral obstruction to the outflow of sperm. Testing for fructose in the seminal fluid was once performed because fructose is produced in the seminal vesicles, and its absence in the semen implies an obstruction of the ejaculatory ducts. This test is currently used sparingly, with more emphasis placed on low semen volume as a screening test and transrectal ultrasound of the prostate as a confirmatory test. Obstruction of the ejaculatory ducts is strongly suggested by a seminal vesicle anteroposterior diameter of more than 1. Testicular biopsy may also be helpful in distinguishing intrinsic testicular pathology from ductal obstruction. The diagnosis of benign prostatic hyperplasia is suspected based on the history and physical examination. Prostatic enlargement may be focal or diffuse, and the degree of enlargement does not necessarily correlate with the degree of symptoms. Blood urea nitrogen and serum creatinine are measured to exclude renal failure, and urinalysis is performed to rule out infection. In most patients, this is enough to make the diagnosis of benign prostatic hyperplasia. A urodynamic evaluation with uroflowmetry and cystometry may be undertaken to assess the significance of the disorder. These pressure-flow studies can help determine which patients are less likely to benefit from prostatic surgery by providing information on detrusor function. Renal ultrasonography or intravenous urography may be performed on patients with hernaturia or suspected hydronephrosis. Ultrasonography of the prostate with possible biopsy may be necessary to exclude prostate cancer as the cause of symptoms. Although the actual cause of benign prostatic hyperplasia is unclear, several factors have been identified as contributing factors. These are caused by distortion and narrowing of the bladder neck and prostatic urethra, leading to incomplete bladder emptying. Therapy for an acute gouty attack should target the proinflammatory mediators described previously. Because gouty flares are typically self-limited events, treatment is offered to alleviate symptoms and reduce the duration ofthe flare. On the other hand, probenecid (which is a uricosuric agent, inhibiting renal tubular urate resorption), allopurinol and febuxostat (which are xanthine oxidase inhibitors, interfering with the conversion of hypoxanthine and xanthine to uric acid), and pegloticase, (which converts uric acid to allantoin, an inactive and soluble metabolite readily excreted by the kidneys) are typically reserved for the prevention of future attacks. When it manifests itself in the skin, it is also called cutaneous small vessel or leukocytoclastic vasculitis. In this case, the antigen is the penicillin that the person has been taking regularly for a week. The penicillin stimulated an antibody response, leading to antibody production against, and then binding to , the penicillin. The antigen-antibody complexes are soluble and are deposited in the subendothelial space; in this case, in the small vessels of the skin. If the supply of new antigen is cut off (eg, by stopping the medication), the immune complexes are cleared by the immune system, and the process resolves. The same process can also affect the joints and the kidneys, both areas rich in small blood vessels. The specific organ(s) affected depend on the solubility of the specific antigenantibody complex. Gout flares are typically precipitated by a combination of metabolic and physical stressors in the setting of either urate underexcretion, seen in the vast majority of cases, or urate overproduction. The mild renal insufficiency may be associated with a decreased glomerular filtration rate and thus poor urate excretion. Multiple inflammatory pathways are invoked by the negatively charged urate crystals. For example, they activate the classic complement pathway whose cleavage products serve as effective neutrophil chernoattractants. The kinin system is stimulated by crystals as well, contributing to the inflammatory signs seen on examination, such as tenderness and erythema from local vasodilation. Neutrophils are able to simulate their own recruitment by releasing leukotriene B4 in response to urate crystal phagocytosis. The symptoms are highly variable but tend to be stereotyped in a given individual (ie, the prominent clinical features often remain constant over years). Patients may manifest a variety ofhematologic disturbances (including hemolytic anemia, thrombocytopenia, and leukopenia), inflammation of serosal surfaces (including pleuritis, pericarditis, and peritonitis), as well as several neurologic syndromes (eg, seizures, organic brain syndrome). The inflammatory myopathies, polymyositis and dermatomyositis, share several similar pathologic features but possess distinctive ones as well. These include patchy involvement, the presence of inflammatory infiltrates, and areas of muscle damage and regeneration. It has been suggested that the inflammation seen in polymyositis is driven by autoantigens expressed in the muscle environment, given the restricted T-cell repertoire in both circulating and muscle-infiltrating lymphocytes. In dermatomyositis, the pathology looks quite different, although the outcome-profound muscle weakness-is the same. Major involvement of the capillaries has led many experts to suggest that the primary disorder in dermatomyositis is a small-vessel vasculitis, with myositis occurring later as a result of tissue ischemia and repair. These mechanisms include (I) subendothelial deposition of immune complexes, in which antigens are derived from damaged or dying cells; (2) autoantibody binding to extracellular molecules in the target organs (eg, skin, joints, kidneys, blood elements), which activates inflammatory effector functions and induces damage at that site; and (3) the induction of cell death by autoantibodies. Flares reflect immunologic memory, sparked by rechallenge of a primed immune system with antigen. Numerous stimuli such as viral infections, ultraviolet light exposure, and endometrial and breast epithelial involution may induce apoptosis, which resupplies immune-inciting antigens. There are four characteristic criteria for the diagnosis of polymyositis: (1) weakness; (2) elevated laboratory parameters of muscle tissue (eg, creatine phosphokinase or aldolase); (3) an irritable electromyogram upon electrodiagnostic evaluation (producing sharp waves and spontaneous discharges); and (4) an inflammatory infiltrate upon histologic evaluation. In adult patients, the new diagnosis of an inflammatory myopathy frequently heralds the co-occurrence or subsequent development (within 1-5 years) of a malignancy. The veracity of this observation has been confirmed in several populationbased studies that link the diagnoses of dermatomyositis and polymyositis with various types of cancer in cancer registries. A diagnosis of dermatomyositis carries a twofold greater risk of incident malignancy, particularly cancers of the stomach, lung, breast, colon, and ovary. This patient has Sjogren syndrome, which occurs in approximately 1-3% of the adult population. Affected individuals frequently manifest intense dryness of the eyes (xerophthalmia) and mouth (xerostomia), giving rise to the alternative name keratoconjunctivitis sicca. Dryness in the respiratory tract may give rise to hoarseness and recurrent bronchitis. Moreover, when immune activation is severe, patients experience systemic symptoms, including fatigue, arthralgia, myalgia, and low-grade fever. Other potentially affected organ systems include the kidneys, lungs, joints, and liver (resulting in interstitial nephritis, interstitial pneumonitis, nonerosive polyarthritis, and intrahepatic bile duct inflammation, respectively). The pathophysiology of rheumatoid arthritis is centered around the synovial linings of joints. In rheumatoid arthritis, the synovium is markedly thickened and contains inflammatory cells in the interstitium, including T cells, B cells, and macrophages. This inflammatory tissue can invade adjacent bone and cartilage, accounting for the bony erosions and joint destruction. No definite infectious agents have been identified as causal agents in rheumatoid arthritis. Genetic factors have been found, arising from the observation that identical twins have a 15-35% concordance rate of developing rheumatoid arthritis. For many years, the mainstay of treatment for rheumatoid arthritis involved nonspecific immunosuppressant agents. More recently, biologic modifiers of defined pathogenic pathways have been used successfully to treat disease. A third hypothesis is that, when expressed at the cell surface, B27 free heavy chains are recognized by cells bearing killer immunoglobulin-like receptors and trigger an inflammatory response. The cytokine milieu is also an important component of the inflanunation associated with this spondyloarthropathy. Older, established agents used in the treatment of ankylosing spondylitis are anti-inflammatory drugs, including nonsteroidal anti-inflammatory agents, methotrexate, and sulfasalazine. A Abaloparatide,545 AbdDmab, 162 Abdominal ucltes, 456-457 Acne clinical manlfestatiom of, 238 clinical preaent&tion of. Further, long-term stress responses such as anxiety and negative affect increase the risk for cardiovascular events and mortality. Add alcohol abuse to the mix, and an individual might face a reduction in life expectancy of as much as 23 years. Knowledge of the pathophysiological and neurobiological processes involved in these energy imbalances will help nurses better assess and care for their clients, as well as help them develop client education for individual clients and activities aimed at helping individuals and communities prevent the complications that arise from obesity, substance use, and alterations in sleep. Positive and negative attributes and risk for coronary and aortic calcification in healthy women. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Obesity, alcohol and drug use, and sleep dysfunction alone are sufficient to tax physiological systems and affect morbidity and mortality rates. But any combination of these will overwhelm systems, increase mortality, and shorten lifespan. There has been a dramatic increase in the prevalence of obesity in the United States over the last two decades. The total excess cost related to the current prevalence of overweight and obesity among adolescents is estimated to be $254 billion. In addition, these objectives emphasize that efforts to modify diet and weight should address individual behaviors along with the policies and environments that support these behaviors. Those objectives are broadly divided into the following categories: HealthCare and Worksite Settings, Weight Status, Food Insecurity, Food and Nutrient Consumption, and Iron Deficiency. Food and Nutrient Consumption Increase the number of states with nutrition standards for foods and beverages provided to preschool-aged children in child care. Increase the proportion of schools that offer nutritious foods and beverages outside of school meals. Increase the number of states that have state-level policies that incentivize food retail outlets to provide foods that are encouraged by the Dietary Guidelines for Americans. Increase the proportion of Americans who have access to a food retail outlet that sells a variety of foods that are encouraged by the Dietary Guidelines for Americans. Increase the proportion of primary care physicians who regularly measure the body mass index of their patients. Increase the proportion of physician office visits that include counseling or education related to nutrition or weight. Increase the proportion of worksites that offer nutrition or weight management classes or counseling. Healthcare and Worksite Settings Increase the contribution of fruits to the diets of the population aged 2 years and older. Increase the variety and contribution of vegetables to the diets of the population aged 2 years and older. Increase the contribution of whole grains to the diets of the population aged 2 years and older.

Discount famvir online master card. Citing high HIV infection rates UN report urges 'chain of prevention' to shield youth.