The enzyme is heme synthase or ferrochelatase which is also located in mitochondria. Iron atom is coordinately linked with 5 nitrogen atoms (4 nitrogen of pyrrole rings of protoporphyrin and 1st nitrogen atom of a histidine residue of globin). When the ferrous iron (Fe ++) in heme gets oxidized to ferric (Fe+++) form, hematin is formed, which loses the property of carrying the oxygen. When there is excess of free heme, the Fe++ is oxidized to Fe+++ (ferric), thus forming hematin. This classification is based on the major site, where the enzyme deficiency is manifested. Porphyrins are not excreted or elevated in blood; so there is no photosensitivity. As the name indicates, the symptoms appear intermittently and they are quite vague. The patients often land up with the surgeon as a case of acute abdomen and on. Enzyme deficiencies in porphyrias several instances exploratory laparotomies had been done. An attack is precipitated by starvation and symptoms are alleviated by a high carbohydrate diet. This would lead to ineffective feedback inhibition which further increases the rate of formation of type I porphyrins. Their excretion in urine makes the urine dark red in color (port wine appearance). Another group may have neurological manifestations like sensory and motor disturbances, confusion and agitation. Some patients may present with psychiatric problems and may be treated accordingly. Many of his obstinate decisions, including the ones which led to war of American independence, were made when he had acute attacks of intermittent porphyria. This in turn leads to excessive production of heme intermediaries causing neurological porphyrias. Diet, liver disease, chronic renal failure, some malignancies, hexachloro benzene, lead, mercury, arsenic. A characteristic difference from congenital porphyrias is that there is associated anemia in the acquired variety. When urine is observed under ultraviolet light; porphyrins if present, will emit strong red fluorescence. The iron atom in the centre of porphyrin is hexavalent and bonded to the 4 pyrrole nitrogens by coordinate valencies. When the ferrous iron (Fe++) in heme gets oxidized to ferric (Fe+++) form, hematin is formed, which loses the property of carrying the oxygen. When hemoglobin or porphyrin solutions are viewed through a spectroscope, the absorbed wave lengths are seen as dark bands. All porphyrins will have an absorption band near 400 nm; this distinguishing band is called the Soret band, after its discoverer. Reactive oxygen species (free radicals) are the cause for cell destruction (Chapter 20). On the other hand, being more lipophilic, protoporphyrin associates with cell membranes and causes burning sensation and inflammatory reaction in skin exposed to sun. Hence biochemical diagnosis of porphyria will be considered based on the major clinical features, namely: (a) neurovisceral (Table 21. Microsomal Heme Oxygenase System: Heme is degraded primarily by a microsomal enzyme system; heme oxygenase. The liver plays the central role in the further disposal of the bilirubin (Figs 21. The binding sites for bilirubin on albumin can be occupied by aspirin, penicillin, etc. Hence, care should be taken while administering such drugs to newborn babies to avoid kernicterus.
Tumor with minimal optic nerve and/or choroidal invasion Focal vitreous and/or subretinal seeding of fine aggregates of tumor cells is present, but no large clumps or "snowballs" of tumor cells. Tumor superficially invades optic nerve head but does not extend past lamina cribrosa or tumor exhibits focal choroidal invasion. Massive vitreous and/or subretinal seeding is present, defined as diffuse clumps or "snowballs" of tumor cells. Tumor superficially invades optic nerve head but does not extend past lamina cribrosa and exhibits focal choroidal invasion. Severe intraocular disease Tumor with significant optic nerve and/or choroidal invasion Tumor fills more than 2/3 of the eye. Tumor invades optic nerve past lamina cribrosa but not to surgical resection line or tumor exhibits massive choroidal invasion. One or more complications present, which may include tumor-associated neovascular or angle closure glaucoma, tumor extension into the anterior segment, hyphema, vitreous hemorrhage, or orbital cellulitis. Tumor invades optic nerve past lamina cribrosa but not to surgical resection line and exhibits massive choroidal invasion. Tumor invades optic nerve to resection line or exhibits extraocular extension elsewhere. Tumor invades optic nerve to resection line but no extraocular extension identified Invasion into the orbit. Tumor invades optic nerve to resection line and extraocular extension identified Intracranial extension not past chiasm. The historic works of Forrest (1954) and Zimmerman (1962) alleviated confusion by applying to epithelial tumors of the lacrimal gland the histopathologic classification of salivary gland tumors. In the normal, fully developed orbit, the lacrimal gland is clinically impalpable and is situated in the lacrimal fossa posterior to the superotemporal orbital rim. This includes a complete history (with emphasis on duration of symptoms, pain, or dysesthesia) Carcinoma of the Lacrimal Gland 569 In order to view this proof accurately, the Overprint Preview Option must be set to Always in Acrobat Professional or Adobe Reader. Job Name: - /381449t and physical examination (including globe displacement or distortion, palpation, and sensory and motor examination). Computed tomography and/or magnetic resonance imaging can provide critical diagnostic and staging data. Orbital imaging should evaluate size, shape, extent, and invasion of adjacent structures, including the bone, skull base, and periorbital areas. The lateral orbital wall and roof are often involved with adenoid cystic carcinoma of the lacrimal gland; thus, en-bloc excision of these orbital walls may be indicated when the bony walls look either clinically (intraoperatively) or radiographically involved. Evaluation of the cervical lymph nodes, the lungs, and bone should be included to stage disease. The specimen should be thoroughly sampled for evaluation of histologic type and grade of tumor, size, possible presence of a preexistent pleomorphic adenoma, and surgical margins (including the periosteum). Perineural spread, most characteristic of adenoid cystic carcinoma, can result in a clinical underestimation of the true anatomic extent of disease. Any bone removed during surgical treatment should be fully examined pathologically for evidence of involvement by carcinoma. Prognostic significance of Ki-67 and p53 as tumor markers in salivary gland malignancies in Finland: An evaluation of 212 cases. Epithelial lacrimal gland tumors: pathologic classification and current understanding. Epithelial tumors of the lacrimal gland: prognostic and therapeutic significance of histologic types. Orbit has two unique histopathological features that may have some influence on tumor dissemination to and from this location. Orbit does not contain a lymphatic vascular network and its venous channels do not have valves. All the support systems of the globe, including the optic nerve and its meninges, lacrimal gland and lymphoid tissue, extraocular muscles, fibroadipose tissue, peripheral nerves, ganglionic tissue, and blood vessels are designed to be confined within approximately 25 ml of space surrounding the eyeball.
Diseases
Thus, 6 numbers of 5carbon units are condensed to form a 30 carbon compound, Squalene. Cholesterol biosynthesis 5C + 5C10C; 10C+5C15C; 15C+15C 30C Chapter 12; Cholesterol and Lipoproteins 149. Next, the 3 additional methyl groups on carbon atoms 4 and 14 are removed to produce zymosterol. Then the double bond migrates from 8-9 position to 5-6 position, when desmosterol is formed. Covalent modification: Short-term regulation is by covalent modification of the enzyme. Comparison of sizes of lipoproteins cholesterol is partly reabsorbed from intestines. The unabsorbed portion is acted upon by intestinal bacteria to form cholestanol and coprostanol. Another 500 mg of cholesterol is converted to bile acids, which are excreted in the bile as bile salts. Classification of Lipoproteins Depending on the density (by ultra centrifugation) or on the electrophoretic mobility, the lipoproteins in plasma are classified into five major types (see Figs 12. Cholesterol Pool and Cholesterol Metabolism the total body cholesterol content varies from 130-150 grams. Excretion of Cholesterol Average diet contains about 300 mg of cholesterol per day. Characteristics of different classes of lipoproteins Chylomicron Density g/ml Diameter (nm) <0. General Characteristics of Lipoproteins Their salient characteristics and compositions are given in Table 12. Structure of chylomicrons a polar periphery made of proteins, polar heads of phospholipids and cholesterol. Separation by Ultracentrifugation the lipoproteins are characterised on the basis of their density. Lipoproteins with high lipid content will have a low density and so float on centrifugation. Depending on the floatation constant (Sf), different fractions can be separated (Table 12. Separation by Electrophoresis the basic principle of electrophoresis is given in chapter 54. The serum is applied on cellulose acetate, electric current is applied for 2 hours, the strip is dried and stained with lipid dyes, such as Oil Red O. As a general rule, those with higher protein content will move faster towards the anode and those with fewer proteins have minimum mobility. Apo-lipoproteins the protein part of lipoprotein is called apolipoprotein (apo-Lp) or apoprotein. All apoproteins are mainly synthesised in liver; but small quantities are produced from almost all organs. Apart from solubilising the lipid part, the protein components have specific functions. Apo-B-100 is one of the biggest proteins, having 4536 amino acids, with a molecular weight of 550 kDa. So, a stop codon is generated in the middle, and a short protein is produced in intestine (B48). If lipemic serum is kept overnight in the refrigerator, chylomicrons rise as a creamy layer to the top, leaving the subnatant clear. The enzyme lipoprotein lipase (LpL) is located at the endothelial layer of capillaries of adipose tissue, muscles and heart; but not in liver. The LpL hydrolyses triglycerides present in chylomicrons into fatty acids and glycerol. Following injection of heparin, the LpL is released from the tissues and lipemia is thus cleared. These remnants containing apo-B-48 and apo-E are taken up by hepatic cells by receptor mediated endocytosis.
Richard Feynmann (1918-1988) is considered to be the father of modern nanotechnology. Then the contents of each tube are simultaneously examined on polyacrylamide electrophoresis. The radiation from 32P labelled primer will be available in all pieces and will be seen as dark bands in the X-ray plate. Bioinformatics In a broad perspective, bioinformatics describes any use of computers to handle biological information. Bioinformatics may be regarded as a synonym for "computational molecular biology". It is the use of computers to characterize the molecular components of living things. It can be applied to store, retrieve, analyze or predict the composition or the structure of biomolecules. Many tools of nanotechnology are derived from biotechnology and have wider applications in medicine. When nanotechnology is used for biotechnological advances it is known as nanobiotechnology. Biodegradable nanomaterials, nanocosmetics, fabrics etc are also using nanotechnology principles. In nature, the hanging of geckos (small lizards) from the rooftop and the folding of the flowers of touch-me-not plant are said to be based on nanobiology. Because of this special adaptation of Geckos can adhere to most surfaces without the use of liquids or surface tension. Drug Delivery Nanoparticles could be used to deliver drugs to specific types of cells (such as cancer cells). Particles are attracted to diseased cells, which allow direct treatment of those cells. This technique reduces damage to healthy cells in the body and allows for earlier detection of disease. The drug to be administered is encapsulated in a nanoparticle which helps it pass through the stomach to deliver the drug into the bloodstream. Efforts are underway to develop oral administration of several different drugs using a variety of nanoparticles. Therapeutics Nanoshells may be used to concentrate the heat from infrared light to destroy cancer cells with minimal damage to surrounding healthy cells. Nanoparticles, when activated by X-rays, generate electrons that cause the destruction of cancer cells to which they have attached themselves. This is intended to be used in place radiation therapy with much less damage to healthy tissue. Aluminosilicate nanoparticles can quickly reduce bleeding time in trauma patients by absorbing water, causing blood in a wound to clot quickly. Imaging Techniques Quantum Dots (qdots) may be used in the future for locating tumors in patients and for performing diagnostic tests. The nanoparticle is coated with a peptide that binds to a cancer cell, once the nanoparticles are attached to the tumor the magnetic property of the iron oxide enhances the images from the Magnetic Resonance Imagining scan. Nanoparticles can attach to proteins or other molecules, allowing detection of disease indicators in a sample at a very early stage. Antimicrobial Techniques One of the earliest nanomedicine applications was the use of nanocrystalline silver which is an antimicrobial agent for the treatment of wounds. Cellular Repair Nanorobots could be programmed to repair specific diseased cells, functioning in a similar way to antibodies in our natural healing processes. Aquasomes these are recently developed delivery systems that are making a niche as the peptide/protein carriers. These are nanoparticle carrier systems with three layered self-assembled structures. The carbohydrate coating acts as dehydroprotectant and stabilizes the biochemically active molecules. Due to this property of maintaining the conformational integrity of bioactive molecules, aquasomes are being proposed as a carrier system for delivery of peptide based pharmaceuticals.
Troponins the muscle contraction is modulated by troponin and tropomyosin through Ca++ which is the physiological regulator of muscle contraction. The nerve impulse releases Ca++ from the sarcoplasmic stores and increases its cytosolic concentration about 10 times (1 mM to 10 mM). The action of calcium is brought about by 2 proteins, troponin complex and tropomyosin located in the thin filament. Its level in serum is increased within 4 hours of myocardial infarction, and remains high for about 7 days. The cardiac form of TnI is 31 amino acids longer than the skeletal muscle form of TnI. Two isoforms of cardiac TnT, called TnT1 and TnT2 are present in adult human cardiac tissue. Serum levels of TnT2 increases within 4 hours of myocardial infarction, and remains high for up to 14 days. The TnC has both high affinity (C-terminal) and low affinity (N-terminal) calcium binding sites. In the resting muscle, only the high affinity sites are occupied by Calcium, but when Ca++ is released from sarcoplasmic reticulum, low affinity sites are also occupied by Ca ++. The red striated muscle has an active aerobic metabolism compared to white muscle. In smooth muscle, the contraction is not regulated by the troponin-tropomyosin mechanism, but through calcium mediated phosphorylation of myosin light chains. The calcium ion Chapter 52; Tissue Proteins in Health and Disease 587 concentration in the cytoplasm is increased to 3000 fold. The TnC-4Ca++ complex attaches with TnI and TnT, which then interacts with tropomyosin. The receptor is so named because Ryanodine, a plant alkaloid could bind with the receptor. The sequence of events in the muscle contraction and relaxation are summarized in Box 52. Inherited Diseases due to Abnormality of Proteins In Malignant hyperthermia, halothane and succinylcholine (used in anesthetic practice) will cause high fever. Here calcium channels remain open, and so cytosolic calcium concentration remains high. The drug of choice in the treatment is dantrolene, which inhibits release of calcium from the sarcoplasmic reticulum, so that cytoplasmic calcium is kept at a reduced rate. Dystrophin is part of a large complex, consisting of dystroglycan, laminin and sarcoglycans. Dystrophin links the actin of cytoskeleton of the cell into the extracellular matrix. Mutations in the dystrophin gene cause Duchenne muscular dystrophy or a milder form called Becker muscular dystrophy. Mutations in the genes for the glycosyl transferases (which add the sugar groups to proteins) are also responsible for some types of muscle dystrophies. Mutations in the cardiac myosin heavy chain cause familial hypertrophic cardiomyopathy. Cellular and Sub-cellular Movements In multicellular organisms, maintenance of the size and shape of the cell is essential for cellular function. At subcellular levels, transfer of secretory granules from its sites of production to the exterior of the cells is important. It is made up of a network of microfilaments and microtubules, and is responsible for the shape of the cell, its mobility and chromosomal movements. A meshwork of actin filaments and spectrin is attached to the plasma membrane by ankyrin. Calmodulin It controls the contractile apparatus and cytoskeleton through calmodulin-binding proteins. Spectrin (erythrocyte) and spectrin-like proteins (brain and other tissues), are major members of the cytoskeleton. Tau protein (brain micro-tubules) and caldesmon (smooth muscle) are collectively referred to as flip-flop switch proteins. These proteins interact with calmodulin and cytoskeletal proteins (tubulin or actin). Calcium first binds calmodulin, that attaches to calmodulin-binding protein, which in turn connect with the target proteins in cytoskeleton.
Ergot. Indocin.
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The loss and ineffective utilization of glucose leads to breakdown of fat and protein. Often the presenting complaint of the patient may be chronic recurrent infections such as boils, abscesses, etc. When glucose level in extracellular fluid is increased, bacteria get good nutrition for multiplication. At the same time, macrophage function of the host is inefficient due to lack of efficient utilization of glucose. Acute Metabolic Complications Diabetic Keto Acidosis Ketosis is more common in type 1 diabetes mellitus. Normally the blood level of ketone bodies is less than 1 mg/dl and only traces are excreted in urine (not detectable by usual tests). But when the rate of synthesis exceeds the ability of extrahepatic tissues to utilize them, there will be accumulation of ketone bodies in blood. Add a few drops of freshly prepared sodium nitroprusside followed by 2 ml of liquor ammonia along the sides of the test tube. The increased rate of lipolysis provides excess acetyl CoA which is channeled to ketone bodies. Hyperemesis (vomiting) in early pregnancy may also lead to starvation-like condition and may lead to ketosis. Oxaloacetate is diverted for gluconeogenesis; then citric acid cycle cannot function optimally. Thus, on the one hand, acetyl CoA is generated in excess; on the other hand, its utilization is reduced. When they Chapter 24; Regulation of Blood Glucose, Insulin and Diabetes Mellitus 289 accumulate, metabolic acidosis results (see Chapter 29). Sodium loss: the ketone bodies are excreted in urine as their sodium salt, leading to loss of cations from the body. High potassium: Due to lowered uptake of potassium by cells in the absence of insulin. Coma: Hypokalemia, dehydration and acidosis contribute to the lethal effect of ketosis. Vascular Diseases: Atherosclerosis in medium sized vessels, plaque formation and consequent intravascular thrombosis may take place. In the case of small vessels, the process is called micro-angiopathy, where endothelial cells and mural (cement) cells are damaged. This leads to micro angiopathy, which may lead to diabetic retinopathy and nephropathy. Complications in Eyes: Early development of cataract of lens is due to the increased rate of sorbitol formation, caused by the hyperglycemia. Decreased glucose utilization and its diversion to sorbitol in Schwann cells may be caused for neuropathy. Kimmelstiel-Wilson syndrome is another complication of diabetes, resulting from nephrosclerosis, characterized by proteinuria and renal failure. Persistent hyperglycemia leading to glycation of basement membrane proteins may be the cause of nephropathy. Pregnancy: Diabetic mothers tend to have big babies, because insulin is an anabolic hormone. Chances of abortion, premature birth and intrauterine death of the fetus are also more, if the diabetes is not properly controlled. Under conditions of decreased oxygen availability, as in vigorous excercise, the rate of lactate production increases. The term lactic acidosis denotes a pathological state, when the lactate level in blood is more than 5 mMol/L. Collection of blood for lactate estimation has to be done avoiding tissue hypoxia, so that falsely elevated values are not obtained. Parenteral administration of insulin and glucose by intravenous route to control diabetes. Insulin induces glycogen deposition, and along with that, extracellular potassium is distributed intracellularly.
With more severe cases, irrigation of the eyes with cool water or saline may be necessary. Visual acuity may be slightly reduced immediately after eye contamination, but rapidly returns to normal (Rengstorff, 1969; Yih, 1995). If ocular discomfort is marked or persists, the use of local anesthetic eye drops. Those with marked 376 Chemical Warfare Agents: Chemistry, Pharmacology, Toxicology, and Therapeutics and persistent eye discomfort should have a detailed ophthalmoscopic examination, including fluorescein staining and slit-lamp biomicroscopy, to exclude corneal and anterior segment injury (Balho and Stark, 2000; Brown et al. Because capsaicin disrupts the corneal epithelium, those with impaired corneal integrity may be more susceptible (Smith and Stopford, 1999). Thus, it is generally advised that contact lenses be removed to ensure adequate eye irrigation. Hydrophilic soft contact lenses, due to their network structure, may absorb chemicals and thus be a source of sustained exposure (Loriot and Tourte, 1990). Some solvents in irritant solutions may lead to solubilization, fragmentation, or hardening of soft lenses (Holopainen et al. This may result in further irritation and possibly superficial corneal injury, which may be enhanced by digital rubbing of the eye that characteristically occurs with ocular irritation. Weigand (1969) recommended use of the following solution for rapid hydrolysis and relief of symptoms: aqueous 7% sodium bicarbonate, 3% sodium carbonate, and 1% benzalkonium chloride. Also, as noted above, Diphoterine can prevent or rapidly ameliorate the effects of irritant compounds on the skin. If high concentration exposure has been sustained, particularly in an enclosed space, then the individual should be kept under observation and, as dictated by the clinical condition, radiological, and pulmonary function studies undertaken (Park and Giammona, 1972; Sanford, 1976). Patients with gross overexposure to grenade-generated smokes may develop laryngotracheobronchitis, possibly requiring treatment with bronchodilators, postural drainage, corticosteroids, and prophylactic antibiotics (Thornburn, 1982). Those with established pulmonary disease, including asthma, may have an exacerbation of signs and symptoms. This could be compounded because of the emotional experience of being involved in a civil disturbance. Those with a history of cardiovascular disease may require hospital admission and further investigation. The possible use and abuse of illicit drugs, and the resultant complications, should be considered in the context of some civil disturbances (Hayman and Berkely, 1971). If a peaceful demonstration erupts into a violent event, this will enormously increase the requirements for health care services, and therefore there should be ongoing communications between those controlling the disturbance (law enforcement officers) and the emergency services and involved health care institutions. With the current international sociopolitical structure and its extreme legislation, domination by self-interest groups, untrustworthy elected representatives in government, and polarized viewpoints on issues such as capitalization, multiculturalization, globalization, immigration, and unfair labor problems, it is inevitable that there will be continuing and perhaps increasing expressions of dissatisfaction by demonstrations and counter demonstrations as the only pointed and public manner by which to convey opinion and objection to specific issues (Ballantyne, 2006). It is thus clear that there is a need for advance planning by health care facilities with respect to staffing, facility requirements, equipment, expertise, education, training, and communication needs for conditions of civil unrest. Some health care facilities have already undertaken meetings and training sessions against the possibility of terrorist activities. This activity could perhaps also be used as a starting point for discussions on the need to preplan for civil unrest. Although the natures of these two generic issues have some commonalities, there may be working differences with respect to legal, sociopolitical, acceptable, and workable approaches to terrorism versus civil unrest. A local permanent advisory and functional group should be formed to act as a focus for discussing and dealing with practical issues relevant to the wide health-related issues related to civil disturbances. Such a group should ideally be centralized at an appropriately located and equipped health care institution. This regional development team should include at least the following among its members: trauma surgeon, ophthalmologist, psychiatrist (ideally experienced in crowd psychology), general physician, anesthetist, clinical toxicologist (or representative from regional Poison Control Center), senior law enforcement officers, emergency and support services representatives, and access to communications experts. They should have responsibility for the planning, organization, preparation, and initiation of the following essential elements, policies, procedures, and strategies with respect to potential local civil unrest activities. Ensure the existence of an adequate reference (information) base on the agents and equipments that may be employed in a civil disturbance and on the management of casualties from such disturbances. Ensure all necessary medical equipments and treatment needs are readily available and stocked for emergency mobilization and use. Chemical Warfare Agents: Chemistry, Pharmacology, Toxicology, and Therapeutics Decide on suitable sites for reception, decontamination, and triage functions, and ensure their working appropriateness and readiness for an emergency. Establish a rapid access integrated communications system with law enforcement, transport, ``on call' medical=nursing=support staff, and emergency services.
Sulfur mustard-induced neutropenia: treatment with granulocyte colony-stimulating factor. Bittner M, Meltzer P, Chen Y, Jiang Y, Seftor E, Hendrix M, Radmacher M, Simon R, Yakhini Z, Ben-Dor A, Sampas N, Dougherty E, Wang E, Marincola F, Gooden C, Lueders J, Glatfelter A, Pollock P, Carpten J, Gillanders E, Leja D, Dietrich K, Beaudry C, Berens M, Alberts D, Sondak V, Hayward N, Trent J. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Isoelectric focusing in immobilized pH gradients: principle, methodology and some applications. Silencing of the novel p53 target gene Snk=Plk2 leads to mitotic catastrophe in Paclitaxel (Taxol)-exposed cells. Field Manual: Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries. Genomic analysis of rodent pulmonary tissue following bis-(2-chloroethyl) sulfide exposure. Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis. Comparative evaluation of mass spectrometry platforms used in large scale proteomics investigations. Potential role of p53 on metallothionein induction in human epithelial breast cancer cells. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Expression profiling using microarrays fabricated by an ink-jet oligonucleotide synthesizer. Modification-specific proteomics: characterization of post-translational modifications by mass spectrometry. Protein mapping by combined isoelectric focusing and electrophoresis of mouse tissues. Metabonomics techniques and applications to pharmaceutical research and development. Effects of benzodiazepine derivatives on soman-induced seizure activity and convulsions in the monkey. Hugh sensitivity mass spectrometric methods for obtaining intact molecular weights from gel separated proteins. Bifunctional alkylating agent-induced p53 and nonclassical nuclear factor kappa B responses and cell death are altered by caffeic acid phenethyl ester: a potential role for antioxidant=electrophilic response-element signaling. New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible. Gene expression analysis using oligonucleotide arrays produced by maskless photolithography. Medical Defense Against Mustard Gas: Toxic Mechanisms and Pharmacological Implications. An assessment of Motorola CodeLink microarray performance for gene expression profiling applications. Parallel human genome analysis: microarray-based expression monitoring of 1000 genes. The fate of antioxidant enzymes in bronchoalveolar lavage fluid over seven days in mice with acute lung injury. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. Maskless fabrication of light-directed oligonucleotide microarrays using a digital micromirror array. Increased transcription of the regulatory subunit of g-glutamylcysteine synthetase in rat lung epithelial L2 cells exposed to oxidative stress or glutathione depletion. Tokuoka S, Hayashi Y, Inai K, Egawa H, Aoki Y, Akamizu H, Eto R, Nishida T, Ohe K, Kobuke T, Nambu S, Takemoto T, Kou E, Nishina H, Fujihara M, Yonehara S, Tsuya T, Suehiro S, Horiuchi K. Early cancer and related lesions in the bronchial epithelium in former workers of mustard gas factory. The most likely route of exposure to these agents is through inhalation or by absorption through the skin.
In an actively contracting muscle, pyruvate is reduced to lactic acid which may tend to accumulate in the muscle. The muscle cramps, often associated with strenuous muscular exercise, are thought to be due to lactate accumulation. During exercise, lactate production is high, which is utilized by liver to produce glucose. According to his studies, cancer cells utilize energy from glycolysis and they require less oxygen than their normal counterparts; this is called Warburg hypothesis (1923). Rapidly growing tumor cells produce increased quantities of lactic acid, causing high acidity in the local environment. When this lactate is used for gluconeogenesis by the liver; energy consumption increases. See summary in the inset Chapter 9; Major Metabolic Pathways of Glucose 101 essential for utilization of pyruvate. The two carbon unit remains attached to the enzyme, as hydroxyethyl thiamine pyrophosphate. Dihydro Lipoyl Dehydrogenase (Enzyme 3): the last step is the oxidation of lipoamide. The lipoic acid, otherwise called thioctic acid has two sulphur atoms and 8 carbon atoms. Lactic acidosis may be seen in hypoxia, shock, pulmonary failure, alcohol abuse (Chapter 10), and diabetes mellitus (Chapter 24). These conditions are rare, out of which pyruvate kinase deficiency and hexokinase deficiency are comparatively common. Key enzymes Irreversible steps in glycolysis Pyruvate kinase (Step 9) Corresponding key gluconeogenic enzymes Pyruvate carboxylase; Phosphoenol pyruvatecarboxy kinase Phosphofructokinase (Step 3) Fructose-1,6bisphosphatase. First step in gluconeogenesis acetyl CoA from which fatty acids can be synthesized. But the backward reaction is not possible, and so there is no net synthesis of glucose from fat. Thus, pyruvate dehydrogenase step is the committed step towards oxidation of glucose. Pyruvate dehydrogenase is regulated by end product inhibition as well as by covalent modification. Pyruvate as a Junction Point Pyruvate occupies an important junction between various metabolic pathways. Definition It is the process by which glucose molecules are produced from non-carbohydrate precursors. These include lactate, glucogenic amino acids, glycerol part of fat and propionyl CoA derived from odd chain fatty acids. Site Gluconeogenesis occurs mainly in the liver, and to a lesser extent in the renal cortex. Phospho enol pyruvate carboxy kinase Chapter 9; Major Metabolic Pathways of Glucose 103 Gluconeogenesis involves several enzymes of glycolysis, but it is not a reversal of glycolysis. The irreversible steps in glycolysis are circumvented by four enzymes which are designated as the key enzymes of gluconeogenesis (Table 9. Then, carboxylation of pyruvate to oxaloacetate is catalysed by a mitochondrial enzyme, pyruvate carboxylase. Malate Aspartate Shuttle the carboxylation of pyruvate (previous reaction) takes place in mitochondria. This oxaloacetate has to be transported from mitochondria to cytosol, because further reactions of gluconeogenesis are taking place in cytosol. Oxaloacetate is first converted to malate, which traverses the membrane and reaches cytoplasm. Oxaloacetate may also be transported as aspartate formed by transamination of oxaloacetate. The net effect of these two reactions is the conversion of pyruvate to phosphoenol pyruvate. This circumvents the irreversible step in glycolysis catalyzed by pyruvate kinase (step 9 of glycolysis). Partial Reversal of Glycolysis the phosphoenol pyruvate undergoes further reactions catalyzed by the glycolytic enzymes to form fructose-1,6-bisphosphate (see glycolysis steps 8,7,6,5 and 4). Fructose-1,6-bisphosphatase Fructose 1,6-bis-phosphate is then acted upon by fructose 1,6-bisphosphatase to form fructose.
The characteristic offensive odor of urine is the first sign of the abnormal excretion of this metabolite. The histidine residues present in proteins provide additional charge and polarity to the molecule. Histidine residues of albumin and hemoglobin play a significant role in buffering action. In addition, the iron of the heme moiety of hemoglobin is attached to globin through two specific histidine residues designated as the proximal and distal histidine residues. Histidine is first non-oxidatively deaminated by histidase to form urocanic acid (step 1. Blood vessels Effect Pulmonary venous dilation; superficial temporal artery dilation (migraine). Exocrine glands Stimulates gastric acid secretion fluids and increased excretion of imidazole pyruvic acid in urine. Step 1: Phenylalanine to tyrosine the reaction involves addition of a hydroxyl group to the aromatic ring, by phenylalanine hydroxylase (step 1. The need for phenylalanine becomes minimal, if adequate tyrosine is supplied in the food. Catabolism of Tyrosine (and Phenylalanine) Step 2: Transamination Degradative pathway of phenylalanine and tyrosine are the same, since phenylalanine is converted to tyrosine and then metabolized. Tyrosine is transaminated to give para hydroxy phenyl pyruvic acid by tyrosine transaminase (step 2. It is a 204 Textbook of Biochemistry; Section B: General Metabolism phenyl acetic acid or homogentisic acid. Step 4: Cleavage of aromatic ring Homogentisic acid oxidase opens the ring (step 4. Step 5: Isomerization It then undergoes cis to trans isomerisation to form fumaryl acetoacetate by an isomerase (step 5. Step 6: Hydrolysis Fumaryl acetoacetate is then hydrolyzed to fumarate and acetoacetate by a hydrolase (step 6. This results in the production of a glucogenic product (fumarate) and a ketone body (acetoacetate). Synthesis of Melanin Melanin pigment gives the black color to the skin and hair (Greek word Melan means black). Formation of indolequinone: It is converted to indolequinone through a series of reactions. Catabolism of phenylalanine and tyrosine di-oxygenase, which means that both oxygen atoms are incorporated into the product. Interestingly, the reaction involves shifting of the side chain from para position to meta position. Thus even in Tyrosinasedeficient person (albinism), epinephrine synthesis is normal. Clinical Applications of Melanin Copper deficiency: Since tyrosinase is a copper containing enzyme, there may be disturbances in pigmentation during copper deficiency. If copper deficiency is intermittent, alternate black and white regions may be seen in the hair (flag-type of hair). Malignant melanoma: Melanoblasts, especially in junctional naevi, may multiply to give rise to malignant melanoma. Leukoderma: When tyrosinase or melanin forming cells or both are absent from epidermis, leukoderma (white patches) results. Graying of hair is also due to the disappearance of melanocytes from the hair root. Regulation of Color of Skin Melanocytes in the deeper layers of epidermis synthesise melanin in granular form in melanosomes. The color of the skin depends upon the distribution of melanoblasts, the concentration of melanin and its state of oxidation. Melanin is found in the pigment epithelium in the eye, which gives the characteristic color of the eye. It is different from tyrosinase involved in melanin synthesis which catalyzes a similar reaction. It is also an important neurotransmitter especially in extrapyramidal tract, substantia nigra and striatal tract. Melanin synthesis pathway; 1 and 2 steps have the same enzyme, tyrosinase 206 Textbook of Biochemistry; Section B: General Metabolism Box 17.
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