Associate Professor, Duke University School of Medicine
His vomiting became Nitrogen enters the urea cycle as NH4 and aspartate (Fig symptoms 2 buy disulfiram with a mastercard. NH4 forms car- intractable medicine ball slams generic disulfiram 500 mg visa, and his friend noted jerking bamoyl phosphate symptoms for pneumonia generic disulfiram 500 mg fast delivery, which reacts with ornithine to form citrulline. Ornithine is the motions of his arms (asterixis), facial grimac- compound that both initiates and is regenerated by the cycle (similar to oxaloacetate ing, restlessness, slowed mentation, and slight disorientation. Aspartate reacts with citrulline, eventually donating its nitrogen with a diagnosis of hepatic failure with incipi- for urea formation. Cleavage of arginine ent hepatic encephalopathy (brain dysfunction by arginase releases urea and regenerates ornithine. SYNTHESIS OF CARBAMOYL PHOSPHATE viral hepatitis alone. The possibility of a super- imposed acute hepatic toxicity caused by the In the first step of the urea cycle, NH4 , bicarbonate, and ATP react to form car- use of acetaminophen was considered. The cleavage of 2 ATPs is required to form the high-energy phosphate bond of carbamoyl phosphate. Carbamoyl phosphate syn- thetase I (CPSI), the enzyme that catalyzes this first step of the urea cycle, is found mainly in mitochondria of the liver and intestine. The Roman numeral suggests that When ornithine transcarbamoylase another carbamoyl phosphate synthetase exists, and indeed, CPSII, located in the (OTC) is deficient, the carbamoyl cytosol, produces carbamoyl phosphate for pyrimidine biosynthesis, using nitrogen phosphate that normally would from glutamine (see Chapter 41). PRODUCTION OF ARGININE BY THE UREA CYCLE (orotate), an intermediate in pyrimidine Carbamoyl phosphate reacts with ornithine to form citrulline (see Fig. It pro- high- energy phosphate bond of carbamoyl phosphate provides the energy required duces no ill effects but is indicative of a for this reaction, which occurs in mitochondria and is catalyzed by ornithine tran- problem in the urea cycle. The product citrulline is transported across the mitochondrial mem- branes in exchange for cytoplasmic ornithine and enters the cytosol. The carrier for this transport reaction catalyzes an electroneutral exchange of the two compounds. In the cytosol, citrulline reacts with aspartate, the second source of nitrogen for Carbamoyl phosphate urea synthesis, to produce argininosuccinate (see Fig. This reaction, cat- alyzed by argininosuccinate synthetase, is driven by the hydrolysis of ATP to adeno- CPSII Pathway when OTC sine monophosphate (AMP) and pyrophosphate. Aspartate is produced by transam- is defective ination of oxaloacetate. Orotate The urea cycle was proposed in 1932 by Hans Krebs and a medical student, Kurt Henseleit, based on their laboratory observations. Subsequently, Krebs used this concept of metabolic Pyrimidines Urine cycling to explain a second process that also bears his name, the Krebs (or TCA) cycle. CHAPTER 38 / FATE OF AMINO ACID NITROGEN: UREA CYCLE 705 Mitochondrion CO2 + H2O Cytosol Urine HCO – + NH 3 + NH4 2 Urea C O NH2 NH2 H2O C NH 2 ATP carbamoyl 5 phosphate CH2 NH synthetase I arginase CH (CPSI) 2 CH2NH2 CH 2 ADP + P 1 2 i CH2 C CH2NH2 2 CH2 CH2 COOH COOH O O C 2 Arginine CH2 – HC H2N O P COOH H 2 – Ornithine 4 CH O COOH Carbamoyl ornithine argininosuccinate COOH 2 Ornithine lyase phosphate transcarbamoylase Fumarate NH2 NH2 NH COOH Pi C O C O C NH CH CH2 NH CH2 NH CH2 NH CH2 CH2 COOH CH2 CH2 CH2 CH2 CH2 H C 2 3 H C 2 C 2 COOH argininosuccinate COOH synthetase COOH Citrulline Citrulline Argininosuccinate ATP AMP + PPi COOH H2 H CH2 COOH Aspartate Fig. Argininosuccinate is cleaved by argininosuccinate lyase to form fumarate and arginine (see Fig. Fumarate is produced from the carbons of argininosucci- nate provided by aspartate. Fumarate is converted to malate (using cytoplasmic fumarase), which is used either for the synthesis of glucose by the gluconeogenic pathway or for the regeneration of oxaloacetate by cytoplasmic reactions similar to those observed in the TCA cycle (Fig. The oxaloacetate that is formed is transaminated to generate the aspartate that carries nitrogen into the urea cycle. Thus, the carbons of fumarate can be recycled to aspartate. CLEAVAGE OF ARGININE TO PRODUCE UREA Arginine, which contains nitrogens derived from NH4 and aspartate, is cleaved by arginase, producing urea and regenerating ornithine (see Fig. Urea is pro- duced from the guanidinium group on the side chain of arginine.
Production of a membrane-bound antibody (IgM) and a smaller secreted antibody (IgD) from the same gene symptoms for hiv purchase 250mg disulfiram with mastercard. Initially treatment variable buy disulfiram 250 mg with mastercard, the lympho- cytes produce a long transcript that is cleaved and polyadenylated after the second stop codon medications list template generic disulfiram 500 mg free shipping. The intron that contains the first stop codon is removed by splicing between the 5 - and 3 -splice sites. Therefore, translation ends at the second stop codon, and the protein contains a hydrophobic exon at its C-terminal end that becomes embedded in the cell membrane. After antigen stimulation, the cells produce a shorter tran- script by using a different cleavage and polyadenylation site. This transcript lacks the 3 -splice site for the intron, so the intron is not removed. In this case, translation ends at the first stop codon. The IgD antibody does not contain the hydrophobic region at its C-terminus, so it is secreted from the cell. Apoprotein B gene CAA Transcription CAA Transcript heme Intestine kinase Liver (inactive) RNA editing Heme mRNA CAA UAA mRNA kinase (active) (stop) eIF2 eIF2 P Translation active inactive Liver Intestinal ApoB ApoB Initiation 4563 2152 of translation Amino acids Amino acids Fig. In liver, the apoprotein B (ApoB) gene produces a protein that con- eIF2. When eIF2 is phosphorylated by heme tains 4,563 amino acids. In intestinal cells, the same gene produces a protein that contains kinase, it is inactive, and protein synthesis can- only 2,152 amino acids. Conversion of a C to a U (through deamination) in the RNA tran- not be initiated. Heme inactivates heme kinase, script generates a stop codon in the intestinal mRNA. Thus, the protein produced in the intes- thereby preventing phosphorylation of eIF2 tine (B-48) is only 48% of the length of the protein produced in the liver (B-100). The mRNA for ferritin has an iron mRNA for the transferrin receptor. When the iron response element binding protein, IRE-BP does not tion of the mRNA is prevented by binding of contain bound iron, it binds to IRE, preventing translation. When IRE-BP binds iron, it dis- the iron response element binding protein sociates, and the mRNA is translated. When iron lev- els are high, IRE-BP binds iron and is not protein located in cell membranes that permits cells to take up transferrin, the pro- bound to the mRNA. The mRNA is rapidly tein that transports iron in the blood. The rate of synthesis of the transferrin recep- degraded, preventing synthesis of the transfer- tor increases when intracellular iron levels are low, enabling cells to take up more rin receptor. Synthesis of the transferrin receptor, like that of the ferritin receptor, is regu- lated by the binding of the iron response element binding protein (IRE-BP) to the iron response elements (IRE). However, in the case of the transferrin receptor mRNA, the IREs are hairpin loops located at the 3 -end of the mRNA, and not at the 5 end where translation is initiated. When the IRE-BP does not contain bound iron, it has a high affinity for the IRE hairpin loops.
Stimu- lants are used very commonly in pediatrics for attention deficit disorder oxygenating treatment buy discount disulfiram, with the most common drugs being amphetamine (Benzedrine) medicine naproxen 250 mg disulfiram with amex, dextro- amphetamine (Dexedrine) treatment 6th nerve palsy generic disulfiram 250mg with visa, and methylphenidate hydrochloride (Ritalin). These drugs have no significant recognized side effects or drug interactions that might cause problems during or after surgical treatment. The drugs can be held until the child is recovering, but after the child is taking a normal diet, they should be restarted. The hyperactivity for which these drugs are prescribed will be well controlled with the use of high-dose diazepam, which is typically used in the immediate postoperative period. A new treatment for children with severe mental retardation and self- injurious behavior, such as head banging or self-biting, is naltrexone. Nal- trexone hydrochloride is an opiate agonist similar to Narcane (naloxone hydrochloride), which competitively blocks the opioid receptors. If these children need significant pain medication, such as for an acute fracture, they need to be treated with an NSAID such as ibuprofen or naproxen. For more severe pain, Ketorolac (tromethamine) injections are the only injectable NSAID available. In this event, the naltrexone hydrochloride should be dis- continued so opioids can also be used. The ketogenic diet is a very rigid diet in which the in- dividual gets all her calories from proteins or fats, completely avoiding car- bohydrates. This treatment has a well-documented efficacy that is similar to the best pharmacologic treatment. Usually, the diet is maintained for 2 years, during which time the antiepileptics are reduced or eliminated. The diet is difficult for some children to tolerate and for some families to maintain; therefore, there is a substantial dropout rate. During the time the child is on the ketogenic diet, she may need surgery, such as hip muscle lengthening, hip reconstruction, or scoliosis correction. There is no pub- lished literature on doing surgery in children being treated with the ketogenic diet. We operated on eight children, including spinal fusions and hip surgery, during the time they were on the ketogenic diet. It is mandatory that all drugs used while the child is on the ketogenic diet are completely free of carbohy- drate carriers, which are very common, especially in elixir preparations. For children having a posterior spinal fusion, central venous hyperalimentation can be prepared, which will maintain the ketogenic state of the child and provide sufficient calories. We have had one postoperative spinal infection that we were able to manage successfully and clear the infection without hardware removal while the child was on the ketogenic diet. It is very important that the nurs- ing service has good education and assistance from dietitians for direction on what the child may and may not eat. Managing a child on the ketogenic diet also requires the active participation of a pharmacist who is aware of all the ingredients of all medications and can give direction concerning specific drug preparations with reference to the presence of carbohydrates. Patient Management 91 Pain WorkUp Non-communicating child with pain of unknown origin Do careful complete physical examination Check ears Check abdomen Check teeth to Check extremities Check hip to Check sinus to rule out to rule out rule out impacted or to rule out low rule out pain to rule out otitis media constipation infected wisdom teeth energy fractures from subluxation chronic sinusitus Is the physical examination normal? YES NO Get AP pelvis X-ray to check for Treat the positive findings constipation & hip subluxation X-ray of the pelvis X-ray of the pelvis is positive is negative Treat constipation Get urinalysis or hip subluxation and GI workup as indicated Urine positive Urine normal. Gastroenterology for blood Wait until child evaluation for or infection has had pain reflux positive for one week Treat as ––– indicated After one week is pain still Start medical Gastroscopy often treatment needed if pain of the reflux not improving with medical YES NO treatment or Do whole body Further workup unclear diagnosis technetium bone scan not needed Abnormal kidney Abnormal Sinus Abnormal bone Abnormal teeth Normal bone scan & pain continuous or joint for over one month Do further Get an ENT Get dental GU workup workup usually Get an X-ray evaluation Get evaluation for seizures, hydrocephalus, as indicated with CT scan of the abnormal ultrasound abdomen for gall bladder and kidneys of sinus area; maybe CT scan If all normal–monitor and wait for pain resolution 92 Cerebral Palsy Management References 1.
Syndromes
Vegetable oil-based wax
Try changing your nighttime sleep habits before taking drugs for insomnia.
Skin lesion biopsy
Muscle strain
Smooth muscles (also called involuntary muscle), such as the muscles contained in the stomach and other internal organs
Abnormal sounds in the lung (lung crackles) or a heart murmur
Muscle stiffness in face or neck
Labial or inguinal (groin) masses -- which may turn out to be testes -- in girls
Treat the cancer, along with chemotherapy, if surgery is not possible
In the emergency room administering medications 7th edition ebook cheap disulfiram 500mg with amex, physicians passed a nasogastric tube for stomach lavage medications overactive bladder cheap 500 mg disulfiram free shipping, started intravenous fluids symptoms for mono buy discount disulfiram online, and recorded vital signs. Dennis’s pulse rate was 48 beats per minute (slow), and his blood pressure was 78/48 mm Hg (low). The physicians noted involuntary twitching of the muscles in his extremities. Lotta Topaigne was diagnosed with acute gouty arthritis involving her right great toe (see Chapter 5). The presence of insoluble urate crystals within the joint space confirmed the diagnosis. Several weeks after her acute gout attack subsided, Ms. Topaigne was started on allopurinol therapy in an oral dose of 150 mg twice per day. Al Martini, a 44-year-old man who has been an alcoholic for the past 5 years, had a markedly diminished appetite for food. One weekend he became unusually irritable and confused after drinking two fifths of scotch and eating very little. Physical exam- ination indicated a heart rate of 104 beats/min. His blood pressure was slightly low, and he was in early congestive heart failure. THE ENZYME-CATALYZED REACTION S CH3O P SCHCOOC2H5 Enzymes, in general, provide speed, specificity, and regulatory control to reactions CH3O in the body. Enzymes are usually proteins that act as catalysts, compounds that CH2COOC2H5 increase the rate of chemical reactions. Enzyme-catalyzed reactions have three Malathion basic steps: (1) binding of substrate: E S 4 ES O (2) conversion of bound substrate to bound product: ES 4 EP CH3 (3) release of product : EP 4 E P CH3 P CH3 F An enzyme binds the substrates of the reaction it catalyzes and brings them Sarin together at the right orientation to react. The enzyme then participates in the mak- ing and breaking of bonds required for product formation, releases the products, and Fig. Malathion and parathion are organophospho- Enzymes do not invent new reactions; they simply make reactions occur faster. Nausea, coma, convulsions, The catalytic power of an enzyme (the rate of the catalyzed reaction divided by the respiratory failure, and death have resulted 6 14 rate of the uncatalyzed reaction) is usually in the range of 10 to 10. Without the from the use of parathion by farmers who have catalytic power of enzymes, reactions such as those involved in nerve conduction, gotten it on their skin. Malathion is similar in structure to parathion, but not nearly as toxic. The nerve gas Sarin, another organophospho- Each enzyme usually catalyzes a specific biochemical reaction. The ability of an rus compound, was used in a terrorist attack in enzyme to select just one substrate and distinguish this substrate from a group of a Japanese subway. The enzyme converts CHAPTER 8 / ENZYMES AS CATALYSTS 117 this substrate to just one product. The specificity, as well as the speed, of enzyme- CH2OH catalyzed reactions result from the unique sequence of specific amino acids that O H form the three-dimensional structure of the enzyme. The Active Site H OH To catalyze a chemical reaction, the enzyme forms an enzyme–substrate complex in glucokinase ATP its active catalytic site (Fig. The active site is usually a cleft or crevice in the or enzyme formed by one or more regions of the polypeptide chain.
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