By I. Kadok. Clemson University. 2018.
It also may induce ABC protein expression buy 150 mg trileptal otc medicine joji, but this action is relatively unimportant in reducing net cholesterol absorption order trileptal 150 mg with mastercard symptoms high blood sugar. The reduction of cholesterol absorption from the intestinal lumen has been shown to reduce blood levels of LDL cholesterol. CHOLESTEROL SYNTHESIS 1 9 2 10 14 15 8 Cholesterol is an alicyclic compound whose basic structure includes the perhy- A drocyclopentanophenanthrene nucleus containing four fused rings (Figure 34. The basic ring structure of sterols; the hydrocarbon chain attached to carbon 17 in the D ring, a methyl group (carbon perhydrocyclopentanophenanthrene nucleus. CHAPTER 34 / CHOLESTEROL ABSORPTION, SYNTHESIS, METABOLISM, AND FATE 623 21 22 24 26 O 20 25 23 CH3 C SCoA 18 17 Acetyl CoA 27 O CH3 C SCoA 19 CoA-SH O O 3 CH C CH C SCoA 3 2 HO Acetoacetyl CoA Fig. O HMG-CoA synthase CH3 C SCoA Approximately one third of plasma cholesterol exists in the free (or unesterified) CoA-SH form. The remaining two thirds exists as cholesterol esters in which a long-chain O fatty acid (usually linoleic acid) is attached by ester linkage to the hydroxyl group C O– at C-3 of the A ring. The proportions of free and esterified cholesterol in the blood β-hydroxy- CH2 can be measured using methods such as high-performance liquid chromatography β-methyl- CH3 C OH glutaryl CoA (HPLC). C Acetyl CoA can be obtained from several sources, including the beta oxidation of O SCoA fatty acids, the oxidation of ketogenic amino acids, such as leucine and lysine, and 2NADPH + 2H+ the pyruvate dehydrogenase reaction. Carbons 1, 2, 5, 7, 9, 13, 15, 18, 19, 20, 22, HMG-CoA 2NADP+ 24, 26, and 27 of cholesterol are derived from the methyl group of acetyl CoA and reductase CoA-SH the remaining 12 carbons of cholesterol from the carboxylate atom of acetyl CoA. The synthesis of cholesterol requires significant reducing power, which is sup- O plied in the form of NADPH. The latter is provided by glucose-6-phosphate dehy- C O– drogenase and 6-phosphogluconate dehydrogenase of the hexose monophosphate CH 2 shunt pathway (see Chapter 29). Cholesterol synthesis occurs in the cytosol, requir- CH3 C OH ing hydrolysis of high-energy thioester bonds of acetyl CoA and phosphoanhydride CH2 bonds of ATP. Stage 1: Synthesis of Mevalonate from Acetyl CoA Mevalonate The first stage of cholesterol synthesis leads to the production of the intermediate Fig. The synthesis of mevalonate is the committed, rate-limiting of acetyl-CoA to mevalonic acid. In this cytoplasmic pathway, two molecules of acetyl CoA condense, forming acetoacetyl CoA, which then condenses with a third mole- cule of acetyl CoA to yield the 6-carbon compound -hydroxy- -methylglutaryl- CoA (HMG-CoA). The HMG-CoA synthase in this reaction is present in the cytosol and is distinct from the mitochondrial HMG-CoA synthase that catalyses HMG-CoA synthesis involved in ketone body production. The committed step and Ann Jeina’s serum total and LDL major point of regulation of cholesterol synthesis in stage 1 involves reduction of cholesterol levels improved only HMG-CoA to mevalonate, a reaction catalyzed by HMG-CoA reductase, an enzyme modestly after 3 months on a Step I embedded in the membrane of the endoplasmic reticulum. Three additional months on a more severe contains eight membrane-spanning domains, and the amino terminal domain, which low-fat diet (Step II diet) brought little further improvement. The next therapeutic step would faces the cytoplasm, contains the enzymatic activity. The reducing equivalents for be to initiate lipid-lowering drug therapy (see this reaction are donated by two molecules of NADPH. TRANSCRIPTIONAL CONTROL The rate of synthesis of HMG-CoA reductase messenger RNA (mRNA) is con- trolled by one of the family of sterol regulatory element binding proteins (SREBPs)(Fig. These transcription factors belong to the helix-loop-helix- 624 SECTION SIX / LIPID METABOLISM A SREBP NH2 + SREBP NH3 Degradation + + S2P SCAP SRE Gene transcription – Sterols ER membrane B HMG-CoA Proteolysis, reductase degradation + Sterols ER membrane C + AMP-activated AMP Glucagon protein kinase Sterols ATP ADP + AMP-activated AMP-activated protein kinase protein kinase P (inactive) (active) ATP ADP HMG-CoA HMG-CoA reductase reductase P (active) (inactive) Insulin Pi + Phosphatase Fig. SREBP1-a specifically enhances transcription of genes required for HMG-CoA reductase expression by binding to the sterol regulatory element (SRE) upstream of the reductase gene. SREBPs, after synthesis, are integral ER proteins, and the active component of the protein is released by two proteases, SCAP (SREBP cleavage-activating protein) and S2P (site 2 protease). Once released, the active amino terminal component travels to the nucleus to bind to SREs. The soluble SREBPs are rapidly turned over and need to be continuously produced to effectively stimulate reductase mRNA transcription. When cytoplasmic sterol levels rise, the sterols bind to SCAP and inactivate it, thereby leading to a decrease in transcription of the reductase gene, and less reduc- tase protein being produced. CHAPTER 34 / CHOLESTEROL ABSORPTION, SYNTHESIS, METABOLISM, AND FATE 625 2. PROTEOLYTIC DEGRADATION OF HMG-CoA REDUCTASE Rising levels of cholesterol and bile salts in cells that synthesize these molecules also may cause a change in the oligomerization state of the membrane domain of HMG-CoA reductase, rendering the enzyme more susceptible to proteolysis (see Fig.
In this situation trusted 150 mg trileptal treatment narcissistic personality disorder, the fluoroscope is available in the standard operating proce- dure and checking the degree of anteversion and getting an accurate assess- ment of proximal femoral coxa valga adds no additional time purchase 300 mg trileptal symptoms 7 days after ovulation. Magnetic Resonance Imaging Scan One study reports using magnetic resonance imaging (MRI) scan to meas- ure femoral anteversion and documents that the MRI scan has the same accuracy and problems inherent with CT scan. No other major benefits are known, and certainly the bone image is never quite so good on MRI scan as it is on CT scan. Measurement Summary There are many methods for measuring femoral anteversion and femoral neck shaft angle, each measuring slightly different things and having some variation in the degree of accuracy. There is no consensus about which tech- nique for measuring femoral anteversion is the best, and as noted previously, each has its drawbacks and benefits. There also is no consensus about when femoral anteversion and coxa valga need to be measured accurately. For most of the children being followed, the assessment of femoral anteversion can be done accurately enough by continuing to monitor the physical ex- amination of the internal and external rotation of the hip and occasionally adding the palpation of the lateral trochanter measurement. For research projects in which more accurate measurements of the influence of femoral anteversion on a deformity are necessary, we believe more accurate imaging methods are required. The use of ultrasound is easy, sufficiently accurate, and inexpensive to use for those children who do not have severe deformi- ties and who have not had hip surgery. In more complicated patients who have had hip surgery and have developed recurrent internal rotation, it is often not clear exactly where this deformity is coming from (Case 10. There is often a concern of recurrent or residual uncorrected anteversion be- ing present. In these individuals, the best method for measuring anteversion is the CT scan because low to normal neck shaft angle is usually present as these children already had the coxa valga corrected. The irregular surfaces of the femur can be more easily dealt with by having a whole outline of the proximal femur, which is provided by the CT scan. In the operating room, using the fluoroscope to understand coxa valga and femoral anteversion is routine as part of the operative procedure. However, it is not necessary to make an absolute measurement of the degree of femoral anteversion pre- operatively in all children who have severe internal rotation and are being brought to the operating room to have this corrected. If children have not previously had hip surgery, and are being scheduled for surgical correction of the internal rotation deformity of the femur, increased femoral antever- sion is the problem and measurement of the anteversion beyond the physi- cal examination is not routinely needed. The Etiology of Femoral Anteversion and Coxa Valga Femoral anteversion is a normal position of the femur in infants. Femoral anteversion varies from 40° to 60° at birth, and then slowly resolves with growth until the normal 10° to 20° of anteversion is reached by age 8 years. There is a significant variation in the magnitude of anteversion at birth. In children with spasticity, the normal resolution of this anteversion does not occur because the spasticity and poor motor control do not provide a me- chanical environment in which the femur derotates itself. In addition, chil- dren with spasticity who maintain this high degree of infantile anteversion often have decreased motor control, which means they have less ability to compensate for this tendency to internally rotate from the increased femoral anteversion. A second aspect that may magnify the persistent infantile femoral anteversion begins to show up in middle childhood with the develop- ment of internal rotation contractures, which further magnify the persistent 10. His parents were concerned about the severe internal rotation position of the left hip. A hip re- construction was performed, which gave him excellent position (Figure C10. Following this reconstruction, he did well for 5 years; however, his parents noted the slow returning of the internally rotated posture. They were concerned that he was again developing a dislocated hip; however, the radiographs were normal (Figure C10. On physical examination he was noted to have adduction of the left hip limited to 10°, full flexion, and extension; however, the left hip external rotation was only to −20°. A CT scan showed a posterior displacement of the femoral head with almost posterior subluxation and 30° of ante- version (Figure C10. A soft- tissue release, including adductor lengthening, a gluteus medius and minimus release, and release of the anterior tensor fascia lata allowed the hip to externally rotate, and the femoral head reduced nicely into the joint by 1 year later (Figure C10.
Type 3 pattern has Most orthopaedic surgeons have advocated delaying surgery until age 4 years little active finger extension or grasp func- when adequate maturation of the nervous system has developed and when tion (B) effective trileptal 600mg medications recalled by the fda. Traditional teaching is that the ideal age to consider surgery is between 4 and 9 years order trileptal 600mg free shipping medications after stroke. We have found children between the ages of 7 and 12 years to be ideal candidates for sur- gery. This age range gives children enough maturity to cooperate with oc- cupational therapy and enough skeletal growth where recurrence due to increasing muscle tightness secondary to growth is at less risk. These patients are also not too old for retraining of transferred muscles, and they have reached a plateau in their neurologic development. Neurologic Type Patients with spasticity benefit most from surgery. It is extremely important to distinguish dystonia from spasticity, which can look very similar. Dystonic patients do poorly with muscle transfers and lengthening as do most patients with movement disorders (including athetosis). In general, tendon surgery should be avoided in patients with movement disorders. Some individuals, especially those with athetosis, may benefit from restraining the nondomi- nant extremity during fine motor skill tasks. Typically, these contractures start to become noticeable in 8. Upper Extremity 395 middle childhood and become more noticeable in adolescence. The most common deformity is protraction and elevation of the shoulder through the scapulothoracic joint, with the clavicle becoming more vertical and anteri- orly directed. As severely involved patients become adults, this shoulder po- sition becomes fixed but seldom causes any pain or discomfort. In spastic patients, internal rotation contracture of the shoulder develops as a result of spasticity of the pectoralis major and subscapularis muscle. On rare occa- sions, extension and external rotation abduction contractures develop, often caused predominantly by the long head of the triceps and teres muscles. Natural History The natural history of shoulder contractures is for increasing severity during late childhood and adolescence with minimal change after hormonal and skeletal maturity. Also in middle childhood, primarily in children with quad- riplegia, shoulder adduction, internal rotation, and flexion contractures develop. As these contractures become more severe, especially at puberty with the hormonal changes and the growth of axillary hair, the contractures become so severe that proper cleaning and drying of the axilla becomes very difficult. Also, dressing these children, especially placing arms in sleeves, becomes very difficult. For other functional positions, such as seating and different reclining positions, this upper extremity position is good. During adolescence, there are a small group of children who develop an external rotational abduction contracture of the shoulder. This becomes a functional problem, especially when seated in a wheelchair, as the arms tend to strike walls as these children are being transported. Shoulder and elbow extension For ambulatory children, the most common hemiplegic posturing is with can be disabling because it causes the arm to shoulder elevation and protraction combined with adduction, flexion, and be behind and lateral to the individual. This becomes severe enough to cause functional problems may lead to the arm getting bumped or strik- only in rare ambulatory children with hemiplegia. There are also a few chil- ing furniture, and it is a significant cosmetic dren who develop shoulder extension and external rotation combined with problem (A). In ambulatory children this is usually a sign of dystonia, lateral and long head of the triceps, the although this may be encountered in individuals with spasticity and con- elbow and shoulder flexion are greatly im- tracture (Figure 8. This also allows the arm to hang at the side during ambulation (B). Splinting is of no use, especially the attempt to use figure-of-eight straps on the shoulders to counteract the shoulder pro- traction and elevation. These straps have too little mechanical advantage to make an impact without causing children discomfort. As children with quadriplegia enter puberty and approach maturity, problems related to dressing and hygiene develop.
Box 11-2 offers information on how audiologists help to treat hear- The importance of the sense of smell order 600mg trileptal with amex symptoms kidney infection, or olfaction (ol- ing disorders generic trileptal 150mg otc medications memory loss. 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. The receptors for smell are located in the epithelium of the superior region of the nasal cavity (see Fig. Sense of Pressure Again, the chemicals detected must be in solution in the fluids that line the nose. Because these receptors are high Even when the skin is anesthetized, it can still respond to in the nasal cavity, one must “sniff” to bring odors up- pressure stimuli. These sensory end-organs for deep pres- ward in the nose. THE SENSORY SYSTEM ✦ 239 tivities as walking, running, and many more complicated skills, such as play- ing a musical instrument. They help to provide a sense of body movement, known as kinesthesia (kin-es-THE-ze- ah). Proprioceptors play an important part in maintaining muscle tone and good posture. They also help to assess the weight of an object to be lifted so that the right amount of muscle force is used. The nerve fibers that carry im- pulses from these receptors enter the spinal cord and ascend to the brain in the posterior part of the cord. The cerebellum is a main coordinating cen- ter for these impulses. Checkpoint 11-15 What are examples of general senses? Sense of Pain Pain is the most important protective sense. The receptors for pain are widely distributed free nerve endings. They are found in the skin, muscles, and joints Figure 11-19 Sensory receptors in the skin. One is for acute, sharp pain, Sense of Temperature and the other is for slow, chronic pain. Thus, a single strong stimulus produces the immediate sharp pain, followed in a The temperature receptors are free nerve endings, receptors second or so by the slow, diffuse, burning pain that in- that are not enclosed in capsules, but are merely branchings creases in severity with the passage of time.
Aldose reductase has a relatively high K for galactose 300mg trileptal visa medications 2 times a day, approxi- III buy discount trileptal 600mg line medications 230. THE PENTOSE PHOSPHATE PATHWAY m mately 12 to 20 mM, so that galactitol is The pentose phosphate pathway is essentially a scenic bypass route around the formed only in galactosemic patients who first stage of glycolysis that generates NADPH and ribose-5-P (as well as other have eaten galactose. Glucose 6-phosphate is the common precursor for both path- metabolized and diffuses out of the lens very slowly. The oxidative first stage of the pentose phosphate pathway generates two more likely to cause cataracts than hyper- moles of NADPH per glucose 6-phosphate oxidized. Erin Galway, although only 3 pentose phosphate pathway generates ribose-5-P and converts unused intermedi- weeks old, appeared to have early cataracts ates to fructose-6-P and glyceraldehyde-3-P in the glycolytic pathway (see Fig. All cells require NADPH for reductive detoxification, and most cells One of the most serious problems of clas- require ribose-5-P for nucleotide synthesis. Consequently, the pathway is present sical galactosemia is an irreversible mental in all cells. The enzymes reside in the cytosol, as do the enzymes of glycolysis. Realizing this problem, Erin Gal- way’s physician wanted to begin immediate A. Oxidative Phase of the Pentose Phosphate Pathway dietary therapy. A test that measures galac- tose 1-phosphate uridylyltransferase in ery- 1. The enzyme activity was virtually absent, confirming the diagno- In the oxidative first phase of the pentose phosphate pathway, glucose 6-phosphate is sis of classical galactosemia. The first enzyme of this pathway, glucose 6-phosphate dehydrogenase, oxidizes the alde- hyde at C1 and reduces NADP to NADPH. The gluconolactone that is formed is rap- idly hydrolyzed to 6-phosphogluconate, a sugar acid with a carboxylic acid group at C1. The next oxidation step releases this carboxyl group as CO2, with the electrons being transferred to NADP. This reaction is mechanistically very similar to the one catalyzed by isocitrate dehydrogenase in the TCA cycle. Thus, two moles of NADPH per mole of glucose 6-phosphate are formed from this portion of the pathway. NADPH, rather than NADH, is generally used in the cell for pathways that require the input of electrons for reductive reactions because the ratio of NADPH/NADP is much greater than the NADH/NAD ratio. The NADH generated from fuel oxidation is rap- idly oxidized back to NAD by NADH dehydrogenase in the electron transport chain, so the level of NADH is very low in the cell. NADPH can be generated from a number of reactions in the liver and other tissues, but not the red blood cell. For example, in tissues with mitochondria, an energy-requiring transhydrogenase located near the complexes of the electron transport chain can transfer reduc- ing equivalents from NADH to NADP to generate NADPH. NADPH, however, cannot be directly oxidized by the electron transport chain, and the ratio of NADPH to NADP in cells is greater than one. The reduction potential of NADPH therefore can contribute to the energy needed for biosynthetic processes and provide a constant source of reducing power for detoxification reactions. CHAPTER 29 / PATHWAYS OF SUGAR METABOLISM: PENTOSE PHOSPHATE PATHWAY, FRUCTOSE, AND GALACTOSE METABOLISM 533 2. RIBOSE 5-PHOSPHATE FROM THE OXIDATIVE ARM OF H O THE PATHWAY C To generate ribose 5-phosphate from the oxidative pathway, the ribulose 5-phos- H phate formed from the action of the two oxidative steps is isomerized to produce HO ribose 5-phosphate (a ketose-to-aldose conversion, similar to fructose 6-phos- phate being isomerized to glucose 6-phosphate; see section III. The H C OH ribose 5-phosphate can then enter the pathway for nucleotide synthesis, if needed, H or can be converted to glycolytic intermediates, as described below for the nonox- CH OPO2– 2 3 idative phase of the pentose phosphate pathway. The pathway through which the Glucose 6–phosphate ribose 5-phosphate travels is determined by the needs of the cell at the time of its synthesis. The Nonoxidative Phase of the Pentose dehydrogenase NADPH + H+ Phosphate Pathway The nonoxidative reactions of this pathway are reversible reactions that allow inter- O mediates of glycolysis (specifically glyceraldehyde-3-P and fructose-6-P) to be C converted to five-carbon sugars (such as ribose-5-P), and vice versa. The needs of H the cell will determine in which direction this pathway proceeds. If the cell has pro- O HO duced ribose-5-P, but does not need to synthesize nucleotides, then the ribose-5-P will be converted to glycolytic intermediates.