Lisa G. Winston MD

• Associate Professor, Department of Medicine, Division of infectious Diseases
• University of California, San Francisco Hospital Epidemiologist, San Francisco General Hospital

https://profiles.ucsf.edu/lisa.winston

Calcitonin secretion is stimulated by an increase in blood levels of calcium (hypercalcemia) hypertension 65 years and older cheap dipyridamole online amex. When the demands of calcium in blood have been satisfied prehypertension quizlet buy 25 mg dipyridamole with amex, calcitonin binds to its receptor on the osteoclast surface and the ruffled border disappears arteria epigastrica superficialis discount 25mg dipyridamole amex. Low Ca2+ in serum stimulates 1 -hydroxylase to produce 1 pulse pressure 20 order generic dipyridamole canada,25-hydroxycholecalciferol (biologically active calcitriol) blood pressure chart doc order cheap dipyridamole. High Ca2+ in serum stimulates 24-hydroxylase to produce biologically inactive 24 blood pressure chart readings for ages cheap dipyridamole 100mg mastercard,25-hydroxycholecalciferol. In the jejunum and ileum, Ca2+ is transported across the intercellular space into the blood by passive transport. Vitamin D (calcitriol) (19-7) Vitamin D initiates its synthesis in the skin by the conversion of 7-dehydrocholesterol to cholecalciferol following exposure to ultraviolet light. Cholecalciferol is then absorbed into the blood circulation and transported to the liver, where it is converted to 25-hydroxycholecalciferol by the addition of a hydroxyl group to the side chain. The main function of vitamin D is to stimulate the absorption of Ca2+ by the intestinal mucosa. The active absorption process involves the import by enterocytes of Ca2+ through voltage-insensitive channels. By paracellular absorption (passive mechanism) in the jejunum and ileum, through tight junctions into the intercellular spaces and into blood. A small fraction (about 10%) of Ca2+ absorption takes place in the large intestine by active and passive mechanisms. Vitamin D, like all steroids, is transported to the nucleus of the intestinal cell to induce the synthesis of calbindin, the calcium-binding protein. By the third month after birth, the celomic-derived fetal cortex regresses, then disappears within the first year of life. Ectopic adrenocortical or medullary tissue may be found retroperitoneally, inferior to the kidneys, along the aorta and in the pelvis. Aggregates of ectopic chromaffin cells, called paraganglia, can be a site of tumor growth (pheochromocytoma). Functions of the fetal adrenal cortex the adrenal (or suprarenal) glands develop from two separate embryologic tissues: 1. Cells from the celomic epithelium aggregate on each side, between the developing gonads and the dorsal mesentery, to form the fetal adrenal cortex. The medulla originates from neural crest cells migrating from the adjacent sympathetic ganglia into the medial region of the fetal cortex. Small clusters of chromaffin cells synthesize chromogranin A and tyrosine hydroxylase. Mesenchymal cells surround each developing adrenal gland and differentiate into fibroblasts, which form the perirenal fascia and capsule. At this time, an extensive blood vasculature develops from branches supplied by the descending aorta. The adrenal vasculature is essential for organ growth and for receiving and delivering hormone products. At birth, the adrenal glands are 20 times relatively 644 During the early stage of gestation, the fetal adrenal cortex synthesizes large amounts of the androgen dehydroepiandrosterone. The fetal adrenal cortex has the capability to produce steroids early in gestation. The interaction between the fetal adrenal cortex and the placenta constitutes the fetoplacental unit (see Chapter 23, Fertilization, Placentation and Lactation). The function of the fetoplacental unit is essential for fetal maturation and perinatal survival. Histology of the adrenal cortex (19-8 to 19-10) the adrenal glands (Latin ad, near; ren, kidney) are associated with the superior poles of each kidney. Each gland consists of a yellowish outer cortex (80% to 90% of the gland) and a reddish inner medulla (10% to 20%). Each adrenal gland is surrounded by perinephritic fat and enclosed by the renal fascia. An arterial plexus, derived from three adrenal arteries, is located in the adrenal gland capsule. The outermost layer of the cortex is the zona glomerulosa, just under the capsule (see 19-8). The zona glomerulosa consists of concentrically arranged cells surrounded by a stroma containing capillaries. The cells contain a few lipid droplets and a well-developed smooth endoplasmic reticulum. It consists of polygonal cells arranged in vertical columns or fascicles perpendicular to the capsule. The cells contain a vacuolated cytoplasm, reflecting the accumulation of lipid droplets containing cholesterol and its metabolites. It consists of anastomosing cells forming a reticulum or network surrounded by fenestrated capillaries. The cells contain a brown pigment (lipofuscin) contrasting with the lighter staining of the zona fasciculata. Catecholamines of the medulla generate a brown color when exposed to air or the oxidizing agent potassium dichromate (chromaffin reaction). Like steroid-producing cells of the theca interna and corpus luteum of the ovaries and Leydig cells of the testes, cells of the zona fasciculata display three characteristic structural features representative of steroidogenesis: (1) lipid droplets containing cholesterol; (2) mitochondria with tubular cristae housing the enzymes involved in steroidogenesis; and (3) smooth endoplasmic reticulum, also containing membrane-associated enzymes involved in the production of steroids. A structural feature not prominent in the cells of the other cortical zones is the presence of lysosomes and deposits of lipofuscin. Lipofuscin is a remnant of lipid oxidative metabolism, reflecting degradation within the adrenal cortex. Adrenogenital syndrome Although dehydroepiandrosterone, androstenedione and dehydroepiandrosterone sulfate are weak androgens, they can be converted outside the adrenal cortex into more potent androgens and also estrogens. This androgen conversion property has clinical significance in pathologic conditions such as the adrenogenital syndrome. An excessive production of androgens in the adrenogenital syndrome in women leads to masculinization (abnormal sexual hair development, hirsutism and enlargement of the clitoris). In the male, adrenal androgens do not replace testicular androgens produced by Leydig cells. In women, adrenal androgens are responsible for the growth of axillary and pubic hair. The innermost layer of the cortex, adjacent to the adrenal medulla, is the zona reticularis (see 19-8 and 19-10). Zona glomerulosa (19-11 and 19-12; see 19-8) the zona glomerulosa (Latin glomus, ball) has the following characteristics (see 19-8): 1. Its cells aggregate into a glomerulus-like arrangement and have a moderate amount of lipid droplets in the cytoplasm. During aldosterone action, aldosterone binds to intracellular receptor proteins to activate transcription factors, which enhance the expression of specific genes. Aldosterone-responsive cells do not respond to the glucocorticoid cortisol because cortisol is converted in the liver to cortisone by the enzyme 11 -hydroxysteroid dehydrogenase. Zona fasciculata (see 19-8, 19-9, 19-11 and 19-12) the zona fasciculata (Latin fascis, bundle) makes up 75% of the cortex. It consists of cuboid cells, with the structural features of steroid-producing cells, arranged in longitudinal cords separated by cortical fenestrated capillaries, or sinusoids (see 19-8 and 19-9). Cholesterol is esterified by acylCoA cholesterol acyltransferase to be stored in cytoplasmic lipid droplets. Enzymes located in the mitochondria and smooth endoplasmic reticulum participate in the reactions. The substrates shuttle from mitochondria to smooth endoplasmic reticulum to mitochondria during steroidogenesis. Aldosterone is lacking and hypoaldosteronism develops (with hypotension and low Na+ in plasma). When lipids are extracted during histologic preparation or are unstained by the standard hematoxylin-eosin (H&E) procedures, the cells of the zona fasciculata display a foamy appearance and are called spongiocytes. Well-developed smooth endoplasmic reticu- lum, also with enzymes involved in the synthesis of steroid hormones. In the liver, cortisol stimulates gluconeogenesis to increase the concentration of glucose in blood. It becomes useful to understand fluctuations in blood glucose levels in the diabetic patient. An anti-inflammatory effect: Cortisol suppresses tissue responses to injury and decreases cellular and humoral immunity. Cells of the zona reticularis form an anastomosing network of short cellular cords separated by fenestrated capillaries. The cells of this zone are acidophilic, due to abundant lysosomes, large lipofuscin granules and fewer lipid droplets (see 19-8 and 19-10). Note that the female hormone estradiol derives from the male hormone testosterone, and that testosterone has the female hormone progesterone as a precursor. The adrenal gland is the major source of androgens in women; these androgens stimulate the growth of pubic and axillary hair during puberty. These individuals are hypotensive because of a difficulty in retaining salt and maintaining extracellular volume. A more common cause of hyperaldosteronism is an increase in renin secretion (secondary hyperaldosteronism). Adrenocortical adenoma, a functional tumor of the adrenal cortex can also result in overproduction of cortisol, as well as of aldosterone and adrenal androgens. Zona reticularis: When compared with the gonads, the zona reticularis secretes insignificant amounts of sex hormones. However, sex hormone hypersecretion becomes significant when an adrenocortical adenoma is associated with virilization or feminization. An acute destruction of the adrenal gland by meningococcal septicemia in infants is the cause of Waterhouse-Friderichsen syndrome (or hemorrhagic adrenalitis), producing adrenocortical insufficiency. A loss of cortisol decreases vasopressive responses to catecholamines and leads to an eventual drop in peripheral resistance, thereby contributing to hypotension. Adrenal medulla (19-13; see 19-8) the adrenal medulla contains chromaffin cells, so named because of their ability to acquire a brown coloration when exposed to an aqueous solution of potassium dichromate. This reaction is due to the oxidation of catecholamines by chrome salts to produce a brown pigment. Chromaffin cells (see 19-8) are modified sympathetic postganglionic neurons, without postganglionic processes, derived from the neural crest and forming epithelioid cords surrounded by fenestrated capillaries. Epinephrine is produced by about 80% of the chromaffin cells; the remaining 20% produce norepinephrine. Chromaffin cells are arranged in clusters, or cords, and supplied by abundant capillaries (sinusoids) lined by fenestrated endothelial cells. Cortex Fenestrated cortical capillaries (also called sinusoids) percolate through the zonae glomerulosa and fasciculata and form a network within the zona reticularis before entering the medulla. Medullary venous sinuses Mineralocorticoids, cortisol, and sexual steroids enter the medullary venous sinuses. Central vein Medulla Capsule the medullary artery, derived from the inferior adrenal artery, enters the cortex within a connective tissue trabecula and supplies blood directly to the adrenal medulla. In the medulla, the artery joins with branches from the cortical capillaries to form medullary venous sinuses. Thus, the medulla has two blood supplies: one from cortical capillaries and the other from the medullary artery. The cytoplasm of chromaffin cells contains membrane-bound dense granules consisting of part of matrix proteins, called chromogranins and one class of catecholamine, either epinephrine or norepinephrine (adrenaline or noradrenaline). Minimal secretion of dopamine also occurs, but the role of adrenal dopamine is not known. Catecholamines are secreted into the blood instead of being secreted into a synapse, as in postganglionic terminals. These two cell populations can be distinguished at the electron microscope level by the morphology of the membrane-bound granules: 652 1. Epinephrine-containing granules are smaller and occupy a central core (see 19-13). Note an important difference with cells of the adrenal cortex: cells from the adrenal cortex do not store their steroid hormones in granules. Dopamine is transported into existing granules and converted inside them by dopamine -hydroxylase to norepinephrine. When the conversion step to epinephrine is completed, epinephrine moves back to the membranebound granule for storage. Blood supply to the adrenal gland (19-14) Similar to all endocrine organs, the adrenal glands are highly vascularized. Microscopically, the tumor displays a cellular cluster and/or a trabecular pattern surrounded by an abundant sinusoidal-capillary network. All three adrenal arteries enter the adrenal gland capsule and form an arterial plexus. The second set enters the cortex forming straight fenestrated capillaries (also called sinusoids), percolating between the zonae glomerulosa and fasciculata and forming a capillary network in the zona reticularis before entering the medulla.

The remainder of culturenegative cases represent infection by fastidious organisms blood pressure urination cheap dipyridamole 25 mg overnight delivery, such as the nutritionally variant bacteria Granulicatella and Abiotrophia spp blood pressure in psi order dipyridamole 25mg free shipping. The temporal course of disease is dictated in large part by the causative organism: S arteria umbilical discount dipyridamole 25 mg mastercard. Abscesses may burrow from the aortic root into the ventricular septum and interrupt the conduction system or may burrow through the epicardium and cause pericarditis hypertension vascular disease generic 25mg dipyridamole visa. Pts with left-sided cardiac infections present with the typical clinical features of endocarditis arterial nephrosclerosis generic dipyridamole 25 mg mastercard. Endocarditis associated with a transvenous pacemaker or an implanted defibrillator may be associated with a generator pocket infection and result in fever prehypertension jnc 8 order dipyridamole 100 mg overnight delivery, minimal murmur, and pulmonary symptoms due to septic emboli. Evidence of endocardial involvement Positive echocardiogramb Oscillating intracardiac mass on valve or supporting structures or in the path of regurgitant jets or in implanted material, in the absence of an alternative anatomic explanation, or Abscess, or New partial dehiscence of prosthetic valve, or New valvular regurgitation (increase or change in preexisting murmur not sufficient) Minor Criteria 1. Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions 4. Microbiologic evidence: positive blood culture but not meeting major criterion, as noted previously,d or serologic evidence of active infection with an organism consistent with infective endocarditis Definite endocarditis is defined by documentation of two major criteria, of one major criterion and three minor criteria, or of five minor criteria. Tests to detect renal, hepatic, and/or hematologic toxicity should be performed periodically. If the isolate is resistant to all commonly used agents, surgical therapy is advised (see next and Table 83-3). The inclusion of two other agents in addition to rifampin helps prevent the emergence of rifampin resistance in vivo. Testing for gentamicin susceptibility should be performed before rifampin is given; if the strain is resistant, another aminoglycoside, a fluoroquinolone, ceftaroline, or another active agent should be substituted. Ceftriaxone alone or with gentamicin can be used in pts with non-immediate -lactam allergy. Use vancomycin plus gentamicin only for penicillin-allergic pts (preferable to desensitize to penicillin) and for isolates resistant to penicillin/ampicillin. Use gentamicin during initial 2 weeks; determine gentamicin susceptibility before initiating rifampin. Doses of gentamicin, streptomycin, and vancomycin must be adjusted for reduced renal function. Ideal body weight is used to calculate doses of gentamicin and streptomycin per kilogram (men = 50 kg + 2. Source: Adapted from Olaison L, Pettersson G: Current best practices and guidelines indications for surgical intervention in infective endocarditis. Circulation 116:1736, 2007; Habib G et al: Guidelines on the prevention, diagnosis, and treatment of infective endocarditis. Organisms contained within the bowel or an intraabdominal organ enter the sterile peritoneal cavity, causing peritonitis and-if the infection goes untreated and the pt survives-abscesses. Primary peritonitis has no apparent source, whereas secondary peritonitis is caused by spillage from an intraabdominal viscus. The etiologic organisms and the clinical presentations of these two processes are different. The specific organisms depend on the flora present at the site of the initial process. Once infection has spread to the peritoneal cavity, pain increases; pts lie motionless, often with knees drawn up to avoid stretching the nerve fibers of the peritoneal cavity. There is marked voluntary and involuntary guarding of anterior abdominal musculature, tenderness (often with rebound), and fever. Vancomycin should be used instead of cefazolin if methicillin resistance is prevalent, if the pt has an overt exit-site infection, or if the pt appears toxic. Abscesses develop in untreated peritonitis as an extension of the disease process and represent host defense activity aimed at containing the infection. Serum levels of alkaline phosphatase are elevated in 70% of pts, and leukocytosis is common. Gram-negative bacilli can cause splenic abscess in pts with urinary tract foci, with associated bacteremia, or with infection from another intraabdominal source; salmonellae are fairly commonly isolated, particularly from pts with sickle cell disease. Percutaneous drainage has been successful for single, small (<3-cm) abscesses and may also be useful for pts at high surgical risk. More than 75% of these abscesses are due to ascending infection and are preceded by pyelonephritis. The most important risk factor is the presence of renal calculi that produce local obstruction to urinary flow. This diagnosis should be considered if pts with pyelonephritis have persistent fever after 4 or 5 days of treatment, if a urine culture yields a polymicrobial flora, if the pt has known renal stone disease, or if fever and pyuria occur in conjunction with a sterile urine culture. The wide range of clinical manifestations is matched by the wide variety of infectious agents involved (Table 85-1). Disease lasts <12 h and consists of diarrhea, nausea, vomiting, and abdominal cramping, usually without fever. After an incubation period of 4 h to 4 days, watery diarrhea, abdominal cramps, nausea, vomiting, and occasionally fever and chills develop. Diarrhea lasting >2 weeks is generally defined as chronic; in such cases, many of the causes of acute diarrhea are much less likely, and a new spectrum of causes needs to be considered. Fever often implies invasive disease, although fever and diarrhea may also result from infection outside the gastrointestinal tract, as in malaria. Frequent stools over a given period can provide the first warning of impending dehydration. Abdominal pain may be most severe in inflammatory processes like those due to Shigella, Campylobacter, and necrotizing toxins. Painful abdominal muscle cramps, caused by electrolyte loss, can develop in severe cases of cholera. An appendicitislike syndrome should prompt a culture for Yersinia enterocolitica with cold enrichment. Tenesmus (painful rectal spasms with a strong urge to defecate but little passage of stool) may be a feature of cases with proctitis, as in shigellosis or amebiasis. In the United States, 50% of outbreaks of nonbacterial gastroenteritis are caused by noroviruses. Asking pts whether anyone else they know is sick is a more efficient means of identifying a common source than is constructing a list of recently eaten foods. Current antibiotic therapy or a recent history of treatment suggests Clostridium difficile diarrhea. Antibiotic use may increase the risk of chronic intestinal carriage following salmonellosis. Prevention Rotavirus vaccines, two of which are available in the United States, are included in the routine vaccination schedule for U. Clinical Manifestations After an incubation period of 5 days to 3 weeks, the manifestations of infection range from asymptomatic carriage (most common) to fulminant diarrhea and malabsorption. Prolonged therapy with metronidazole (750 mg tid for 21 days) has been successful. Clinical manifestations include diarrhea, flulike symptoms, flatulence, and burping. Paratyphi survive within macrophages, then disseminate throughout the body via lymphatics, and ultimately colonize reticuloendothelial tissues. Epidemiology and Clinical Manifestations Depending on the specific species, salmonellosis results in typhoid fever or gastroenteritis. Other signs and symptoms may include sweating, cough, malaise, arthralgias, nausea, vomiting, and diarrhea-or, less often, constipation. Enteritidis), poultry, undercooked meat, dairy products, manufactured or processed foods, and fresh produce. Diagnosis Positive cultures of blood, stool, or other specimens are required for diagnosis. Transmission to humans occurs via contact with or ingestion of raw or undercooked food products or direct contact with infected animals. Diagnosis the diagnosis is confirmed by cultures of stool, blood, or other specimens on special media and/or with selective techniques. Fluoroquinolones are an alternative choice, although resistance to fluoroquinolones is increasing. Humans are the major reservoir, but Shigella can be found in other higher primates. The toxins target endothelial cells and play a significant role in the microangiopathic complications of Shigella and E. If required, rehydration should be oral, and nutrition should be started as soon as possible. Septicemia can occur in pts with chronic liver disease, malignancy, diabetes mellitus, and other underlying illnesses. Diagnosis Stool culture studies for Yersinia must be specifically requested and require the use of special media. Infection follows ingestion of cysts from fecally contaminated water, food, or hands. Diagnosis Microscopic examination of three stool samples, often combined with serologic testing, remains the standard diagnostic approach. Clinical Manifestations Most commonly, pts develop diarrhea, with stools that are not grossly bloody and are soft to watery, with a characteristic odor. Metronidazole is recommended only for mild to moderately severe disease when these other agents are not readily accessible. Clinical Manifestations Urethritis in men produces urethral discharge, dysuria, or both, usually without frequency of urination. Moxifloxacin can be considered for treatment of refractory nongonococcal, nonchlamydial urethritis.

The secretion in the blood circulation of large amounts of thyroid hormones is unregulated blood pressure medication guidelines 25 mg dipyridamole. Inflammatory cells in the stroma of the thyroid gland produce cytokines (interleukin-1 high blood pressure medication and xanax buy genuine dipyridamole, tumor necrosis factor- and interferon-) that stimulate thyroid cells to also produce cytokines arteriosclerosis vs atherosclerosis purchase on line dipyridamole, thus reinforcing the thyroidal autoimmune process blood pressure chart good and bad buy cheap dipyridamole on line. The immunosuppressive effect of anti-thyroid drugs reduces the production of cytokines heart attack grill locations order dipyridamole with a mastercard, leading to remission in some patients hypertension jnc 7 guidelines buy generic dipyridamole 100 mg on line. Exophthalmos results from the presence of an inflammatory infiltrate (T cells, macrophages and neutrophils) in the extraocular muscles and orbital tissue. Overproduction of fat, and the hygroscopic nature of proteoglycans contribute to the development of exophthalmos. T3 stimulates phospholamban, a protein involved in the release and uptake of Ca2+ into the sarcoplasmic reticulum. Increased diastolic function in patients with hyperthyroidism is related to the role of phospholamban in cardiac muscle contractility, mediated by thyroid hormone. From a functional perspective, an excess of thyroid hormones increases the basal metabolism, the cardiac rate, and the consumption of oxygen and nutrients. Increased body heat production, determined by high oxygen consumption, makes patients feel hot. Increased cardiac rate is caused by the up-regulation of 1 adrenergic receptors in cardiocytes in the sinoatrial node stimulated by thyroid hormones. Increase in cardiac muscle contractibility and cardiac output is triggered by the up-regulation of 1 adrenergic receptors in the ventricular cardiac muscle. The active transport of Ca2+ into the lumen of the sarcoplasmic reticulum of cardiocytes is controlled by phospholamban, whose activity is regulated by thyroid hormones. The objective is to neutralize the effects of thyroid hormones by decreasing their synthesis and actions. Radioiodine can be given orally as a single dose of 131I-labeled sodium iodide (Na131I) in liquid or capsule form. Beta ray emissions of the radionuclide causes tissue necrosis, resulting in the functional reduction or inactivation of follicular thyroid cells over the course of 6 to 18 weeks, when thyroid function normalizes (euthyroidism: characterized by normal serum levels of thyroid hormone). Propranolol, a -adrenergic antagonist, can be used to block 1 adrenergic receptors to manage tachycardia. This treatment also offsets increases in cardiac output and arterial blood pressure as well as the elevated thermogenesis caused by the hyperadrenergic state. A decrease in the basal metabolic rate, hypothermia and cold intolerance are observed. Hypothyroidism in the adult is manifested by coarse skin with a puffy appearance due to the accumulation of proteoglycans and retention of fluid in the dermis of the skin (myxedema). Except 638 for developmental disturbances, most symptoms are reversed when the thyroid disorder is corrected. As previously mentioned, the requirement of thyroid hormone for development is most apparent in the central nervous system, where severe thyroid hormone deficiency in fetal and neonatal periods results in cretinism, a disorder characterized by developmental disabilities, deafness and ataxia. Progressive destruction of the thyroid follicles leads to a decrease in the function of the thyroid gland. Finally, papillary carcinoma is the most frequent malignant tumor of the thyroid gland. Follicular carcinoma, is the second most frequent tumor of the thyroid gland (see Box 19-A). It is a slow-growing tumor, which usually spreads to bone by the hematogenous route. Calcium regulation Ca2+ is found inside and outside cells, is a major component of the skeleton, and is required for muscle contraction, blood clotting, nerve impulse transmission and enzymatic activities. Ca2+ is an essential mediator in cell signaling (for example, through calcium-binding calmodulin). Calcitonin, produced by C cells lodged in the thyroid gland, lowers Ca 2+ levels in blood. Vitamin D (calcitriol, or 1,25-dihydroxycholecalciferol) enhances the uptake of Ca 2+ by the small intestine by stimulating the synthesis of Ca 2+ binding protein calbindin by intestinal epithelial cells (enterocytes). The third branchial pouch differentiates into the inferior parathyroid glands and the thymus. The fourth branchial pouch develops into the superior parathyroid glands and the ultimobranchial body. The parathyroid glands are on the posterolateral regions of the thyroid gland, located between the thyroid capsule and the surrounding cervical connective tissue. The accidental surgical removal of the normal parathyroid glands during thyroid surgery (thyroidectomy) causes tetany, characterized by spasms of the thoracic and laryngeal muscles, leading to asphyxia and death. Functions of the parathyroid hormone the parenchyma of the parathyroid glands consists of two cell populations supplied by sinusoidal capillaries: 1. Oxyphil or acidophilic cells contain abundant mitochondria, which give this cell its typical pinkreddish stain. Cells are arranged in a cord-like arrangement, but a follicular-like arrangement can also be observed. They contain abundant mitochondria, which give this cell type an acidophilic staining in hematoxylin-eosin preparations. Hypercalciuria (increased urinary excretion of Ca2+), leading to the formation of renal stones in the calyces of the kidneys. When stones descend to the ureter, there is severe pain, caused by spasmodic contraction of the smooth muscle, hematuria (blood in the urine) and infections of the renal tract (pyelonephritis). Hypoparathyroidism is seen during the inadvertent removal or irreversible damage (disrupted blood supply) to the parathyroid glands during surgery of the thyroid gland. Within 24 to 48 hours of surgical removal of the parathyroid glands, hypocalcemia causes increased excitability of nervous tissue, including paresthesia (sensation of pins and needles), muscle cramping, twitching and spasms. These severe symptoms require intravenous calcium therapy followed by continuous infusions to achieve safe ionized Ca2+ blood levels. Neuromuscular symptoms caused by acute low blood Ca2+ concentration can be clinically tested: 1. The ends of the bones bulge (rachitic rosary at the costochondral junctions) and poor calcification of the long bones causes bending (bowlegs or knock-knees). C cells (thyroid follicle) (19-6) C cells derive from neural crest cells and are associated with thyroid follicles. C cells may be present within or outside the thyroid follicle, but are not in contact with the colloid. C cells produce calcitonin, encoded by a gene located on the short arm of chromosome 11. The third set generates medullary arteries, which travel along the cortex and, without branching, supply blood only to the medulla. The direct supply of blood to the adrenal medulla, involved in rapid responses to stress. The adrenal cortex and medulla are drained by the central vein, present in the adrenal medulla. The ventral pancreas forms the head of the pancreas and associates with the common bile duct. Endocrine cells are first observed along the base of the differentiating exocrine acini by weeks 12 to 16. Islets of Langerhans (19-15 and 19-16) Dual blood supply: Acinar and insuloacinar vascular systems Each islet of Langerhans is supplied by afferent arterioles, forming a network of capillaries lined by fenestrated endothelial cells. Venules leaving the islet supply blood to the pancreatic acini surrounding the islet. This vascular system enables a local action on the exocrine pancreas of hormones produced in the islet. An independent arterial system, the acinar vascular system, supplies the pancreatic acini. Insuloacinar portal system Arteriole Islet of Langerhans Venule Acinar vascular system Pancreatic acini the pancreas has two portions: 1. The exocrine pancreas, consisting of acini involved in the synthesis and secretion of several digestive enzymes transported by a duct system into the duodenum (see Chapter 17, Digestive Glands). The endocrine pancreas (2% of the pancreatic mass), formed by the islets of Langerhans scattered throughout the pancreas. A vascular component, the insuloacinar portal system (see 19-15), which consists of an afferent arteriole giving rise to a capillary network lined by fenestrated endothelial cells. Venules leaving the islets of Langerhans supply blood to adjacent pancreatic acini. Proinsulin consists of a connecting (C) peptide bound to A and B chains, held together by disulfide bonds. Within the secretory vesicle, the protease releases the C peptide from the disulfide-linked A and B chains. Ca2+ influx causes exocytosis of the secretory vesicle and the release of insulin into the bloodstream. An independent vascular system, the acinar vascular system, supplies blood directly to the exocrine pancreatic acini. Anastomosing cords of the endocrine cells A (cells), B (cells), D (cells) and F cells, each secreting a single hormone (see 19-16). A cells (cells) produce glucagon, B cells synthesize insulin, D cells secrete gastrin and somatostatin and F cells produce pancreatic polypeptide. Electron microscopy, to distinguish the size and structure of the secretory granules. B cells are centrally located (core distribution) and surrounded by the other cell types (mantle distribution). Peptides produced by cells of the islets of Langerhans (19-17) of gastrin from enteroendocrine cells, the secretion of pancreatic bicarbonate and enzymes and the contraction of the gallbladder. Pancreatic polypeptide is a 36-amino-acid peptide, which inhibits the secretion of somatostatin. Pancreatic polypeptide also inhibits the secretion of pancreatic enzymes and blocks the secretion of bile by inhibiting contraction of the gallbladder. Cell entry and fate of insulin (19-18) A cells (cells produce glucagon, a 29-amino-acid peptide (3. Glucagon derives from a large precursor, preproglucagon, encoded by a gene present on chromosome 2. About 30% to 40% of glucagon in blood is produced by the pancreas; the remainder comes from the gastrointestinal tract (enteroglucagon). Circulating glucagon, of pancreatic and gastrointestinal origin, is transported to the liver and about 80% is degraded before reaching the systemic circulation. Glucagon stored in granules is released by exocytosis when there is a decrease in the plasma levels of glucose. Insulin derives from a large singlechain precursor, preproinsulin, encoded by a gene located on the short arm of chromosome 11. The large precursor gives rise to proinsulin, consisting of C peptide linking two chains, A and B chains. An increase in blood glucose stimulates the release of insulin and C peptide stored in secretory granules. Removal of C peptide by specific proteases results in the separation of chains A and B. D (cells produce gastrin (see discussion of enteroendocrine cells in Chapter 15, Upper Digestive Segment) and somatostatin. Somatostatin is a 14-amino-acid peptide identical to somatostatin produced in the hypothalamus. Hepatic insulin action, consisting of the suppression of gluconeogenesis and glycogenolysis. These actions ensure that part of dietary glucose is stored in hepatocytes and released between meals or when metabolic demands take place. About 50% of insulin arriving to the liver by the portal vein is degraded during the first clearance round. A second insulin clearance round takes place when insulin returns through the hepatic artery and reaches the hepatic sinusoids for degradation in hepatocytes. Insulin is not detected in the circulation 30 minutes after its release from pancreatic B cells. In addition to the first and second clearance pass through the liver, circulating insulin is internalized and degraded in the convoluted tubules of the nephrons in the kidneys. Cell entry and fate of glucose (19-19) the main action of insulin on peripheral tissues is the regulation of glucose metabolism. The purpose is to store glucose and triglycerides to satisfy the energetic needs of a tissue, such as muscle or adipose tissue. Insulin returns to the liver through the hepatic artery for a second clearance round. An excessive amount of glucose circulating in blood is seen when hepatocytes, skeletal muscle and adipocytes fail to take up glucose because of decreasing mass or function of insular B cells and/or increased insulin resistance. The intracellular domain of the subunit has tyrosine kinase activity, which autophosphorylates and triggers a number of intracellular responses. Normally, thymocytes that recognize self-antigens are eliminated as they mature in the thymus. Increases in circulating glucose and lipid levels can further affect insulin secretion and action.

Molecular motors transport proteins associated with a protein raft 3 along microtubules blood pressure herbs order dipyridamole 25mg with visa. We discuss in Chapter 1 prehypertension high blood pressure order dipyridamole 25 mg mastercard, Epithelium Cell Biology blood pressure infant normal value cheap dipyridamole master card, the involvement of microtubules in the intracellular traffic of vesicles and non-vesicle cargos arrhythmia future cure purchase dipyridamole 25mg line. The ring fastens the descending recess of the acrosome to the spermatid nuclear envelope blood pressure yoga 25 mg dipyridamole. During acrosome development blood pressure chart explained buy genuine dipyridamole on line, Golgi-derived proacrosomal vesicles are transported to the acroplaxome, where they dock and fuse to form the acrosome. Sertoli cell F-actin hoops embrace the acrosomeacroplaxome region of the elongating spermatid head. Shaping spermatids into fertilizing sperm (see Primer 20-E; see 20-10) Completion of spermiogenesis (see 20-10) the elongated shape of the sperm head is essential for fertilization. The juxtaposed acroplaxome and manchette rings, embracing the caudal region of the spermatid nucleus, reduce their diameter in parallel with nuclear elongation. The cell apical region, containing the elongating spermatid nucleus, is encircled by several F-actin hoops of an adjacent Sertoli cells. From a mechanical perspective, it is likely that the exogenous clutching forces exerted by the Sertoli cell F-actin hoops, combined with the reduction in diameter of the acroplaxome and manchette rings, contribute to the gradual elongation of spermatid head (see Primer 20-E; see 20-10). The manchette disassembles when the elongation and condensation of the spermatid nucleus and tail development are near completion. They are formed by the polymerization of tubulin dimers with post-translational modifications (such as acetylation). Filamentous actin (F-actin), aligned along microtubules, is present to a lesser extent. Mitochondria complete their alignment along the proximal segment of the developing axoneme, surrounded by outer dense fibers (see 20-10/C). The residual body discards from the mature spermatid the Golgi apparatus and an excess of cytoplasm. Spermiation implies the release of single mature spermatids into the lumen of the seminiferous tubule (see 20-10/D). The intercellular bridges, linking members of a spermatid progeny, become part of the residual body. Mature spermatids are in fact non-motile sperm upon their release into the seminiferous tubular lumen. They are propelled toward the epididymal duct, where they undergo a maturation process, resulting in the acquisition of forward motility leading to fertilization capability. Structure of the sperm (20-12) the mature sperm consists of two components: the head and the tail. The head houses a flattened, condensed and elongated nucleus partially capped by the acrosome. It contains hydrolytic enzymes (proteases, acid phosphatase, hyaluronidase and neuraminidase, among others), usually found in lysosomes. Nucleus Implantation fossa Proximal centriole Distal centriole Axoneme Plasma membrane 6 End piece 2 the head consists of two components: (1) the nucleus and (2) the acrosome-acroplaxome complex. Middle piece of the tail Mitochondria the end piece includes the axoneme, surrounded only by the plasma membrane. The lower limit of the middle piece is marked by the termination of the mitochondrial helical sheath and the presence of the annulus, a cortical ring containing the protein septin 4. Septin 4 is a member of the septin family of cytoskeletal proteins distinct from microfilaments, microtubules and intermediate filaments. Septin 4 mutant male mice are sterile due to sperm immotility (a condition known as asthenospermia, see Box 20-E). Sperm lack the cortical 684 ring at the annulus region and the kinesin-mediated intraflagellar transport of cargo proteins, required for sperm tail development, stalls at the annulus. The fibrous sheath is formed by concentric ribs projecting from equidistant longitudinal columns. This temperature is achieved in the scrotum by the pampiniform plexus of veins surrounding the spermatic artery and functions as a countercurrent heat exchanger to dissipate heat. When the temperature is below 35oC, contraction of the cremaster muscle in the spermatic cord and of the dartos muscle in the scrotal sac brings the testes close to the body wall to increase the temperature. Cryptorchidism In cryptorchidism (or undescended testes), one or both testes fails to reach the scrotal sac during development and remains in the abdominal cavity or inguinal canal. The gubernaculum consists of a core of mesenchymal cells surrounded by striated muscle innervated by the genitofemoral nerve. A high incidence of testicular tumors is associated with the untreated cryptorchid testes. Cryptorchidism is an asymptomatic condition detected by physical examination of the scrotal sac after birth and before puberty. Hormonal treatment (administration of human chorionic gonadotropin) may induce testicular descent. If unsuccessful, surgery is the next step, in which the testis (or testes) is attached to the wall of the scrotal sac (a process called orchidopexy). Inguinal hernia, cysts and hydrocele acteristics: concentration, morphology and motility. Normal sperm should display a regular oval head connected to a long straight tail. Abnormal sperm have atypical shaped heads (round heads, pin heads, large heads, or double heads) and short or absent tails. Grade b: sperm have slow forward or slow nonlinear motility (curved or crooked line). Grade c: sperm lack forward motility; sperm move their tails but do not advance forward. Sperm classified Grade c or d are regarded as poor and associated with male infertility. You may remember from your study of embryology that the descent of the testes to the scrotal sac involves: 1. The gubernaculum, a ligament that originates at the testis-epidydymal complex and inserts in the genital swelling, the future scrotal sac. An evagination of the peritoneum, the vaginal process, which facilitates the sliding of the descending testes through the inguinal canal. Between week 7 and 12, the gubernaculum shortens and drags the testes, the deferent duct and blood vessels toward the scrotal sac by a mechanism described above. During the first year of life, the upper section of the vaginal process closes, leaving behind the peritonealvaginal ligament. The lower section becomes the tunica vaginalis, consisting of a parietal and a visceral layer. A congenital inguinal hernia will occur if the vaginal process is wide enough and does not close. If the unclosed space above the testis is narrow, fluid, instead of an intestinal loop, can accumulate, forming a cyst of the spermatic cord. If fluid collects between the parietal and visceral layers of the tunica vaginalis, a testicular hydrocele is formed. Crystals of Reinke are inclusions of proteins in the cytoplasm of human Leydig cells. Note the different types of spermatids (arrows) in the adjacent seminiferous tubules. We discuss later the timing and dynamics of spermatogenesis, concepts that enable the physician to determine the recovery time frame of spermatogenesis upon completion of cancer chemotherapy. In general, no alterations in spermatogenic function can be expected following mumps-caused orchitis. Recall that veins in the spermatic cord play a significant role in maintaining testicular temperature at 35oC by a countercurrent exchange mechanism with the spermatic artery. Testosterone binds to the androgen receptor in Sertoli cells and maintains spermatogenesis, male libido and the function of the male accessory glands (prostate and seminal vesicles). Aggregates of Leydig cells are present in the intertubular space in proximity to blood vessels and lymphatic channels or sinusoids. Like most steroid-producing cells, Leydig cells contain lipid droplets, mitochondria with characteristic tubular cristae and a well-developed smooth endoplasmic reticulum. In the human testes, the cytoplasm of Leydig cells contains crystals of Reinke, inclusions of proteins in a geometric array, which become more apparent with age. Testosterone can also be aromatized to estrogens in many tissues, in particular adipose tissue. This condition, which generally may appear up to adolescence and can affect one side, is caused by physical trauma or an abnormally mobile testis within the tunica vaginalis. If torsion is not treated immediately (within the first 6 hours), hemorrhagic infarction and necrosis of the whole testis occur. Fetal Leydig cells are steroidogenically active between 8 and 18 weeks of gestation. The androgens produced by fetal Leydig cells at this time are critical for the development of the male reproductive tract (see the development of the testes in Chapter 21, Sperm Transport and Maturation). In the neonate, testicular steroidogenesis reaches high levels at 2 to 3 months post partum and then decreases. Excessive prolactin can decrease the production of androgens by Leydig cells, diminish spermatogenesis and lead to erectile dysfunction and infertility. During the synthesis of testosterone, plasma cholesterol enters the cell, is esterified by acetyl coenzyme A (acetyl CoA) and is stored in the cytoplasm as lipid droplets. Fatty acids are processed to cholesterol in the smooth endoplasmic reticulum (see Chapter 19, Endocrine System, for a detailed discussion of Steroidogenesis). Enzymes in the smooth endoplasmic reticulum convert pregnenolone to progesterone to testosterone. Bioregulation of spermatogenesis (20-14; see 20-7) Examine 20-14 to integrate the major aspects of the hormonal regulation of spermatogenesis. Spermatogenesis and steroidogenesis coexist in different testicular compartments: the seminiferous epithelium and the intertubular space (where Leydig cells reside), respectively. The dynamic structural plasticity of Sertoli cells facilitates spermatogenesis: (i) Sertoli cells assist in the translocation of spermatogonia cell progenies from the basal compartment to the adluminal compartment of the seminiferous epithelium. Fas ligand, expressed by spermatocytes and spermatids, can activate the apoptotic machinery required for the disposal of defective members that can compromise the fate of the entire meiotic and postmeiotic progeny (see Chapter 3, Cell Signaling Cell Biology Pathology). Tolerance to spermatogenic cell autoantigens supports the immune privilege status of the testes. By this mechanism, Sertoli cells maintain an input-output equilibrium between the number of spermatogonia being produced (input) and the number of sperm released (output). Inhibins and activins are synthesized in the ovaries, testes, hypophysis, and probably in other tissues. Cells are arranged into well-defined combinations called cellular associations (see 20-15 and 20-16). For example, in a particular region of the seminiferous epithelium, differentiating spermatids can be seen in company with spermatogonia and spermatocytes, also engaged in their corresponding steps of development (see 20-4 and 20-13). Cellular associations, designated by Roman numerals, are distinctive and succeed one another along the length of a seminiferous tubule. Imagine that you are able to monitor the progression of the cell associations of a cycle using a time-lapse camera left at a given site of the seminiferous tubule. Seminiferous tubule Wave Stage I Stage I Spermatogenic wave the distance between two identical stages, or cellular associations, along the length of the seminiferous tubule. In other words, upon completion of a cycle of cellular associations, a new cycle starts. Let us examine a hypothetical example in 2017, wherein a cycle consists of 6 cellular associations. Also note that a new spermatogenic cell progeny coexists with earlier and later spermatogenic progenies. Therefore, the cellular associations represent the combination of cell members of the overlapping spermatogenic progenies at a given point in the seminiferous tubule. A spermatogenic cycle is defined as the time it takes for the reappearance of the same stage, or cellular association, within a given segment of the seminiferous tubule (see 20-15, left). A spermatogenic wave is defined by the distance between two identical stages, or cellular associations, along the length of the seminiferous tubule (see 2015, right). It can be done experimentally in laboratory animals by an intratesticular injection of 3H thymidine. The spermatogenic cycle is monitored by autoradiography at regular time intervals to determine the progression of radiolabeled spermatogenic cells in their development. Stage I In rodents, the stages or cell associations are aligned in a consecutive linear arrangement. The number of cycles necessary for the completion of a spermatogenic cell progeny is species-dependent. Note that each spermiation event represents the completion a cell progeny (indicated by bars). The major objectives are to erase and reprogram methylation patterns to reset imprints and/or eliminate acquired epigenetic modifications. Both syndromes have an epigenetic defect caused by a lack of methylation of several paternally derived alleles. After examining a number of serial cross sections covering a distance of a few millimeters or centimeters, we determine the successive cellular associations (or stages of a cycle) along the length of the seminiferous tubule. The distance separating two identical stages defines the length of a spermatogenic wave.

The synovial-lining cells are designated type A (macrophage-like synovial cells) and type B (fibroblast-like synovial cells) arteria haemorrhoidalis media discount generic dipyridamole canada. Neutrophils synthesize prostaglandins heart attack the voice cheap 100mg dipyridamole with amex, proteases and reactive oxygen species arteria braquial order dipyridamole 100mg with mastercard, contributors to synovitis pulse pressure table proven dipyridamole 25mg. A proliferative process (hyperplasia) of the synovial cell lining arteria inominada cheap 100 mg dipyridamole, together with a loss in the expression of wear protective lubricin heart attack telugu movie review buy generic dipyridamole, leads to the destruction of the articular cartilage by apoptosis of chondrocytes, followed by destruction of the subjacent bone. Bone erosion, a result of osteoclasts invading the periosteum adjacent to the articular surface, is detected in 80% of the affected patients within 1 year after diagnosis. Inflammatory granuloma within the joint causes degeneration and destruction of the articular cartilage. Within the pannus, cellular responses lead to release of collagenase and metalloproteases 4 and other effector molecules. Synovial macrophages secrete proinflammatory cytokines, tumor necrosis factor ligand and interleukins-1 and -6, to induce the proliferation of synovial cells, which then release collagenase and matrix metalloproteases. Neutrophils contribute prostaglandins, proteases and reactive oxygen species targeted to the destruction of the articular cartilage and subjacent bone tissue. The chronic destruction of the articular cartilage, erosion of the periarticular periosteal bone by activated osteoclasts and the hypertrophy of the synovial membrane are characteristic features of rheumatoid arthritis. Rheumatoid factor is a high affinity autoantibody against the Fc domain of immunoglobulins. Rheumatoid factor has a dual role: it is a diagnostic marker of rheumatoid arthritis and also participates in its pathogenesis. A post-translational conversion of the amino acid arginine into citrulline modifies the folding of citrullinated proteins that become a selective target of the immune system. From a clinical perspective, rheumatoid arthritis causes a systemic illness, including cardiovascular, pulmonary and skeletal disorders determined by inflammatory mediators (cytokines and immune complexes) circulating in blood. Both processes have a common aspect: the transformation of a primary trabecular network (also called primary spongiosa) into mature bone. However, they differ in the starting point: intramembranous ossification consists in the transformation of a mesenchymal template into bone; endochondral ossification consists of the replacement of pre-existing hyaline cartilage template into bone. The following sequence is observed: (1) Aggregates or mesenchymal condensations are formed in several sites. Several trabeculae enlarge by appositional growth and fuse together to form woven bone. Note that intramembranous ossification starts as interstitial growth and continues by appositional growth. The final steps include the conversion of woven bone in the outer and inner layers into compact or lamellar bone of haversian type (concentric lamellae around a space containing blood vessels). The external and internal connective layers become the periosteum and endosteum, respectively. The periosteal collar forms woven bone, by the intramembranous bone formation process, beneath the future periosteum. Preosteoblasts and blood development cells arrive through the perivascular tissue. The primary ossification center now consists of two components: the periosteal collar and the ossification center in the interior of the cartilage template. The growth in length of the long bones depends on the interstitial growth of the hyaline cartilage while the center of the cartilage is being replaced by bone. The secondary centers of ossification consist of the replacement of hyaline cartilage by spongy bone, except the articular cartilage and a thin disk, the epiphyseal growth plate, in the metaphyses (linking the diaphysis to the epiphyses). The epiphyseal growth plate retains the capacity of cartilage development (chondrogenesis) and, after puberty, is replaced by the epiphyseal line. Cartilage development of the growth plate and the formation of the bony collar are regulated by Indian hedgehog (Ihh) secretory protein in a paracrine manner. A spicule consists of a longitudinal core of calcified cartilage, coated by osteoid produced by osteoblasts lining the surface. A trabecula is an osteocyte lamellar core (instead of a calcified cartilage core), covered by osteoblasts depositing osteoid on the surface. Trabeculae, built by osteoblasts and remodeled by osteoclasts, results in the formation of woven or cancellous bone. Woven bone will change into a lamellar bone of the haversian system type using the blood vessel as the axial center for the concentric deposit and organization of lamellae. Osteoblasts lining the endosteum form the inner circumferential lamellae, also by appositional bone growth. At the same time, woven bone is gradually reabsorbed at the inner side, or endosteum, of the shaft and the width of the marrow cavity increases. Consequently, the shaft becomes wider, but the periosteal wall, formed by compact bone, does not increase significantly in thickness. Note that woven bone, persisting at the endosteal surface of the bone, is lamellar but not haversian. This means that the lamellae of woven or trabecular bone do not enclose a blood vessel. Cortical bone remodeling occurs in an old haversian system followed by the reorganization of a new one. Osteoclasts begin eroding the lamellae facing the central canal until they reach the outermost lamella. Residual lamellae of the ongoing degradation process are pushed in between the existing intact osteons, forming the interstitial lamellae. The osteoclasts disappear and osteoblasts emerge to begin the reconstruction process by forming new lamellae from the periphery to the central canal where a blood vessel is located. The starting point of the reconstruction of a new osteon is marked by the cement line, a structure that absorbs microcracking created by load forces acting on the microarchitecture of bone (the osteon). Trabecular bone remodeling follows the same osteoclast resorption and osteoclast-to-osteoblast reversal sequence. A major difference is that this process occurs on the bone surface instead of in an osteon. Fractures can be: (1) Complete fractures (when the bone fragments are separated from each other). The healing of a fracture involves the following phases: (1) Hematoma/inflammatory phase. Bleeding and an inflammatory process lead to the formation of temporary granulation tissue during the first week after fracture. The bone fragments are connected and proper immobilization of the fracture site is required. A soft non-calcified cartilagenous callus connects the two ends of the fractured bone. Excess material of the bone callus is removed by osteoclasts and woven bone is replaced by lamellar compact bone. Osteopetrosis includes a group of hereditary diseases characterized by abnormal or non-existing osteoclast function. Osteoporosis is a bone loss condition associated with aging in which the osteoclast-driven bone degradation process is not fully compensated by the same bone production volume by osteoblasts. The thinning of bone trabeculae in men and the reduction in number of bone trabeculae in women are characteristics of aging. Osteogenesis imperfecta is a genetic disorder defined by fragile bones and fractures ("brittle bone disease"). Missense mutations leading to a defective peptide chain results in abnormalities in most of the collagen triple helix. A diarthrodial joint consists of a vascularized outer layer of dense connective tissue capsule continuous with the periosteum. The capsule surrounds the joint and encloses the synovial cavity, containing fluid produced by the lining cells of the synovial membrane. Synovitis, the inflammatory process of the synovial membrane, occurs when leukocytes infiltrate the synovial compartment. The production of cytokines by synovial cells is a key factor in the pathogenesis of rheumatoid arthritis. A proliferative process (hyperplasia) of the synovial cell lining, together with a loss in the expression of synovial protective lubricin, causes the destruction of the articular cartilage by apoptosis of chondrocytes, followed by destruction of the subjacent bone. Blood offers valuable diagnostic information about normal body functions and pathologic alterations because of its biochemical composition and easy access. Bone marrow microenvironments, or niches, enable colonies of hematopoietic stem cells to fulfill their commitment of producing and maintaining a steady number of mature cell populations and platelets in blood. This article describes the structural and functional characteristics of blood cells, their development and the distribution of progenitor cells in specific hematopoietic niches. These components may be separated by centrifugation when blood is collected in the presence of anticoagulants. This percentage of erythrocyte volume is the hematocrit (Greek, haima, blood; krino, to separate). Sitting on top of the erythrocyte layer is the buffy coat layer, which contains leukocytes (Greek leukos, white; kytos, cell) and platelets. Cytoskeletal and hemoglobin abnormalities of red blood cells (6-2) Plasma is the fluid component of blood. Plasma contains salts and organic compounds (including amino acids, lipids, vitamins, proteins and hormones). In the absence of anticoagulants, the cellular elements of blood, together with plasma proteins (mostly fibrinogen), form a clot in the test tube. Spherocytosis is also an autosomal dominant condition involving a deficiency in spectrin. The common clinical features of elliptocytosis and spherocytosis are anemia, jaundice (resulting from increased bilirubin production) and splenomegaly (enlargement of the spleen). Splenectomy is usually curative, because the spleen is the primary site responsible for the destruction of elliptocytes and spherocytes. Hemoglobin defects: Hemoglobin genetic defects (2 S2) cause sickle cell anemia and thalassemia (Greek thalassa, sea; observed in populations along the Greek and Italian coasts). Sickle cell anemia results from a point mutation in which glutamic acid is replaced by valine at the sixth position in the -globin chain. Adducin is a calmodulin-binding protein that stimulates the association of actin with spectrin. The two polypeptides associate in antiparallel pairs to form a rod about 100 nm long. Two chains join head to head to form a tetramer, found in the cortical region of the red blood cell. This alteration is caused by cytoskeletal abnormalities involving sites of interactions between spectrin and and protein 4. Hb S leads to severe chronic hemolytic anemia and obstruction of postcapillary venules (see Spleen in Chapter 10, Immune-Lymphatic System). Thalassemia syndromes are heritable anemias characterized by defective synthesis of either the or chains of the normal hemoglobin tetramer (2 2). The specific thalassemia syndromes are designated by the affected globin chain: -thalassemia and -thalassemia. Thalassemia syndromes are defined by anemia caused by defective synthesis of the hemoglobin molecule and hemolysis. Determination of glycated hemoglobin is an efficient way to assess pre-diabetes or diabetes mellitus conditions as well as the treatment to achieve longterm regulation of serum glucose levels to prevent cardiovascular, renal and retinal complications. The normal range for the hemoglobin A1c is be- Erythroblastosis fetalis is an antibody-induced hemolytic disease in the newborn that is caused by blood group incompatibility between mother and fetus (see Box 6-A). Essentially, the mother becomes sensitized to blood group antigens on red blood cells, which can reach maternal circulation during the last trimester of pregnancy (when the cytotrophoblast is no longer present as a barrier, as we discuss in Chapter 23, Fertilization, Placentation and Lactation) or during childbirth. Maternal circulation 2 the mother produces antibodies against D antigen present in the Rh system of fetal red blood cells. Fetal red blood cell Fetal circulation D antigen Hemolysis 4 Hemolytic disease occurs because of blood incompatibility between mother and fetus. Subsequent exposure to D antigen during the second or third pregnancy leads to a strong immunoglobulin G (IgG) response (IgGs can cross the placenta). Rh-negative mothers are given anti-D globulin soon after the delivery of an Rh-positive baby. Granulocytes contain primary and specific, or secondary, cytoplasmic granules (see Box 6-C). Granulocytes Granulocytes are phagocytic cells with a multilobed nucleus and measuring 12 to 15 m in diameter. Three types of granulocytes can be distinguished by their cytoplasmic granules: Neutrophils (6-4) Neutrophils have a multilobed nucleus. Neutrophils, which constitute 50% to 70% of circulating leukocytes, have a life span of 6 to 7 hours and may live for up to 4 days in the connective tissue. They measure 12 to 15 m in diameter with a very pale pink cytoplasm (close in color to the erythrocyte). Neutrophils contain primary granules that can barely be resolved, and smaller specific (secondary) granules. The nucleus (stained dark blue) is usually segmented into three to five indented lobes. Specific (secondary) granules Primary granules Trilobed nucleus Tetralobed nucleus Primary granule Granular contents of a neutrophil Neutrophils, so called because of the appearance of their cytoplasmic granules following Wright-Giemsa staining, migrate to the sites of infection where they recognize and phagocytose bacteria. Specific (secondary) Primary (or azurophilic) granules granules contain elastase, defensins and myeloperoxidase. Secondary (or specific) granules contain lysozyme, Golgi region lactoferrin, gelatinase and other proteases. The weak staining properties of secondary Nuclear lobes granules are responsible for the cytoplasmic light-colored appearance.

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