Ragnar Asplund, MD, PhD

• Centre of Family Medicine (CEFAM), Karolinska
• Institute, Stockholm, Sweden
• Research and
• Development Unit, Jamtland County Council,
• Ostersund, Sweden

Contraction of the detrusor muscle of the bladder compresses the entire organ and forces the urine into the urethra impotence xanax discount 100/60 mg viagra with fluoxetine with amex. The ejaculatory ducts of the genital system enter the posterior wall of this segment impotence natural treatment clary sage discount viagra with fluoxetine, and many small prostatic ducts also empty into this segment erectile dysfunction videos discount viagra with fluoxetine 100/60 mg overnight delivery. Membranous urethra extends for about 1 cm from the apex of the prostate gland to the bulb of the penis erectile dysfunction doctor cape town viagra with fluoxetine 100/60mg visa. It passes through the deep perineal pouch of the pelvic floor as it enters the perineum erectile dysfunction treatment in sri lanka cheap viagra with fluoxetine 100/60mg otc. Skeletal muscle of the deep perineal pouch surrounding the membranous urethra forms the external (voluntary) sphincter of the urethra erectile dysfunction when drugs don't work buy generic viagra with fluoxetine from india. This segment is lined with a stratified or pseudostratified columnar epithelium that resembles the epithelium of the genital duct system more than it resembles the epithelium of the more proximal portions of the urinary duct system. Penile (spongy) urethra extends for about 15 cm through the length of the penis and opens on the body surface at the glans penis. The penile urethra is surrounded by the corpus spongiosum as it passes through the length of the penis. It is lined with pseudostratified columnar epithelium except at its distal end, where it is lined with stratified squamous epithelium continuous with that of the skin of the penis. Parasympathetic fibers originate from S2 to S4 segments of the spinal cord and travel with pelvic splanchnic nerves into the bladder. They end in terminal ganglia in the muscle bundles and the adventitia and are the efferent fibers of the micturition reflex. Sensory fibers from the bladder to the sacral portion of the spinal cord are the afferent fibers of the micturition reflex. Urethra the urethra is the fibromuscular tube that conveys urine from the urinary bladder to the exterior through the external In the female, the urethra is short, measuring 3 to 5 cm in length from the bladder to the vestibule of the vagina, where it normally terminates just posterior to the clitoris. As in the male urethra, the lining is initially transitional epithelium, a continuation of the bladder epithelium, but changes to stratified squamous epithelium before its termination. Some investigators have reported the presence of stratified columnar and pseudostratified columnar epithelium in the midportion of the female urethra. Numerous small urethral glands, particularly in the proximal part of the urethra, open into the urethral lumen. Other glands, the paraurethral glands, which are homologous to the prostate gland in the male, secrete into the common paraurethral ducts. The lamina propria is a highly vascularized layer of connective tissue that resembles the corpus spongiosum in the male. Where the urethra penetrates the urogenital diaphragm (membranous part of the urethra), the striated muscle of this structure forms the external (voluntary) urethral sphincter. Essential functions of the kidneys include homeostasis via control of electrolyte and water balance, plasma pH, tissue osmolality, and blood pressure; filtration and excretion of metabolic waste products; and endocrine activities such as secretion of Urinary System hormones to regulate bone marrow erythropoiesis (erythropoietin), blood pressure (renin), and Ca2 metabolism (activation of vitamin D). The nephron consists of the renal corpuscle and a long tubular part that includes a proximal thick segment (proximal convoluted tubule and proximal straight tubule), thin segment, (thin part of the loop of Henle), and distal thick segment (distal straight tubule and distal convoluted tubule). The distal convoluted tubule connects to the collecting tubule mids from each other. The cortex is characterized by renal corpuscles and their associated convoluted and straight tubules. Aggregation of straight tubules and collecting ducts in the cortex form the medullary rays. The base of each renal pyramid faces the cortex and the apical portion (papilla) projects into the minor calyx, a branch of the major calyx that in turn is a division of the renal pelvis. At the hilum, the renal pelvis extends into the ureter, which carries urine into the urinary bladder. Each kidney receives blood from the renal artery, which branches into the interlobar arteries (run between pyramids) that then turn along the base of the pyramid (arcuate arteries) and further branch into smaller interlobular arteries that supply the cortex. In the cortex, the interlobular artery gives off the afferent arterioles (one to each glomerulus), which give rise to the capillaries that form the glomerulus. The glomerular capillaries reunite to form a single efferent arteriole that, in turn, gives rise to a second network of capillaries, the peritubular capillaries. Some of the peritubular capillaries form long loops called the vasa recta, which accompany the thin segments of the nephrons. The peritubular capillaries drain into the interlobular veins, which in turn drain into the arcuate veins, interlobar veins, and the renal vein. Podocytes extend their processes around the capillaries and develop numerous secondary processes called pedicels (foot processes), which interdigitate with other foot processes of the neighboring podocytes. The spaces between the interdigitating foot processes form filtration slits that are covered by the filtration slit diaphragm. Mesangial cells are involved in phagocytosis and endocytosis of residues trapped in the filtration slits, secretion of paracrine substances, structural support for podocytes, and modulation of glomerular distention. The juxtaglomerular apparatus includes the macula densa (monitors Na concentration in tubular fluid), juxtaglomerular cells (secrete renin), and extraglomerular mesangial cells. This tubule is the initial and major site for reabsorption of glucose, amino acids, polypeptides, water, and electrolytes. Reabsorption of the ultrafiltrate continues as it flows from the proximal convoluted into the proximal straight tubule (the thick descending limb of the loop of Henle) that descends into the medulla. The loop of Henle, with both the descending limb (highly permeable to water) and ascending limb (highly permeable to Na and Cl), concentrates the ultrafiltrate. The distal straight tubule (thick ascending limb) ascends back into the cortex to reach the vicinity of its renal corpuscle, where it makes contact with the afferent arteriole. The distal convoluted tubule empties it into the cortical collecting duct that lies in the medullary ray. The medullary collecting duct is lined by cuboidal cells, with a transition to columnar cells as the duct increases in size. The collecting ducts open at the renal papilla, and the modified ultrafiltrate, now called urine, flows sequen- tially via the excretory passages. Transitional epithelium is a specialized stratified epithelium with large dome-shaped (umbrella) cells that bulge into the lumen. The dome-shaped cells have a modified apical membrane containing plaques and fusiform vesicles that accommodate the invaginated excess of the plasma membrane, which is needed for the extension of the apical surface when the organ is stretched. It is lined by transitional epithelium, underlying smooth muscle arranged in three distinct layers, and connective tissue adventitia. The urinary bladder is also lined by transitional epithelium and possesses many mucosal folds, except in the trigone region. The urethra conveys urine from the urinary bladder to the external urethral orifice. The female urethra is short and lined by transitional epithelium (upper half), pseudostratified columnar epithelium (lower half), and stratified squamous epithelium (before its termination). The male urethra is much longer than the female and is divided into three regions: the prostatic urethra (lined by transitional epithelium), a short membranous urethra that pierces the external urethral sphincter (lined by stratified or pseudostratified columnar epithelium), and a long penile urethra (lined by pseudostratified columnar epithelium). The kidneys conserve body fluid and electrolytes and remove metabolic wastes such as urea, uric acid, creatinine, and breakdown products of various substances. They produce urine, initially an ultrafiltrate of blood that is modified by selective resorption and specific secretion by kidney tubule cells. The kidneys also function as endocrine organs, producing erythropoietin, a growth factor that regulates red blood cell formation, and renin, a hormone involved in blood pressure and blood volume control. They also hydroxylate vitamin D, a steroid prohormone, to produce its active form. The concave medial border of each kidney contains a hilum, an indented region through which blood vessels, nerves, and lymphatic vessels enter and leave the kidney. The funnel-shaped origin of the ureter, the renal pelvis, also leaves the kidney at the hilum. A cut, hemisected fresh kidney reveals two distinct regions: a cortex, the reddish-brown outer region, and a medulla, a much lighter inner part continuous with the renal pelvis. The cortex is characterized by renal corpuscles and their tubules, including the convoluted and straight tubules of the nephron, the cortical collecting ducts, and an extensive vascular supply. A frontal section through the cortex and medulla of an unembalmed kidney obtained from autopsy is shown here. The visible hilar region consists of minor calyces (grey/ white) surrounded by yellow in appearance adipose tissue. The medulla consists of renal pyramids, which have their base facing the cortex and their apex in the form of a papilla (P) directed toward the hilum. The majority of the outer part of the pyramid on the left has not been included in the plane of section. The minor calyces drain into major calyces, and in turn, these open into the renal pelvis, which funnels urine into the ureter. An interesting feature in this specimen is that the blood has been retained in many of the vessels, thereby allowing for visualization of several renal vessels in their geographic location. Also seen in the cortex are groups of tubules that are more or less straight and disposed in a radial direction from the base of the medulla (arrows); these are the medullary rays. In contrast, the medulla presents profiles of tubular structures that are arranged as gentle curves in the outer part of the medulla, turning slightly to become straight in the inner part of the medulla. The disposition of the tubules (and blood vessels) gives the cut face of the pyramid a slightly striated appearance that is also evident in the gross specimen (see figure above). They are responsible for the production of urine and correspond to the secretory part of other glands. The collecting ducts, responsible for the final concentration of the urine, are analogous to the ducts of exocrine glands. The tubular parts of the nephron are the proximal thick segment (consisting of the proximal convoluted tubule and the proximal straight tubule), the thin segment, which constitutes the thin limb of the loop of Henle, and the distal thick segment, consisting of the distal straight tubule and the distal convoluted tubule. The loop of Henle is the U-shaped portion of the nephron consisting of the thick straight portions of the proximal and distal tubules and the thin segment between them. The distal convoluted tubule joins the cortical collecting duct via either the connecting tubule or arched connecting tubule. The convoluted tubules, particularly the proximal, because of their tortuosity, present a variety of profiles, most of which are oval or circular; others, more elongate, are in the shape of a letter J, a C, or even an S. The medullary rays are composed of groups of straight tubules oriented in the same direction and appear to radiate from the base of the pyramid. When the medullary rays are cut longitudinally, as they are in this figure, the tubules present elongated profiles. The medullary rays contain proximal straight tubules (thick segments; descending limb of loop of Henle), distal straight tubules (thick segments; ascending limbs of loop of Henle), and cortical collecting ducts. This figure presents another profile of the renal cortex, at a somewhat higher magnification, cut in a plane at a right angle to the section in figure above. The peripheral part of the micrograph shows the cortical labyrinth in which the tubules display chiefly round and oval profiles but also some that are more elongate and curved. In contrast, the profiles presented by the tubules of the medullary ray in this figure are quite different from those seen in figure above. A general survey of the tubules within the medullary ray reveals that several distinct types can be recognized on the basis of the size of the tubule, shape of the lumen, and size of the tubule cells. These features as well as those of the cortical labyrinth are considered in Plate 76. Proximal convoluted tubules generally have a larger diameter than distal tubules have; cross-sections of the lumen often appear stellate. Also, the proximal convoluted tubule is more than twice as long as the distal convoluted tubule; thus, the majority of tubular profiles in the cortical labyrinth will be of proximal tubules. Mesangial cells and their extracellular matrix constitute the mesangium of the renal corpuscle. They underlie the endothelium of the capillaries of the glomerular tuft and extend to the vascular pole, where they become part of the juxtaglomerular apparatus. The terminal portion of the distal thick segment of the nephron lies close to the afferent arteriole. Tubule epithelial cells closest to the arteriole are thinner, taller, and more closely packed than other tubule cells and constitute the macula densa. Arterial smooth muscle cells opposite the macula densa are modified into juxtaglomerular cells that secrete renin in response to decreased blood NaCl concentration. The proximal convoluted tubules (unlabeled) have a slightly larger outside diameter than the distal tubules have. The proximal tubules have a brush border, whereas the distal tubules have a cleaner, sharper luminal surface. The lumen of the proximal tubules is often starshaped; this is not the case with distal tubules. Typically, fewer nuclei appear in a cross-section of a proximal tubule than in an equivalent segment of a distal tubule. Most of the above points can also be utilized in distinguishing the straight portions of the proximal and distal thick segments in the medullary rays, as shown in figure on right. Second, the number of proximal straight (P) and distal straight (D) tubular profiles are about equal in the medullary ray, as is shown by the labeling of each tubule in this figure. Note that, in contrast to the distal straight tubules, the proximal straight tubules display a brush border and have a larger outside diameter, with many displaying a star-shaped lumen. The renal corpuscle appears as a spherical structure whose periphery is composed of a thin capsule that encloses a narrow clear-appearing space, the urinary space (asterisks), and a capillary tuft or glomerulus that appears as a large cellular mass. The visceral layer consists of cells called podocytes (Pod) that lie on the outer surface of the glomerular capillary. Except where they clearly line the urinary space, as the labeled cells do in figure on left, podocytes may be difficult to distinguish from the capillary endothelial cells. To complicate matters, the mesangial cells are also a component of the glomerulus. In general, nuclei of podocytes are larger and stain less intensely than do the endothelial and mesangial cell nuclei. In figure on right, both the vascular pole and the urinary pole of the renal corpuscle are evident.

The intercellular space is also occupied by electron-dense material (arrowheads) containing desmocollins and desmogleins erectile dysfunction aids discount 100/60mg viagra with fluoxetine fast delivery. The intercellular space above and below the macula adherens is not well defined because of extraction of the plasma membrane to show components of this structure impotence young male order viagra with fluoxetine 100/60mg without a prescription. The extracellular portions of desmocollins and desmogleins from opposing cells interact with each other in the localized area of the desmosome erectile dysfunction icd 9 code cheap 100/60mg viagra with fluoxetine with amex, forming the cadherin "zipper erectile dysfunction at 65 buy discount viagra with fluoxetine 100/60 mg online. Various procedures have been used to study gap junctions age related erectile dysfunction causes order viagra with fluoxetine toronto, including the injection of dyes and fluorescent or radiolabeled compounds and the measurement of an electric current flow between cells fluoride causes erectile dysfunction buy cheap viagra with fluoxetine 100/60mg. After a short period, the dye can be readily visualized in immediately adjacent cells. Electrical conductance studies show that neighboring cells joined by gap junctions exhibit a low electrical resistance between them and current flow is high; therefore, gap junctions are also called low-resistance junctions. Connexins expressed in transfected cells produce gap junctions, which can be isolated and studied by molecular and biochemical methods as well as by the improved imaging techniques of electron crystallography and atomic force microscopy. Each connexon contains six symmetrical subunits of an integral membrane protein called connexin (Cx) that is paired with a similar structure from the adjacent membrane. The subunits are configured in a circular arrangement to surround a 10-nm-long cylindrical transmembrane channel with a diameter of 2. Most connexons pair with identical connexons (homotypic interaction) on the adjacent plasma membrane. These channels allow molecules to pass evenly in both directions; however, heterotypic channels can be asymmetrical in function, passing certain molecules faster in one direction than in another. Conformational changes in connexins leading to opening or closing gap junction channels have been observed with atomic force microscopy. High-resolution imaging techniques such as cryoelectron microscopy have been used to examine the structure of gap junctions. These studies reveal groups of tightly packed channels, each formed by two half-channels called connexons embedded in the facing membranes. These channels are represented by pairs of connexons that bridge the extracellular space between adjacent cells. Channels in gap junctions can fluctuate rapidly between an open and a closed state through reversible changes in the conformation of individual connexins. However, other calcium-independent gating mechanisms responsible for closing and opening of the cytoplasmic domains of gap junction channels have also been identified. Electron micrograph showing the plasma membranes of two adjoining cells forming a gap junction. The unit membranes (arrows) approach one another, narrowing the intercellular space to produce a 2-nm-wide gap. Drawing of a gap junction showing the membranes of adjoining cells and the structural components of the membrane that form channels or passageways between the two cells. Each passageway is formed by a circular array of six subunits, dumbbell-shaped transmembrane proteins that span the plasma membrane of each cell. These complexes, called connexons, have a central opening of about 2 nm in diameter. The channels formed by the registration of the adjacent complementary pairs of connexons permit the flow of small molecules through the channel but not into the intercellular space. Conversely, substances in the intercellular space can permeate the area of a gap junction by flowing around the connexon complexes, but they cannot enter the channels. The diameter of the channel in an individual connexon is regulated by reversible changes in the conformation of the individual connexins. For instance, a mutation in the gene encoding connexin-26 (Cx26) is associated with congenital deafness. The gap junctions formed by Cx26 are found in the inner ear and are responsible for recirculating K in the cochlear sensory epithelium. Other mutations affecting Cx46 and Cx50 genes have been identified in patients with inherited cataracts. Both proteins are localized within the lens of the eye and form extensive gap junctions between the epithelial cells and lens fibers. These gap junctions play a crucial role in delivering nutrients to and removing metabolites from the avascular environment of the lens. A summary of the features of all of the junctions discussed in this chapter is found in Table 5. These images show the extracellular surface of a plasma membrane preparation from the HeLa cell line. Multiple copies of the connexin-26 gene were incorporated into the HeLa cell genome to achieve overexpression of the connexin protein. Note the clear profiles of individual connexin molecules assembled into the connexon. Note that the conformational change of the connexin molecules has caused the channel to close and has reduced the height of the connexon. Communicating Junction (Cell-to-Cell) Gap junction (nexus) Connexin Connexin in adjacent cell Not known Creates a conduit between two adjacent cells for passage of small ions and informational micromolecules Morphologic Specializations of the Lateral Cell Surface Lateral cell surface folds (plicae) create interdigitating cytoplasmic processes of adjoining cells. These infoldings increase the lateral surface area of the cell and are particularly prominent in epithelia that are engaged in fluid and electrolyte transport, such as the intestinal and gallbladder epithelium. Anions then diffuse across the membrane to maintain electrical neutrality, and water diffuses from the cytoplasm into the intercellular space, driven by the osmotic gradient between the salt concentration in the intercellular space and the concentration in the cytoplasm. The intercellular space distends because of the accumulating fluid moving across the epithelium, but it can distend only to a limited degree because of junctional attachments in the apical and basal portions of the cell. Hydrostatic pressure gradually builds up in the intercellular space and drives an essentially isotonic fluid from the space into the underlying connective tissue. The occluding junction at the apical end of the intercellular space prevents fluid from moving in the opposite direction. Cell-to-extracellular matrix junctions anchor the cell to the extracellular matrix; they are represented by focal adhesions and hemidesmosomes. Basal cell membrane infoldings increase the cell surface area and facilitate morphologic interactions between adjacent cells and extracellular matrix proteins. This electron micrograph shows infoldings or interdigitations at the lateral surfaces of two adjoining intestinal absorptive cells. The basement membrane appears as a thick homogeneous layer immediately below the epithelium. It is actually a part of the connective tissue and is composed largely of densely packed collagen fibrils. The glands in this specimen have been crosssectioned and appear as round profiles. Note that neither the basement membrane nor the mucin that is located within the goblet cells is stained. It reveals the basement membrane as a thin, magenta layer (arrows) between the base of the epithelial cells of the glands and the adjacent connective tissue. In the trachea, the structure that is often described as basement membrane includes not only the true basement membrane but also an additional layer of closely spaced and aligned collagen fibrils that belong to the connective tissue. It appears as a thin, well-defined magenta layer between the epithelium and the connective tissue. The stain reacts with the sugar moieties of proteoglycans, accumulating in sufficient amounts and density to make the basement membrane visible in the light microscope. Techniques involving the reduction of silver salts by the sugars blacken the basement membrane and are also used to demonstrate this structure. That most connective tissue cells are not surrounded by basement membrane material is consistent with their lack of adhesion to the connective tissue fibers. In fact, they must migrate within the tissue under appropriate stimuli to function. The basal lamina is the structural attachment site for overlying epithelial cells and underlying connective tissue. As the plane of section passes through each smooth muscle cell, it may or may not pass through the portion of the cell that includes the nucleus. Therefore, in some of the polygonal profiles, nuclei can be seen; in other profiles, no nuclei are seen. Former descriptions of basal lamina were based on the investigation of specimens routinely prepared for electron microscopy. Some authors use basement membrane when referring to both light and electron microscopic images. Others dispense with the term basement membrane altogether and use basal lamina in both light and electron microscopy. Because the term basement membrane originated with light microscopy, it is used in this book only in the context of light microscopic descriptions and only in relation to Functional Considerations: Basement Membrane epithelia. In this context, the light microscopy term basement membrane actually describes basal lamina and the underlying reticular lamina combined. The term external lamina is used to identify basal lamina when it forms a peripheral cellular investment, as in muscle cells and peripheral nerve supporting cells. Between the basal lamina and the cell is a relatively clear or electron-lucent area, the lamina lucida (also about 40 nm wide). The lamina lucida may thus be an artifact of chemical fixation that appears as the epithelial cells shrink away from a high concentration of macromolecules deposited next to the basal domain of the epithelial cells. It probably results from the rapid dehydration that resembles the basal lamina of epithelium. The basal lamina contains molecules that come together to form a sheet-like structure. The micrograph shows only the basal portions of the two cells and parts of their nuclei (N). The intercellular space is partially obscured by lateral interdigitations between the two cells (arrows). This electron micrograph shows basal domain of an epithelial cell obtained from human skin. The specimen was prepared by low-temperature, high-pressure freezing, which retains more tissue components than does chemical fixation. Note that a separate lamina densa or lamina lucida is not seen in this preparation. The lamina lucida is most likely an artifact that appears as the epithelial cell shrinks away from a high concentration of macromolecules just beneath the epithelial cell. This region of highly concentrated macromolecules precipitates into the artifact known as the lamina densa. Laminins possess binding sites for different integrin receptors in the basal domain of the overlying epithelial cells. They also play roles in the development, differentiation, and remodeling of epithelium. Most of the volume of the basal lamina is probably attributable to its proteoglycan content. Because of their highly anionic character, these molecules are extensively hydrated. They also carry a high negative charge; this quality suggests that proteoglycans play a role in regulating the passage of ions across the basal lamina. The most common heparan sulfate proteoglycan found in all basal laminae is the large multidomain proteoglycan perlecan (400 kDa). Agrin (500 kDa) is another important molecule found almost exclusively in the glomerular basement membrane of the kidney. It plays a major role in renal filtration as well as in cell-to-extracellular matrix interactions. These proteins are synthesized and secreted by the epithelial cells and other cell types that possess an external lamina. These cross-shaped glycoprotein molecules (140 to 400 kDa) are composed of three polypeptide chains. The 7S domain of the tetramer (called the 7S box) determines the geometry of the tetramer. The primary sequence of these molecules contains information for their self-assembly (other molecules of the basal lamina are incapable of forming sheet-like structures by themselves). These two structures are joined together primarily by entactin/nidogen bridges and are additionally secured by other proteins (perlecan, agrin, fibronectin, etc. Next, four dimers join together at their 7S domains to form tetramers connected by the 7S box. The reticular lamina, as such, belongs to the connective tissue and is not a product of the epithelium. Several structures are responsible for attachment of the basal lamina to the underlying connective tissue. To produce a basal lamina, each epithelial cell must first synthesize and secrete its molecular components. The calcium-dependent polymerization of laminin molecules that occurs at the basal cell surface initiates basal lamina formation. These two structures are connected by entactin or nidogen bridges and are additionally secured by other proteins. The epithelial cell is located on the outer (abluminal) surface of the endothelial cell. Note that the endothelial cells and epithelial cells are separated by the shared basal lamina and that no collagen fibrils are present. Photomicrograph of a silver preparation revealing two longitudinally sectioned venous sinuses in the spleen. These blood vessels are surrounded by a modified basement membrane, which takes the form of a ring-like structure, much like the hoops of a barrel, rather than a continuous layer or lamina. The rings are blackened by the silver and appear as bands where the walls of the vessel have been tangentially sectioned (arrows). To the right, the cut has penetrated deeper into the vessel and shows the lumen (L). In the lower vessel, the cut rings have been sectioned in a virtually perpendicular plane, and the rings appear as a series of dots.

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The ultimate objective of hemopoiesis is to maintain a constant level of the different cell types found in the peripheral blood erectile dysfunction doctor dublin order generic viagra with fluoxetine from india. Both the human erythrocyte (life span of 120 days) and the platelet (life span of 10 days) spend their entire life in the circulating blood erectile dysfunction 19 year old male buy generic viagra with fluoxetine line. Leukocytes erectile dysfunction generics cheap 100/60mg viagra with fluoxetine fast delivery, however erectile dysfunction at age 26 order 100/60 mg viagra with fluoxetine visa, migrate out of the circulation shortly after entering it from the bone marrow and spend most of their variable life spans (and perform all of their functions) in the tissues erectile dysfunction and diabetic neuropathy cheap viagra with fluoxetine 100/60mg without prescription. In the adult erectile dysfunction medication muse cheap viagra with fluoxetine 100/60 mg otc, erythrocytes, granulocytes, monocytes, and platelets are formed in the red bone marrow; lymphocytes are also formed in the red bone marrow and in the lymphatic tissues. To study the stages of blood cell formation, a sample of bone marrow aspirate (see page 302) is prepared as a stained smear in a manner similar to that of a smear of blood. During fetal life, both erythrocytes and leukocytes are formed in several organs before the differentiation of the bone marrow. The first or yolk-sac phase of hemopoiesis begins in the third week of gestation and is characterized by the formation of "blood islands" in the wall of the yolk sac of the embryo. Blood cell formation in these sites is largely limited to erythroid cells, although some leukopoiesis occurs in the liver. The liver is the major blood-forming organ in the fetus during the second trimester. The third or bone marrow phase of fetal hemopoiesis and leukopoiesis involves the bone marrow (and other lymphatic tissues) and begins during the second trimester of pregnancy. Cytokines (including hemopoietic growth factors) may and do act individually and severally at any point in the process from the first stem cell to the mature blood or connective tissue cell. If committed to enter the mast cell lineage, the basophil/mast cell progenitor cell migrates to the spleen where it differentiates into a mast cell progenitor cell. After further differentiation in the spleen, it migrates to the intestine to become a mast cell precursor. Although it is difficult to discern, these cells are located between developing liver cells and the wall of the vascular sinus. Monophyletic Theory of Hemopoiesis According to the monophyletic theory of hemopoiesis, blood cells are derived from a common hemopoietic stem cell. Essentially, three major organs involved in hemopoiesis can be sequentially identified: the yolk sac in the early developmental stages of the embryo, the liver during the second trimester of pregnancy, and the bone marrow during the third trimester. The spleen participates to a very limited degree during the second trimester of pregnancy. In children and young adults, hemopoiesis occurs in the red bone marrow of all bones, including long bones such as the femur and tibia. The cytoplasm shows strong basophilia because of the large number of free ribosomes (polyribosomes) that synthesize hemoglobin. At the stage when the cytoplasm displays both acidophilia, because of the staining of hemoglobin, and basophilia, because of the staining of the ribosomes, the cell is called a polychromatophilic erythroblast. The polychromatophilic erythroblast shows both acidophilic and basophilic staining of cytoplasm. The nucleus of the cell is smaller than that of the basophilic erythroblast, and coarse heterochromatin granules form a checkerboard pattern that helps identify this cell type. The orthochromatophilic erythroblast is recognized by its increased acidophilic cytoplasm and dense nucleus. At this stage, the orthochromatophilic erythroblast is no longer capable of division. The first microscopically recognizable precursor cell in erythropoiesis is called the proerythroblast. The orthochromatic erythroblast loses its nucleus by extruding it from the cell; it is then ready to pass into the blood sinusoids of the red bone marrow. The polyribosomes of the new erythrocytes can also be demonstrated with special stains that cause the polyribosomes to clump and form a reticular network. Consequently, polychromatophilic erythrocytes are also (and more commonly) called reticulocytes. In normal blood, reticulocytes constitute about 1% to 2% of the total erythrocyte count. However, if increased numbers of erythrocytes enter the bloodstream (as during increased erythropoiesis to compensate for blood loss), the number of reticulocytes increases. Kinetics of Erythropoiesis Mitoses occur in proerythroblasts, basophilic erythroblasts, and polychromatophilic erythroblasts. Although recognizable, the proerythroblast is not easily identified in routine bone marrow smears. The basophilic erythroblast is smaller than the proerythroblast, from which it arises by mitotic division. The nucleus of the basophilic erythroblast is smaller (10 to 16 m in diameter) and progressively more heterochromatic At each of these stages of development, the erythroblast divides several times. It takes about a week for the progeny of a newly formed basophilic erythroblast to reach the circulation. Nearly all erythrocytes are released into the circulation as soon as they are formed; bone marrow is not a storage site for erythrocytes. Erythrocyte formation and release are regulated by erythropoietin, a 34 kDa glycoprotein hormone synthesized and secreted by the kidney in response to decreased blood oxygen concentration. Shown here are normal human bone marrow cells as Erythrocytes have a life span of about 120 days in humans. The macrophage system of the spleen, bone marrow, and liver phagocytoses and degrades the senescent erythrocytes. The heme and globin dissociate, and the globin is hydrolyzed to amino acids, which enter the metabolic pool for reuse. The iron on the heme is released, enters the iron-storage pool in the spleen in the form of hemosiderin or ferritin, and is stored for reuse in hemoglobin synthesis. The rest of the heme moiety of the hemoglobin molecule is partially degraded to bilirubin, bound to albumin, released into the bloodstream, and transported to the liver, where it is conjugated and excreted via the gallbladder as the bilirubin glucuronide of bile. The cytoplasm contains a group of mitochondria located below the nucleus and small cytoplasmic vacuoles. The thrombocytopoiesis from the bone marrow progenitors is a complex process of cell divisions myeloid series. Under stimulation by thrombopoietin, a 30 kDa glycoprotein hormone produced by liver and kidney, ploidy increases from 8n to 64n before chromosomal replication ceases. The cell then becomes a platelet-producing megakaryocyte, a cell measuring 50 to 70 m in diameter with a complex multilobed nucleus and scattered azurophilic granules. Both the nucleus and the cell increase in size in proportion to the ploidy of the cell. When bone marrow is examined in a smear, platelet fields are seen to fill much of the peripheral cytoplasm of the megakaryocyte. Thrombocytopenia (a low blood platelet count) is an important clinical problem in the management of patients with immune-system disorders and cancer. It increases the risk of bleeding and in cancer patients often limits the dose of chemotherapeutic agents. The neutrophil progenitor (NoP) undergoes six morphologically identifiable stages in the process of maturation: myeloblast, promyelocyte, myelocyte, metamyelocyte, band (immature) cell, and mature neutrophil. Eosinophils and basophils undergo a morphologic maturation similar to that of neutrophils. The nucleus is no longer present, and the cytoplasm shows the characteristic fimbriated processes that occur just after nuclear extrusion. Myeloblasts are the first recognizable cells that begin the process of granulopoiesis. The myeloblast is the earliest microscopically recognizable neutrophil precursor cell in the bone marrow. The promyelocyte has a large spherical nucleus with azurophilic (primary) granules in the cytoplasm. Azurophilic granules are produced only in promyelocytes; cells in subsequent stages of granulopoiesis do not make azurophilic granules. For this reason, the number of azurophilic granules is reduced with each division of the promyelocyte and its progeny. Recognition of the neutrophil, eosinophil, and basophil lines is possible only in the next stage-the myelocyte- when specific (secondary) and tertiary granules begin to form. The mitotic (proliferative) phase in granulopoiesis lasts about a week and stops at the late myelocyte stage. The postmitotic phase, characterized by cell differentiation-from metamyelocyte to mature granulocyte-also lasts about a week. The time it takes for half of the circulating segmented neutrophils to leave the peripheral blood is about 6 to 8 hours. Neutrophils leave the blood randomly-that is, a given neutrophil may circulate for only a few minutes or as long as 16 hours before entering the perivascular connective tissue (a measured half-life of circulating human neutrophils is only 8 to 12 hours). Neutrophils live for 1 to 2 days in the connective tissue, after which they are destroyed by apoptosis and are subsequently engulfed by macrophages. Also, large numbers of neutrophils are lost by migration into the lumen of the gastrointestinal tract from which they are discharged with the feces. Bone marrow maintains a large reserve of fully functional neutrophils ready to replace or supplement circulating neutrophils at times of increased demand. Specific granules begin to emerge from the convex surface of the Golgi apparatus, whereas azurophilic granules are seen at the concave side. The metamyelocyte is the stage at which neutrophil, eosinophil, and basophil lines can be clearly identified by the presence of numerous specific granules. A few hundred granules are present in the cytoplasm of each metamyelocyte, and the specific granules of each variety outnumber the azurophilic granules. In the neutrophil, this ratio of specific to azurophilic granules is about 2 to 1. Theoretically, the metamyelocyte stage in granulopoiesis is followed by the band stage and then the segmented stage. Although these stages are obvious in the neutrophil line, they are rarely, if ever, observed in the eosinophil and basophil lines in which the next easily recognized stages of development are the mature eosinophil and mature basophil, respectively. In the neutrophil line, the band (stab) cell precedes development of the first distinct nuclear lobes. In normal conditions, the bone marrow produces more than 1011 neutrophils each day. As a result of the release of neutrophils from the bone marrow, approximately 5 to 30 times as many mature and near-mature neutrophils are normally present in the bone marrow as are present in the circulation. This bone marrow reserve pool constantly releases neutrophils into the circulation and is replenished by maturing cells. The reserve neutrophils can be released abruptly in response to inflammation, infection, or strenuous exercise. This reserve consists of a freely circulating pool and a marginated pool, with the latter contained in small blood vessels. The normally marginated neutrophils, however, loosely adhere to the endothelium through the action of selectin and can be recruited very quickly. They are in dynamic equilibrium with the circulating pool, which is approximately equal to the size of the marginated pool. The size of the reserve pool in the bone marrow and in the vascular compartment depends on the rate of granulopoiesis, the life span of the neutrophils, and the rates of migration into the bloodstream and connective tissue. Transcription factors control the fate of hemopoietic cells, whereas cytokines and local mediators regulate all stages of hemopoiesis. Blood the nucleus of the band (stab) cell is elongated and of nearly uniform width, giving it a horseshoe-like appearance. Nuclear constrictions then develop in the band neutrophil and become more prominent until two to four nuclear lobes are recognized; the cell is then considered a mature neutrophil, also called a polymorphonuclear neutrophil or segmented neutrophil. Although the percentage of band cells in the circulation is almost always low (0% to 3%), it may increase in acute or chronic inflammation and infection. Signaling molecules from a variety of bone marrow cells initiate intracellular pathways that ultimately target a select group of synergistic and inhibitory proteins known as transcription factors. Times indicated along vertical lines are the approximate time between recognizable stages. M-1 wk indicates increase in number by mitosis for 1 week before differentiation begins. In addition to identifying the various intracellular transcription factors, recent studies have identified and begun to characterize numerous signaling molecules found in the bone marrow. These include glycoproteins that act as both circulating hormones and local mediators to regulate the progress of hemopoiesis and the rate of differentiation of other cell types (Table 10. Specific hormones such as erythropoietin or thrombopoietin, discussed in a previous section, regulate erythrocyte and thrombocyte development, respectively. Interleukins, produced by lymphocytes, act on other leukocytes and their progenitors. Any particular cytokine may act at one or more stages in hemopoiesis, affecting cell division, differentiation, or cell function. The isolation, characterization, manufacture, and clinical testing of cytokines (proteins and peptides that are signaling compounds) in the treatment of human disease are major activities of the rapidly growing biotechnology industry. Nearly all of them act on progenitor stem cells, lineage-restricted progenitor cells, committed cells, and maturing and mature cells. Therefore, the targets listed above are target lines rather than individual target cells. Although lymphocytes continuously proliferate in the peripheral lymphatic organs, the bone marrow remains the primary site of lymphopoiesis in humans. In mammals, these cells originate in bursa-equivalent organs such as the bone marrow, gut-associated lymphatic tissue, and spleen. The production and differentiation of lymphocytes are discussed in more detail in Chapter 14, Lymphatic System. The bone marrow sinusoids provide the barrier between the hemopoietic compartment and the peripheral circulation.

A distinctive feature of mammalian centrioles is the difference between individual centrioles in the pair erectile dysfunction homeopathic drugs viagra with fluoxetine 100/60mg generic. In nondividing cells erectile dysfunction doctor in nj purchase viagra with fluoxetine cheap, centrioles are arranged in pairs in which one centriole is aligned at a right angle to the other erectile dysfunction treatment ppt discount 100/60 mg viagra with fluoxetine visa. One centriole is also more mature (generated at least two cell cycles earlier) than the other centriole erectile dysfunction treatment cost in india viagra with fluoxetine 100/60 mg cheap, which was generated in the previous cell cycle erectile dysfunction exam what to expect buy 100/60mg viagra with fluoxetine visa. The mature centriole is characterized by the presence of satellites and appendages impotence nerve buy viagra with fluoxetine 100/60 mg without a prescription. The basic components of each centriole are microtubule triplets that form the cylindrical structure surrounding an internal lumen. The proximal part of the lumen is lined by -tubulin, which provides the template for nucleation and arrangement of the microtubule triplets. In some species, two protein bridges, the proximal and distal connecting fibers, connect each centriole in a pair. The primary cilium formation first occurs during G1 phase in which the centrosome migrates toward the cell membrane and initiates the process of ciliogenesis. Necessary structural and transport proteins are acquired and activated to build primary cilium axoneme (9 0) directly on the top of the mature centriole. Duplication of centrioles begins near the transition between the G1 and S phases of the cell cycle, and the two centrioles are visible in S phase. During the late G2 phase, centrioles reach their full maturity, whereas the primary cilium is disassembled. This allows centrioles to migrate away from the cell membrane and participate in the mitotic spindle formation. Once cell division is complete, the centrioles can proceed to ciliary reassembly in G1 phase. In most cells, duplication begins with the splitting of a centriole pair, followed by the appearance of a small mass of fibrillar and granular material at the proximal lateral end of each original centriole. Microtubules begin to develop in the mass of fibrous granules as it grows (usually during the S to late G2 phases of the cell cycle), appearing first as a ring of nine single tubules, then as doublets, and finally as triplets. Before the onset of mitosis, centrioles with surrounding amorphous pericentriolar material position themselves on opposite sides of the nucleus and produce astral microtubules. In doing so, they define the poles between which the bipolar mitotic spindle develops. The important difference between duplication of centrioles during mitosis and during ciliogenesis is the fact that during mitosis, only one daughter centriole buds from the lateral side of parent organelle, whereas during ciliogenesis, as many as 10 centrioles may develop around the parent centriole. Basal Bodies Development of cilia on the cell surface requires the presence of basal bodies, structures derived from centrioles. The generation of centrioles, which occurs during the process of ciliogenesis, is responsible for the production of basal bodies. The newly formed centrioles migrate to the apical surface of the cell and serve as organizing centers for the assembly of the microtubules of the cilium. The core structure (axoneme) of a motile cilium is composed of a complex set of microtubules consisting of two central microtubules surrounded by nine microtubule doublets (9 2 configuration). The axonemal microtubule doublets are continuous with the A and B microtubules of the basal body from which they develop by addition of - and -tubulin dimers at the growing plus end. A detailed description of the structure of cilia, basal bodies, and the process of ciliogenesis can be found in Chapter 5, Epithelial Tissue. Inclusions are cytoplasmic or nuclear structures with characteristic staining properties that are formed from the metabolic products of cell. Some of them, such as pigment granules, are surrounded by a plasma membrane; others. It is easily seen in nondividing cells such as neurons and skeletal and cardiac muscle cells. Lipofuscin accumulates during the years in most eukaryotic cells as a result of cellular senescence (aging); thus, it is often called the "wear-and-tear" pigment. Lipofuscin is a conglomerate of oxidized lipids, phospholipids, metals, and organic molecules that accumulate within the cells as a result of oxidative degradation of mitochondria and lysosomal digestion. Phagocytotic cells such as macrophages may also contain lipofuscin, which accumulates from the digestion of bacteria, foreign particles, dead cells, and their own organelles. Recent experiments indicate that lipofuscin accumulation may be an accurate indicator of cellular stress. Hemosiderin is most easily demonstrated in the spleen, where aged erythrocytes are phagocytosed, but it can also be found in alveolar macrophages in the lung tissue, especially after pulmonary infection accompanied by small hemorrhage into the alveoli. It is visible in light microscopy as a deep brown granule, more or less indistinguishable from lipofuscin. Hemosiderin granules can be differentially stained using histochemical methods for iron detection. Liver and striated muscle cells, which usually contain large amounts of glycogen, may display unstained regions where glycogen is located. Lipid inclusions (fat droplets) are usually nutritive inclusions that provide energy for cellular metabolism. Low-magnification electron micrograph showing a portion of a hepatocyte with part of the nucleus (N, upper left). Even the smallest aggregates (arrows) appear to be composed of several smaller glycogen particles. The density of the glycogen is considerably greater than that of the ribosomes (lower left). During mitosis, centrioles are responsible for forming the bipolar mitotic spindle, which is essential for equal segregation of chromosomes between daughter cells. The resulting changes in chromosomal number (aneuploidy) may increase the activity of oncogenes or decrease protection from tumor-suppressor genes. Electron micrograph of an invasive breast tumor cell showing abnormal symmetrical tripolar mitotic spindle in the metaphase of cell division. This drawing composed by color tracings of microtubules (red), mitotic spindle poles (green), and metaphase chromosomes (blue) (obtained from six nonadjacent serial sections of dividing tumor cell) shows more clearly the organization of this abnormal mitotic spindle. Detailed analysis and three-dimensional reconstruction of the spindle revealed that each spindle pole had at least two centrioles and that one spindle pole was composed of two distinct but adjacent foci of microtubules. Altered centrosome structure is associated with abnormal mitoses in human breast tumors. Lipid droplets are usually extracted by the organic solvents used to prepare tissues for both light and electron microscopy. What is seen as a fat droplet in light microscopy is actually a hole in the cytoplasm that represents the site from which the lipid was extracted. In individuals with genetic defects of enzymes involved in lipid metabolism, lipid droplets may accumulate in abnormal locations or in abnormal amounts. Crystalline inclusions contained in certain cells are recognized in the light microscope. In humans, such inclusions are found in the Sertoli (sustentacular) and Leydig (interstitial) cells of the testis. Although some of these inclusions contain viral proteins, storage material, or cellular metabolites, the significance of others is not clear. This network provides a structural substratum on which cytoplasmic reactions occur, such as those involving free ribosomes, and along which regulated and directed cytoplasmic transport and movement of organelles occur. Cells have two major compartments: the cytoplasm (contains organelles and inclusions surrounded by cytoplasmic matrix) and the nucleus (contains genome). Organelles are metabolically active complexes or compartments that are classified into membranous and nonmembranous organelles. It is composed of phospholipids, cholesterol, embedded integral membrane proteins, and associated peripheral membrane proteins. Integral membrane proteins have important functions in cell metabolism, regulation, and integration. They include pumps, channels, receptor proteins, linker proteins, enzymes, and structural proteins. Lipid rafts represent microdomains in the plasma membrane that contain high concentrations of cholesterol and glycosphingolipids. They are movable signaling platforms that carry integral and peripheral membrane proteins. Vesicle budding permits molecules to enter the cell (endocytosis), leave the cell (exocytosis), or travel within the cell cytoplasm in transport vesicles. It is dependent on three different mechanisms: pinocytosis (uptake of fluids and dissolved small proteins), phagocytosis (uptake of large particles), and receptor-mediated endocytosis (uptake of specific molecules that bind to receptors). Exocytosis is the process of cellular secretion in which transport vesicles, when fused with plasma membrane, discharge their content into the extracellular space. In constitutive exocytosis, the content of transport vesicles is continuously delivered and discharged at the plasma membrane. In regulated secretory exocytosis, the content of vesicles is stored within the cell and released pending hormonal or neural stimulation. Lysosomes are digestive organelles containing hydrolytic enzymes that degrade substances derived from endocytosis and from the cell itself (autophagy). They have a unique membrane made of specific structural proteins resistant to hydrolytic digestion. Lysosomes develop from endosomes by receiving newly synthesized lysosomal proteins (enzymes and structural proteins) that are targeted via the mannose-6-phosphate (M-6-P) lysosomal targeting signals. Proteasomes are nonmembranous organelles that also function in degradation of proteins. They represent cytoplasmic protein complexes that destroy damaged (misfolded) or unwanted proteins that have been labeled for destruction with ubiquitin without the involvement of lysosomes. It is the site of protein synthesis and posttranslational modification of newly synthesized proteins. It contains detoxifying enzymes (liver) and enzymes for glycogen and lipid metabolism. The Golgi apparatus represents a series of stacked, flattened cisternae and functions in the posttranslational modification, sorting, and packaging of proteins directed to four major cellular destinations: apical and basolateral plasma membrane, endosomes and lysosomes, and apical cytoplasm (for storage and/or secretion). They are abundant in cells that generate and expend large amounts of energy, and they regulate apoptosis (programmed cell death). Peroxisomes are small organelles involved in the production and degradation of H2O2 and in the degradation of fatty acids. Microtubules form tracts for intracellular vesicular transport and mitotic spindles; they are also responsible for the movement of cilia and flagella and for the maintenance of cell shape. Movement of intracellular organelles along microtubules is generated by molecular motor proteins (dyneins and kinesins). Actin filaments (microfilaments) are thinner (6 to 8 nm in diameter), shorter, and more flexible than microtubules. They are composed of polymerized G-actin (globulin actin) molecules that form F-actin (filamentous actin). Actin filaments are also responsible for cell-to-extracellular matrix attachment (focal adhesions), movement of membrane proteins, formation of the structural core of microvilli, and cell motility through the creation of cell extensions (lamellipodia and filopodia). Intermediate filaments are rope-like filaments (8 to 10 nm in diameter) that add stability to the cell and interact with cell junctions (desmosomes and hemidesmosomes). Intermediate filaments are formed from nonpolar and highly variable intermediate filament subunits that include keratins (found in epithelial cells), vimentin (mesodermally derived cells), desmin (muscle cells), neurofilament proteins (nerve cells), lamins (nucleus), and beaded filament proteins (eye lens). Centrioles are paired, short, rod-like cytoplasmic cylinders built from nine microtubule triplets. The nuclear envelope is a double membrane system that surrounds the nucleus of the cell. It consists of an inner and an outer membrane separated by a perinuclear cisternal space and perforated by nuclear pores. A simple microscopic evaluation of the nucleus provides a great deal of information about cell well-being. This is accomplished by the formation of a unique nucleoprotein complex called chromatin. Further folding of chromatin, such as that which occurs during mitosis, produces structures called chromosomes. Chromatin proteins include five basic proteins called histones along with other nonhistone proteins. The nuclear wall consists of a double membrane envelope that surrounds the nucleus. The inner membrane is adjacent to nuclear intermediate filaments that form the nuclear lamina. This electron micrograph, prepared by the quick-freeze deep-etch technique, shows the nucleus, the large spherical object, surrounded by the nuclear envelope. Sequencing of the human genome took about 13 years and was successfully completed in 2003 by the Human Genome Project. For years, it was thought that genes were usually present in two copies in a genome. For instance, genes that were thought to always occur in two copies per genome have sometimes one, three, or more copies. In general, two forms of chromatin are found in the nucleus: a condensed form called heterochromatin and a dispersed form called euchromatin. There are two recognizable types of heterochromatin: constitutive and facultative. Large amounts of constitutive heterochromatin are found in chromosomes near the centromeres and telomeres. Facultative heterochromatin is also condensed and is not involved in the transcription process. In contrast to constitutive heterochromatin, facultative heterochromatin is not repetitive and has inconsistent nuclear and chromosomal localization when compared with other cell types. Facultative heterochromatin may undergo active transcription in certain cells (see Barr body description on page 78) due to specific conditions such as explicit cell cycle stages, nuclear localization changes.