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X. Rathgar. Temple University.

Liver The liver is the major site of amino acid metabolism discount 100 mg dilantin. It is the major site of amino acid catabolism and converts most of the carbon in amino acids to intermediates of the TCA cycle or the glycolytic pathway (which can be converted to glucose or oxi- dized to CO2) generic dilantin 100 mg line, or to acetyl CoA and ketone bodies dilantin 100mg online. The liver is also the major site for urea synthesis order dilantin 100mg overnight delivery. It can take up both glutamine and alanine and convert the 774 SECTION SEVEN / NITROGEN METABOLISM nitrogen to urea for disposal (see Chapter 38) buy discount dilantin 100mg on-line. Other pathways in the liver provide it with an unusually high amino acid requirement. The liver synthesizes plasma pro- teins, such as serum albumin, transferrin, and the proteins of the blood coagulation cascade. It is a major site for the synthesis of nonessential amino acids, the conju- gation of xenobiotic compounds with glycine, the synthesis of heme and purine nucleotides, and the synthesis of glutathione. AMINO ACID POOL AND NEUROTRANSMITTER SYNTHESIS A major function of amino acid metabolism in neural tissue is the synthesis of neu- rotransmitters. More than 40 compounds are believed to function as neurotransmit- ters, and all of these contain nitrogen derived from precursor amino acids. They include amino acids, which are themselves neurotransmitters (e. In general, neurotransmitters are formed in the presynaptic terminals of axons and stored in vesicles until released by a transient change in electrochemical potential along the axon. Subsequent catabolism of some of the neurotransmitter results in the formation of a urinary excretion product. The rapid metabolism of neurotransmitters requires the continuous availability of a precursor pool of amino acids for de novo neurotransmitter synthesis (see Chapter 47). METABOLISM OF GLUTAMINE IN THE BRAIN The brain is a net glutamine producer owing principally to the presence of gluta- mine synthetase in astroglial cells (see Chapter 47). Glutamate and aspartate are synthesized in these cells, using amino groups donated by the BCAA (principally valine) and TCA cycle intermediates formed from glucose and from the carbon skeletons of BCAA (Fig. This glu- tamine may efflux from the brain, carrying excess NH4 into the blood, or serve as a precursor of glutamate in neuronal cells. Blood- brain Blood barrier Astroglial cell Neurons BCAA BCAA α–KG Purine nucleotide BCKA Glutamate cycle GABA + + glutamine NH4 NH3 NH3 NH4 synthetase + CO2 NH4 Glutamine Glutamine Glutamate Fig. Glutamine serves as a nitrogen transporter in the brain for the synthesis of many different neurotransmitters. Different neurons convert glutamine to -aminobutyric acid (GABA) or to glutamate. Glutamine also transports excess NH from the brain into the blood. BCKA branched-chain keto acids; -KG 4 -ketoglutarate. CHAPTER 42 / INTERTISSUE RELATIONSHIPS IN THE METABOLISM OF AMINO ACIDS 775 Glutamine synthesized in the astroglial cells is a precursor of glutamate (an exci- During hyperammonemia, ammo- tatory neurotransmitter) and GABA (an inhibitory neurotransmitter) in the neuronal nia (NH3) can diffuse into the brain cells (see Fig. It is converted to glutamate by a neuronal glutaminase from the blood. The ammonia is able to inhibit the neural isozyme of glutam- isozyme. In GABAergic neurons, glutamate is then decarboxylated to GABA, inase, thereby decreasing additional ammo- which is released during excitation of the neuron. GABA is one of the neurotrans- nia formation in the brain and inhibiting the mitters that is recycled; a transaminase converts it to succinaldehyde, which is then formation of glutamate and its subsequent oxidized to succinate. This effect of ammo- nia might contribute to the lethargy associ- ated with the hyperammonemia found in III. CHANGES IN AMINO ACID METABOLISM WITH patients with hepatic disease. DIETARY AND PHYSIOLOGIC STATE The rate and pattern of amino acid utilization by different tissues change with dietary and physiologic state. Two such states, the postprandial period following a The levels of transthyretin (binds high-protein meal and the hypercatabolic state produced by sepsis or surgical to vitamin A and thyroid hormones trauma, differ from the postabsorptive state with respect to the availability of amino in the blood) and serum albumin in acids and other fuels and the levels of different hormones in the blood. As a result, the blood may be used as indicators of the the pattern of amino acid utilization is somewhat different. In the absence of hepatic disease, decreased levels A.

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BIOCHEMICAL PROPERTIES Selegiline is a selective irreversible MAO-B inhibitor generic dilantin 100mg line. Taken orally order 100 mg dilantin otc, it is readily absorbed from the intestine and reaches plasma levels in 30–120 minutes purchase dilantin 100mg line. Its major metabolites generic dilantin 100mg online, L- methamphetamine and L-amphetamine dilantin 100mg with amex, have half-lives of 20. At doses of 5 and 10 mg it has mild antiparkinsonian effects without causing pressor effects. At higher doses such as 30 and 60 mg it has greater antidepressant effects but is associated with an increased pressor effect via tyramine, requiring patients to adhere to a low-tyramine diet. It has an extremely long half-life as confirmed with positron emission tomography (PET) imaging (27,28). Withdrawal from selegiline is not associated with an amphetamine-like withdrawal. Selegiline also signifi- cantly increases phenylethylamine (PEA) output. PEA is a strong dopamine uptake inhibitor and induces dopamine release (29). CLINICAL APPLICATIONS Selegiline is primarily used in patients with early PD as monotherapy or as adjunctive therapy to levodopa. It is usually used as 5 mg every morning or 5 mg twice a day, in the morning and afternoon. It is not given at night to avoid insomnia from methamphetamine metabolites. The Quality Standards Subcommittee of the American Academy of Neurology (32) confirmed that selegiline has only mild symptomatic antiparkinsonian effects when used as monotherapy. Compared to placebo, selegiline improves motor scores in PD patients (33–35). Withdrawal of selegiline results in a worsening of the Unified Parkinson’s Disease Rating Scale (UPDRS) tremor and bradykinesia scores (36). Selegiline decreases the amount of disability in early PD. DATATOP STUDY The DATATOP study was a large prospective double-blind, four-arm study that included over 800 patients. It compared the effects of placebo, selegiline, tocopherol (vitamin E), and selegiline plus tocopherol in early PD. Endpoints were the need to start levodopa therapy and the onset of disability. Patients were evaluated by clinical exams and cerebrospinal fluid analysis (38). Selegiline delayed the onset of levodopa therapy and slowed parkinsonian disability. Patients on placebo demonstrated a 50% faster decline than those on drug. However, this phenomenon occurred largely in the first year and was not sustained (39). A 53% reduction in the development of freezing of gait (FOG) was also observed with selegiline (40). Benefit with selegiline on FOG waned after selegiline was discontinued. The mechanism behind selegiline’s protection against FOG is unknown. A potential benefit in FOG would be important because there are no proven treatments to help FOG. However, the clinical significance of the reduction in FOG with selegiline is questionable. ADJUNCTIVE THERAPY As adjunctive therapy MAO-B inhibitors decrease motor fluctuations, improve UPDRS scores, and allow for a reduction in levodopa dosing. However, Golbe (43) found that selegiline added to levodopa therapy only reduced ‘‘off’’ time without an increase in ‘‘on’’ time. Lieberman (44) showed that selegiline added to levodopa improved UPDRS scores in early PD patients without motor fluctuations more than in patients with fluctuations. In various studies selegiline allows a reduction in the total dosage of levodopa.

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These scars tend to initially be red dilantin 100 mg online, thick purchase dilantin 100mg on line, and very ap- parent cheap 100 mg dilantin mastercard. Use of gentle circular massage and vitamin A oil may gradually cause the scar to decrease buy 100mg dilantin visa. Individuals should seldom consider any scar revision for 1 to 2 years postoperatively purchase dilantin 100 mg with amex. By that time, most of the concerns have dissi- pated as the scar thins and develops relatively normal skin color. For the first year or two, caretakers and patients should be warned against getting a sun- burn on the operative scar, which tends to cause it to become inflamed and thicken more. Sunburn is of most concern for scars on the anterior thigh from rectus femoris transfers. These scars seem to be especially sensitive to inflammation and thickening and are in a location where the scar is readily apparent. Treating General Complications of Foot Deformities The most common complication of foot surgery in individuals with CP is recurrent deformity. Recurrent planovalgus is especially common, as are re- current bunions and hallux valgus after realignment procedures. The rate of recurring deformity has to always be weighed against the advantage of doing a procedure that preserves the joint. Recurrent deformity is primarily a problem when joint fusions are avoided. This balance requires a difficult choice, but saving the subtalar joint, even with a 25% recurrence rate, may be acceptable in high-functioning ambulatory individuals. This recurrence rate would be much more difficult to justify in nonambulatory individuals because they presumably will not place the same stress on their feet over a lifetime; therefore, saving the subtalar joint is of less benefit. Treatment of recurrent deformities follows the algorithm of the standard treatment, ex- cept it is seldom wise to repeat the same operation. If the procedure failed once, there is probably something about the anatomy and milieu that sug- gests this is not the ideal operation for the foot. There is a tendency for sur- geons to understand this concept when treating their own failures, but they too quickly blame poor technique or technical errors with the original pro- cedure when they are treating someone else’s failures. In general, surgeons should resist the temptation to think that they can do a better job than the original surgeon. Knee, Leg, and Foot 791 Vascular Infarction After Foot Surgery or Tibial Osteotomy Vascular compromise can occur from derotation osteotomies, especially when they are combined with correction of severe foot deformities. If one side of the foot seems to have less blood flow in the acute postoperative pe- riod, the cast should be removed and the whole foot inspected. Some of the correction may have to be compromised to improve the circulation. If there is an exceptionally great amount of pain, inspection of the whole foot is in- dicated as well. The risk of this vascular compromise is highest when more than 30° of tibial derotation is required. Fibular osteotomy, which seems to decrease the risk, should be added to the tibial osteotomy. We have seen one partial infarction of the lateral border of the foot. The area was allowed to demarcate and then granulated closed without any other treatment required. The use of epidural anesthesia in the postoperative period may make the diagnosis more difficult as well. Ulcers on the Sole of the Foot After Surgery Ulcers develop on the sole of the foot from inappropriate cast techniques. Plantar surface ulcers are especially high risk if gastrocnemius lengthening is performed and then a cast is applied with some stretch on the gastrocsoleus. This cast has to be well molded on the sole of the foot. Flat plates used to apply pressure on the plantar surface of the foot must be avoided. We had one individual use a flat plate in a cast of a child, and a 2-cm-diameter, full- thickness ulcer developed over the third metatarsal head. This ulcer required 3 months to heal, and even 6 years after the operative procedure, this young adult continues to have intermittent problems with recurrent callus for- mation from the residual scar over this ulcer.

Matrix Inner membrane folded into cristae If a significant amount of undigestible material remains within the lysosome after the digestion process is completed purchase 100mg dilantin free shipping, the lysosome is called a residual body cheap dilantin 100 mg. Electron micro- Depending on the cell type dilantin 100mg visa, residual bodies may be expelled (exocytosis) or remain graph (top) buy dilantin 100mg with visa; three-dimensional drawing (bot- tom) order dilantin 100 mg visa. MITOCHONDRIA Mitochondria contain most of the enzymes for the pathways of fuel oxidation and oxidative phosphorylation and thus generate most of the ATP required by mammalian cells. Each mitochondrion is surrounded by two membranes, an outer membrane and an inner membrane, separating the mitochondrial matrix from the cytosol (Fig. The inner membrane forms invaginations known as cristae containing the electron transport chain and ATP synthase. Most of the enzymes for the TCA cycle and other pathways for oxidation are located in the mitochondrial matrix, the compartment enclosed by the inner mitochondrial membrane. Mitochon- dient that is built up across this membrane during oxidative phosphorylation is dria contain DNA and can repro- essential for ATP generation from ADP and phosphate. The transport of ions occurs duce by replicating their DNA and then dividing in half. Although nuclear DNA principally through facilitative transporters in a type of secondary active transport encodes most of the enzymes found in mito- powered by the proton gradient established by the electron transport chain. The chondria, mitochondrial DNA encodes some outer membrane contains pores made from proteins called porins and is permeable of the subunits of the electron transport to molecules with a molecular weight up to about 1000 g/mole. Mutations Mitochondria can replicate by division; however, most of their proteins must in mitochondrial DNA result in a number of be imported from the cytosol. Mitochondria contain a small amount of DNA, genetic diseases that affect skeletal muscle, which encodes for only 13 different subunits of proteins involved in oxidative neuronal, and renal tissues. Most of the enzymes and proteins in mitochondria are encoded cated in aging. They are imported 172 SECTION TWO / CHEMICAL AND BIOLOGICAL FOUNDATIONS OF BIOCHEMISTRY Compound through membrane pores by a receptor-mediated process involving members of O the heat shock family of proteins. PEROXISOMES catalase Peroxisomes are cytoplasmic organelles, similar in size to lysosomes, that are involved in oxidative reactions using molecular oxygen (Fig. These reac- tions produce the toxic chemical hydrogen peroxide (H2O2), which is subsequently used or degraded within the peroxisome by catalase and other enzymes. Peroxi- somes function in the oxidation of very long chain fatty acids (containing 20 or Oxidized O H O more carbons) to shorter chain fatty acids, the conversion of cholesterol to bile 2 2 compound acids, and the synthesis of ether lipids called plasmalogens. Like mitochondria, peroxisomes can replicate by division. However, they are dependent on the import of proteins to function. NUCLEUS affecting either the synthesis of The largest of the subcellular organelles of animal cells is the nucleus (Fig. For example, nucleus, which are composed of DNA, an equal weight of small, positively charged adrenoleukodystrophy probably involves a proteins called histones, and a variable amount of other proteins. This nucleoprotein mutation that decreases the content of a transporter in the peroxisomal membrane. Zellweger’s syndrome is caused by the failure to complete the synthesis of peroxisomes. Nucleolus Pores Nuclear envelope Euchromatin Heterochromatin 3–10 µm Nucleolus Pores Nuclear envelope Chromatin Outer (DNA + histones membrane and other proteins) (continuous with RER) Fig. Electron micrograph (top); three-dimensional drawing (bottom). CHAPTER 10 / RELATIONSHIP BETWEEN CELL BIOLOGY AND BIOCHEMISTRY 173 complex is called chromatin. The nucleolus, a substructure of the nucleus, is the site of rRNA transcription and processing, and of ribosome assembly. Replication, tran- scription, translation, and the regulation of these processes are the major focus of the molecular biology section of this text (see Section Three). The nucleus is separated from the rest of the cell (the cytoplasm) by the nuclear envelope, which consists of two membranes joined at nuclear pores. The outer nuclear membrane is continuous with the rough endoplasmic reticulum. To convert the genetic code of the DNA into the primary sequence of a protein, DNA is tran- scribed into RNA, which is modified and edited into mRNA.

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