Neelam K. Patel, PharmD, BCOP

• Clinical Pharmacy Specialist—Breast Medical Oncology, Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas

Each contains a large core of connective tissue with numerous vessels and small nerves erectile dysfunction doctor toronto order viagra professional 100 mg online. The epithelium covering the lateral surfaces of these papillae contains numerous taste buds that may number 250 or more per papilla erectile dysfunction zoloft discount viagra professional 100mg overnight delivery. Their thin serous secretions continuously flush the furrow and provide an environment suitable for sensory reception by the taste buds erectile dysfunction pills images buy cheap viagra professional 50mg online. Foliate papillae are rudimentary in humans but in species such as the rabbit are well developed and contain many taste buds erectile dysfunction venous leak generic viagra professional 50mg with visa. They form oval bulges on the posterior erectile dysfunction treatment saudi arabia buy discount viagra professional 100 mg, dorsolateral aspect of the tongue and consist of parallel ridges and furrows erectile dysfunction natural cure best 100mg viagra professional. Taste buds lie in the epithelium on the lateral surfaces of the ridges, and small serous glands drain into the bottoms of the adjacent furrows. Taste buds are present in fungiform, circumvallate, and foliate papillae and may be scattered in the epithelium of the soft palate, glossopharyngeal arches, pharynx, and epiglottis. They appear as lightly stained, oval structures that extend from the basement membrane almost to the surface of the lining epithelium. Taste buds consist of supporting (sustentacular) cells, between which are neuroepithelial cells; the cells are arranged somewhat like the segments of a peeled orange. Both types of cells have large microvilli called taste hairs that project into the taste pore and are embedded in an amorphous, polysaccharide material. Neuroepithelial cells are stimulated by tastant molecules that enter the taste pore. Binding of tastants with taste binding receptor proteins occurs on the microvilli of the neuroepithelial cells. The taste sensation is transmitted to club-shaped nerve endings that pass between both cell types of the taste bud but apparently make synaptic contact only with neuroepithelial cells. Depolarization of the neuroepithelial cells as a result of receptor binding stimulates the release of glutamate, which then generates an action potential in adjacent afferent nerve terminals. Peripheral and basal cells, also associated with taste buds, are thought to represent undifferentiated progenitors of the supporting and neuroepithelial cells. The sensations may be detected regionally in the tongue -sweet and salty at the tip of the tongue, sour at the sides of the tongue, and bitter in the area of the circumvallate papillae - but structural differences in taste buds from these areas have not been seen. Stimulation of the umami receptor results in foods that are ingested to "taste good". The major salivary glands are the parotid, submandibular, and sublingual glands and lie outside the oral cavity. Numerous smaller, intrinsic salivary glands are present in the limiting wall of the oral cavity and tongue and make up the minor salivary glands (Table 14-1), which secrete continuously to lubricate the mucosa of the oral cavity, vestibule, and lips. Amylase, maltase, and salivary lipase also are present to begin digestion of some carbohydrates and fats. Saliva moistens the oral cavity, softens ingested materials, cleanses the oral cavity, and acts as a solvent to permit materials to be tasted. Some heavy metals are eliminated in the salivary secretions, and decreased secretion during dehydration helps initiate the sensation of thirst. Salivary mucins, particularly those of the submandibular gland are largely monomeric in molecular form and have the capacity to bind to and form aggregates with the microflora within the oral cavity thereby keeping the number of 172 microorganisms in check. The glycoproteins plus the bound microbes are then swallowed and removed from the oral cavity. This is one mechanism by which the bacterial flora of the oral cavity is kept in check. Other components within the saliva also are important in controlling the bacterial population in the mouth. In addition to producing lysozyme, the serous cells of the salivary glands participate in the production of immunoglobulin to suppress bacterial growth. Immunoglobulin A (IgA) synthesized and released by B-lymphocytes and plasma cells is taken up by the serous cells and complexed to a protein known as secretory piece before being released into the oral cavity. Secretory piece is synthesized by the epithelial cells and prevents the IgA from being broken down. Major Salivary Glands the major salivary glands - parotid, submandibular, and sublingual - secrete only in response to nervous stimulation. The response is reflexive and can be stimulated by the smell, sight, or even the thought of food. The main excretory duct passes through the cheek to open into the vestibule of the mouth opposite the upper second molar tooth. The parotid is enclosed in a fibrous capsule and subdivided into lobes and lobules by connective tissue septa. A delicate stroma surrounds the secretory units and ducts and contains numerous blood capillaries and scattered nerve fibers. Myoepithelial cells lie between the limiting basement membrane and the bases of the secretory cells and may aid in expressing secretions out of the secretory units and into the duct system. Acini are composed of pyramidal-shaped, serous cells with basally placed, oval nuclei, basophilic cytoplasm, and discrete, apical secretory granules. Small channels, the intercellular secretory canaliculi, are found between serous cells and provide an additional route secretory products can take to reach the lumen. The initial segment of the duct system is the intercalated duct, which is especially prominent in the parotid gland. It is lined by a simple squamous or low cuboidal epithelium and may be associated with surrounding myoepithelial cells. Intercalated ducts are continuous with striated ducts, which are lined by columnar cells that show numerous basal striations. The intralobular ducts of all the major salivary glands are intimately related to a surrounding network of capillaries that aid in this function. The intercalated and striated ducts constitute the duct system within the lobule and collectively form the intralobular duct system. The remaining ducts are found in the connective tissue between lobules and are referred to as interlobular ducts. They are continuous with the intralobular ducts and at first are lined by a simple columnar epithelium that becomes pseudostratified and then stratified as the diameter of the duct increases. The surrounding connective tissue becomes more abundant as these ducts join to form the major excretory duct. The distal part of the major excretory duct is lined by nonkeratinized stratified squamous epithelium that becomes continuous with the interior lining epithelium of the cheek. The mucous tubules present usually show serous demilunes (crescents) at their blind ends. Small channels, the intercellular secretory canaliculi, pass between the mucous cells and extend between the serous cells of the demilune. Thus, the secretory product of the demilunes has direct access to the lumen of the mucous tubule. Myoepithelial cells lie between the secretory cells and the basement membrane and invest the secretory units as well as the initial portions of the ductal system. Generally, the duct system is similar to that of the parotid, but the striated ducts are much longer and hence more conspicuous in sections of the submandibular gland. The major excretory duct of each submandibular gland empties onto the floor of the oral cavity on either side of the lingual frenulum. Each tooth contains a small pulp cavity that corresponds in shape to the external form of the tooth. The pulp cavity communicates with the alveolar cavity and periodontal membrane through the apical foramen, a small opening at the tip of the root. Soft tissues associated with the tooth are the pulp, periodontal membrane, and gingiva. Each gland opens independently onto the floor of the mouth or into the excretory ducts of the submandibular gland. It is a mixed compound tubuloacinar gland with most of the secretory units being mucous. Segments of the intralobular duct system are short and not as readily seen as they are in the other two major salivary glands. It is harder than compact bone and consists of 80% inorganic material and 20% organic substance. Most of the organic material is collagen, while the inorganic component is in the form of hydroxyapatite crystals. Dentin has a radially striated appearance due to numerous minute canals called dentinal tubules that pursue an S-shaped course as they extend from the pulp chamber to the dentinoenamel junction. The cell body of the odontoblast lies within the pulp cavity adjacent to the dentin. The odontoblast lays down the organic matrix of dentin (predentin) and is active throughout life so that there is a progressive narrowing of the pulp cavity with age. Teeth In humans, the teeth appear as two distinct sets: primary (deciduous) and permanent. Primary teeth erupt 6 to 8 months after birth and form a complete set of 20 by 2 years of age. They are shed between the sixth and thirteenth year and gradually are replaced by the permanent set of 32. Sensation is thought to be perceived by the processes of odontoblasts, which in turn transmit the sensory stimulation to adjacent nerves in the pulp chamber. It contains numerous thin, collagenous fibers embedded in an abundant gelatinous ground substance. Stellate fibroblasts are the most prominent cells of the pulp, although mesenchymal cells, macrophages, and lymphocytes are found in limited numbers. The cell bodies of the odontoblasts also are found in the pulp, lining the perimeter of the pulp cavity immediately adjacent to the dentin. Blood vessels, lymphatics, and nerves enter and exit the pulp cavity through the apical foramen. It is acellular and consists primarily of calcium salts in the form of apatite crystals. Enamel consists of thin rods called enamel prisms that lie perpendicular to the surface of the dentin and extend from the dentinoenamel junction to the surface of the tooth. A small amount of organic matrix surrounds each enamel prism and is called the prismatic rod sheath. The organic matrix of enamel consists primarily of proteins called enamelins that bind to crystallites of the enamel prisms. Between the enamel prisms is the interprismatic substance, which also consists of apatite crystals in a small amount of organic matrix. Each enamel prism is the product of a single ameloblast, the enamelproducing cells that are lost during eruption of the tooth. The orientation of the fibers in the periodontal membrane varies at different levels in the alveolar socket. Although firmly attached to the surrounding alveolar bone, the fibers are not taut, and the tooth is able to move slightly in each direction. In addition to typical connective tissue cells, osteoblasts and osteoclasts may be found where the periodontal membrane enters the alveolar bone. The periodontal membrane has a rich vascular supply and is sensitive to pressure changes. Nearest the neck of the tooth, the cementum is thin and lacks cells, forming the acellular cementum. The remainder, which covers the apex of the tooth root, contains cells, the cementocytes, that lie in lacunae and are surrounded by a calcified matrix similar to that of bone. Immediately beneath the lamina propria is a well-developed layer of elastic fibers that is continuous with the muscularis mucosae of the esophagus. Proximally, the elastic layer blends with the connective tissue between the muscle bundles of the pharyngeal wall. A submucosa is present only where the pharynx is continuous with the esophagus and in the lateral walls of the nasopharynx. The muscularis of the pharyngeal wall consists of the skeletal muscle of the three pharyngeal constrictor muscles, which, in turn, are covered by connective tissue of the adventitia. Near the tooth, collagenous fibers of the gingival lamina propria blend with the uppermost fibers of the periodontal membrane. Some collagenous fibers extend from the lamina propria into the cervical (upper) cementum and constitute the gingival ligament, which provides a firm attachment to the tooth. The keratinized stratified squamous epithelium of the gingiva also is attached to the surface of the tooth and at this point forms the epithelial attachment cuff. Attachment of the cuff to the tooth is maintained by a thickened basal lamina and hemidesmosomes that seal off the dentogingival junction. Tubular Digestive Tract the tubular digestive tract consists of the esophagus, stomach, small intestine, colon, and rectum. Each region of the digestive tube consists of the four basic layers, but the components of these layers vary according to the functions of the region. It is continuous above with the oropharynx at the inferior border of the cricoid cartilage and below becomes continuous with the cardia of the stomach. The epithelial lining is thick and consists of nonkeratinized stratified squamous epithelium that is continuous with a similar epithelium lining the oropharynx. Antigen-presenting (Langerhans) cells have been identified in the esophageal epithelium. Pharynx the oral cavity continues posteriorly into the pharynx, which extends from the base of the skull to the level of the cricoid cartilage, where it is continuous with the esophagus.

The filtration process is driven by the hydrostatic pressure of blood erectile dysfunction 19 years old generic 100 mg viagra professional with visa, which is sufficient to overcome the colloidal osmotic pressure of plasma and the capsular pressure at the filtration membrane impotence vacuum pump purchase viagra professional 50 mg without a prescription. The resulting filtrate contains ions does erectile dysfunction cause low libido buy generic viagra professional 50 mg, glucose impotence quoad hoc meaning viagra professional 50 mg discount, amino acids impotence sentence examples viagra professional 100 mg otc, small proteins impotence libido purchase viagra professional 100 mg with mastercard, water soluble vitamins, and the nitrogenous wastes of metabolism. Blood cells, proteins of large molecular weight, and large negatively charged molecules are prevented from entering the capsular space by the filtration barrier. The glomerular filtrate is reduced to about 35% of its original volume in the proximal convoluted tubule. In addition to the obligatory absorption of sodium chloride and water, glucose, amino acids, proteins, and ascorbic acid are actively absorbed in the proximal convoluted tubules. Exogenous organic cations and anions are actively secreted into the lumen by the epithelium of the proximal convoluted tubule, thus fulfilling the requirements of an exocrine gland. Most of the materials that have passed through the filtration barrier are immediately resorbed by the epithelium of the uriniferous tubules and put back into the circulation. Parathyroid hormone acts on the proximal convoluted tubule to decrease phosphate reabsorption and on the thick ascending limb of the loop of Henle and distal tubule to increase calcium reabsorption. The loop of Henle is essential for the conservation of water and production of hypertonic urine. An active sodium pump mechanism resides in the cells of the thick ascending limb of the loop of Henle and creates and maintains a gradient of osmotic pressure that increases from the base of the medullary pyramid to the papillary tip. The distal tubule is the principal site for acidification of urine and is the site for further absorption of bicarbonate in exchange for secretion of hydrogen ions. The conversion of ammonia to ammonium ions also occurs in the distal tubule trapping hydrogen ions for elimination in the urine. Therefore this region of the nephron plays an important role in acid-base balance. Absorption of sodium ions in the distal tubule is referred to as facultative absorption and is controlled by the steroid hormone aldosterone, which increases the rate of absorption of sodium ion and excretion of potassium ion. Parathyroid hormone also acts on the distal convoluted tubule of the nephron to promote absorption of calcium ion and inhibit absorption of phosphate ion from the developing urine. Aldosterone targets the distal convoluted tubule and collecting duct to increase reabsorption of sodium, chloride, and water and increases potassium secretion. These actions result in increased sodium excretion (natriuresis) in a large volume of dilute urine. Aldosterone stimulates the terminal distal tubule and collecting tubule to absorb sodium ions in exchange for potassium ions. The renin-angiotensin system is influenced by blood flow through the kidney and is an important factor in hypertension. The juxtaglomerular apparatus also produces a bloodborne factor called erythropoietin, which stimulates erythropoiesis in the bone marrow. A minor calyx is attached around each renal papilla and represents the beginning of the extrarenal passageways. Minor calyces undergo periodic rhythmic contractions that aid in moving urine from the papillary ducts into the extrarenal system. The walls gently contract around each renal papillae and transport the urine to the renal pelvis. Periodic contractions of the muscular walls propel small amounts of urine from the renal pelvis through the ureter to the urinary bladder, where it is temporarily stored until a sufficient volume is obtained for urine to be evacuated through the urethra. Contraction of the muscularis of the bladder wall (the detrusor muscle) together with voluntary relaxation of the skeletal muscle that forms the sphincter urethrae accomplishes this process during micturition. The generative organs for the production of male gametes (sperm) are the testes, while in the female the ovary is the site of production of female gametes, the ova. Gametes cannot contain the diploid (somatic) number of chromosomes, since their fusion would result in a doubling of the chromosomes with each new generation. Thus, the gametes can contain only half the somatic number of chromosomes, and reduction to the haploid number occurs through a special form of cell division called meiosis. The stages of meiotic division are the same as those of mitosis, namely, prophase, anaphase, metaphase, and telophase. It customarily is divided into five stages: leptotene, zygotene, pachytene, diplotene, and diakinesis. In leptotene the chromosomes begin to condense and become visible as individual, slender threads that resemble those of early prophase of mitosis. The ends of the chromosomes become oriented to the side of the nucleus nearest the centrosome, with the bodies of the chromosomes extending in loops into the interior of the nucleus. During zygotene, the homologous chromosomes come together in pairs in which the chromosomes lie side by side, aligned point for point along their lengths. Because of the close apposition of the homologous chromosomes at this stage, they appear to be present in the haploid number. This pairing is called synapsis (or conjugation), and each pair of homologous chromosomes forms a bivalent. Each chromosome of the bivalent begins to split lengthwise and then can be seen to consist of two chromatids; the bivalent therefore consists of four chromatids and is frequently called a tetrad. In the diplotene stage, each chromosome splits into its constituent chromatids, which remain attached only at their centromeres (kinetochores). The homologous chromatids move apart slightly, and the tetrad formation becomes more obvious. At points along their lengths, the homologous chromatids make contact with each other and exchange segments; this exchange constitutes crossing over. The exchange of segments between homologous chromatids results in re-assortment or recombination of the genetic material. The chromosomes continue to shorten and thicken, and the nucleolus begins to fragment and disappear. Diakinesis is marked by an even greater contraction of the chromosomes that are scattered throughout the cell. At the end of prophase I, the nuclear envelope and nucleoli have disappeared, and the tetrads have begun their migration to the equator of the cell. Differences in Meiosis of Male and Female Germ Cells the mechanics of meiosis are the same regardless of whether sperm or ova are produced, but there are marked differences in the net yield of the two types of gametes and in the times at which meiosis is initiated. In the male, four viable, functioning sperm are produced from each germ cell that enters meiosis, whereas the same events in the female yield only a single functioning ovum. After the first and second meiotic divisions, the cytoplasm is distributed evenly among the developing sperm, but in the formation of ova, the bulk of the cytoplasm is passed to only one cell. The remaining ova, called polar bodies, receive so little cytoplasm that they are unable to survive. The time at which meiotic division is initiated in the male and female germ cells is remarkably different. In the human female, the germ cells begin their meiotic divisions in the embryo, and by the fifth month of intrauterine life, the developing ova are in the diplotene stage of the first meiotic division, but the division is not complete until just before ovulation. Hence, many of the ova remain suspended in the diplotene stage for several decades. The second meiotic division and the formation of the second polar body occur only after fertilization. In contrast, meiotic division in the male germ cells is not initiated until puberty, and once the cell has entered meiosis, the process is carried to completion with no prolonged interruption. Metaphase I Metaphase I is similar to the metaphase of mitotic division except that pairs of chromosomes (bivalents), not single chromosomes, are arranged about the spindle. The homologous pairs are aligned so that the members of each pair lie at either side of the equatorial plate, with the centromeres of homologous chromosomes facing opposite poles. Anaphase I and Telophase I Anaphase I and telophase I also are similar to those of mitotic cell division. However, at anaphase I of meiosis, the centromeres have not split so that rather than chromatids separating and moving to opposite poles, whole chromosomes, each consisting of two chromatids, are separated. Reconstruction of the nuclei and cytoplasmic separation occur at telophase I to yield two new cells. However, since the orientation of the bivalents on the equatorial plate is random, there is a random assortment of maternal and paternal chromosomes in each of the telophase nuclei. Unlike mitosis, the sister chromatids are not identical, due to the crossing over that occurred during the first meiotic prophase and to the random alignment of the homologous chromosomes at the first division. Summary the primary function of the reproductive systems is to provide haploid germ cells for procreation, and one of the consequences of meiotic division is to reduce the number of chromosomes to half that present in somatic cells. This ensures that on union of gametes, the normal diploid number of chromosomes will be maintained. A second consequence of meiosis that is of great importance is provision of genetic variation as the result of the exchange of genetic material between homologous chromosomes and from the random distribution of homologous chromosomes between daughter nuclei. The unequal division of cytoplasm among ova provides one cell with sufficient material to nourish the zygote until other forms of nourishment can be established. The gonads supply the male germ cells or gametes (sperm), which are conducted to the exterior by an excretory duct system. The accessory sex glands contribute secretions that, together with the sperm, form the semen. The testes are dual organs that act as exocrine glands producing a holocrine secretion, the sperm, and as endocrine organs that secrete the male sex hormone, testosterone. Each normal adult testis weighs between 12-15 gm and the right testis is commonly slightly larger and heavier than the left testis. Each testis is covered anteriorly and laterally by a simple squamous epithelium (mesothelium) called the visceral layer of tunica vaginalis. On the posterior aspect of the testis, this mesothelium reflects onto the scrotal sac and lines its interior as the parietal layer of the tunica vaginalis. The serous cavity between visceral and parietal layers allows the testes to move freely and reduces the chance of injury from increased pressure on the exterior of the scrotum. A thick, fibrous capsule, the tunica albuginea, lies beneath the visceral layer of tunica vaginalis, separated from it only by a basal lamina. Tunica albuginea consists of a dense fibroelastic connective tissue that contains scattered smooth muscle cells. The muscle cells are concentrated in the posterior region, where the tunica albuginea thickens and projects into the testis to form the mediastinum testis. Connective tissue partitions, the septula testis, extend from the mediastinum into the interior of the testis and subdivide it into approximately 250 pyramid-shaped compartments called lobuli testis. The apices of the compartments are directed toward the mediastinum, and each lobule contains one to four convoluted seminiferous tubules that represent the exocrine portion of the testis. The inner region of the tunica albuginea, the tunica vasculosa, consists of loose connective tissue and contains numerous small blood vessels that supply the testis. The connective tissue extends into each lobule and fills the spaces between the seminiferous tubules, forming the interstitial tissue of the testis. The interstitial tissue is rich in extracellular fluid and contains abundant small blood and lymphatic vessels that form a plexus around the seminiferous tubules. These are the interstitial cells (of Leydig), which commonly occur in groups and make up the endocrine portion of the testis. Interstitial cells usually contain single, large, spherical nuclei, but binucleate cells are not uncommon. In electron micrographs, the cytoplasm shows abundant smooth endoplasmic reticulum, well-developed Golgi complexes, and numerous mitochondria, which contain tubular rather than lamellar cristae. Morphologically, interstitial cells are characterized by large cytoplasmic crystals called the crystals of Reinke. These proteinaceous bodies are highly variable in shape and size but are readily seen with the light microscope. The crystals appear in the interstitial cells of most postpubertal individuals and vary considerably in number. Most of the enzymes involved in the synthesis of testosterone are located in the smooth endoplasmic reticulum and mitochondria of interstitial cells. Only about 1 to 2% of circulating testosterone is in free form with the remainder being bound to a sex steroid-binding globulin or albumin produced by the liver. Testosterone and its metabolites are essential for the proliferation and the differentiation of excretory ducts and male accessory sex glands and for maintaining these structures in a functional state. Testosterone and its derivatives influence other tissues and are responsible for beard growth, low pitch of the voice, muscular build, and male distribution of body hair. The cell has an elaborate shape with numerous lateral processes with recesses or concavities that surround differentiating spermatogenic cells. The apical portion of the cells also envelops developing germ cells and releases them into the lumen of the seminiferous tubule. The expanded portion of the cell contains an irregularly shaped nucleus distinguished by a large, prominent nucleolus that is readily seen with the light microscope. The basal cytoplasm contains abundant smooth endoplasmic reticulum, and a large, welldeveloped Golgi complex occupies the supranuclear region. The cytoplasm contains many lipid droplets, lysosomes, thin elongated mitochondria, scattered profiles of granular endoplasmic reticulum, and a sheath of fine filaments that envelops the nucleus and separates it from the organelles. Microtubules are present also, their numbers depending on the state of activity of the cell. Tight junctions occur between adjacent Sertoli cells near their bases and subdivide the germinal epithelium into basal and adluminal compartments, each of which has a separate, distinct population of spermatogenic cells. The basal compartment extends from the basal lamina of the germinal epithelium to the tight junctions; the adluminal compartment lies between the tight junctions and the lumen of the tubule. The tight junctions between the Sertoli cells appear to form, at least in part, a blood-testis barrier.

Cerebrosides are ceramide monohexosides erectile dysfunction protocol by jason generic 50 mg viagra professional fast delivery, the most common of which is galactocerehroside erectile dysfunction pump hcpc buy generic viagra professional 50mg on-line, also called galactolipid buy erectile dysfunction drugs uk buy discount viagra professional 50 mg on line. Most galactocerebroside is found in the brain impotence marriage buy cheap viagra professional 100mg line, where it is a major component of the myelin sheath erectile dysfunction 5gs buy viagra professional 100mg cheap. Medical Biochemistry: Human Metabolism in Health and Disease Copyright 02009 John Wiley & Sons erectile dysfunction beat filthy frank safe 100mg viagra professional, Inc. Globosides are sphingolipids that contain two or more sugar residues, usually a combination of galactose, glucose, and N-acetylgalactosamine. The oligosaccharides of globosides are uncharged and contain no free amino groups. Gangliosides are sialic acid-containing glycosphingolipids which are highly concentrated in ganglion cells of the central nervous system, particularly in the nerve endings. Lesser amounts of gangliosides are present in the plasma membrane of cells of most extraneural tissues. Sialic acid, which is found in glycoproteins and mucins as well as gangliosides, is the N-acetyl derivative of the nine-carbon amino sugar neuraminic acid (Neu). The carbohydrate domains of the various gangliosides serve as receptors for many different classes of ligands, including cytokines, microbial toxins. Gangliosides play roles in diverse cellular processes, such as cell-cell recognition, cell homing and adhesion, and growth regulation and differentiation. Glycoproteins also play important roles in cell growth and development, and in the communication that occurs between cells. A particular glycoprotein can have one or as many as 30 oligosaccharide chains, with the carbohydrate accounting for as little as 1% to as much as 70% of the mass of the glycoprotein. The oligosaccharide chains of a particular glycoprotein usually influence one or more of its biological properties, including intracellular transport, solubility, viscosity, susceptibility to inactivation (by heat, extremes of pH, and proteolysis), and the tendency to aggregate. The carbohydrate chains of glycoproteins are grouped into two classes, depending on how they are linked to the protein. Figure 16-5 illustrates two types of N-asparaginelinked oligosaccharide chains commonly found in mammalian glycoproteins: the high-mannose type and the complex type. They are high molecular weight (200 to 10,000 kDa) glycoproteins that contain dozens to several hundred oligosaccharides 0-linked to serine or threonine residues. Secreted mucins (such as salivary mucin) aggregate into oligomeric gels which form a protective layer over the digestive, respiratory, and reproductive tracts and provide lubrication as well as a barrier against pathogens and toxins. Cancer cells often synthesize abnormal mucins, whose structures can perturb the normal function of a cell, including its immunologic and adhesive properties and its potential to invade and metastasize. For example, in heparan sulfate the disaccharide repeat unit glucuronic acid-N-acetylglucosamine. Both glycolipids and glycoproteins are integral components of the asymmetrical plasma membrane, with the carbohydrate moieties facing outward. Other glycoproteins and proteoglycans are adsorbed onto the extracellular surface of the membrane. Heparan sulfate proteoglycan also serves as the ligand that binds lipoprotein lipase to the luminal surface of the capillary endothelium. For example, chondrocytes (cartilage cells) secrete a variety of proteoglycans, of which a major component is a particular chondroitin sulfate named aggl-ecan. Following its secretion, aggrecan molecules aggregate spontaneously to form a supramolecular structure known as hyaluronan which endows cartilage with its load-bearing properties. Hyaluronic acid is a component of the extracellular matrix of skin and connective tissue where its viscous and elastic nature allows it to function as a lubricant and shock absorber in the synovial fluid of joints. These include the lysosomal-associated membrane glycoproteins as well as lysosomal acid hydrolases. Following its incorporation into glycosaminoglycans, glucuronate may be isomerized to iduronate. Synthesis of amino sugars is initiated by glutamine: fructose 6-phosphate amidotransferase, which catalyzes the synthesis of glucosamine 6-phosphate. Sialic acid (N-acetylneuraminic acid) is synthesized by condensation of the carbon backbone of phosphoenolpyruvate with N-acetylmannosamine 6-phosphate. Galactocerebroside is the major cerebroside found in membranes; by contrast, glucocerebroside is primarily an intermediate in the synthesis of more complex sphingolipids. Sulfatides Galactocerebroside 3-sulfate, a sulfuric acid ester of galac6322 tocerebroside, is the major sulfolipid of brain, accounting for about 15% of the lipids of white matter. Globosides and gangliosides are synthesized in the Golgi apparatus by enzymes that transfer sugars sequentially onto a cerebroside. One such example is the synthesis of the glycosphingolipids containing A, B, and 0 blood group antigens. The core structure of the 0 (or H) oligosaccharide is formed by sequential addition of N-acetylglucosamine, galactose, and fucose to galactocerebroside. Persons with a gene for the type A transferase are able to transfer N-acetylgalactosamine to the core structure to synthesize the A antigen from the 0 core structure, while those with the type B transferase transfer galactose to synthesize the B antigen. Some people have genes for both the A and B transferases and therefore synthesize both A and B antigens. The "0 gene" is actually a mutation which results in premature termination of translation so that no active transferase A or B is formed; persons homozygous for the gene for the 0 blood group therefore synthesize only the core 0 antigen. Additional sugars, including sialic acid, are then added stepwise to the growing glycan chain. Humans contain at least five different sialyltransferases, each with a different specificity with regard to the acceptor. By contrast, the synthesis of N-linked oligosaccharide chains involves a more complex sequence of reactions which is initiated in the endoplasmic reticulum and continues in the Golgi complex. The first phase of N-linked oligosaccharide synthesis takes place on an isoprene lipid, dolichol pyrophosphate. The core oligosaccharide, containing two N-acetylglucosamine, nine mannose, and three glucose residues, is assembled on dolichol pyrophosphate by the successive transfer of glycosyl residues from their respective nucleoside diphosphate sugar donors. The asparagine that accepts the core oligosaccharide always occurs in the sequence AsnX-Thr/Ser, where X is any amino acid except proline. The next phase of N-linked oligosaccharide-chain processing involves aglucosidase-catalyzed stepwise removal of the three glucose residues and one mannose from the core oligosaccharide. The properly folded glycoprotein then moves by vesicular transport to the Golgi complex, where it undergoes a variety of additional posttranslational modifications, including the removal of additional mannose residues and the sequential addition of single residues each of N-acetylglucosamine, galactose, fucose, and sialic acid. A xylose residue is attached to the hydroxyl group of a serine, followed by addition of two galactose residues to form what is called the liizk trisaccharide. Two glycosyltransferases enzymes then alternate adding sugar residues to generate the repeating disaccharide units. The glycosphingolipids are catabolized in lysosomes by sequential, irreversible removal of the carbohydrate residues-one at a time-followed by the hydrolysis of ceramide to sphingosine and a free fatty acid. This pathway requires enzymes that cleave specific bonds, including a - and P-galactosidases, a p-glucosidase, a neuraminidase, a hexosaminidase, a sphingomyelinase, a sulfatase, and a ceramide-specific amidase (ceramidase). The enzymes that hydrolyze glycosphingolipids often require sphingolipid activator proteins, which promote interaction between these enzymes and their water-insoluble lipid substrates. Sphingolipid catabolism normally functions smoothly, all of the glycosphingolipids and sphingomyelin being degraded to their constituents. However, when the activity of one enzyme in the pathway is markedly reduced due to a genetic error, the substrate for that defective enzyme accumulates within the lysosomes of the tissue in which catabolism of that sphingolipid normally occurs. Gaucher disease is caused by a genetic deficiency of lysosomal glucocerebrosidase. The accumulation of glucocerebroside, primarily in macrophages of the reticuloendothelial system, results in hepatomegaly, splenomegaly, anemia, and bone pain. Gaucher disease is now treated effectively by enzyme replacement therapy using recombinant glucocerebrosidase, which is produced in human cells so as to obtain appropriate glycosylation of the enzyme with oligosaccharide chains terminating in mannose residues. Mannose receptors on the surface of macrophages bind the mannose-terminated enzymes and through a process of endocytosis deliver them into lysosomes, where they degrade the accumulated lipid, glucocerebroside. Deficiency of lysosomal a-galactosidase A results in Fabry disease and accumulation of globotriaosylceramide (Cer -+ P-Glu -+ pGlu -+ a-Gal) in tissues, mainly the walls of blood vessels. Unlike the other sphingolipidoses, which are autosomal recessive diseases, Fabry disease is X-linked. Tay-Sachs disease is a gangliosidosis caused by the absence of P-hexosaminidase A and results in neural accumulation of the ganglioside G M. The disease is characterized by mental retardation, ~ a cherry-red spot on the macula which reflects ganglioside accumulation in retinal ganglia, blindness, and for the most severe, infantile form, death before age 3. Because of the primary involvement of ganglion cells of the central nervous system, effective enzyme replacement therapy has not proven feasible. Since there is some digestion of the oligosaccharide chains by lysosomal endoglycosidases, urinary excretion of shorter oligosaccharides is often diagnostic. The mucopolysaccharidoses are classified according to the substrate that accumulates (Table 16-1). They can result from deficiencies in any one of a number of enzymes, including a-mannosidase, P-mannosidase, a-fucosidase, and a-sialidase. Oligosaccharidoses are usually named for the deficient enzyme; for example, a deficiency in a-mannosidase is called a-mannosidosis. Patients with I-cell disease secrete large amounts of many different lysosomal enzymes into body fluids but have deficient enzyme activity within the lysosomes. Two enzymes are required to attach a phosphate group to a mannose moiety of oligosaccharide chains of lysosomal enzymes. The second enzyme in the pathway, N-acetylglucosamine- 1-phosphodiester-a-N-acetylglucosaminidase, removes the terminal a-N-acetylglucosamine residue, leaving the phosphate group attached to the underlying mannose residue. Lysosomal enzymes bearing the mannose 6-phosphate marker bind to the mannose 6-phosphate receptor in the trans Golgi, are packaged into clathrin-coated vesicles, and are transported to late endosomes, where the low pH causes the lysosomal enzymes to dissociate from the receptors. Patients with I-cell disease have a deficiency of the phosphotransferase, which impairs targeting of enzymes to the lysozyme. This leads to activation of adenylyl cyclase, which stimulates secretion of chloride ion and produces diarrhea. Cholesterol has a hydroxyl group at C3, a C5-C6 carbonsarbon double bond, and two methyl groups, attached at positions C 10 and C13 of the sterol ring. In addition, cholesterol has a branched eight-carbon hydrocarbon chain attached to the D ring at C17. In contrast to plasma, where most of the circulating cholesterol exists esterified to a fatty acid, most cholesterol in cellular membranes is present in the free (unesterified) form. The fluidity of membranes is regulated in part by changing their cholesterol content. The solubilization of free cholesterol in bile is achieved Medical Biochemistry: Human Mefaholism in Health and Disrase Copyright 02009 John Wiley & Sons, Inc. Bile acids, which are metabolites of cholesterol, also aid in solubilizing cholesterol in bile. Increased biliary secretion of cholesterol or decreased secretion of phospholipids or bile acids into bile may lead to deposition of cholesterolrich gallstones. Indeed, the name cholesterol was derived some 200 years ago from the Greek words chole (bile) stereos (solid). Cholesterol and phospholipids in bile protect gallbladder membranes from potentially irritating or harmful effects of bile salts. Posttranslational prenylation of these proteins increases their tendency to associate with membranes, and prenylation is usually required for their full activity. Covalent attachment of cholesterol to protein is required for the membrane tethering that is necessary for the activation of the Hedgehog family of proteins, which are essential to embryonic patterning; the cholesterol moiety is attached via an ester bond to the C-terminal glycine during autocatalytic cleavage and maturation of the initially soluble protein. The brain is the most cholesterol-rich organ of the body; however, since plasma lipoproteins that transport cholesterol in the circulation do not cross the blood-brain barrier, all cholesterol in the brain must be synthesized within the central nervous system. Cholesterol synthesis in the brain occurs at a high rate during the period of active myelination and declines substantially thereafter. Within the cell, cholesterol synthesis takes place in the cytosol and endoplasmic reticulum. Although there is wide individual variation, on average about half of the cholesterol that enters the small intestine is absorbed into the body. Animal products contain both cholesterol and cholesteryl esters; the latter are hydrolyzed in the small intestine by pancreatic cholesteryl esterase: cholesteryl ester + H20 + cholesterol + fatty acid Cholesterol is absorbed by the cells of the intestinal mucosa and incorporated into the surface of chylomicrons. Cholesterol in excess of that required for the chylomicron surface is esterified to cholesteryl esters and incorporated into the triacylglycerol-rich chylomicron core. Both free and esterified cholesterol are delivered to the liver as components of chylomicron remnants. Cholesterol that is not secreted from the intestinal mucosa in chylomicrons is returned to the intestinal lumen as a component of sloughed mucosal cells and excreted. The fecal sterols are a mixture of cholesterol and cholesterol metabolites, such as cholestanol and coprostanol, generated by intestinal bacteria. As with fatty acid synthesis, nearly all of the acetyl-CoA used for cholesterogenesis is generated in the mitochondrion; the acetyl moieties are transported to the cytosol in the form of citrate. Synthesis starts with the as condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA in a reaction catalyzed by acetoacetyl-CoA thiolase (acetyl-CoA:acetyl-CoA acetyltransferase). The two reactions are catalyzed by mevalonate kinase and phosphomevalonate kinase, respectively. A second prenyltransferase then adds another 3-isopentenyl pyrophosphate unit to form the 15-carbon intermediate, farnesyl pyrophosphate, with the release of a second molecule of pyrophosphate. The last condensation step in cholesterol synthesis involves head-to-head fusion of two molecules of farnesyl pyrophosphate to form squalene. Cholesterol synthesis from squalene proceeds through the intermediate lanosterol, which contains the fused tetracyclic ring system and an eight-carbon side chain. The endoplasmic reticulum enzyme that catalyzes this cyclization reaction is bifunctional and has both squalene epoxidase and lanosterol cyclase activity. Transformation of the 30-carbon lanosterol to the 27-carbon cholesterol molecule requires at least eight different enzymes which catalyze removal of the methyl group at C14, removal of two methyl groups at C4, migration of the double bond from C8 to C5, and reduction of the double bond between C24 and C25 in the side chain. In this reaction, the source of the fatty acid is the phospholipid phosphatidylcholine: phosphatidylcholine + cholesterol + cholesteryl ester + 2-lysophosphatidylcholine 17. The other is a cytosolic enzyme that acts on cholesteryl esters in lipid droplets present in steroidogenic cells and which releases free cholesterol for synthesis of steroid hormones. The total fasting cholesterol concentration in plasma of healthy people is usually 150 to 200 mg per 100 mL, which is about twice the normal plasma glucose concentration.

Monitoring the dates (both start and end) will keep your landscape analysis up-to-date impotence nerve order viagra professional 100 mg amex. Identify databases: Some databases let you search their content for free erectile dysfunction protocol reviews order 50 mg viagra professional visa, while others require payment erectile dysfunction treatment comparison purchase 100 mg viagra professional free shipping. Choose your search terms: By carefully defining your search terms champix causes erectile dysfunction generic viagra professional 50mg with visa, you will identify the most appropriate results otc erectile dysfunction drugs walgreens discount 100mg viagra professional free shipping. See Table 1 for an example of search terms used in an anemia landscape analysis search erectile dysfunction statin drugs 100 mg viagra professional otc. Always include the relevant terms for your country, which may not be on this list. Note: A space is included for you to add your country at the end of both search term groups. Conduct the search: to identify the most data sources, first search for each group of terms separately. Use the "Methodology" section of your report to describe the decision-making process and include details of the sources. While many sources for data relating to anemia causes and interventions are available, often important data are not regularly collected. In particular, National Micronutrient Surveys usually provide the most comprehensive picture of the anemia situation in a country. These surveys often include information on micronutrient status, but also the prevalence of other infections, as well as coverage of relevant interventions. These surveys are expensive, but they will provide the most comprehensive data on anemia-related issues. As you start to use the findings from your landscape analysis, having recent and representative data can greatly aid the process of planning and targeting programs. If your country does not have up-todate information on anemia prevalence, causes of anemia, anemia policies, and status of anemia interventions, note this in your landscape analysis and consider working with policymakers in your country to collect the relevant data. It is important to keep in mind that there is value to conducting a landscape analysis, even when you lack some of the "ideal" data-understanding the available data and gaps is necessary for planning future activities. Because of these biological factors, most data on anemia are collected for these three target groups. While men can suffer from anemia, women and children are most vulnerable and are the focus of most public health interventions. Anemia is diagnosed if the amount of hemoglobin present in the bloodstream is below the set thresholds, based on age, sex, and physiological status. The thresholds of hemoglobin in Table 3 are the suggested cutoffs for anemia severity, with differences based on sex, age, and pregnancy status. Often, these different levels of anemia are presented as "any anemia" that combines those with mild, moderate, and severe anemia into one grouping. The HemoCue system, commonly used in the field, includes a portable photometer, a microcuvette (for collecting blood), and dry hemoglobin conversion reagents. Many research and evaluation activities collect biomarker data related to anemia and its causes. Consider the usage of health care services in your context when interpreting findings, because not all people suffering from anemia will seek services at a facility. If these factors are not properly adjusted, the results will underestimate anemia for populations at higher altitudes and for smokers. If they have not, and they include populations living 1,000 meters above sea level, or data are from a population of frequent smokers, include it as a weakness in your limitations. Studies in the field in low- and middle-income countries report that hemoglobin measurement in capillary blood samples trend higher than from venous samples: 10 of 13 studies, with the difference ranging from 1 to 17 g/L. Thus, when reviewing studies or reports, consider the blood collection methods when comparing results between surveys that used different techniques. An example of this is in Bangladesh in which the prevalence of anemia differed, despite being collected the same year; it was hypothesized this was the result of using capillary blood in one survey and venous blood in the other survey (see Box 3). If you find that surveys used different collection methods, include it as a weakness in your limitations. These subnational variations are important for programmers and policymakers interested in targeting their interventions to the most affected populations. Reviewing disaggregated national anemia data can help identify areas or groups with an anemia burden higher than the national average. As seen in Figure 1, the Demographic and Health Survey data (capillary) showed higher levels of anemia than the national micronutrient survey results (venous) held in the same year. Discuss with stakeholders the specific factors that could influence the anemia rates at the national and subnational levels. If data are available, review the anemia prevalence for your target groups by geographic area, income, education, or other similar factors to see if any populations are disproportionately affected by anemia. Disaggregation of data by additional indicators- such as sex, pregnancy status, age, education levels, and urban versus rural residence-may also reveal important information. You can prepare graphs of anemia prevalence by target group, or by various characteristics, to illustrate the variation in the anemia burden in your country. These types of basic data are often collected in surveys as part of a "Background" or "Household" characteristics section. An example (based on wealth quintile) is poorest, poorer, middle, richer, and richest. Examples include no formal schooling, some primary schooling, completed primary, completed some secondary schooling, completed secondary, and completed postsecondary education. Urban and rural populations have different risk factors for anemia; they often do not have access to the same delivery platforms for anemia prevention and control programs. In many countries, anemia can vary significantly across social groups that may face different risk factors and have different access to anemia prevention and control programs. Food security, inadequate maternal and child care, and health services and the environment are highlighted in the left-hand side of the figure to represent the main underlying causes of anemia. Knowing the causes that contribute to the anemia burden can help you identify which actions will be necessary to prevent and control the disease in your country. To illustrate the variations in your country, you can also include graphs of the prevalence of each cause by target group, or by various characteristics. Looking at these causes of anemia, over time, may help you identify whether their prevalence, and the resulting risk of anemia, has increased or decreased. Some causes may include a measure of the public health significance, which you can include in your landscape analysis. You do not need to do additional or complex analysis linking anemia to these risk factors unless your team has the epidemiological expertise. The rest of this section describes the four main types of causes of anemia and how to capture information about them in your landscape analysis. The subsequent sections of this guidance-Step 3: Review Anemia Policies and Step 4: Assess Status of Anemia Interventions-include more information on how to address anemia. To understand the relative importance of each cause, you must collect data that illustrate the role each cause plays in the burden of anemia. You should understand a number of common issues while reviewing data on the causes of anemia, and we discuss them here. Data from different years or sources may use different techniques to calculate the same indicator. For each data point included in your landscape analysis, to ensure that the data are comparable and representative at the same level, note the sampling method, technique, and season when the data were gathered. However, these sources will only capture confirmed cases or diagnoses that are reported through the health care system. The quality of data available through these data sources will vary depending on their design and the in-country capacity for monitoring. A systematic search of electronic databases-for example, PubMed and the Cochrane libraries- may be helpful (see Box 2 in Gathering Information on Anemia). Use specific keywords for the cause you are interested in, as well as the name of the country. You can limit the search by specifying population groups of interest- women of reproductive age, pregnant women, adolescents, school-age children, young children, children, or infants. Remember, it is important to state as a limitation in your landscape analysis that the findings are linked to specific geographic areas within a country, or to specific target groups, and cannot be generalized to the whole country. Even so, these data may offer a gauge and range of the prevalence of causes of anemia within your country. Certain infections cause anemia directly by destroying red blood cells or by decreasing their production. Some infections can also cause anemia directly by blood loss, or indirectly through depletion of iron stores (see Iron Deficiency section). These chronic conditions go beyond the scope of this guidance, although some countries may want to address them in the context of anemia. The inflammation that accompanies acute infections and chronic conditions can also indirectly cause anemia (see Inflammation section). For more information about these interventions, go to Step 4: Assess Status of Anemia Interventions. Malaria causes anemia by destroying red blood cells; decreasing the production of new red blood cells, which also leads to iron deficiency (see Iron Deficiency section); and general inflammation (see Inflammation section) (Spottiswoode, Duffy, and Drakesmith 2014). Children under 5 years of age and pregnant women are at a much higher risk for contracting malaria and becoming seriously ill. School-age children are also increasingly recognized as an important population group because, as transmission of malaria among young children is successfully decreased, children fail to build immunity to malaria until later in life. This means that school-age children in previously endemic areas will most likely experience an increase of severe and uncomplicated malaria cases, because they are no longer building an immunity during early childhood (Nankabirwa et al. Malaria associated anemia is defined as hemoglobin <80 g/L, which is an indication of malaria morbidity and, thus, useful for tracking the impact of malaria interventions (Korenromp et al. The gold standard measure of malaria prevalence is microscopy-blood smears are examined under a microscope to identify malaria parasites. However, rapid diagnostic tests, which can provide results in 15 minutes, can also be used to assess malaria prevalence. They are, generally, becoming the norm to obtain crude estimates of malaria prevalence. The most common rapid diagnostic tests look for antigens that occur with current or recent infection (Florey 2014). The gold standard for measuring malaria transmission is entomological inoculation, but it is difficult to measure and lacks precision at low levels of transmission. Consider the usage of health care services in your context when interpreting findings, because not all people suffering from malaria will seek services at the facility. However, in Africa, care seeking for fever is generally high for children under 5 years of age. Generally, rapid diagnostic tests show higher malaria prevalence than microscopy, because the former test can show false positivity after the infection has been treated (Mappin et al. Adjustment approaches have been developed to compare malaria prevalence between rapid diagnostics and microscopy data using a regression approach (Mappin et al. Check to see if this adjustment approach was used when comparing malaria prevalence data collected at different points in time. If you have the raw data available, you can apply these adjustments yourself using instruction included in Mappin et al. Also, countries sometimes make a distinction between "confirmed" and "nonconfirmed" malaria. Confirmed implies that some test (either a rapid diagnostic test or microscopy) was conducted for a parasitological-based diagnosis, whereas clinical malaria are cases that are diagnosed with malaria but do not have parasitological confirmation. As a result, crosssectional data may not capture the full extent of the anemia caused by malaria. Malaria transmission is seasonal in most places, with peaks during and just after the rainy season. Thus, it is important to consider the season when comparing malaria prevalence data collected at different points in time. Often, you will not have information on the quality of microscopy data collection unless you were directly involved in the data collection or have obtained this information from those that undertook the survey. They can also become infected with hookworms if their skin comes in contact with soil that contains infective larvae of hookworm. Young children, including schoolage children, bear most of the infection burden (Albonjco et al. Laboratory technicians can use many methods to prepare and examine samples, with varying levels of sensitivity, specificity, and cost (Nikolay, Brooker, and Pullan 2014). The Kato-Katz technique, useful for field surveys, estimates the intensity of the infection. Because school-age children are most at risk, and for logistical purposes, surveys are often done in schools. This is because when using the Kato-Katz technique with high infection intensity, there will be many eggs, so the infection will be easy to detect. But, with low infection intensity, there will be just a few eggs, so the infection may be missed. You may not have adequate information on the extent to which samples were examined at the appropriate time unless you were directly involved in the data collection or obtained this information from someone directly involved in the survey. Therefore, if the data were collected shortly after a deworming campaign, note this as a limitation. This will be especially problematic when comparing prevalence levels collected at two points in time, if one of the time points was collected much closer to the time of deworming campaign. Fecal matter or urine from infected individuals pass eggs into the water; the parasites live in a snail host before releasing the larvae that cause the human infections. The mechanisms by which schistosomiasis causes anemia likely involve a combination of effects, including blood loss, red blood cell destruction associated with sequestration in the spleen, immune mechanisms, iron deficiency as a result of blood loss/destruction, and general inflammation (Friedman, Kanzaria, and McGarvey 2005).

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