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By E. Marik. Utah Valley State College.

Consequently patients with gout (which results from precipitated uric acid crystals in the joints) are advised not to drink excessive amounts of ethanol generic 500 mg keftab fast delivery infection you catch in hospital. Increased degradation of purines also may contribute to hyperuricemia buy generic keftab 500mg on-line infection 4 weeks after abortion. The increased NADH/NAD ratio also can cause hypoglycemia in a fasting indi- vidual who has been drinking and is dependent on gluconeogenesis to maintain blood glucose levels (Fig. Alanine and lactate are major glu- coneogenic precursors that enter gluconeogenesis as pyruvate. The high NADH/NAD ratio shifts the lactate dehydrogenase equilibrium to lactate, so that pyruvate formed from alanine is converted to lactate and cannot enter gluconeoge- nesis. The high NADH/NAD ratio also prevents other major gluconeogenic precursors, such as oxaloacetate and glycerol, from entering the gluconeogenic pathway. In contrast, ethanol consumption with a meal may result in a transient hyper- glycemia, possibly because the high NADH/NAD ratio inhibits glycolysis at the glyceraldehyde-3-P dehydrogenase step. Acetaldehyde Toxicity Many of the toxic effects of chronic ethanol consumption result from accumula- tion of acetaldehyde, which is produced from ethanol both by alcohol dehydroge- nases and MEOS. Acetaldehyde accumulates in the liver and is released into the blood after heavy doses of ethanol (Fig. It is highly reactive and binds cova- lently to amino groups, sulfhydryl groups, nucleotides, and phospholipids to form “adducts. ACETALDEHYDE AND ALCOHOL-INDUCED HEPATITIS chronic ethanol ingestion that led Ivan Applebod to believe ethanol One of the results of acetaldehyde-adduct formation with amino acids is a general has no calories may be partly attributable to decrease in hepatic protein synthesis (see Fig. Calmodulin, ribonu- uncoupling of oxidative phosphorylation. Proteins in the heart and other The hepatic mitochondria from tissues of tissues also may be affected by acetaldehyde that appears in the blood. Consequently, a coagulation factors, and transport proteins for vitamins, steroids, and iron. These greater proportion of the energy in ethanol proteins accumulate in the liver, together with lipid. The accumulation of pro- would be converted to heat. Metabolic dis- teins results in an influx of water (see Fig. ACETALDEHYDE AND FREE RADICAL DAMAGE Acetaldehyde adduct formation enhances free radical damage. Acetaldehyde binds directly to glutathione and diminishes its ability to protect against H2O2 and prevent lipid peroxidation (see Fig. Damage to mitochondria from acetaldehyde and free radicals perpetuates a cycle of toxicity (see Fig. With chronic consumption of ethanol, mitochondria become damaged, the rate of electron transport is inhib- ited, and oxidative phosphorylation tends to become uncoupled. Fatty acid CHAPTER 25 / METABOLISM OF ETHANOL 467 H2O Lipid Oxidized peroxidation glutathione Amino Proteins Proteins acids – (clotting – Toxic Binding to 1 factors) Impaired radicals glutathione Binding to protein (ROS) glutathione secretion 3 2 Binding to NADPH NADP+ microtubules ADH MEOS Ethanol Acetylaldehyde Acetylaldehyde + NAD NADH Acetylaldehyde 4 NADH Acetate Acetate Free e – radical t injury c Release Fatty acids of enzymes 6 ALT and Glycerol-3-P AST Swelling 5 Triacylglycerols H2O VLDL VLDL Protein and lipid accumulation due to impaired secretion H2O Fig. The mitochondrial changes further impair mitochondrial acetaldehyde oxidation, thereby initiating a cycle of progressively increasing acetaldehyde damage. Ethanol and Free Radical Formation Increased oxidative stress in the liver during chronic ethanol intoxication arises from increased production of free radicals, principally by CYP2E1. FAD and FMN in the reductase and heme in the cytochrome P450 system transfer single electrons, thus operating through a mechanism that can generate free radicals. The hydrox- yethyl radical (CH3CH2O ) is produced during ethanol metabolism and can be. Induction of CYP2E1, as well as other cytochrome P450 enzymes, can increase the generation of free radicals from drug metabolism and from the activation of toxins and carcinogens (see Fig. These effects are enhanced by acetaldehyde-adduct damage. Phospholipids, the major lipid in cellular membranes, are a primary target of per- oxidation caused by free radical release.

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Although the behavioral benefits of adrenal medullary tissue transplantation in animals were modest generic 375mg keftab with amex lafee virus, early human investigations focused on transplantation of adrenal medulla cells buy keftab 125mg with mastercard antibiotics sore throat. Direct stereotactic implantation of autologous adrenal medullary tissue into the caudate (29) and putamen (30) failed to show long-term changes. Revising the surgical procedure by placing the adrenal grafts into the intraventricular surface of the right caudate, Madrazo et al. Preopera- tively, Patient 1 was wheelchair-bound and had bilateral rigidity, bradykinesia, resting tremor, and speech impairment. At 5 months postsurgery, he was reported to be speaking more clearly, ambulating and performing routine activities independently, and had less tremor and virtually no rigidity or akinesia on either side. Improvement persisted, and at 10 months, the patient visited the clinic independently, was playing soccer Copyright 2003 by Marcel Dekker, Inc. Likewise, Patient 2, who was severely disabled prior to transplantation, exhibited impressive improvement at 3 months postsurgery, as he had no tremor, was ambulating independently, and was speaking clearly with almost normal facial expression (31). Both patients were able to discontinue antiparkinsonian medications postoperatively. Unfortunately, these results were not repli- cated by subsequent studies using the same techniques (32–34). Evaluation at 6 months postsurgery revealed that the mean duration of on time increased from 48 to 75%, on time without dyskinesias increased from 27 to 59%, and off time decreased from 53 to 25%. Off Unified Parkinson’s Disease Rating Scale (UPDRS) Activities of Daily Living (ADL) and Schwab and England scores showed significant improvement during off time. Off UPDRS motor subscale scores showed a trend toward improvement, while off Hoehn and Yahr scores did not change. Overall, the benefits observed in this study were quite modest compared to those of Madrazo et al. Long-term evaluations found that benefits were maximal at 6 months and progressively and gradually declined thereafter with deterioration in most parameters by 18 months. Nonetheless, off UPDRS motor and ADL and Hoehn-Yahr scores were still statistically improved compared with baseline (36). Another study noted no benefits that could be ascribed to bilateral adrenal medulla graft placement (37). Autopsy results from one patient whose performance level improved at 4 months postsurgery revealed necrotic adrenal tissue and no definite viable cells (38). Autopsy of another patient (who experienced marked and persistent benefit for 18 months) at 30 months postsurgery revealed that within the graft site there was a paucity of tyrosine hydroxylase (TH) immunoreactive (IR) cells, which lacked neurite extension into the host striatum (39). However, located lateral and ventral to the few surviving grafts was an enhanced fiber network of TH-IR terminals and processes, thought to represent sprouting by residual host dopaminergic neurons mediated by the host striatal response to injury (39). Similar observations have been noted in both rat (40) and monkey models (41–45). The poor survival of adrenal medullary grafts following transplantation suggests other factors are responsible for the clinical benefits observed. It has been hypothesized that the secretion of trophic factors from the graft or reactive host cells may be responsible for transplant-related functional improvement (39). However, these were uncontrolled studies, and some or all of the observed benefits could have been due to placebo effects or examiner or patient bias. The use of adrenal autografts has been abandoned as only modest improvement was observed. Significant morbidity was associated with the surgery, including procedure-related deaths and medical and neuropsychia- tric complications. The failure of adrenal cells to produce significant benefit caused investigators to turn again to fetal mesencephalic cells, as these had produced greater benefit in animal models. The first report described two patients who received fetal grafts aged 7–9 weeks postconception (PC) unilaterally in the caudate and putamen. Patients received immunosuppression with cyclosporine, azothioprine, and steroids. Evaluation 6 months after surgery revealed no major therapeutic benefit in most outcome measures, but a small yet significant improvement in motor performance during off time, specifically in movement speed for pronation- supination, fist clenching, and foot lifting. There was no increase in the duration of levodopa benefit, and there was also no significant increase in fluorodopa (FD) uptake by positron emission tomography (PET) at the graft site (46). Due to minimal benefit from the initial procedures, the same team performed subsequent transplantation studies under a modified protocol (implantation cannula was thinner, storage medium was a balanced PH- stable solution and not saline, time of storage was shorter, transplantation was solely in the putamen).

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Having good balance requires that the individual have a stable physical base of support and a good sensory feedback system that can inter- pret where the body is in space and how its position should be corrected buy generic keftab 125mg on-line antibiotic shot. The lack of a stable base of support is demonstrated by an individual’s experi- ence of walking on slippery ice where the physical base of support is poor purchase 500 mg keftab amex antibiotic 4 cs. An example of decreased balance occurs when an individual is under the in- fluence of alcohol, in which sensory feedback and interpretation are dulled. On physical examination she had normal re- mental retardation, started walking independently at 4 flexes, muscle strength, and motor control. She had made very little progress in the typical pattern of primary ataxia. The main treatment is control of her gait, often having periods when she seemed to try to teach her to know her own limitations and to use to have more problems with her balance around periods assistive devices, such as crutches or canes, which she re- of rapid growth. However, by the time she reached full sists because she does not feel she needs them. Most of the balance studies in adults and children involve an assessment of postural stability by measuring the impact of different sensory systems, such as eyesight, the in- ner ear vestibular system, and joint sensory position feedback. The gross motor function measure (GMFM) has become a com- mon clinical evaluation tool for children with CP. Although this test does not specifically evaluate and measure ataxia, it has a significant component, es- pecially in domain 4, where tasks such as single-leg stands are evaluated. These tasks require separating out balance from motor control problems based on subjective evaluation of these children. Also, on gait analysis, tem- poral spatial characteristics such as step length and cadence tend to have high variability in children with significant ataxia. Children with only spasticity but good balance have less variability than normal children, and those with predominantly ataxia will have much higher variability. This variability is also true of trunk motion and the ability to walk in a straight line. Understanding balance deficits during walking is difficult be- cause momentum can make unstable children look much more stable than they really are. An example is a child who seems to walk very well while walking; however, every time she tries to stop, she has to grab the wall or fall to the floor. This is the analogy of riding a bicycle where the rider is very stable due to the momentum of motion. However, if the rider stops the motion and tries to sit on the bicycle, she becomes very unstable. A child who can walk well only at a certain speed may be an excellent walker; however, developing good functional walking skills requires that an individual be able to stop without falling over. Treatment of Ataxia Therapy to help children with ataxia improve their walking should focus on two areas. First, they must learn how to fall safely and develop protective responses when falling. They should be taught to recognize when they are falling, direct the fall away from hazards, and fall forward with their arms out in front to protect themselves. Neurologic Control of the Musculoskeletal System 139 tective response to falling, they should be wearing protective helmets and have supervision when walking. There are some children who cannot learn this protective response, and they will have a tendency to fall like a cut tree; this is especially dangerous if the individual has a tendency to fall backward, which places them at high risk of head injury. These children will have to be kept in wheelchairs except when they are under the direct supervision of an- other individual. The second area of treatment focus for children with ataxia should be directed at exercises that stimulate balancing. These exercises in- clude single-leg stance activities, walking a narrow board, roller skating, and other activities that stimulate the balancing system. These exercises have to be carefully structured to the individual child’s abilities, with the goal of maximizing each child’s ability safely and effectively. Walking effectively as an adult requires an individual to be able to alter gait, speed, and especially to slow down speed to reserve energy as she tires. This may mean using an assistive device, such as forearm crutches.

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The ability to metabolize galactose is even higher in infants which galactosemia and galactosuria occur than in adults purchase keftab 375mg with visa virus maker. Newborn infants ingest up to 1 g galactose per kg per feeding (as lac- but galactose 1-phosphate is not formed buy discount keftab 125mg line antibiotic drops for pink eye. Yet the rate of metabolism is so high that the blood level in the systemic Both enzyme defects result in cataracts from circulation is less than 3 mg/dL, and none of the galactose is lost in the urine. Aldose reductase has a relatively high K for galactose, approxi- III. 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.

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The scissoring is part of the primitive stepping mass reflex that children are using to advance the limbs keftab 500 mg low price antibiotics for sinus infection dosage. Often 250mg keftab free shipping infection 3 weeks after tonsillectomy, as these children mature, they learn to overcome scissoring and subsequently will slowly do less scissoring. If the musculoskeletal im- pairment is blocking progress, it is reasonable to correct the deformity, usu- ally around 5 to 7 years of age at the youngest. If there is a question of the significance of the musculoskeletal impairment, it may be beneficial to wait until 8 to 10 years of age when a better assessment can be made, with more time to evaluate how these children are changing. Middle Childhood Quadriplegic Ambulators In middle childhood, most children will reach a plateau with motor function. An evaluation of the benefits of correction of musculoskeletal deformities should be performed. If there are limitations that are significantly impairing the children, correction should be made. Correcting the contractures that are causing impairments is often beneficial, and these contractures may include equinus contractures, hamstring contractures, knee flexion contractures, hip flexion contractures, and adductor contractures. Sometimes the parents report that these releases help the caretakers provide personal hygiene more easily, such as easier bathing or dressing. Severe planovalgus foot defor- mities merit correction when they limit orthotic wear. During this time, if children have good cognitive function, a decision should be made to focus less on walking and more on cognitive learning and fine motor skills. If chil- dren have moderate or severe mental retardation, continuing to focus on ambulation is a reasonable option. Some of the children with severe mental retardation will make significant progress in ambulatory skills in middle childhood, even up to age 12 or 13 years. As children approach adolescence, the gait trainer is less useful because the device has to be so large that it does not fit through doors and cannot be functionally used in most homes. Care- takers and parents are encouraged to continue to walk holding the hands of the patients, so as not to lose the ability to do weightbearing transfers. Cor- rection of foot deformities and knee contractures should also be directed at the goal of maintaining these individuals’ ability to do standing weightbearing transfers. Adolescent Quadriplegic Ambulation Adolescence is when individuals will continue to do household ambulation if they can walk with a standard walker, but usually stop walking if it re- quires the use of a gait trainer. Most individuals will be able to maintain weight bearing as a transfer ability. If the limitation is due to a musculo- skeletal deformity, correction should be considered. Typical problems that occur at this age are severe planovalgus feet, which limit the ability of indi- viduals to stand or wear AFOs. This correction is easy to maintain and will not be lost at this age. The second most common major problem is hamstring contractures and fixed knee flexion contractures. Gait 373 idly, the hamstrings will often rapidly recontract after lengthening. If there is a severe knee flexion contracture of more than 30°, this too gets worse. As the knee flexion contracture goes over 30° to 40°, standing rapidly becomes more difficult. Correcting the knee flexion contracture is a difficult decision because the contracture may make standing more difficult, but if individu- als can only stand and spend most of their time sitting in their wheelchairs, correction of knee flexion contracture is not likely to be successful, as the knee will just recontract. Therefore, correction of significant knee flexion contractures should be reserved for individuals who do some community ambulation, or who surgeons believe have the ability to do some community ambulation. Correction of torsional malalignment, such as tibial torsion or femoral anteversion, is indicated if the correction will improve an individ- ual’s ability to sit. Often, the benefit from treatment for sitting takes prece- dence over problems of ambulation unless it is a very severe torsional mal- alignment.

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