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However order 130 mg malegra dxt otc, in the patient’s cell membrane receptor cheap 130 mg malegra dxt with mastercard, transmits a signal through G proteins that activates glycogen sample, with the short outer adenylate cyclase, causing cAMP levels to increase (see Fig. The catalytic subunits of protein kinase A are activated by the dissocia- -1,6 branch. Normal glycogen has 8-10 glu- tion and phosphorylate the enzyme phosphorylase kinase, activating it. Phospho- cosyl residues per branch, and thus gives a rylase kinase is the protein kinase that converts the inactive liver glycogen ratio of approximately 9 moles of glucose phosphorylase b conformer to the active glycogen phosphorylase a conformer 1-phosphate to 1 mole of glucose. Regulation of glycogen synthesis and degradation in the liver. Glucagon binding to the glucagon receptor or epinephrine binding to a receptor in the liver activates adenylate cyclase, via G proteins, which synthesizes cAMP from ATP. Protein kinase A activates phosphorylase kinase by phosphoryla- tion. Phosphorylase kinase adds a phosphate to specific serine residues on glycogen phosphorylase b, thereby converting it to the active glyco- gen phosphorylase a. Protein kinase A also phosphorylates glycogen synthase, thereby decreasing its activity. As a result of the inhibition of glycogen synthase and the activation of glycogen phosphorylase, glycogen is degraded to glucose 1-phosphate. The blue dashed lines denote reactions that are decreased in the livers of fasting individuals. As a result of the activation of glycogen phosphorylase, enzyme has been activated or glycogenolysis is stimulated. INHIBITION OF GLYCOGEN SYNTHASE BY ited under fasting conditions (In a PHast, GLUCAGON-DIRECTED PHOSPHORYLATION PHosphorylate). When glycogen degradation is activated by the cAMP-stimulated phosphorylation cascade, glycogen synthesis is simultaneously inhibited. The enzyme glycogen syn- thase is also phosphorylated by protein kinase A, but this phosphorylation results in a less active form, glycogen synthase b. The phosphorylation of glycogen synthase is far more complex than glycogen phosphorylase. Glycogen synthase has multiple phosphorylation sites and is acted on by up to 10 different protein kinases. Phosphorylation by protein kinase A does not, by itself, inactivate glycogen synthase. Instead, phosphorylation by protein kinase A facilitates the subsequent addition of phosphate groups by other kinases, and these inactivate the enzyme. A term that has been applied to changes of activ- ity resulting from multiple phosphorylation is hierarchical or synergistic phospho- Most of the enzymes that are regu- rylation-the phosphorylation of one site makes another site more reactive and eas- lated by phosphorylation have mul- tiple phosphorylation sites. Glyco- ier to phosphorylate by a different protein kinase gen phosphorylase, which has only one serine per subunit, and can be phosphory- lated only by phosphorylase kinase, is the 5. For some enzymes, the phospho- At the same time that protein kinase A and phosphorylase kinase are adding rylation sites are antagonistic, and phospho- phosphate groups to enzymes, the protein phosphatases that remove this phos- rylation initiated by one hormone counter- phate are inhibited. Protein phosphatases remove the phosphate groups, bound to acts the effects of other hormones. For other enzymes, the phosphorylation sites are syn- serine or other residues of enzymes, by hydrolysis. Hepatic protein phosphatase- ergistic, and phosphorylation at one site 1 (hepatic PP-1), one of the major protein phosphatases involved in glycogen stimulated by one hormone can act synergis- metabolism, removes phosphate groups from phosphorylase kinase, glycogen tically with phosphorylation at another site. During fasting, hepatic PP-1 is inacti- vated by a number of mechanisms. One is dissociation from the glycogen parti- cle, such that the substrates are no longer available to the phosphatase. A second is the binding of inhibitor proteins, such as the protein called inhibitor-1, which, when phosphorylated by a glucagon (or epinephrine)-directed mechanism, binds to and inhibits phosphatase action. Insulin indirectly activates hepatic PP-1 through its own signal transduction cascade initiated at the insulin receptor Most of the enzymes that are regu- tyrosine kinase. INSULIN IN LIVER GLYCOGEN METABOLISM thase b, the less active form of glycogen syn- thase, can be activated by the accumulation Insulin is antagonistic to glucagon in the degradation and synthesis of glycogen. Glucose stimulates insulin release and suppresses glucagon release; one by glucose 6-phosphate may be important in increases while the other decreases after a high carbohydrate meal. However, individuals with glucose 6-phosphatase defi- insulin levels in the blood change to a greater degree with the fasting-feeding cycle ciency, a disorder known as type I or von than the glucagon levels, and thus insulin is considered the principal regulator of Gierke’s glycogen storage disease. The role of insulin in glycogen metabolism is glucose 6-phosphate produced from gluco- often overlooked because the mechanisms by which insulin reverses all of the neogenesis accumulates in the liver, it acti- effects of glucagon on individual metabolic enzymes is still under investigation. In vates glycogen synthesis even though the addition to the activation of hepatic PP-1 through the insulin receptor tyrosine individual may be hypoglycemic and have kinase phosphorylation cascade, insulin may activate the phosphodiesterase that low insulin levels. Glucose 1-phosphate is also elevated, resulting in the inhibition of converts cAMP to AMP, thereby decreasing cAMP levels and inactivating protein glycogen phosphorylase. Regardless of the mechanisms involved, insulin is able to reverse all of large glycogen deposits accumulate, and the effects of glucagon and is the most important hormonal regulator of blood hepatomegaly occurs. CHAPTER 28 / FORMATION AND DEGRADATION OF GLYCOGEN 521 7. BLOOD GLUCOSE LEVELS AND GLYCOGEN SYNTHESIS An inability of liver and muscle to AND DEGRADATION store glucose as glycogen con- tributes to the hyperglycemia in When an individual eats a high-carbohydrate meal, glycogen degradation immedi- patients, such as Di Abietes, with type 1 dia- ately stops. Although the changes in insulin and glucagon levels are relatively rapid betes mellitus and in patients, such as Ann (10–15 minutes), the direct inhibitory effect of rising glucose levels on glycogen Sulin, with type 2 diabetes mellitus. Glucose, as an allosteric effector, inhibits liver absence of insulin in type 1 diabetes mellitus glycogen phosphorylase a by stimulating dephosphorylation of this enzyme. As patients and the high levels of glucagon result insulin levels rise and glucagon levels fall, cAMP levels decrease and protein kinase in decreased activity of glycogen synthase.

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Comparison of 1-year follow-up evaluations of patients with indication for pallidotomy who did not undergo surgery versus patients with Parkinson’s disease who did undergo pallidotomy: a case control study cheap malegra dxt 130 mg overnight delivery. Alterman RL 130 mg malegra dxt overnight delivery, Kelly P, Sterio D, Fazzini E, Eidelberg D, Perrine K, Beric A. Selection criteria for unilateral posteroventral pallidotomy. Dalvi A, Winfield L, Yu Q, Cote L, Goodman RR, Pullman SL. Stereotactic posteroventral pallidotomy: clinical methods and results at 1-year follow up. Unilateral pallidotomy in advanced Parkinson’s disease: A retrospective study of 26 patients. Fazzini E, Dogali M, Sterio D, Eidelberg D, Beric A. Sterotactic pallidotomy for Parkinson’s disease: a long-term follow-up of unilateral pallidotomy. Hirai T, Ryu H, Nagaseki Y, Gaur MS, Fujii M, Takizawa T. Image-guided electrophysiologically controlled posteroventral pallidotomy for the treatment of Parkinson’s disease: a 28-case analysis. Jankovic J, Ben Arie L, Schwartz K, Chen K, Khan M, Lai EC, Krauss JK, Grossman R. Movement and reaction times and fine coordination tasks following pallidotomy. Usefulness of pallidotomy in advanced Parkinson’s disease. Lang AE, Lozano AM, Montgomery EB, Tasker RR, Hutchison WD. Posteroventral medial pallidotomy in advanced Parkinson’s disease. Masterman D, DeSalles A, Baloh RW, Frysinger R, Foti D, Behnke E, Cabatan Awang C, Hoetzel A, Intemann PM, Fairbanks L, Bronstein JM. Motor, cognitive, and behavioral performance following unilateral ventro- posterior pallidotomy for Parkinson disease. Shannon KM, Penn RD, Kroin JS, Adler CH, Janko KA, York M, Cox SJ. Stereotactic pallidotomy for the treatment of Parkinson’s disease. Efficacy and adverse effects at 6 months in 26 patients. Fine J, Duff J, Chen R, Chir B, Hutchison W, Lozano AM, Lang AE. Long- term follow-up of unilateral pallidotomy in advanced Parkinson’s disease. Roberts-Warrior D, Overby A, Jankovic J, Olson S, Lai EC, Krauss JK, Grossman R. Postural control in Parkinson’s disease after unilateral poster- oventral pallidotomy. Effects of bilateral posteroventral pallidotomy on gait of subjects with Parkinson disease. Neuropsychological consequences of posteroventral pallidotomy for the treatment of Parkinson’s disease. Lang AE, Lozano A, Tasker R, Duff J, Saint-Cyr J, Trepanier L. Neuropsychological and behavioral changes and weight gain after medial pallidotomy. Ondo WG, Ben Aire L, Jankovic J, Lai E, Contant C, Grossman R. Weight gain following unilateral pallidotomy in Parkinson’s disease. Gross RE, Lombardi WJ, Hutchison WD, Narula S, Saint Cyr JA, Dostrovsky JO, Tasker RR, Lang AE, Lozano AM. Variability in lesion location after microelectrode-guided pallidotomy for Parkinson’s disease: anatomical, physiological, and technical factors that determine lesion distribution. Gross RE, Lombardi WJ, Lang AE, Duff J, Hutchison WD, Saint Cyr JA, Tasker RR, Lozano AM. Relationship of lesion location to clinical outcome following microelectrode-guided pallidotomy for Parkinson’s disease [see comments]. Bejjani B, Damier P, Arnulf I, Bonnet AM, Vidailhet M, Dormont D, Pidoux B, Cornu P, Marsault C, Agid Y. Krack P, Pollak P, Limousin P, Hoffmann D, Benazzouz A, Le Bas JF, Koudsie A, Benabid AL. Opposite motor effects of pallidal stimulation in Parkinson’s disease. Neuronal activity in the MPTP model of parkinsonism.

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This high concentration of negative charges attracts cations that create a high osmotic pressure within cartilage best 130mg malegra dxt, drawing water into this specialized connective tissue and placing the collagen network under tension order malegra dxt 130 mg. At equilibrium, the resulting tension balances the swelling pressure caused by the proteo- glycans. The complementary roles of this macromolecular organization give cartilage its resilience. Cartilage can thus withstand the compressive load of weight bearing and then reexpand to its previous dimensions when that load is relieved. CHAPTER 49 / THE EXTRACELLULAR MATRIX AND CONNECTIVE TISSUE 913 Table 49. Some Specific Functions of the Glycosaminoglycans and Hyaluronate Proteoglycans COO– CH OH Glycosaminoglycan Function 2 O O Hyaluronic acid Cell migration in: H H H H O Embryogenesis Morphogenesis OH O H H Wound healing Chondroitin sulfate proteoglycans Formation of bone, cartilage, cornea H OH H NHCOCH3 Keratan sulfate proteoglycans Transparency of cornea Dermatan sulfate proteoglycans Transparency of cornea Glucuronic β(1 3) N–Acetyl- Binds LDL to plasma walls acid glucosamine Heparin Anticoagulant (binds antithrombin III) Causes release of lipoprotein lipase from capillary walls Heparan sulfate (syndecan) Component of skin fibroblasts and aortic Chondroitin 6–sulfate wall; commonly found on cell surfaces – – COO CH2OSO3 O O H H O HO H O OH H H the precursors that add sugar units, one at a time, first to the protein and then to the nonreducing end of the growing carbohydrate chain (Fig. Glycosylation H OH H NHCOCH3 occurs initially in the lumen of the ER and subsequently in the Golgi complex. Gly- Glucuronic β(1 3) N–Acetyl- cosyltransferases, the enzymes that add sugars to the chain, are specific for the acid galactosamine sugar being added, the type of linkage that is formed, and the sugars already pres- ent in the chain. Once the initial sugars are attached to the protein, the alternating Heparin action of two glycosyltransferases adds the sugars of the repeating disaccharide to – H CH2OSO3 the growing glycosaminoglycan chain. O O 3 -Phosphoadenosine 5 -phosphosulfate (PAPS), also called active sulfate, provides H COO– H H H O the sulfate groups (see Fig. An epimerase converts glucuronic acid residues O OH H H OH H to iduronic acid residues. H OSO H NHSO After synthesis, the proteoglycan is secreted from the cell. Its structure resem- 3 3 bles a bottle brush, with many glycosaminoglycan chains extending from the core Glucuronic α(1 4) Glucosamine protein (Fig. The proteoglycans may form large aggregates, noncovalently acid attached by a “link” protein to hyaluronic acid (Fig. The proteoglycans interact with the adhesion protein, fibronectin, which is attached to the cell mem- Keratan sulfate brane protein integrin. Cross-linked fibers of collagen also associate with this com- – CH2OH CH2OSO3 plex, forming the ECM (Fig. O O HO H H O O H OH H H The functional properties of a normal joint depend, in part, on the presence of H OH H NHCOCH3 a soft, well-lubricated, deformable, and compressible layer of cartilaginous tis- Galactose β(1 4) N–Acetyl- sue covering the ends of the long bones that constitute the joint. Dermatan sulfate H –O S CH OH 3 2 O O Bone H – O O COO H O Synovial OH H H lining H OH H NHCOCH3 Cartilage Iduronic β(1 3) N–Acetyl- Calcified acid galactosamine cartilage Fig. Repeating disaccharides of some gly- Synovial cosaminoglycans. These repeating disaccharides cavity Capsule usually contain an N-acetylated sugar and a uronic acid, which usually is glucuronic acid or iduronic acid. Sulfate groups are often present but are not included in the sugar names in this figure. The sugars are linked to a serine or threonine residue of the protein. A and B represent the sugars of the repeating disaccharide. Sugars are added to the protein one at a time, with UDP-sugars serving as the precursors. Initially a xylose residue is added to a serine in the protein. Then two galactose residues are added, followed by a glucuronic acid (GlcUA) and an N- acetylglucosamine (GalNAc). Subsequent additions occur by the alternating action of two enzymes that produce the repeating disaccharide units. One enzyme (6) adds GlcUA residues, and the other (7) adds GalNAc. As the chain grows, sulfate groups are added by phosphoadenosine phos- phosulfate (PAPS). Metabolic Conjugation and Metabolic Hydrolysis, vol II. CHAPTER 49 / THE EXTRACELLULAR MATRIX AND CONNECTIVE TISSUE 915 Table 49. Defective Enzymes in the Mucopolysaccharidoses – – – – – – Disease Enzyme Deficiency Accumulated Products – – – – – n n Hunter Iduronate sulfatase Heparan sulfate, Dermatan sulfate – – – – – – – Hurler Scheie -L-Iduronidase Heparan sulfate, Dermatan sulfate – – – – – n Maroteaux-Lamy N-Acetylgalactosamine sulfatase Dermatan sulfate n Mucolipidosis VII -Glucuronidase Heparan sulfate, Dermatan sulfate – – – – – – Sanfilippo A Heparan sulfamidase Heparan sulfate n Sanfilippo B N-Acetylglucosaminidase Heparan sulfate Sanfilippo D N-Acetylglucosamine 6-sulfatase Heparin sulfate Core Repeating protein disaccharide These disorders share many clinical features, although there are significant variations between disorders, and even within a single disorder, based on the amount of residual activity remaining. In most cases, multiple organ systems are affected (with bone and cartilage being a primary target). For some disorders, there is significant neuronal involvement, leading to mental retardation. DEGRADATION OF PROTEOGLYCANS Lysosomal enzymes degrade proteoglycans, glycoproteins, and glycolipids, which are brought into the cell by the process of endocytosis. Lysosomes fuse with the endocytic vesicles, and lysosomal proteases digest the protein component. The car- bohydrate component is degraded by lysosomal glycosidases. Lysosomes contain both endoglycosidases and exoglycosidases.

As the head moves buy 130 mg malegra dxt with amex, the thick fluid above the receptor cells 130 mg malegra dxt visa, weighted with otoliths, pulls on the cilia of the cells, generating a nerve impulse. ZOOMING IN ✦ What happens to the cilia on the receptor cells when the fluid around them moves? Box 11-2 • Health Professions AudiologistsAudiologists udiologists specialize in preventing, diagnosing, and treat- levels and teach the public how to prevent hearing loss. To per- Aing hearing disorders caused by injury, infection, birth de- form these duties, audiologists need a thorough understanding fects, noise, or aging. They diagnose hearing disorders by tak- of anatomy and physiology. Audiologists design and implement or university and must pass a national licensing exam. Job prospects are cochlear implants and educating them about their use, or good, as the need for audiologists’ specialized skills will in- teaching alternate communication skills, such as lip reading. For more informa- Audiologists also measure workplace and community noise tion, contact the American Academy of Audiology. THE SENSORY SYSTEM ✦ 237 ◗ Other Special Sense Organs The sense organs of taste and smell are designed to respond to chemical stimuli. Sense of Taste The sense of taste, or gustation (gus- TA-shun), involves receptors in the tongue and two different nerves that carry taste impulses to the brain (Fig. The taste receptors, known as taste buds, are located along the edges of small, depressed areas called fis- sures. Taste buds are stimulated only if the substance to be tasted is in solu- tion or dissolves in the fluids of the mouth. Receptors for four basic tastes are localized in different regions, 11 forming a “taste map” of the tongue (see Fig. As the body spins or moves in different directions, the cilia bend as the head changes posi- terior part of the tongue. Taste maps vary among people, but in each person certain regions of the tongue are more sen- sitive to a specific basic taste. Other tastes are a combina- the vestibulocochlear nerve, or the brain areas concerned tion of these four with additional smell sensations. It may result from prolonged exposure to recently, researchers have identified some other tastes be- loud noises, from the use of certain drugs for long peri- sides these basic four: water, alkaline (basic), and metal- ods, or from exposure to various infections and toxins. Another is umami (u-MOM-e), a pungent or savory People with severe hearing loss that originates in the taste based on a response to the amino acid glutamate. This pros- Glutamate is found in MSG (monosodium glutamate), a thetic device stimulates the cochlear nerve directly, by- flavor enhancer used in Asian food. Water taste receptors passing the receptor cells, and may restore hearing for are mainly in the throat and may help to regulate water medium to loud sounds. Presbycusis (pres-be-KU-sis) is a slowly progressive The nerves of taste include the facial and the glos- hearing loss that often accompanies aging. The condition sopharyngeal cranial nerves (VII and IX). The interpreta- involves gradual atrophy of the sensory receptors and tion of taste impulses is probably accomplished by the cochlear nerve fibers. The affected person may experience lower frontal cortex of the brain, although there may be a sense of isolation and depression, and psychological no sharply separate gustatory center. Because the ability to hear high- pitched sounds is usually lost first, it is important to ad- Sense of Smell dress elderly people in clear, low-pitched tones. Box 11-2 offers information on how audiologists help to treat hear- The importance of the sense of smell, or olfaction (ol- ing disorders. This sense helps to 238 ✦ CHAPTER ELEVEN factory center in the brain’s temporal cortex. The interpretation of smell is closely related to the sense of taste, but a greater variety of dissolved chemicals can be detected by smell than by taste. The smell of foods is just as important in stimulating appetite and the flow of Olfactory digestive juices as is the sense of taste. Nostril The olfactory receptors deteriorate with age and food may become less ap- pealing. It is important when present- ing food to elderly people that the food Facial nerve look inviting so as to stimulate their (VII) appetites. Glossopharyngeal Checkpoint 11-14 What are the special nerve (IX) senses that respond to chemical stimuli? Papillae Tongue with A taste receptors ◗ The General Senses Unlike the special sensory receptors, which are localized within specific TASTE ZONES: sense organs, limited to a relatively small area, the general sensory recep- Sweet Salty Sour Bitter tors are scattered throughout the body. These include receptors for touch, pressure, heat, cold, position, and pain (Fig. Sense of Touch The touch receptors, tactile (TAK-til) corpuscles, are found mostly in the dermis of the skin and around hair fol- licles. Sensitivity to touch varies with B the number of touch receptors in dif- ferent areas. They are especially nu- Figure 11-18 Special senses that respond to chemicals. The lips and the tip of the tongue also contain detect gases and other harmful substances in the environ- many of these receptors and are very sensitive to touch. Smells can trig- Other areas, such as the back of the hand and the back of ger memories and other psychological responses. Smell is the neck, have fewer receptors and are less sensitive to also important in sexual behavior.

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