By G. Jens. Elms College. 2018.

For example buy uroxatral 10 mg with amex, cells of the intestinal muscosa generic uroxatral 10mg with visa, which trans- port fatty acids from the intestine to the blood buy uroxatral 10 mg fast delivery, use ketone bodies and amino acids during starvation effective uroxatral 10 mg, rather than fatty acids 10 mg uroxatral sale. Adipocytes, which store fatty acids in tri- acylglycerols, do not use fatty acids as a fuel during fasting but can use ketone bod- ies. Ketone bodies cross the placenta, and can be used by the fetus. Almost all tis- Why can’t red blood cells use sues and cell types, with the exception of liver and red blood cells, are able to use ketone bodies for energy? Regulation of Ketone Body Synthesis A number of events, in addition to the increased supply of fatty acids from adipose triacylglycerols, promote hepatic ketone body synthesis during fasting. The decreased insulin/glucagon ratio results in inhibition of acetyl CoA carboxylase and decreased malonyl CoA levels, which activates CPTI, thereby allowing fatty acyl CoA to enter the pathway of -oxidation. When oxidation of fatty acyl CoA to acetyl CoA generates enough NADH and FAD(2H) to supply the ATP needs of the liver, acetyl CoA is diverted from the TCA cycle into ketogenesis and oxaloacetate in the TCA cycle is diverted toward malate and into glucose synthesis (gluconeogenesis). This pattern is regulated by the NADH/NAD ratio, which is relatively high during -oxidation. As the length of time of fasting continues, increased transcription of the gene for mitochondrial HMG-CoA synthase facili- tates high rates of ketone body production. Although the liver has been described as “altruistic” because it provides ketone bodies for other tissues, it is simply getting rid of fuel that it does not need. CLINICAL COMMENTS As Otto Shape runs, he increases the rate at which his muscles oxidize all fuels. The increased rate of ATP utilization stimulates the electron trans- port chain, which oxidizes NADH and FAD(2H) much faster, thereby increasing the rate at which fatty acids are oxidized. During exercise, he also uses muscle glycogen stores, which contribute glucose to glycolysis. In some of the fibers, the glucose is used anaerobically, thereby producing lactate. Some of the lac- tate will be used by his heart, and some will be taken up by the liver to be converted to glucose. As he trains, he increases his mitochondrial capacity, as well as his oxy- gen delivery, resulting in an increased ability to oxidize fatty acids and ketone bod- ies. As he runs, he increases fatty acid release from adipose tissue triacylglycerols. In the liver, fatty acids are being converted to ketone bodies, providing his muscles with another fuel. As a consequence, he experiences mild ketosis after his 12-mile run. As ATP levels increase, less NADH is oxidized, and the NADH/NAD ratio is increased. Recently, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, More than 25 enzymes and specific the cause of Lofata Burne’s problems, has emerged as one of the most transport proteins participate in common of the inborn errors of metabolism, with a carrier frequency rang- mitochondrial fatty acid metabo- ing from 1 in 40 in northern European populations to less than 1 in 100 in Asians. At least 15 of these have been impli- Overall, the predicted disease frequency for MCAD deficiency is 1 in 15,000 per- cated in inherited diseases in the human. MCAD deficiency is an autosomal recessive disorder caused by the substitution of a T for an A at position 985 of the MCAD gene. This mutation causes a lysine to replace a glutamate residue in the protein, resulting in the production of an unsta- ble dehydrogenase. The most frequent manifestation of MCAD deficiency is intermittent hypoke- totic hypoglycemia during fasting (low levels of ketone bodies and low levels of glucose in the blood). Fatty acids normally would be oxidized to CO2 and H2O under these conditions. In MCAD deficiency, however, fatty acids are oxidized only until they reach medium-chain length As a result, the body must rely to a greater extent on oxidation of blood glucose to meet its energy needs. However, hepatic gluconeogenesis appears to be impaired in MCAD. Inhibi- tion of gluconeogenesis may be caused by the lack of hepatic fatty acid oxida- tion to supply the energy required for gluconeogenesis, or by the accumulation of unoxidized fatty acid metabolites that inhibit gluconeogenic enzymes.

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The most abundant immediate source of ATP is creatine phosphate purchase uroxatral 10mg overnight delivery. ATP also can be generated from glycogen stores either anaerobically (generating lactate) or aerobically buy uroxatral 10 mg on line, in which case pyru- vate is converted to acetyl CoA for oxidation via the TCA cycle buy 10 mg uroxatral overnight delivery. All human skele- tal muscles have some mitochondria and thus are capable of fatty acid and ketone body oxidation discount 10 mg uroxatral amex. Skeletal muscles are also capable of completely oxidizing the car- bon skeletons of alanine 10 mg uroxatral overnight delivery, aspartate, glutamate, valine, leucine, and isoleucine, but not other amino acids. Each of these fuel oxidation pathways plays a somewhat unique role in skeletal muscle metabolism. ATP and Creatine Phosphate ATP is not a good choice as a molecule to store in quantity for energy reserves. Many reactions are allosterically activated or inhibited by ATP levels, especially those that generate energy. Muscle cells solve this problem by storing high-energy phosphate bonds in the form of creatine phosphate. When energy is required, crea- tine phosphate will donate a phosphate to ADP, to regenerate ATP for muscle con- traction (Fig. Creatine synthesis begins in the kidney and is completed in the liver. In the kid- ney, glycine combines with arginine to form guanidinoacetate. In this reaction, the guanidinium group of arginine (the group that also forms urea), is transferred to 870 SECTION EIGHT / TISSUE METABOLISM O– – H H2N NH O P~N NH ATP ADP C C O N 3 3 creatine CH2 (phospho) CH2 kinase C (CPK or CK) C O HO O Creatine Creatine phosphate Fig. The high-energy bond is the unusual nitro- gen–phosphate bond, as indicated by the blue squiggle. Guani- dinoacetate then travels to the liver, where it is methylated by S-adenosyl methionine to form creatine (Fig 47. The creatine formed is released from the liver and travels through the blood- stream to other tissues, particularly skeletal muscle, heart, and brain, where it reacts with ATP to form the high-energy compound creatine phosphate (see Fig. This reaction, catalyzed by creatine phosphokinase (CK, also abbrevi- ated as CPK), is reversible. Therefore, cells can use creatine phosphate to regen- erate ATP. Creatine phosphate serves as a small reservoir of high-energy phosphate that can readily regenerate ATP from ADP. As a result, it plays a particularly important role in muscle during exercise. It also carries high-energy phosphate from NH2 NH C NH Arginine (CH2)3 NH2 NH H C 2 C NH2 COOH NH CH2 CH2 C NH C 2 O OH Ornithine O OH (CH2)3 Glycine Guanidino- H C 2 acetate COOH SAM Kidney Liver S-adenosyl homocysteine NH2 NH C To: Brain N CH3 Heart CH 2 Skeletal muscle C O OH Creatine Fig. The synthesis of creatine from arginine, glycine, and S-adenosyl methionine. Syn- thesis originates in the kidney and is completed in the liver. CHAPTER 47 / METABOLISM OF MUSCLE AT REST AND DURING EXERCISE 871 – O– O – H NH – O P~N O P OH Pi H C O N NH O C N 3 O C Spontaneous N CH cyclization CH2 CH3 2 (non-enzymatic) C HO O Creatine phosphate Creatinine Muscle and Brain Fig. The spontaneous production of creatinine from creatine phosphate. It spontaneously cyclizes, forming Each kidney normally contains creatinine (Fig. Creatinine cannot be further metabolized and is excreted in approximately one million glomeru- the urine. The amount of creatinine excreted each day is constant and depends on lar units. Each unit is supplied by arterial blood via the renal arteries and acts as body muscle mass. Therefore, it can be used as a gauge for determining the amounts a “filter. The daily volume of urine is determined by such factors as the volume of nels in the glomerular capillaries and enter blood reaching the renal glomeruli and the amount of renal tubular fluid reabsorbed the fluid within the proximal kidney tubule for from the tubular urine back into the interstitial space of the kidneys over time.

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Fuel composition of the average 70-kg man after an overnight fast (in kilograms and as percentage of total stored calories) 10 mg uroxatral mastercard. Body protein purchase uroxatral 10 mg line, particularly the protein of our large muscle masses discount 10 mg uroxatral mastercard, also serves to some extent as a fuel store quality uroxatral 10 mg, and we draw on it for energy when we fast discount uroxatral 10mg line. Fat Our major fuel store is adipose triacylglycerol (triglyceride), a lipid more commonly known as fat. The average 70-kg man has approximately 15 kg stored triacylglycerol, which accounts for approximately 85% of his total stored calories (see Fig. In biochemistry and nutrition, the Two characteristics make adipose triacylglycerol a very efficient fuel store: the standard reference is often the fact that triacylglycerol contains more calories per gram than carbohydrate or pro- 70-kg (154-lb) man. This standard tein (9 kcal/g versus 4 kcal/g) and the fact that adipose tissue does not contain much probably was chosen because in the first half of the 20th century, when many nutri- water. Adipose tissue contains only about 15% water, compared to tissues such as tional studies were performed, young muscle that contain about 80%. Thus, the 70-kg man with 15 kg stored triacylglyc- healthy medical and graduate students (who erol has only about 18 kg adipose tissue. Glycogen Our stores of glycogen in liver, muscle, and other cells are relatively small in quan- tity but are nevertheless important. Liver glycogen is used to maintain blood What would happen to a 70-kg glucose levels between meals. Thus, the size of this glycogen store fluctuates dur- man if the 135,000 kcal stored as ing the day; an average 70-kg man might have 200 g or more of liver glycogen after triacylglycerols in his 18 kg of adi- a meal but only 80 g after an overnight fast. Muscle glycogen supplies energy for pose tissue were stored instead as skeletal muscle contraction during exercise. At rest, the 70-kg man has approximately 150 g muscle glycogen? It would take approxi- mately 34 kg glycogen to store as many calo- of muscle glycogen. Almost all cells, including neurons, maintain a small emer- ries. Glycogen, because it is a polar mole- gency supply of glucose as glycogen. Protein serves many important roles in the body; unlike fat and glycogen, it is not solely a fuel store. Other proteins serve as enzymes (catalysts of biochemical reactions) or as structural components of cells and tissues. Only a limited amount of body protein can be degraded, approx- imately 6 kg in the average 70-kg man, before our body functions are compromised. DAILY ENERGY EXPENDITURE Daily energy expenditure If we want to stay in energy balance, neither gaining nor losing weight, we must, on RMR Physical Activity DIT average, consume an amount of food equal to our daily energy expenditure. The where RMR is the resting meta- daily energy expenditure (DEE) includes the energy to support our basal metabolism bolic rate and DIT is diet-induced thermoge- (basal metabolic rate or resting metabolic rate) and our physical activity, plus the nesis. BMR (basal metabolic rate) is used energy required to process the food we eat (diet-induced thermogenesis). Resting Metabolic Rate The resting metabolic rate (RMR) is a measure of the energy required to maintain life: the functioning of the lungs, kidneys and brain, the pumping of the heart, the maintenance of ionic gradients across membranes, the reactions of biochemical path- ways, and so forth. Another term used to describe basal metabolism is the basal metabolic rate (BMR). The BMR was originally defined as the energy expenditure of a person mentally and bodily at rest in a thermoneutral environment 12 to18 hours after a meal. However, when a person is awakened and their heat production or oxy- gen consumption is measured, they are no longer sleeping or totally at mental rest, and their metabolic rate is called the resting metabolic rate (RMR). It is also some- times called the resting energy expenditure (REE). Factors Affecting BMR The BMR, which is usually expressed in kcal/day, is affected by body size, age, Expressed per kg Body Weight sex, and other factors (Table 1. It is proportional to the amount of metabolically active tissue (including the major organs) and to the lean (or fat-free) body mass. Gender (males higher than females) Obviously, the amount of energy required for basal functions in a large person is Body temperature (increased with fever) Environmental temperature (increased in cold) greater than the amount required in a small person. However, the BMR is usually Thyroid status (increased in hyperthyroidism) lower for women than for men of the same weight because women usually have Pregnancy and lactation (increased) more metabolically inactive adipose tissue. Body temperature also affects the BMR, Age (decreases with age) which increases by 12% with each degree centigrade increase in body temperature (i. The ambient temperature affects the BMR, which increases slightly in colder climates as thermogenesis is activated.

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This inability to socialize is the handicap and discount uroxatral 10mg amex, for many adults purchase 10mg uroxatral free shipping, is what impedes them from being integrated into full society of jobs cheap 10mg uroxatral fast delivery, friends buy discount uroxatral 10 mg on line, and social entertainment purchase uroxatral 10 mg free shipping. In 1993, the National Center for Medical Rehabilitation Research (NCMRR) added to the WHO classification by dividing impairments into “pathophysiology” and “impairment. The WHO initially developed a model for disability that was later expanded by the USA National Center for Medical Re- habilitation Research. The concepts of both models are similar, with a focus that expands the understanding that problems of function are related beyond the isolated anatomic prob- lem of an individual person. Anatomic Classification The most useful primary classification for children with CP is based on the anatomic pattern of involvement. This involvement is the first classification used by physicians treating motor impairments, as it gives a very general sense of severity and a general overview of what patients’ problems likely are. Classification into hemiplegia, which involves one half of the body; diplegia, which involves primarily the lower extremities with mild upper ex- tremity involvement; and quadriplegia, which involves all four limbs, is most useful. In general, individuals with hemiplegia and diplegia can walk, and those with quadriplegia use wheelchairs as their primary mobility device. For patients who do not clearly fit these patterns, many other names have been suggested. Double hemiplegia has been suggested for children with upper and lower extremity involvement that is much more severe on one side than the other. Triplegia has been suggested for individuals who have a hemiplegic pattern on one side and a diplegic pattern in the lower extremities. There are rare children who appear to have hemiplegia and diplegia, which would make anatomic sense, so this term triplegia has some merit; however, it does not aid in treatment planning. Etiology, Epidemiology, Pathology, and Diagnosis 41 Monoplegia is used when one limb is primarily involved; however, from a motor treatment perspective, these children are treated as if they had mild hemiplegia. In North America, the term paraplegia implies a pure lower ex- tremity paralysis and is used only for spinal cord paralysis because almost all children with brain origin disability will also have some upper extremity involvement, although it may be very minor. Pentiplegia is occasionally used to define the most severely impaired individuals who have no independent head control. This term adds little over the use of quadriplegia in planning motor impairment treatment; therefore, it has not gained widespread use. Evolutionary Pathology Even though there are many causes of CP, there are few recurring anatomic patterns of involvement because damage to specific areas, regardless of how the damage occurs, creates similar patterns of impairment. However, a spe- cific region of brain injury can cause variation in the impairments because the initial injury also overlies normal development, which continues after the injury. Because all these injuries occur in the young and immature brain, growth and development over time affects the impairment. A brain injury occurring in early pregnancy, meaning most congenital syndromes, has a dif- ferent presentation than an injury occurring in a 4-year-old child. The first aspect of this pathology is to understand the presence of very early primitive reflexes that should disappear as normal children grow. The cutaneous reflexes, mainly finger and toe grasp, occur with stroking of the skin on the palm or on the sole. The sucking and rooting reflexes are simi- larly initiated with stroking of the face and lips (Figure 2. The labyrinthine reflex is a response to the inner ear being stimulated by changing a child’s position (Figure 2. When held prone, a child will flex, and when placed supine, a child will extend. The proprioceptive reflexes are initiated by stim- ulating the stretch receptors in the muscles and the position sensors in the joints. This reflex creates the asymmetric tonic neck reflex (ATNR) such that when the head is turned to one side, the leg and arm on that side extend (Fig- ure 2. The symmetric tonic neck reflex (STNR) causes the arms to flex and Figure 2. The most primitive reflex is the sucking reflex, which is stimulated by contact of the infant’s perioral area (A). The hand (B) and toe grip (C) grasp reflexes are also pres- ent at birth and are stimulated by stroking the palm or plantar surfaces.

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