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In addition purchase 20mg tadalis sx, he had lost 4 lb Pituitary over the course of the last 6 weeks in spite of GHRH Somatostatin a good appetite generic 20mg tadalis sx mastercard. Atotrope had developed diabetes mellitus generic 20 mg tadalis sx overnight delivery, perhaps related to the chronic hypersecretion of GH generic 20 mg tadalis sx visa. This suspicion was + – confirmed when Sam’s serum glucose level purchase tadalis sx 20mg with amex, drawn before breakfast, was reported to be Growth hormone 236 mg/dL. Liver Muscle • IGF–I Growth Adipose Glucose uptake Gluconeogenesis plate tissue Protein synthesis Glycogen synthesis • Growth Lipolysis Fig. Anabolic effects of growth hormone on various tissues. EFFECTS OF GROWTH HORMONE ON ADIPOSE TISSUE of GH, the clinical course of acro- megaly may be complicated by Growth hormone increases the sensitivity of the adipocyte to the lipolytic action of impaired glucose tolerance or even overt the catecholamines and decreases its sensitivity to the lipogenic action of insulin. GH also decreases esterification of fatty acids, thereby reducing triacylglycerol synthesis within the fat cell. Recent evidence suggests that GH may impair glucose uptake by both fat and muscle cells by a postreceptor inhi- Aminergic neurons bition of insulin action. EFFECTS OF GROWTH HORMONE ON MUSCLE The lipolytic effects of GH increase free fatty acid levels in the blood bathing mus- GHRH GHRIH cle. These fatty acids are preferentially used as fuel, indirectly suppressing glucose + uptake by muscle cells. Through the effects on glucose uptake, the rate of glycoly- sis is proportionately reduced. Somatotroph – GH increases the transport of amino acids into muscle cells, providing substrate for protein synthesis. Through a separate mechanism, GH increases the synthesis of DNA and RNA. The positive effect on nitrogen balance is reinforced by the protein- GH sparing effect of GH-induced lipolysis that makes fatty acids available to muscle as an alternative fuel source. EFFECTS OF GROWTH HORMONE ON THE LIVER synthesis When plasma insulin levels are low, as in the fasting state, GH enhances fatty acid IGF oxidation to acetyl CoA. This effect in concert with the increased flow of fatty acids tyrosine kinase Growth, from adipose tissue enhances ketogenesis. The increased amount of glycerol reach- Other Sulfation tissues ing the liver as a consequence of enhanced lipolysis acts as a substrate for gluco- of bone neogenesis. IGF receptor Hepatic glycogen synthesis is also stimulated by GH in part because of the Protein– P increased gluconeogenesis in the liver. Finally, glucose metabolism is suppressed by GH at several steps in the glycolytic pathway. Mitogenic A major effect of GH on liver is to stimulate production and release of IGFs. The two somatomedins in humans share structural homologies with proinsulin, and both have substantial insulin-like growth Growth activity; hence the designations, insulin-like growth factor I (human IGF-I, or somatomedin-C) and insulin-like growth factor II (human IGF-II, or somatomedin Fig 43. IGF-I is a single-chain basic peptide having 70 amino acids, and IGF-II is hypothalamus produces growth hormone– slightly acidic with 67 amino acids. These two peptides are identical to insulin in releasing hormone (GHRH), which stimulates half of their residues. In addition, they contain a structural domain that is homolo- somatotrophs in the anterior pituitary to release gous to the C-peptide of proinsulin. Growth hormone release-inhibiting hormone (GHRIH) inhibits A broad spectrum of normal cells respond to high doses of insulin by increasing GH release. GH binds to cell surface receptors thymidine uptake and initiating cell propagation. In most instances, IGF-I causes and stimulates IGF production and release by the same response as insulin in these cells but at significantly smaller, more physi- liver and other tissues. Thus, the IGFs are more potent than insulin in their growth- receptors and stimulates the phosphorylation of promoting actions. Evidence suggests that the IGFs exert their effects through either an endocrine or a paracrine/autocrine mechanism. IGF-I appears to stimulate cell propagation and High levels of circulating IGF-1 has growth by binding to specific IGF-I receptors on the plasma membrane of target been linked to the development of cells, rather than binding to GH receptors (Fig.

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THE CONVERSION OF RIBOSE 5-PHOSPHATE TO H+ GLYCOLYTIC INTERMEDIATES The nonoxidative portion of the pentose phosphate pathway consists of a series O O– of rearrangement and transfer reactions that first convert ribulose 5-phosphate to C ribose 5-phosphate and xylulose 5-phosphate order 20mg tadalis sx free shipping, and then the ribose 5-phosphate H and xyulose 5-phosphate are converted to intermediates of the glycolytic path- HO way cheap 20mg tadalis sx with amex. The enzymes involved are an epimerase cheap tadalis sx 20mg fast delivery, an isomerase buy discount tadalis sx 20mg line, transketolase buy 20mg tadalis sx, and transaldolase. H C OH The epimerase and isomerase convert ribulose 5-phosphate to two other 5-carbon H C OH sugars (Fig. The isomerase converts ribulose 5-phosphate to ribose 5-phos- CH OPO2– 2 3 phate. The epimerase changes the stereochemical position of one hydroxyl group (at 6–Phosphogluconate carbon 3), converting ribulose 5-phosphate to xylulose 5-phosphate. Transketolase transfers 2-carbon fragments of keto sugars (sugars with a keto NADP+ group at C2) to other sugars. Transketolase picks up a 2-carbon fragment from xylu- 6–phosphogluconate + dehydrogenase NADPH + H lose 5-phosphate by cleaving the carbon–carbon bond between the keto group and CO2 the adjacent carbon, thereby releasing glyceraldehyde 3-phosphate (Fig. The 2-carbon fragment is covalently bound to thiamine pyrophosphate, which transfers CH2OH C Xyulose 5-phosphate has recently been identified as an activator of protein phos- H phatase 2A (PP2A). PP2A removes phosphates from PFK-2 and from a transcription H C OH factor that binds to carbohydrate response elements in promoters of genes such as CH OPO2– pyruvate kinase. The hydrolysis of the phosphates activates both proteins, such that xyulose 2 3 5-phosphate can regulate pathways relating to both carbohydrate and fat metabolism. Carbon 1 of glucose 6-phosphate is oxidized to an acid and then released as CO2 in an oxidative decarboxylation reaction. The red blood cell is dependent on this enzyme for a source of NADPH to maintain reduced levels of glutathione, one of its major defenses against oxidative stress (see Chapter 24). Glucose 6-phosphate dehydrogenase defi- ciency is the most common known enzymopathy, and affects approximately 7% of the world’s population and about 2% of the U. Most glucose 6-phosphate dehydrogenase–deficient individuals are asymptomatic but can undergo an episode of hemolytic anemia if exposed to certain drugs, to certain types of infections, or if they ingest fava beans. When questioned, Al Martini replied that he did not know what a fava bean was and had no idea whether he was sensitive to them. CH2OH C it to the aldehyde carbon of another sugar, forming a new ketose. The role of thiamine-pyrophosphate here is thus very similar to its role in the oxidative decar- HO boxylation of pyruvate and -ketoglutarate (see Chapter 20, section I. Two H C OH reactions in the pentose phosphate pathway use transketolase; in the first, the 2-car- CH OPO2– 2 3 bon keto fragment from xylulose 5-phosphate is transferred to ribose 5-phosphate Xylulose 5–phosphate to form sedoheptulose 7-phosphate, and in the other, a 2-carbon keto fragment (usu- + ally derived from xyulose 5-phosphate) is transferred to erythrose 4-phosphate to H O form fructose 6-phosphate. C H H C OH H O H C CH OPO2– 2 3 H Ribose 5–phosphate H C OH thiamine H pyrophosphate transketolase CH OPO2– 2 3 H O Ribose 5–phosphate C isomerase H CH OPO2– 2 3 CH2OH Glyceraldehyde 3–phosphate + H CH2OH H C OH C CH OPO2– 2 3 HO Ribulose 5–phosphate H epimerase H H CH2OH CH OPO2– 2 3 Sedoheptulose 7–phosphate HO H C OH Fig. Two-carbon unit transferred by trans- CH OPO2– ketolase. Transketolase cleaves the bond next to 2 3 the keto group and transfers the 2-carbon keto Xylulose 5–phosphate fragment to an aldehyde. Thiamine pyrophos- phate carries the 2-carbon fragment, forming a Fig. Ribulose 5-phosphate is epimerized (to xyulose 5-phosphate) and isomerized (to covalent bond with the carbon of the keto group. CHAPTER 29 / PATHWAYS OF SUGAR METABOLISM: PENTOSE PHOSPHATE PATHWAY, FRUCTOSE, AND GALACTOSE METABOLISM 535 Transaldolase transfers a 3-carbon keto fragment from sedoheptulose 7-phos- The transketolase activity of red phate to glyceraldehyde 3-phosphate to form erythrose 4-phosphate and fructose 6- blood cells is used to measure thi- phosphate (Fig. The aldol cleavage occurs between the two hydroxyl carbons amine nutritional status and diag- nose the presence of thiamine deficiency. This reaction is simi- The activity of transketolase is measured in lar to the aldolase reaction in glycolysis, and the enzyme uses an active amino the presence and absence of added thiamine group, from the side chain of lysine, to catalyze the reaction. If the thiamine intake of a The net result of the metabolism of 3 moles of ribulose 5-phosphate in the pen- patient is adequate, the addition of thiamine tose phosphate pathway is the formation of 2 moles of fructose 6-phosphate and pyrophosphate does not increase the activ- 1 mole of glyceraldehyde 3-phosphate, which then continue through the glycolytic ity of transketolase because it already pathway with the production of NADH, ATP, and pyruvate. Because the pentose contains bound thiamine pyrophosphate. If phosphate pathway begins with glucose 6-phosphate, and feeds back into the the patient is thiamine deficient, transketo- lase activity will be low, and adding thiamine pyrophosphate will greatly stimulate the reaction. Al Martini was diagnosed in Chap- ter 19 as having beriberi heart disease result- CH2OH ing from thiamine deficiency. The diagnosis C was based on laboratory tests confirming HO the thiamine deficiency. H H H CH OPO2– 2 3 Sedoheptulose 7–phosphate + H O C H CH OPO2– 2 3 Glyceraldehyde 3–phosphate transaldolase H O C H H CH OPO2– 2 3 Erythrose 4–phosphate + CH2OH C HO H C OH H C OH CH OPO2– 2 3 Fructose 6–phosphate Fig.

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As children grow tadalis sx 20mg with visa, the fingers open first purchase tadalis sx 20 mg line, and as more maturity and development occur order 20 mg tadalis sx otc, the thumb relaxes out of the palm order tadalis sx 20 mg on-line. Often cheap tadalis sx 20 mg overnight delivery, in children with hemiplegia, the fingers are out of the flexed position by 2 to 3 years of age, and over the next several years the thumb slowly frees up. By 6 to 9 years of age, the thumb may be at the level of maximum abduction, and wrist flexion is becoming the predominant po- sition. There is also significant elbow flexion with forearm pronation from early childhood. As children move through middle childhood and into ado- lescence, the elbow flexion and pronation often slowly decrease but almost never resolve or become insignificant. By late childhood and early adolescence, the upper extremity deformity has developed the position it will maintain throughout the remainder of individuals’ lives, except some of the contrac- tures such as the contracted finger and wrist flexors may slowly become more fixed and more severe. These progressive contractures seem to be more com- mon in quadriplegia than hemiplegia. Throughout childhood, the evaluation of individual children has to focus on their current function, physical defor- mity in the context of their age, and cognitive abilities. Functional Type: A Extremity is not functional B Can use hand as a paperweight, pressure assist, or posting device; is able to swipe a toy and turn a switch on and off C Hand has mass grasp but poor active control D Hand has active grasp and release and can place an object with some degree of accuracy E Hand has fine pinch useful for holding a pen or pencil, has key pinch with the thumb F Normal function, can be used for buttoning and shoestring tying, thumb has fine tripod opposition Within each type, also assess level of contractures: I. Fixed contractures Evaluation of Patients Perhaps one of the most difficult tasks is to accurately determine children’s maximum functional abilities to perform tasks of daily living that are age appropriate. This can be done by taking a careful history from the parents, and if possible, questioning the children’s occupational therapists to deter- mine tasks that they are working on and tasks that they have recently achieved. For example, in toddlers, the parents should be asked if these chil- dren are able to hold a cup or bottle, pick up finger foods, pass a toy from one hand to the other, or hold a piece of paper or crayon. Another question to ask is if the children tend to ignore one of their extremities or do they vol- untarily use the extremity? In older children, assessing their ability to dress and toilet themselves, comb their hair, button clothing, tie shoes, etc. Older children may be too embarrassed to admit to some functional limitations and questions may best be asked of parents and patients separately. Also ask about the children’s cognitive ability: are they grade appropriate for age, what kind of grades are they making? We have found a parent/patient questionnaire helpful in asking some of these questions (Table 8. Physical Examination A careful physical examination is done of passive and active range of mo- tion of all joints from the shoulder distally. Evaluation of fixed muscle con- tractures versus dynamic muscle contractures, as well as recognition of joint contractures and/or joint subluxations and dislocations, are all very impor- tant. Even though the Ashworth scale is subjective, it is a good estimate of the tone of the extremity being tested. Particular attention is paid to children’s abilities to abduct and flex the shoulder, fully extend the elbow, supinate the forearm, and extend the wrist. The ability of children to do active finger ex- tension with the wrist held in passive extension provides a means of separat- ing out lack of wrist extensor power from contracture of the finger flexors. If children can do active finger extension with the wrist extended 20° to 30°, finger motor function is good (Figure 8. If the fingers cannot be actively extended but can be passively extended, lack of extensor motor power is the problem. If the fingers cannot be passively extended, the primary problem is lack of contracture of the finger flexors. Upper extremity involvement covers a wide spectrum of muscle contrac- abduction and extension. Particular attention is paid to whether the defor- tures and postures. The typical arm has mity is a result of a muscle group being spastic with a fixed contracture elbow flexion, wrist flexion, and forearm and/or an opposing muscle group that has excessive weakness. It is important to assess the finger examination, the thumb should be examined with the wrist in 20° to degree of wrist and finger flexion contrac- 30° of dorsiflexion.

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Thyroid hormone also may increase heat production by stimulating ATP utiliza- In hypothyroid patients buy tadalis sx 20mg, insulin tion in futile cycles (in which reversible ATP-consuming conversions of substrate to release may be suboptimal tadalis sx 20mg visa, product and back to substrate use fuels and buy generic tadalis sx 20 mg online, therefore purchase tadalis sx 20mg line, produce heat) discount tadalis sx 20mg line. In hyperthyroidism, the degradation and the clearance of insulin are increased. Gastrointestinal-Derived Hormones Affecting effects, plus the increased demand for Fuel Metabolism insulin caused by the changes in glucose metabolism, may lead to varying degrees of In addition to insulin and the counterregulatory hormones discussed, a variety of glucose intolerance in these patients (a con- peptides synthesized in the endocrine cells of the pancreatic islets, or the cells of dition called metathyroid diabetes mellitus). Some of these peptides and their tissue of ori- cant diabetes mellitus. In addition to these peptides, others such as gastrin, motilin, pancreatic polypeptide (PP), peptide YY (PYY), and secretin may also influence fuel metabolism but by indirect effects on the synthesis or secretion of insulin or the counterregulatory hormones (Table 43. For example, gastrin induces gastric acid secretion, which ultimately affects nutrient absorption and metabolism. Motilin, secreted by enteroendocrine M cells of the proximal small bowel, stimulates gastric and pancreatic enzyme secretion, which, in turn, influ- ences nutrient digestion. Pancreatic polypeptide (PP) from the pancreatic islets reduces gastric emptying and slows upper intestinal motility. Peptide YY (PYY) from the alpha cells in the mature pancreatic islets inhibits gastric acid secretion. Finally, secretin, produced by the enteroendocrine S cells in the proximal small bowel, regulates pancreatic enzyme secretion and inhibits gastrin release and gas- tric acid secretion. Although not directly influencing fuel metabolism, these “gut” hormones have a significant impact on how ingested nutrients are digested and pre- pared for absorption. If digestion or absorption of fuels is altered through a distur- bance in the delicate interplay of all of the peptides, fuel metabolism will be altered as well. Several of these gastrointestinal peptides such as GLP-1 and GIP do not act as direct insulin secretagogues when blood glucose levels are normal but do so after a meal large enough to cause an increase in the blood glucose concen- tration. The release of these peptides may explain why the modest postprandial increase in serum glucose seen in normal subjects has a relatively robust stimulatory effect on insulin release, whereas a similar glucose concentration in vitro elicits a signifi- cantly smaller increase in insulin secretion. Likewise, this effect (certain factors potentiating insulin release), known as the “incretin effect,” could account for the greater beta cell response seen after an oral glucose load as opposed to that seen after the administration of glucose intravenously. Gastrointestinal-Derived Hormones Directly Affecting Fuel Metabolism Primary Cell/ Secretory Stimuli Hormone Tissue of Origin Actions (and Inhibitors) Amylin Pancreatic beta cell, endocrine 1. Inhibits arginine-stimulated and Co-secreted with insulin in cells of stomach and small postprandial glucagon secretion response to oral nutrients intestine 2. Inhibits insulin secretion Calcitonin gene-related Enteric neurons and Inhibits insulin secretion Oral glucose intake and gastric peptide (CGRP) enteroendocrine cells of the acid secretion rectum Galanin Nervous system, pituitary, Inhibits secretion of insulin, Intestinal distension neurons of gut, pancreas, somatostatin, enteroglucagon, thyroid, and adrenal gland pancreatic polypeptide, and others Gastric inhibitory polypeptide/ Neuroendocrine K cells of 1. Increases insulin release via an Oral nutrient ingestion, especially glucose-dependent duodenum and proximal "incretin" effect long-chain fatty acids insulinotropic polypeptide (GIP) jejunum 2. Regulates glucose and lipid metabolism Gastrin-releasing peptide (GRP) Enteric nervous system and Stimulates release of pancreas cholecystokinin; GIP, gastrin, glucagon, GLP-1, GLP-2, and somatostatin Ghrelin Central nervous system, Stimulates growth hormone release Fasting stomach, small intestine, and colon Glucagon Pancreatic alpha cell, central Primary counter-regulatory hormone Neural and humoral factors nervous system that restores glucose levels in released in response to hypoglycemic state (increases hypoglycemia glycogenolysis and gluconeogenesis as well as protein-lipid flux in liver and muscle) Glucagon-like peptide-1 (GLP-1) Enteroendocrine L cells in 1. Oral nutrient ingestion ileum, colon, and central meals by inhibiting glucagon 2. Vagus nerve nervous system secretion and stimulating insulin 3. Acts through second messengers in beta cells to increase sensitivity of these cells to glucose (an incretin) Glucagon-like peptide-2 (GLP-2) The same as for GLP-1 Stimulates intestinal hexose Same as GLP-1 transport Neuropeptide Y Central and peripheral nervous Inhibits glucose-stimulated insulin Oral nutrient ingestion and system, pancreatic islet cells secretion activation of sympathetic nervous system Neurotensin (NT) Small intestinal N cells In brain, modulates dopamine 1. Luminal lipid nutrients (especially ileum), enteric neurotransmission and anterior 2. Somatostatin inhibits secretion gland, pancreas Pituitary adenylate cyclase Brain, lung, and enteric nervous Stimulates insulin and Activation of central nervous activating peptide (PACAP) system catecholamine release system Somatostatin Central nervous system, 1. Luminal nutrients pancreatic delta cells, and glucagon and PP (islets), and gas- 2. GLP-1 enteroendocrine delta cells trin, secretin, GLP-1, and 3. Beta-adrenergic stimulation Vasoactive intestinal peptide Widely expressed in the central May regulate release of insulin and 1. Mechanical stimulation of gut (VIP) and peripheral nervous pancreatic glucagon 2.

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Cells of the immune system cannot proliferate at a normal rate tadalis sx 20 mg low price, and Host-cell Therapeutic children with SCID usually die at an early age because they cannot combat infections generic tadalis sx 20mg with mastercard. To genome gene survive discount tadalis sx 20mg with visa, they must be confined to a sterile cheap 20 mg tadalis sx fast delivery, environmental “bubble order tadalis sx 20 mg on-line. Use of retroviruses for gene ther- In 1990, a 4-year-old girl, for whom no donor was available, was treated with infu- apy. The retrovirus carries an RNA copy of the sions of her own lymphocytes that had been treated with a retrovirus containing a nor- therapeutic gene into the cell. Although she had not responded to previous therapy, she improved sig- that contains the virus dissolves, and the RNA nificantly after this attempt at gene therapy. This disease is still being treated with gene and viral reverse transcriptase are released. This enzyme copies the RNA, making a dou- ble-stranded DNA that integrates into the host In familial hypercholesterolemia, a condition associated with a high incidence cell genome. Transcription and translation of of heart attacks, the low-density lipoprotein (LDL) receptor is deficient. After ply because its genes were removed and these dividing cells were infected with a retrovirus containing the gene for the LDL recep- replaced by the RNA copy of the therapeutic tor, they were reinfused into the hepatic portal vein of the patient. CHAPTER 17 / USE OF RECOMBINANT DNA TECHNIQUES IN MEDICINE 313 Adenoviruses, which are natural human pathogens, can also be used as vectors. Adenoviral vectors have been used As in retroviral gene therapy, the normal viral genes required for synthesis of viral in a aerosal spray to deliver normal particles are replaced with the therapeutic genes. The advantages to using an aden- copies of the CFTR (cystic fibrosis transmembrane conductance regulator) ovirus are that the introduced gene can be quite large (~36 kb), and infection does gene to cells of the lung. Some cells took up not require division of host cells. The disadvantage is that genes carried by the ade- this gene, and the patients experienced novirus do not stably integrate into the host genome, resulting in only transient moderate improvement. However, stable expression of the therapeutic proteins (but preventing disruption of host genes). Another problem with adenovi- not occur, and cells affected by the disease ral gene therapy is that the host can mount an immune response to the pathogenic other than those in the lung (e. Nevertheless, this To avoid the problems associated with viral vectors, researchers are employing approach marked a significant forward step treatment with DNA alone or with DNA coated with a layer of lipid (i. Adding a ligand for a receptor located on the target cells could aid delivery of the liposomes to the appropriate host cells. Many problems still plague the field In an attempt to treat ornithine transcarbamoylase deficiency (a of gene therapy. In many instances, the therapeutic genes must be targeted to the disorder of nitrogen metabolism) cells where they normally function—a difficult task at present. Deficiencies in dom- using adenoviral vectors, a volunteer died of inant genes are more difficult to treat than those in recessive genes, and the expres- a severe immune response to the vector. Although the This unfortunate result has led to a reevalu- field is moving forward, progress is slow. These oligonucleotides are designed to hybridize either with the target gene to prevent transcription or with mRNA to prevent translation. Again One approach to in vivo gene ther- technical problems have plagued the development of therapy based on this theoret- apy involves the direct injection of ically promising idea. DNA for certain HLA antigens into malignant melanomas (skin cancers). Transgenic Animals HLA gene chosen for therapy should not be the one expressed by the patient. Thus, if the The introduction of normal genes into somatic cells with defective genes corrects gene is incorporated into the cells and the defect only in the treated individuals, not in their offspring. To eliminate the expressed, the body should recognize the defect for future generations, the normal genes must be introduced into the germ tumor cells as foreign tissue and mount an cell line (the cells that produce sperm in males or eggs in females). Preliminary results using with animals indicate that gene therapy in germ cells is feasible. In fact, if the nucleus isolated from the cell of one animal is injected into the enu- cleated egg from another animal of the same species and the egg is implanted in a foster mother, the resulting offspring is a “clone” of the animal from which the nucleus was derived (Fig. Clones of sheep and pigs have been produced, and similar techniques could be used to clone humans. Obviously, these experiments raise many ethical questions that will be difficult to answer.

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