By N. Umul. Chicago State University.

During prolonged fasting order buspirone 10 mg line, they may centration (see Chapter 36) buy 5 mg buspirone otc. Preferential utilization of fatty acids does not buspirone 5 mg amex, how- rise to 4 to 5 mM. Levels above 7 mM are ever, restrict the ability of glycolysis to respond to an increase in AMP or ADP considered evidence of ketoacidosis, levels, such as might occur during exercise or oxygen limitation. Tissues That Use Ketone Bodies tem in the blood and compensatory respira- tion (Kussmaul’s respiration) (see Chapter 4). Skeletal muscles, the heart, the liver, and many other tissues use fatty acids as their major fuel during fasting and other conditions that increase fatty acids in the blood. However, a number of other tissues (or cell types), such as the brain, use ketone bodies to a greater extent. For example, cells of the intestinal muscosa, which trans- port fatty acids from the intestine to the blood, use ketone bodies and amino acids during starvation, rather than fatty acids. 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 generic buspirone 10mg with mastercard, there is little concern about managing seizures postoperatively because they are seldom a problem cheap buspirone 5 mg line. If a grand mal seizure occurs in the postoperative phase purchase 5 mg buspirone free shipping, the Unit rod is strong enough to resist failure and we have never seen any related problems. Intraoperative Complications Respiratory Problems Many children with severe neurologic involvement have some level of aspi- ration, which may lead to reactive airway disease. As children are anes- thetized, asthma may become more noticeable. Appropriate treatment with inhalers and steroids should be started, and if the patients respond quickly, the surgery can proceed. If there are prolonged periods of hypoxia or dif- ficulty with ventilation, the surgery should be canceled if it has not been started, and if this occurs during the operative procedure, very rarely surgery may need to be abandoned. Dislodgment of the endotracheal tube is a serious respiratory emergency and the whole team must understand the protocol in the event this occurs. Children need to be turned emergently into a supine position on a stretcher that should always remain immediately accessible to the operating room. The endotracheal tube may also occasionally move distally into the right mainstem bronchus and cause hypoventilation on the left side. If there is hypoxia and decreased breath sounds on one side during surgery, the move- ment of the endotracheal tube should be the first thing to check. If the tube is fine, then an acute pneumothorax on the side with decreased breath sounds should be considered. It is very difficult to get a good chest radiograph in the prone position on a spine frame, so if the problem persists, it is better to pro- phylactically place a chest tube on the side with decreased breath sounds. By only minimal movement of the surgical drapes, the midthoracic level of the posterior axillary line is ac- cessible and a tube can be easily inserted from the surgical field. If no pneu- mothorax is present, no damage is done; however, this can potentially avoid 9. He was the proximal end of the rod with rod connectors (Figure only comfortable lying in one position. For the first 3 months after surgery, he was again treatment for severe gastroesophageal reflux, and was much better with decreased gastroesophageal reflux but taking tegretol to treat seizures. He was very thin and then had a sudden onset of reflux and the parents felt his weighed 23 kg. After the reflux was under maximum body shape changed. Repeat examination demonstrated medical management, he had spinal surgery with a Unit rod that the rod connectors had failed, which required a third instrumentation to correct the scoliosis. During surgery, procedure with rod replacement (Figure C9. Fol- he had a high blood loss, totaling four blood volumes, lowing the third operation, his reflux was again under easy due to a coagulopathy that was not treated aggressively control (Figure C9. This case demonstrates how enough early in the case. As a result of the coagulopathy, responsive reflux is to spine deformity correction in a few and the surgical technique at that time in which the pelvic children. This holes were drilled just before to rod insertion, pelvic fix- case also demonstrates two major errors. One is that the ation was abandoned and he was only instrumented to L5 procedure needs to be planned for progressive increase in (Figure C9. Postoperative radiographs showed good blood loss, which the team must be prepared to address; but not complete correction of the pelvic obliquity. His that means the pelvic holes should be drilled early in the postoperative recovery was uneventful with greatly di- case when there is little blood loss. The second error is minished gastroesophageal reflux. Immediately after sur- that end-to-end rod connectors located at the same level gery, sitting was much improved. He again presented have a high failure rate and this should be avoided. We 9 months following surgery with increased sitting difficulty had three such failures until we learned this lesson.

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These bind cytosolic pro- teins such as hexokinase (HK) safe buspirone 10 mg, which enables HK to have access to newly exported ATP order buspirone 10 mg with visa. ATP-ADP translocase (also called ANT for adenine nucleotide translocase) trans- ports ATP formed in the mitochondrial matrix to the intermembrane space in a specific ANT is an antiport buy 5 mg buspirone overnight delivery, an exchange 1:1 exchange for ADP produced from energy-requiring reactions outside of the mito- protein that translocates one ion in chondria (see Fig. Because ATP contains four negative charges and ADP only exchange for a molecule of similar three, the exchange is promoted by the electrochemical potential gradient, because the charge. In contrast, the phosphate transporter and the pyruvate transporter are symports, net effect is the transport of one negative charge from the matrix to the cytosol. Simi- which are translocases that co-transport two lar antiports exist for most metabolic anions. In contrast, inorganic phosphate and pyru- molecules of opposite charge. The Ca2 chan- vate are transported into the mitochondrial matrix on specific transporters called sym- ports together with a proton. A specific transport protein for Ca2 uptake, called the nel is called a uniporter because no other ions are involved. All of the metabolites entering 2 Ca uniporter, is driven by the electrochemical potential gradient, which is negatively or leaving the TCA cycle are transported charged on the matrix side of the membrane relative to the cytosolic side. Transport through the Outer Mitochondrial dicarboxylate transporter (phosphate–malate Membrane exchange), the tricarboxylate transporter (cit- rate–malate exchange), the aspartate-gluta- Whereas the inner mitochondrial membrane is highly impermeable, the outer mito- mate transporter, and the malate- -ketoglu- chondrial membrane is permeable to compounds with a molecular weight up to tarate transporter. Unlike most transport proteins, which are membrane-spanning Investigators reported finding anti- bodies against cardiac ATP-ADP helices with specific binding sites, VDACs are composed of porin homodimers that translocase in an individual who form a -barrel with a relatively large nonspecific water-filled pore through the cen- died of a viral cardiomyopathy. These channels are “open” at low transmembrane potential, with a preference these antibodies result in death? CHAPTER 21 / OXIDATIVE PHOSPHORYLATION AND MITOCHONDRIAL FUNCTION 395 As ATP is hydrolyzed during muscular contraction, ADP is formed. This ADP must In addition to a normal role in move- exchange into the mitochondria on ATP-ADP translocase to be converted back to ment of molecules across the mito- ATP. Inhibition of ATP-ADP translocase results in rapid depletion of the cytosol ATP chondrial outer membrane, VDACs levels and loss of cardiac contractility. These roles are influenced by pro- teins that bind to the VDACs. By forming a VDACs thus facilitate translocation of these anions between the intermembrane component of the mitochondrial permeability space and the cytosol. A number of cytosolic kinases, such as the hexokinase that transition pore, VDACs may contribute to initiates glycolysis, bind to the cytosolic side of the channel, where they have ready events leading to cell necrosis. The Mitochondrial Permeability Transition Pore permeability of the outer membrane so as to either favor or block events leading to pro- The mitochondrial permeability transition involves the opening of a large nonspecific grammed cell death (apoptosis). The basic components of the mitochondrial permeability transition pore Outer are adenine nucleotide translocase (ANT), the voltage-dependant anion channel Inner mitochondrial mitochondrial membrane (VDAC), and cyclophilin D (which is a cis-trans isomerase for the proline peptide membrane bond). Normally ANT is a closed pore that functions specifically in a 1:1 exchange of matrix ATP for ADP in the intermembrane space. However, increased mitochondrial Bax matrix Ca2 , excess phosphate, or ROS (reactive oxygen species that form oxygen or 2+ Ca + V oxygen–nitrogen radicals) can activate opening of the pore. Conversely, ATP on the Pi D – ATP ANT [H+] cytosolic side of the pore (and possibly a pH below 7. Opening of the MPTP can be C ∆p CD triggered by ischemia (hypoxia), which results in a temporary lack of O2 for maintain- Bcl-2 ing the proton gradient and ATP synthesis. When the proton gradient is not being gen- erated by the electron transport chain, ATP synthase runs backward and hydrolyzes Inter ATP in an attempt to restore the gradient, thus rapidly depleting cellular levels of ATP. This can lead to a downward spiral of cellular events. A lack of ATP for maintaining the low intracellular Ca2 can con- Fig. The mitochondrial permeability tribute to pore opening. When the MPTP pore opens, protons will flood in, and main- transition pore (MPTP). In the MPTP, ANT is taining a proton gradient becomes impossible. Anions and cations enter the matrix, thought to complex with VDAC. The confor- mation of ANT is regulated by cyclophilin D mitochondrial swelling ensues, and the mitochondria become irreversibly damaged. VDACs bind a number of pro- The result is cell lysis and death (necrosis).

These muscle lengthenings are especially beneficial in nonambulatory children in whom all the anterior abductors are tight and are causing internal rotation generic buspirone 10mg fast delivery. These mus- cles can be released off the greater trochanter without any risk of causing functional problems order 10 mg buspirone with amex. We have had good success with this procedure in chil- dren who have moderate degrees of internal rotation cheap 5 mg buspirone with amex. However, it is some- times difficult to find all the muscles that are causing an internal rotation force, but they may include adductor brevis and longus, and some contribu- tion from the medial hamstrings. These corrections are best approached by doing careful palpation of the children in different positions of hip flexion when in the operating room to determine what muscles are limiting the ex- ternal rotation. The anterior hip capsule is sometimes contributory and may need to be released as well. In ambulatory children, releasing the anterior ab- ductors should be done with caution. The tendon of the abductors tends to be underneath, or deep to the muscle belly. However, a myofascial lengthen- ing of the anterior abductors improves the internal rotation. Careful length- ening in the myofascial plane of these anterior abductors can substantially improve internal rotation and it can be done safely without causing too much abductor weakness. Although initially reported as very successful,108 many of these patients ended up having little external rotation and many developed relatively severe hip flexion contrac- tures. We have seen several of these patients who continued to have sub- stantial internal rotation, and in spite of this internal rotation, they have very severe fixed hip flexion contractures that are very hard to treat. This proce- dure has no role in the current treatment of children with CP. Hypotonic Hips Hypotonic hip disease includes a poorly defined group of children who have general hypotonia. This discussion is limited to children who have hypoto- nia secondary to an encephalopathy, and therefore excludes all children who have hypotonia secondary to severe myopathy or muscle diseases. However, the problem with these children is very similar to that of children who have severe muscle weakness secondary to spinal muscular atrophy or flaccid paralysis due to spinal cord injury or spina bifida. Many of the children with static encephalopathy and hypotonia end up having some chromosomal anomalies, which are often undefined or poorly defined. In addition, this condition may be combined with soft-tissue hyperlaxity such as is seen in Down syndrome or Ehlers–Danlos syndrome. However, increased soft-tissue laxity is substantially different from hypotonia and although both may be present concurrently, this is not the typical presentation. The problems of weak and/or hypotonic children are quite different in their response to sur- gical treatment than those with severe soft-tissue laxity. The focus of this discussion is primarily on those children who have hypotonia secondary to a static encephalopathy. Hip 627 Etiology The etiology of hypotonic hip disease is opposite that of spastic hip disease. With hypotonic hip disease, the hip comes out of the joint because there is insufficient muscle force to hold it in the joint. This poor muscle force also leads to the development of poor acetabular depth because there is not enough pressure against the medial wall of the acetabulum to foster good ac- etabular depth growth. For this reason, most of these children will have a global acetabular dysplasia and many have MP of 40% or more, although no instability is present and there is a good medial shape to the acetabulum. These children often have wide hip abduction; however, they frequently want to position themselves with internal rotation. They are at risk for developing both anterior and posterior dislocations. Ambulatory children with sub- stantial hypotonia seem to be at more risk for developing anterior disloca- tion because they spend much more time with their hips extended and often fall into external rotation. Anterior dislocation should be a major consider- ation in any child with substantial hypotonia who suddenly refuses to walk, or stops walking (Case 10. Anterior dislocation should also be consid- ered when the external rotation seems to have suddenly gotten worse. Most of these children with significant external rotation, as demonstrated by ex- ternal foot progression angle, still have increased femoral anteversion or normal femoral anteversion. Anatomical retroversion is very rare, especially in this hypotonic group.

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