Stephen M. Rosenthal MD

  • Professor of Pediatrics, Associate Program Director, Pediatric Endocrinology
  • Director, Pediatric Endocrine outpatient Services, University of California, San Francisco


Acute episodes are managed symptomatically with fluid and electrolyte correction heart attack with pacemaker purchase hydrochlorothiazide discount, and anti-emetics (lorazepam arteria digitalis palmaris communis 25mg hydrochlorothiazide with amex, ondansetron) blood pressure during pregnancy purchase 25mg hydrochlorothiazide with visa. There is some evidence for benefit from migraine prophylactic agents (propranolol blood pressure classification chart hydrochlorothiazide 12.5 mg low price, pizotifen) blood pressure watches order genuine hydrochlorothiazide. Lysinuric protein intolerance Disturbed transport of dibasic amino acids resulting in anorexia blood pressure chart for tracking purchase hydrochlorothiazide on line, growth failure, lethargy, vomiting, and diarrhoea. Neurological associations of hepatocellular failure Commonly seen following an episode of status epilepticus. Rare, but probably accounting for many cases of apparent valproate-induced liver disease. Hepatocellular dysfunction (typically late in the first decade of life) may pre-date development of neurological symptoms, and early chelating therapy may prevent neurological morbidity. Acute presentation: unilateral foot drop due to sacral nerve compression during colonoscopy. Differential diagnosis is of non-epileptic behaviours including jittering, tremor, dyskinesias, dystonia, startle responses. The half-life varies from 100 to 300 h in the newborn (400 h in the pre-term) falling to 60 h after 4 weeks. Further management If seizures continue despite triple therapy in adequate doses consider the following in particular. Their reliable identification requires a thorough approach systematically applied. Conditions whose potential treatability makes them particularly important to rule out are identified in blue. Therefore, it is more efficient to treat with pyridoxal phosphate if available, and define the biochemical defect subsequently in more detail if a response is seen. In term infants, maternal diabetes and hypertension/toxaemia are also risk factors. Results in cystic encephalomalacia, ulegyria (loss of sulcal depth), or porencephaly depending on the territory, and a pyramidal pattern cerebral palsy. Results particularly in parasagittal and parietoccipital white matter loss and auditory, visuospatial and language deficits. Prolonged partial asphyxia causes diffuse cortical necrosis, epilepsy, and learning disability. Acute total asphyxia may spare cortex but cause thalamic, basal ganglia and brainstem injury, and dyskinetic cerebral palsy. Therapeutic hypothermia is achieved by either selective head, or total body cooling. Metabolic encephalopathies A large number of metabolic, toxic, infectious, and genetic abnormalities may cause a neonatal encephalopathy. The placenta usually clears toxic metabolites so the presentation may be delayed from hours to weeks post-partum (cf. These complications of pregnancy are of unknown (probably heterogeneous) aetiology; however, some of the involved children later manifest fatty acid oxidation disorders. Treat hyperammonaemia if a urea cycle defect suspected with Na benzoate (250 mg/kg load followed by 250 mg/kg/24 h infusion) or arginine 0. Risk factors include non-vertex presentation, large foetal head size, primiparous, or older multiparous mother, instrumental delivery or rapid/ prolonged labour. It is usually clinically silent, but may present with a catastrophic syndrome of rapid neurological deterioration with coma, flaccid tone, tonic posturing, absence of spontaneous movements or a subacute deterioration in alertness and spontaneous movement over hours to days. Scoliosis and pooling of secretions with aspiration makes a myopathy (particularly nemaline rod) likely. Once raised pressure has been excluded the assessment is as for other children: primary headaches, especially migraine and tensiontype headache are the most common (see b p. Shunt complications In evaluation of possible shunt malfunction a good history is at least as valuable as neuroimaging data. Relationship of headaches to posture particularly helpful (raised pressure headache due to shunt blockage typically worse after period of lying down. If related to recent shunt revision then the shunt valve needs to be changed (to one with an increased opening pressure). A shunt with a programmable valve (whose opening pressure can be adjusted remotely) is particularly valuable. Other shunt complications Haemorrhage, abdominal pseudo-cysts, viscus penetration, shunt migration. A wide range of neurological symptoms and signs can occur in the context of paediatric oncology. Note that in this case changes are relatively asymmetric and not confined to occipital cortex (c. The characteristic distribution of the sensory disturbance and (if relevant) the motor deficit corresponding to the involved nerve should be sought (see b p. Anticoagulate with low molecular weight heparin once a secondary haemorrhage into a venous infarct has been excluded. Oto-toxicity Carboplatin, cisplatin; cytosine arabinoside (with vestibular involvement). Treatment in all cases is supportive, with consideration of reduction or discontinuation of the responsible agent in conjunction with the oncology team. Diagnosis can be difficult, with a wide range of possible agents including many organisms normally of low pathogenicity. Specific management requires close liaison with oncologists, microbiologists, and virologists. A significant number of children will have an unexplained or cryptogenic encephalopathy despite extensive investigations. Further/subsequent investigations to consider It is not intended that this list be slavishly followed in all cases. Hyponatraemia in a neuro-intensive care setting Hyponatraemia commonly occurs following neurological disease. It is an important preventable cause of secondary neurological insult, aggravating cerebral oedema, precipitating seizures, and sometimes causing irreversible white matter change. Spinal reflexes, including deep tendon reflexes; and spinal myoclonus may (rarely) be preserved. Cranial nerve reflex testing Pupillary light reflexes Test in a dark room with a bright source. The legal time of death is when the first set of tests is completed, not when intensive care is withdrawn. Prognostication after acquired brain injury Neurologists are often requested to assist in assessing prognosis for recovery for a child in a coma. Understanding the pathophysiology of the event, particularly in relation to its onset, is invaluable. If the latter, is this caused by hypoventilation, obstruction or right-to-left shunting This question is often centred on displays of temper or other erratic/ inappropriate behaviour. History the typical story is of gradual emergence of unusual behaviour and/or social withdrawal together with falling school performance. Main differentials of primary psychiatric psychosis are behavioural problems (particularly at school) due to unrecognized learning difficulties (see b p. Examination the presence of motor signs (pyramidal, extrapyramidal, or cerebellar) is incompatible with a diagnosis of primary psychosis. Unwanted drug effects Tardive dyskinesia this is most often associated with neuroleptics (phenothiazine, haloperidol), atypical antipsychotics (olanzapine) and, more rarely, with anti-emetics (metaclopromide or prochlorperazine), but it can also occur with theophylline. It may present with an altered level of consciousness or behaviour, progressing to muscle rigidity, hyperthermia rhabdomyolysis, and autonomic dysfunction. Behavioural management in difficult to control epilepsy Children with poorly-controlled seizures may have difficulties with behaviour and attention interictally. Episodic behavioural episodes may be mistaken for seizures and (for example) lead to excessive and inappropriate use of emergency seizure medication. Aggression, conduct disorder, and oppositional defiant disorder Precise diagnostic criteria for these conditions are established, but their practical value is debated. The main concern with conduct dis-order is that the younger the onset of difficulties, the worse the outcome in terms of risk of serious offending in later life. Described as occurring in two age groups-middle childhood/early adolescence, and adolescence. In the latter, a distinction between socialized (with preservation of peer relationships) and socialized (offending alone with little guilt or concern) is useful. Physical aggression is less common in adolescence-truancy becomes more common; drug taking, sexual offences and prostitution can occur and gang fighting occurs in large cities. Consider assessment for occult learning difficulties, sensory and perceptual difficulties, and autism. Autism and epilepsy Epilepsy is common in children with autism (one of the strongest pieces of evidence for a neurobiological, rather than psychosocial basis for autism), and many general epilepsy management principles apply. For most children with autism and epilepsy, antiepileptic therapy should be long term even if seizure freedom has been achieved. Typically foodborne, initially though person-to-person spread, a risk as it may be shed in the stool for several weeks after resolution of symptoms. Sudden drops in blood pressure risk focal infarction particularly of the optic nerve. Rhabdomyolysis/myoglobinuria Rarely presents primarily to the renal team, although nephrological input may be required for fluid management and/or acute secondary renal failure.

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Electron micrographs suggest that the plasma membranes of the sperm and ovum fuse blood pressure 210120 order hydrochlorothiazide 12.5 mg with visa, that of the spermatozoon being left at the surface of the ovum pulse pressure and icp buy hydrochlorothiazide 25 mg cheap. Penetration is followed by release of electron-dense cortical granules that underlie the plasmalemma of the ovum (cortical granule reaction) and by immediate changes in the permeability of the zona pellucida blood pressure chart 19 year old hydrochlorothiazide 25 mg generic, which thereafter excludes entry by any additional competing sperm (polyspermy) arteria basilar buy hydrochlorothiazide without a prescription. The ovum now completes the second maturation division and extrudes the second polar body blood pressure jump cheap hydrochlorothiazide amex. The nucleus (head) of the spermatozoon swells and forms the male pronucleus pulse pressure under 20 buy generic hydrochlorothiazide 25mg online, and the sperm body and tail are resorbed. The two pronuclei move to the center of the cell, and two centrioles, supplied by the anterior centriole of the spermatozoon, appear. The chromatin of each pronucleus resolves into a set of chromosomes that align themselves on a spindle to undergo a normal mitotic division of the first cleavage. Each cell resulting from this division receives a full diploid set of chromosomes. The cells are bounded by the zona pellucida, and a mulberry-like body, the morula, is formed. Cleavage is a fractionating process: no new cytoplasm is formed, and at each division the cells become smaller until a normal, predetermined, cytoplasmic-nuclear ratio is reached. Cleavage occurs as the morula slowly is moved along the oviduct by the waves of peristaltic contractions in the muscle coat. The fluid increases in amount, the intercellular spaces become confluent, and a single cavity, the blastocele, is formed. The morula has now become a blastocyst that forms a hollow sphere containing, at one pole, a mass of cells called the inner cell mass that will form the embryo proper. The capsule-like wall of the blastocyst consists of a single layer of cells, the trophoblast. After reaching a critical mass, the blastocyst breaks through the surrounding zona pellucida and remains free within the uterine cavity for about a day; then it attaches to the endometrium, which is in the secretory phase. Encasement within the zona pellucida protects the forming blastocyst from the possible damaging effects of oviductal movements, possible adverse effects of oviductal and uterine secretions, and/or destruction by maternal tissues until it reaches a critical mass for survival. During cleavage, the zona pellucida progressively thins and coupled with the expansion of the blastocoele, the blastocyst hatches and crawls through and out of the surrounding zona pellucida. The hatched blastocyst makes contact with the maternal endometrial surface through apposition of its trophectoderm to the uterine lining epithelial cells. The initial contact is mediated by cell surface oligosaccharides that play an important role in recognition, adhesion and attachment to the uterine epithelium. Following these events, trophoblast cells penetrate between surface uterine epithelial cells and establish direct contact with underlying decidual cells. Implantation is initiated by close approximation of the trophoblast to the microvilli and surface projections of the uterine epithelial cells. At the points of contact, the cytoplasm of the trophoblast contains clusters of coated vesicles and numerous lysosomes. The microvilli shorten and disappear, and the trophoblast extends finger-like processes between the uterine epithelial cells, and the two layers become closely locked by numerous tight junctions that develop between them. The uterine epithelial cells degenerate and are engulfed by the trophoblast, the cellular debris appearing in phagosomes within the trophoblast cytoplasm. Where it is fixed to the endothelium, the trophoblast proliferates to form a cellular mass between the blastocyst and maternal tissues. No cell boundaries can be made out in this cell mass, which is called the syncytial trophoblast. The syncytium continues to erode the endometrium at the point of contact, creating a ragged cavity into which the blastocyst sinks, gradually becoming more deeply embedded until it lies entirely within the endometrial stroma. Later, proliferation of surrounding cells restores the surface continuity of the endometrial lining. As the blastocyst sinks into the endometrium, the syncytial trophoblast rapidly increases in thickness at the original site of attachment and progressively extends to cover the remainder of the blastocyst. When completely embedded, the entire wall of the blastocyst consists of a thick outer syncytial trophoblast and an inner cytotrophoblast, which is composed of a single layer of cells with well-defined boundaries. The cytotrophoblast shows active mitosis and contributes cells to the syncytial trophoblast, where they fuse with and become part of that layer. The syncytial trophoblast continues to erode the uterine tissues, opening up the walls of maternal blood vessels. Spaces appear in the syncytial trophoblast and these lacunae expand, become confluent, and form a labyrinth of spaces. Many of the spaces contain blood from eroded maternal blood vessels; this blood supplies nourishment for the embryo and represents the first step in the development of uteroplacental circulation. Trophoblastic cells at the tips of the villi apply themselves to the endometrium and form a lining for the cavity in which the blastocyst lies. When the embryonic germ layers have been established, mesoderm grows out from the embryo as the chorion and forms a lining for the trophoblast that surrounds the blastocyst. Mesoderm extends into the primary villi to form a core of connective tissue and convert the primary villi to secondary villi. The deeply embedded portion of the chorion constitutes the chorionic plate from which numerous villi project to form the chorion frondosum. Villi on that part of the chorion facing the uterine cavity grow more slowly and are less numerous; ultimately, these villi disappear; leaving a smooth surface that forms the chorion laeve. Blood vessels develop in the mesenchymal cores of the secondary villi and soon make connection with the fetal circulation. With vascularization, the secondary villi become the definitive or tertiary placental villi. At parturition, all but the deepest layers of the endometrium are shed; thus the superficial part of the endometrium is called the decidua. A feature of the stroma is the alteration of its cells to form enlarged, decidual cells that contain much glycogen. According to the relationship with the implantation site, three areas of the decidua are recognized. The decidua capsularis is the part that lies over the surface of the blastocyst, while the decidua basalis underlies the implantation site and forms the maternal component of the placenta. The endometrium lining the remainder of the pregnant uterus is the decidua parietalis. Eventually, the decidua capsularis makes contact with decidua parietalis on the opposite surface of the uterus, and the uterine cavity is obliterated. The maternal part is decidua basalis; the fetal portion consists of the chorionic plate and the villi arising from it. Maternal blood circulates through the intervillous spaces and bathes the villi, of which there are two types. Some pass from the chorionic plate to decidua basalis as anchoring villi from which secondary and tertiary branches float in the intervillous spaces as the floating villi. Both types of villi consist of a core of loose connective tissue in which lie fetal capillaries. Covering each villus is an inner layer of cytotrophoblast cells, which have large nuclei and lightly basophilic cytoplasm containing considerable glycogen. External to the cytotrophoblast is a layer of syncytial trophoblast of variable thickness. The cells of the cytotrophoblast decrease in number in the latter half of pregnancy, and only a very few are present at term. The placenta transfers oxygen and nutrients from the maternal to the fetal circulation and waste products from the fetal to the maternal circulation. Although maternal and fetal circulations are closely apposed, they remain separated by the syncytial trophoblast (and early in pregnancy by the cytotrophoblast also), a basement membrane, the connective tissue of the villi, and the wall of the fetal blood vessels. Transport of material between fetal and maternal blood appears to be regulated by the syncytial trophoblast. Being without cell boundaries and intercellular spaces, any materials passing into or out of the fetal blood must pass through the cell membranes and cytoplasm of the syncytium. Electrolytes, steroids, fatty acids, oxygen, and carbon dioxide traverse the syncytial trophoblast by passive diffusion. The cytotrophoblast continues to serve as the source of cells for the syncytial trophoblast. The placenta also is a multipotential endocrine organ essential for maintaining pregnancy. It increases in amount to the fifth week of pregnancy and maintains and stimulates the corpus luteum to secrete estrogens and progesterone during early pregnancy. The placenta also secretes estrogens and progesterone that aid in maintaining the uterine environment for continued fetal development. A variety of other factors, similar to releasing hormones of the hypothalamus as well as pituitary-like hormones, are synthesized and released by the placenta into the maternal blood. Human chorionic somatomammotropin imparts a condition of insulin resistance to the mother so that glucose rather than being rapidly removed from the circulation by maternal tissues is available for the developing fetus. Each lobe represents an individual mammary gland and contains glandular tissue drained by its own ductal components, embedded in connective tissue. In the resting gland, the principal glandular elements are the ducts, which are grouped together to form lobules. The smallest branches of the ductal system are lined by simple cuboidal epithelium, but the lining increases in height as the ducts unite and pass toward the nipple. Just beneath the areola, the ducts expand to form the lactiferous sinuses, which are lined by a two-layered stratified cuboidal epithelium. As the duct ascends through the nipple, it becomes lined by stratified squamous epithelium. The alveolar wall consists of simple cuboidal epithelium resting on a basement membrane. Between the epithelial cells and the basement membrane are highly branched myoepithelial cells whose long, slender processes embrace the alveolus in a basket-like network. Alveoli are not prominent in the resting gland, and there is some question as to whether they are present at all. When present, they usually occur as small, budlike extensions of the terminal ducts. The intralobular connective tissue around the ductules and alveoli is loosely arranged and cellular, whereas that surrounding the larger ducts and lobes (interlobular connective tissue) is variably dense and contains much adipose tissue. Breasts (Mammary Glands) Mammary glands are present in both sexes but in men remain rudimentary throughout life. Prior to puberty, the female breasts are undeveloped but enlarge rapidly at puberty due mainly to accumulation of adipose tissue. In women, the breasts are variably hemispherical and conical in shape, each surmounted by a cylindrical projection, the nipple. Surrounding the nipple is a slightly raised, circular area of hairless pigmented skin, the areola. The dermis projects deeply into the epithelium, forming unusually tall dermal papillae. The skin of the nipple is pigmented and contains many sebaceous glands but is devoid of hair and sweat glands. The nipple is traversed by many lactiferous ducts, each of which drains a lobe and empties onto the tip of the nipple. The outer parts of the ducts also are lined by keratinizing stratified squamous epithelium. The dense collagenous connective tissue of the nipple contains bundles of elastic fibers, and much smooth muscle is present. The smooth muscle cells are arranged circularly and radially and, on contraction, produce erection of the nipple. The latter appear to be intermediate in structure between apocrine sweat glands and true mammary glands. During the first half of pregnancy, the terminal portions of the ductal system grow rapidly, branch, and develop terminal buds that expand to become alveoli. Proliferation of glandular tissue takes place at the expense of the fat and stromal connective tissue, which decrease in amount. The connective tissue becomes infiltrated with lymphocytes, plasma cells, and granular leukocytes. During late pregnancy, proliferation of glandular tissue subsides, but the alveoli expand and there is some formation of secretory materials. It is poor in lipid but contains a considerable amount of immunoglobulin that provides passive immunity to the newborn. True milk secretion begins a few days after parturition, but not all the breast tissue is functioning at the same time. In some areas, alveoli are distended with milk, the epithelial lining is flattened, and the lumen is distended; in other areas, the alveoli are resting and are lined by tall columnar epithelial cells. Secreting cells have abundant granular endoplasmic reticulum, moderate numbers of relatively large mitochondria, and supranuclear Golgi complexes. Milk proteins are elaborated by the granular endoplasmic reticulum and in association with the Golgi body form membranebound vesicles. These are carried to the apex of the cell, where the contents are released by exocytosis. Lipid arises as cytoplasmic droplets that coalesce to form large spherical globules. Ultimately, they pinch off, surrounded by a thin film of cytoplasm and the detached portion of the plasmalemma. This method of release is a form of apocrine secretion, but only minute amounts of cytoplasm are lost. Immunoglobulins in milk are synthesized by plasma cells in the connective tissue surrounding the alveoli of the mammary glands. The secreted immunoglobulin is taken up by receptor-mediated endocytosis along the basolateral plasmalemma of mammary gland epithelial cells and transported in small vesicles to the cell apex, where it is discharged into the lumen by exocytosis.

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Since the underlying deficit in pernicious anemia is malabsorption of vitamin B 12 blood pressure medication causing heart palpitations hydrochlorothiazide 12.5 mg free shipping, treatment involves intramuscular vitamin B 12 injections rather than oral vitamin therapy blood pressure chart while exercising buy cheap hydrochlorothiazide. Therapeutic doses of folate are hypertension 1 stage discount 12.5 mg hydrochlorothiazide overnight delivery, however hypertension in young adults 12.5 mg hydrochlorothiazide sale, ineffective in preventing the ongoing and eventually irreversible neurological degeneration arrhythmia ventricular tachycardia hydrochlorothiazide 12.5mg without prescription. Thus prehypertension 20s order hydrochlorothiazide visa, folic acid supplements may mask the underlying vitamin B12 deficiency and, in some cases, even exacerbate it by promoting utilization of vitamin B I Zby cells in the bone marrow rather than in neural tissues. There are, however, other conditions that can result in poor vitamin B12 status, as described below. Nutritional deficiency of vitamin B12 is relatively rare but can occur in people who consume vegan diets. For people who consume a normal diet with ample intake of animal products, the large stores of vitamin B12 in the liver provide protection for up to 5 to 7 years of reduced vitamin B12 intake or absorption. The proteolytic activity of pepsin is required to release food-bound vitamin B I Z. Hypochlorhydria (decreased stomach acid) can also result from prolonged use of proton-pump inhibitors. As described earlier, the vitamin B 12-intrinsic factor complex is absorbed by a receptor-mediated process in the terminal ileum. Purines (adenine and guanine) contain two fused heterocyclic, nitrogen-containing rings. Pyrimidines are six-membered, heterocyclic, nitrogen-containing carbon structures. When purine or pyrimidine bases are attached to pentoses (ribose or deoxyribose), they are called nucleosides. Thus, the nucleoside adenosine is formed by attachment of adenine to ribose, and deoxyadenosine is formed by attachment of adenine to deoxyribose. Other ribonucleoside triphosphates also participate directly in metabolic pathways. Adenine nucleotides are components of coenzyme A, which is involved in the synthesis of bile acids and the catabolism of branched-chain amino acids as well as providing the activated form of acetate and fatty acids for both biosynthetic and catabolic reactions. The heterotrimeric G proteins are activated by G proteinxoupled receptors, such as the receptors for glucagon, epinephrine, and various prostaglandins. Nonhepatic tissues generally rely on preformed purines salvaged from intracellular turnover and purines synthesized by the liver. The purine salvage pathway is particularly important in the brain, where it serves to regenerate adenine nucleotides from the neurotransmitter adenosine. The end product of purine catabolism in humans is uric acid, a relatively insoluble substance that is excreted in the urine. The reactions involved in the de novo synthesis of purines and pyrimidines take place in the cytosol and mitochondria, and the enzymes of each pathway tend to function as components of multienzyme complexes. Nucleoside diphosphates are the substrate for the reduction of carbon 2 of ribose to deoxyribose; the reaction is catalyzed by ribonucleotide reductase. The reaction results in the oxidation of thioredoxin (shown) or glutaredoxin (not shown). Ribonucleotide reductase is a multifunctional enzyme complex that contains redox-active thiol groups. They are then reduced by either one of two low-molecular weight proteins, thioredoxin or glutaredoxin. Oxidized thioredoxin, in turn, is reduced by the flavoprotein thioredoxin reductase. The multienzyme complex that carries out de novo purine synthesis is called the purinosome. The names of the enzymes and intermediates in the de novo purine pathway are cumbersome and complex; therefore, except for the steps that are regulated or the ones that are implicated in a particular human disease. The subscripts after C and N indicate the location of the atom in the purine ring. Two of the four nitrogen atoms in the ring structure of inosine are derived from glutamine and one each are derived from glycine and aspartate. These reactions underscore the dependency of nucleic acid synthesis on adequate dietary folate. Inadequate folate impairs cell division, as exemplified by the megaloblastic anemia associated with folate deficiency. Inhibitors of dihydrofolate reductase such as methotrexate and aminopterin are useful cancer chemotherapeutic agents. The amino group of adenine is derived from aspartate, whereas glutamine is the source of the amino group of guanine. Unlike most other mammals, humans lack the enzyme urate oxidase, which converts uric acid to allantoin, a more soluble end product than urate. The final enzyme in the pathway of purine catabolism is xanthine oxidase, a molybdenum-containing flavoenzyme that uses molecular oxygen and produces hydrogen peroxide. This process, called the purine nucleotide cycle, serves several interrelated functions, discussed below. Some of the fumarate generated in the purine nucleotide cycle is metabolized and thus represents a source of energy for muscle. Although the immediate nitrogen donor for the transamination of oxaloacetate to aspartate is glutamate, most of the amino groups are ultimately derived from the catabolism of branched-chain amino acids. The next reaction in pyrimidine synthesis is both the committed step and the regulated step, and it is catalyzed by aspartate transcarbamoylase: aspartate + carbamoyl phosphate + N-carbamoyl aspartate + Pi Next, dehydration of N-carbamoyl aspartate by dihydroorotase forms the ring structure dihydroorotic acid. Catabolism of both uracil and thymine involves the same three-enzyme sequence, which releases ammonia and carbon dioxide and generates a @amino acid from the rest of the ring. P-Aminoisobutyrate, the main end product of thymine metabolism, is mostly excreted in the urine. The end product of uracil metabolism is p-alanine, some of which is incorporated into carnosine (histidine-P-alanine) and anserine (methyl histidine-P-alanine), two dipeptides found in brain and muscle. Uric acid is poorly soluble in plasma, especially at lower temperatures; thus the hallmark of gout is deposition of tophi or urate crystals under the skin of the ear, fingers, and toes. Causes of underexcretion of purines include lactic acidosis and drugs such as thiazide diuretics. Hyperuricemia is one of the hallmarks of tumor lysis syndrome, a cluster of metabolic complications of cancer chemotherapy. The catabolism of purines from large numbers of lysed cancer cells results in increased production of uric acid. Gout is also associated with von Gierke disease, the glycogen storage disease that results from a deficiency in glucose 6-phosphatase activity. The drug allopurinol, which is used to treat gout, is oxidized by xanthine oxidase to oxypurinol, which is a potent inhibitor of xanthine oxidase. When xanthine oxidase is inhibited, hypoxanthine and xanthine accumulate and the concentration of uric acid is reduced. Hypoxanthine and xanthine are more water-soluble than uric acid, thereby facilitating the urinary excretion of purine degradation products and reducing the likelihood of urate crystal deposition. Affected children have severe neurologic deficits, retarded motor development, muscle weakness, and self-injurious behavior; the most characteristic feature is loss of tissue from biting themselves, Although the mechanism is not fully understood, it appears that abnormalities in purine metabolism impair dopaminergic function in the basal ganglia. Allopurinol is effective in controlling the hyperuricemia and goutlike symptoms of Lesch-Nyhan disease, but is ineffective in modifying the neurological or behavioral manifestations of the disease. Immunodeficiency can also be caused by a deficiency of purine nucleoside phosphorylase, the enzyme that catalyzes the phosphorolytic cleavage of inosine to hypoxanthine. The metabolic defect is in uridine-5-monophosphate synthase, which contains two enzyme activities in a single protein: orotate phosphoribosyltransferase and orotidylate decarboxylase. One of the earliest chemotherapeutic agents, fluorouracil, inhibits thymidylate synthase. Hydroxyurea, which is used as a component of some cancer protocols, inhibits ribonucleotide reductase. Methotrexate and aminopterin inhibit dihydrofolate reductase, thus impairing synthesis of purines as well as thymidylate. Hemoglobin is the molecule in red blood cells that transports oxygen from the lungs to peripheral tissues. Myoglobin is an intracellular protein that extracts oxygen from the red blood cells and stores it until the oxygen is needed in various oxidation-reduction reactions and respiration. Hemoglobin and myoglobin both contain heme, a porphyrin or tetrapyrrole that consists of four pyrrole rings joined by methylene bridges. All of the double bonds in heme are conjugated: that is, double bonds and single bonds alternate throughout the structure. The iron in the center of the porphyrin ring is in the ferrous (Fe2+) state and is the site where molecular oxygen binds. The iron atom also binds noncovalently to a particular histidine in the hemoglobin and myoglobin proteins. Hemoglobin is a tetrameric molecule with four polypeptide chains, two a and two p chains, each with a bound heme molecule. Medical Biochemistry: Human Metabolism in Health and Disease Copyright 0 2009 John Wiley & Sons, Inc. Heme is also a component of members of the superfamily of cytochrome P450xontaining enzymes that catalyze the oxidation of many molecules, including steroids and xenobiotics. Cytochromes differ from each other in the nature of the side chains attached to the porphyrin ring. Most of heme synthesis takes place in the liver and in erythroid cells within the bone marrow. The first and last three steps take place in the mitochondrion, whereas the second through fifth steps take place in the cytosol. The iron atom is reutilized, while the porphyrin ring is oxidized and cleaved to produce the breakdown product, bilirubin. The liver converts hydrophobic bilirubin to the more water-soluble bilirubin diglucuronide, which is secreted into the bile and ultimately excreted in the feces. Most of the bilirubin arising from the degradation of hemoglobin is produced in splenic phagocytes. This means that bilirubin must be transported from nonhepatic phagocytic cells to the liver. It is critical that bilirubin is transported in the blood bound to albumin; when the binding capacity of albumin is exceeded, the unbound bilirubin can be toxic. The hemoglobin of red blood cells and the myoglobin of muscle cells account for approximately 2500 and 100 mg of this iron, respectively. Ninety-five percent of this iron is recycled and reutilized by the bone marrow to synthesize new red blood cells, which replace those that were broken down. Ferritin is a ubiquitous iron-binding protein that is found mostly in the cytosol. The apoferritin shell, which is formed by assembly of 24 of these dimers, can accommodate up to 4500 atoms of iron in its core. The ratio of H to L subunits is tissue-dependent: Liver and spleen contain mostly L-subunit ferritin, whereas the H subunit predominates in kidney and heart. As ferrous iron enters the pores of the apoferritin shell, it is oxidized to the Fe3+ state and deposited as hydrated ferric oxide crystals. Iron is transported between cells and tissues in the circulation in the ferric form, most of which is complexed to a protein named trunsferrin that is synthesized and secreted by hepatocytes. Dietary iron, absorbed in the proximal small intestine, is also transported on transferrin. The Fe3+-transferrin complex binds to transferrin receptors on the plasma membrane of iron-utilizing cells and is internalized by receptor-mediated endocytosis. A proton pump in the endosome acidifies the endosome, resulting in the release of iron from transferrin, which is then transported out of the endosome to the cytosol, where it becomes available for heme synthesis or storage as ferritin. The transferrin: transferin receptor complex is recycled to the plasma membrane, whereupon transferrin dissociates from its receptor. Small amounts of ferritin are also present in plasma, reflecting slow release of this iron protein from storage sites (mostly liver) during normal cellular turnover. About 1 mg of iron is lost each day through exfoliation of skin and intestinal cells. This iron loss is made up for by the absorption of an equivalent amount of iron from the intestine. Heme synthesis in the liver is most active when there is induction of enzymes of the cytochrome P450 family which participate in the detoxification of drugs and xenobiotics. Next, hydoxymethylbilane is converted to uroporphyrinogen I11 by the combined action of uroporphyrinogen synthase and uroporphyrinogen I11 cosynthase. The function of uroporphyrinogen 111 cosynthase is to direct the fourth pyrrole ring into the inverse orientation relative to that of the other three pyrrole rings. Uroporphyrinogen 111 decarboxylase then converts uroporphyrinogen 111 to coproporphyrinogen 111, which is then transported from the cytosol into the mitochondrion. This reaction generates a molecule that has resonance of double bonds around the entire great ring and the characteristic red color of heme. Hemoglobin cannot bind oxygen when the iron of hemoglobin is in the ferric state (a. Furthermore, methemoglobin is a potent oxidizing agent that can damage red blood cells and shorten their lifespan. About 75% of bilirubin is derived from hemoglobin that has been ingested by phagocytic cells during the process of destroying senescent red cells in the spleen and liver. Some free hemoglobin is released into the circulation when senescent red cells are destroyed. This hemoglobin is complexed to haptoglobins, a family of plasma glycoproteins synthesized by the liver. Haptoglobin: hemoglobin complexes are removed from the circulation by splenic phagocytes and Kupffer cells in the liver. Any free heme that dissociates from hemoglobin in the circulation is complexed immediately by hemopexin, another liver-synthesized plasma glycoprotein, and transported to the liver. Binding of hemoglobin and heme to haptoglobins and hemopexin, respectively, serves both to prevent loss of iron through filtration by the kidney and to protect against oxidative stress. Both the haptoglobins and hemopexin are acutephase proteins whose synthesis is increased in response to infection and which, by removing hemoglobin and heme from the plasma, prevent iron-utilizing bacteria from benefitting from the iron released by hemolysis.

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