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ADP ATP dGTP Which amino acid would be most appropri- GDP ATP dTTP ate to use for this purpose? The nitro- H gen of this glycine also appears in uric acid generic 0.15 mg levlen with amex, + H N N NH4 the product of purine degradation buy 0.15 mg levlen with amex. P P i i Guanosine Inosine Pi Pi R–1–P R–1–P O O HN N HN N H H H2N N N N N H H Guanine Hypoxanthine O2 Allopurinol + xanthine oxidase NH4 O H O 2 2 HN N H O N N H H Xanthine O2 Allopurinol xanthine oxidase Uric acid has a pK of 5 0.15mg levlen amex. Urate is not very soluble in an O aqueous environment buy cheap levlen 0.15mg on-line. O N N H H Uric acid Urine Normally buy 0.15 mg levlen fast delivery, as cells die, their purine nucleotides are degraded to Fig. The reactions inhibited by allopurinol are indi- cated. A second form of xanthine oxidase exists that uses NAD instead of O as the electron hypoxanthine and xanthine, which 2 are converted to uric acid by xanthine oxi- acceptor. Allopurinol (a struc- tural analog of hypoxanthine) is a substrate for xanthine oxidase. It is converted to oxy- purinol (also called alloxanthine), which the enzyme guanase to produce xanthine. The pathways for the degradation of ade- remains tightly bound to the enzyme, pre- nine and guanine merge at this point. Xanthine is converted by xanthine oxidase to venting further catalytic activity (see Fig. It reduces the production of uric acid and Another form of xanthine oxidase exists that uses NAD as the electron acceptor hence its concentration in the blood and tis- sues (e. Xanthine and Note how little energy is derived from the degradation of the purine ring. Thus, hypoxanthine accumulate, and urate levels it is to the cell’s advantage to recycle and salvage the ring, because it costs energy decrease. Overall, the amount of purine to produce and not much is obtained in return. Pyrimidine Bases Therefore, none of the compounds exceeds its solubility constant, precipitation does not The pyrimidine nucleotides are dephosphorylated, and the nucleosides are cleaved occur, and the symptoms of gout gradually to produce ribose 1-phosphate and the free pyrimidine bases cytosine, uracil, and subside. Cytosine is deaminated, forming uracil, which is converted to CO2,NH4 , CHAPTER 41 / PURINE AND PYRIMIDINE METABOLISM 759 + and -alanine. Thymine is converted to CO2,N 4 , and -aminoisobutyrate O (Fig. These products of pyrimidine degradation are excreted in the urine or H2 2 CH2 C O– converted to CO2,HO, and NH2 4 (which forms urea). They do not cause any prob- β-Alanine lems for the body, in contrast to urate, which is produced from the purines and can precipitate, causing gout. As with the purine degradation pathway, little energy can H + O be generated by pyrimidine degradation. H C C 3 2 – O CH3 β-Aminoisobutyrate CLINICAL COMMENTS Fig. Water-soluble end products of Hyperuricemia in Lotta Topaigne’s case arose as a consequence of over- pyrimidine degradation. Treatment with allopurinol not only inhibits xan- thine oxidase, lowering the formation of uric acid with an increase in the excretion of hypoxanthine and xanthine, but also decreases the overall synthesis of purine nucleotides. Hypoxanthine and xanthine produced by purine degradation are salvaged (i. PRPP is a substrate for the glutamine phosphoribosyl amidotransferase reaction that initiates purine biosynthesis. Because the normal cellular levels of PRPP and glutamine are below the Km of the enzyme, changes in the level of either substrate can accelerate or reduce the rate of the reaction. Therefore, decreased lev- els of PRPP cause decreased synthesis of purine nucleotides. BIOCHEMICAL COMMENTS A deficiency in adenosine deaminase activity leads to severe combined immunodeficiency disease, or SCID. In the severe form of combined Once nucleotide biosynthesis and immunodeficiency, both T cells (which provide cell-based immunity, see salvage was understood at the Chapter 44) and B-cells (which produce antibodies) are deficient, leaving the indi- pathway level, it was quickly real- vidual without a functional immune system. Children born with this disorder lack a ized that one way to inhibit cell proliferation thymus gland and suffer from many opportunistic infections because of the lack of would be to block purine or pyrimidine syn- a functional immune system. Death results if the child is not placed in a sterile envi- thesis. Administration of polyethylene glycol–modified adenosine deaminase has would interfere with a cell’s ability to gener- been successful in treating the disorder, and the ADA gene was the first to be used ate precursors for DNA synthesis, thereby in gene therapy in treating the disorder.

Growing children have a higher BMR per method for a rough estimate to val- kilogram body weight than adults levlen 0.15 mg cheap, because a greater proportion of their bodies is ues obtained with equations in Table 1 buy levlen 0.15 mg with amex. The BMR declines in aging individuals because their metabolically active tissue is shrinking and body fat is increasing cheap 0.15mg levlen mastercard. In addition buy levlen 0.15mg visa, large variations exist in BMR from one adult Registered dieticians use extensive to another buy 0.15 mg levlen free shipping, determined by genetic factors. A more accu- rate calculation is based on the fat-free mass remember this is 1 kcal/kg/hr. This estimate works best for young individuals who (FFM), which is equal to the total body mass are near their ideal weight. More accurate methods for calculating the BMR use minus the mass of the person’s adipose tis- empirically derived equations for different gender and age groups (Table 1. With FFM, the BMR is calculated using Even these calculations do not take into account variation among individuals. Physical Activity ences between sexes and between aged ver- sus young individuals that are attributable to In addition to the RMR, the energy required for physical activity contributes to the differences in relative adiposity. The difference in physical activity between a student and a lumberjack is determining FFM is relatively cumbersome— enormous, and a student who is relatively sedentary during the week may be much it requires weighing the patient underwater and measuring the residual lung volume. Equation for Predicting BMR from Body Weight (W) in kg measures O2 consumption and CO2 produc- Males Females tion, can be used when more accurate deter- Age Range BMR Age Range BMR minations are required for hospitalized (years) kcal/day (years) kcal/day patients. From Energy and protein requirements: report of a Joint FAO/WHO/UNU Expert Consultation. Technical From these values, the daily energy expen- report series no. CHAPTER 1 / METABOLIC FUELS AND DIETARY COMPONENTS 9 Table 1. Typical Activities with Corresponding Hourly Activity Factors Mr. Applebod weighs 264 lb or 120 Hourly Activity Factor kg (264 lb divided by 2. His ACTIVITY CATEGORY (for Time in Activity) estimated RMR 24 kcal/kg/day Resting: sleeping, reclining 1. His RMR cal- Very light: seated and standing activities, driving, 1. Miss O’Rexia playing cards, playing a musical instrument weighs 99 lb or 45 kg (99/2. Thus, the rough estimate carrying loads, cycling, skiing, tennis, dancing does not work well for obese patients Heavy: walking uphill with a load, tree felling, 7. Reprinted with permission from Recommended Dietary Allowances, 10th Ed. The hourly activity factor is multiplied by the BMR (RMR) per hour times the number of hours engaged in the activity to give the caloric expenditure for that activity. If this is done for all of the hours in a day, the sum over 24 hours will approximately equal the daily energy expenditure. Based on the activities listed in A rough estimate of the energy required per day for physical activity can be Table 1. Sedentary (such as a medical student who does little but study) and a value of 60 to 70% of habits correlate strongly with risk for cardio- vascular disease, so it is not surprising that the RMR (per day) for a person who engages in about 2 hours of moderate exercise cardiovascular disease is the major cause of per day (see Table 1. A value of 100% or more of the RMR is used for a person death in this country. Diet-Induced Thermogenesis Our DEE includes a component related to the intake of food known as diet-induced thermogenesis (DIT) or the thermic effect of food (TEF). DIT was formerly called the specific dynamic action (SDA). After the ingestion of food, our metabolic rate increases because energy is required to digest, absorb, distribute, and store nutrients. The energy required to process the types and quantities of food in the typical American diet is probably equal to approximately 10% of the kilocalories ingested.

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This obstruction is definitively diagnosed by a swallow study with dilute barium discount levlen 0.15 mg with mastercard. If the first part of the duodenum fills but the barium does not continue to pass purchase levlen 0.15 mg visa, there is a duodenal obstruction order 0.15mg levlen otc. Some children will have a partial obstruction 0.15 mg levlen with mastercard, which can be managed by giving small amounts of fluid purchase levlen 0.15mg without prescription, and a jejunal tube can be passed through the area of the obstruction in some children. The final treat- ment of this problem is getting the child to gain weight, which may require prolonged central venous hyperalimentation. One of our children required hyperalimentation for more than 2 months. Parents must be informed that some of these children are at risk for the obstruction returning if they do not eat adequately and start to lose weight in the months following surgery. In rare chronic cases, jejunal tube feeding may be needed for prolonged periods to prevent recurrence of the obstruction. Constipation Constipation is a persistent and chronic problem for many children. This constipation is not affected much either positively or negatively by the spine fusion; however, families should be instructed on methods to avoid pro- longed impactions postoperatively, which tend to decrease the children’s interest in eating. Poor Feeding As mentioned before, good postoperative nutrition is important. Good nu- trition is especially important for children who have little reserve to heal the very large wound created by doing a posterior spinal fusion, which involves all of the spine and posterior pelvis. This intake may be accomplished with oral nutritional supplements and occa- sionally with short-term nasogastric tube feeding in children who are not eat- ing enough and who do not have a gastric tube. Our experience is that many parents who refuse to use a nasogastric tube preoperatively can be convinced to use it for a short time in the postoperative period when the tube may be seen as part of the surgical treatment. Hair Loss Most children have increased hair loss from the stress of a large operation such as a posterior spinal fusion. Some children will develop spots of alope- cia, usually 2 to 3 cm in diameter. Usually the parents can be assured that the hair will grow back in 6 to 12 months (Figure 9. Following posterior spinal fu- sion, many children are reported by parents to lose hair. Some children develop a com- pletely bald spot, sometimes in an area of inflammatory response. In almost all chil- dren, the hair regrows completely over the next 6 to 12 months. The cause of the hair loss is not known but is probably a stress response to the surgery. Mechanical Problems The mechanical problems occurring with spinal fusions in children with CP are specific to the instrumentation system used. The current state of the art is the use of the Unit rod or similar devices; therefore, the multitude of mechan- ical problems that are specific to other individual systems is not addressed. Pain in the Spine Complaints of pain in the back after the acute postoperative period occur mainly from either the distal or proximal end. At the proximal end, there is often a 3-month period of some discomfort at the cervicothoracic junction. This discomfort has never become a chronic problem in any of our patients. If the rod is too long, or prominent, a bursa can form over the end of the rod and cause chronic discomfort. If this discomfort persists for more than 1 year, the top of the rod can be excised at approximately the T3 level and the dis- comfort will disappear (Case 9. At the distal end, children may occasionally develop very severe halos around the pelvic leg of the rod, which most typically occur 1 to 3 years af- ter surgery (Figure 9. If these individuals are having pain, especially if the pain is increasing, there may be a low-grade infection in this area. Of four children in whom we have removed the pelvic legs, infections were present in two. This infection can be treated by excising the pelvic end of the rod fol- lowed with antibiotics. In both these children, the rest of the rod did not de- velop any signs of infection, and the rod was solidly encased in fusion mass at the time of removal of the distal end. Many children get some halo effect around the rod but it is not painful and probably represents movement of the sacroiliac joint.

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Baclofen has poor absorption across the blood–brain barrier order levlen 0.15mg. Both drugs have a very high rate of accommodation buy levlen 0.15mg on-line, meaning they are effective initially but lose their effectiveness over several weeks cheap levlen 0.15mg free shipping. This accommodation effect can be overcome with larger doses order levlen 0.15mg without a prescription; however purchase 0.15 mg levlen amex, the use of higher doses makes the com- plication rate higher. The use of both these drugs orally for chronic control Table 4. Drug Trade names Benefit for spasticity Side effects Baclofen Lioresal Useful in some patient groups; in CP seldom has a Causes sedation, sudden withdrawal, lasting benefit when given orally, but very effective psychosis; rapid drug tolerance by intrathecal administration develops in the oral doses Diazepam Valium Very useful for acute postoperative spasticity Has long and somewhat variable management, little use for chronic management half-life, very sedating; tolerance Oldest effective antispasticity drug develops with chronic use Chlorazepate Tranxene Little use in CP; is an active metabolite of diazepam; Same as diazepam may have less sedation but no other demonstrated benefit for spasticity management Clonazepam Klonopin, Rivotril Has a quick absorption and an 18-hour half-life; Same problem of drug tolerance as may also be less sedating than diazepam; is useful diazepam for single-dose nighttime treatment of complaint- related sleep difficulty due to spasms Ketazolam Loftran New shorter-acting benzodiazepine, no CP data Claimed to have less sedation Tetrazepam Myolastin New drug, no CP data Claimed to be less sedating Dantrolene Dantrium Works by decreasing muscle fiber excitability; has no Is hepatotoxic so liver enzymes must effective use in children with CP be monitored; causes muscle weakness Tizanidine Zanaflex, Sirdalud Blocks the release of neuroexitatory amino acids; Causes dry mouth, sedating; may no CP data; personal experience is that there is rapid cause drop in blood pressure tolerance, similar to baclofen Clonidine Catapres, Dixirit, Catapresan Blocks alpha-agonist activity in the brainstem and Causes a drop in blood pressure and spinal cord; no data in CP spasticity heart rate Cannabis Cesamet, Marinol Effective to reduce adult spasticity but no data in Significant psychotropic effects and children is addictive Cyclobenzapine Flexeril Widely used to treat back muscle spasm, but studies Not indicated because it is not have shown no effect on spasticity effective 110 Cerebral Palsy Management of spasticity has not been successful in children with CP. The acute use of diazepam in the postoperative period is very useful and safe. Alpha-2- adrenergic receptors have primarily agonist function in the spinal and supraspinal regions. Tizanidine and clonidine hydrochloride are drugs that block these receptors. Although there is some evidence that this type of drug is effective in decreasing spasticity of spinal cord origin,17 their use in chil- dren with CP has little or no experience and no published data. Personal ex- perience with tizanidine suggests that it has very similar problems as the other oral antispasticity medications, which are a significant rate of sedation and a high accommodation effect. Other drugs acting at other sites in the central nervous system have the potential for decreasing spasticity. There are only incidental reports of use of these drugs and no documentation of their use in children with CP. Blockade of voltage-sensitive sodium channels can be done with lamotrigine and riluzole. Serotonin antagonists such as cypro- heptadine decrease tone. Glycine is an inhibitory neurotransmitter that can be given orally and is absorbed by the brain. Cannabis has been shown to decrease spasticity through an unknown mediator. Because there is a general perception that spasticity originates in the spinal segments, a high dose of drug concentrated in this region of the nervous system should be given. This route was initially developed to administer morphine19 but was quickly applied to administer baclofen. This catheter is tunneled subcutaneously around the lateral side of the trunk to the anterior implanted pump site and connected to the pump. The pump is controlled with an ex- ternal radiowave-mediated controller, and the pump reservoir is filled by di- rect injection through the overlying skin (Case 4. The primary medication used to manage spasticity by intrathecal pump administration is baclofen. The administration may be continuous, or the pump can be programmed to have higher doses over a short time, then be turned off for a period of time, and go to lower doses. The use of intrathecal administration of baclofen is very new, having only been approved by the FDA for use in children in 1997. At the time of ap- proval, there were fewer than 200 children with implanted pumps. In the past 4 years, these pumps have become much more common. These pumps have the great advantage of being adjustable and can be discontinued if the results are not thought to be worth the trouble. Usually, a careful assessment with a listing of the caretakers’ concerns is made. If the child has not had a spinal fusion, a trial dose may be done with 75 to 100 mg injected as a bolus dose in the epidural space. Then the child is monitored by caretakers and the medical team and a joint decision is made as to the benefits. For especially difficult cases, an indwelling catheter, which can be left in place for several days, may be used so the dose can be adjusted. This implanted catheter is used for children with greatly variable tone, or individuals in whom adjustable doses of baclofen are to be monitored.

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