By Z. Redge. State University of New York at Binghamton.

Caspase-9 generic aristocort 15 mg without prescription allergy symptoms early pregnancy, in turn buy cheap aristocort 4 mg online allergy girl, member of the Bcl-2 family of proteins that forms an ion channel in the outer mito- activates effector caspases-3, -6, and -7 through proteolytic cleavage, which then chondrial membrane) allows the entry of ions into the intermembrane space, causing degrade cytoplasmic proteins. AIF, which swelling of this space and rupture of the outer mitochondrial membrane. Another the- has a nuclear targeting sequence, is trans- ory is that Bax and VDAC (which is known to bind Bax and other Bcl-2 family mem- ported into the nucleus, where it initiates bers) combine to form an extremely large pore, much larger than formed by either chromatin condensation and degradation. Finally, it is possible that the MPTP or ANT participate in rupture of the outer Caspase-2 and caspase-9 also activate CAD, membrane, but close in a way that still provides the energy for apoptosis. A perspective of the binding change mechanism for ATP synthesis. Control of respiration and ATP synthesis in mammalian mitochondria and cells. CHAPTER 21 / OXIDATIVE PHOSPHORYLATION AND MITOCHONDRIAL FUNCTION 397 Lactic acidosis and mitochondrial myopathy in a young woman. The mitochondrial permeability transition: its molecular mechanism and role in reperfu- sion injury. Towards a molecular understanding of adaptive thermogenesis. Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. The Metabolic and Molecular Bases of Inherited Disease, vol II. Carefully isolated liver mitochondria are incubated in the presence of a limiting amount of malate. Three minutes after adding the substrate, cyanide is added, and the reaction is allowed to proceed for another 7 min- utes. At this point, which of the following components of the electron transfer chain will be in an oxidized state? Carefully isolated liver mitochondria are placed in a weakly buffered solution. Malate is added as an energy source, and an increase in oxygen consumption confirms that the electron transfer chain is functioning properly within these organelles. Valinomycin and potassium are then added to the mitochondrial suspension. Valinomycin is a drug that allows potassium ions to freely cross the inner mitochondrial membrane. What is the effect of valinomycin on the proton motive force that had been generated by the oxidation of malate? Dinitrophenol acts as an uncoupler of oxidative phosphorylation by which of the following mechanisms? A series of blood tests are ordered, and the results suggest that her red blood cell count is low because of iron deficiency anemia. Such a deficiency would lead to fatigue because of which of the following? Without iron, the proton gradient cannot be maintained to produce adequate ATP. Which of the following would be expected for a patient with an OXPHOS disease? Every cell type in the human is able to generate adenosine triphosphate (ATP) from glycolysis, the pathway in which glucose is oxidized and cleaved to form pyruvate. The importance of glycolysis in our fuel economy is related to the availability of glucose in the blood, as well as the ability of glycolysis to generate ATP in both the presence and absence of O2. Glucose is the major sugar in our diet and the sugar that circulates in the blood to ensure that all cells have a continuous fuel supply. The brain uses glucose almost exclusively as a fuel.

Ascending aorta BLOOD VESSELS AND BLOOD CIRCULATION 327 (1) Left and right coronary arteries C order aristocort 15 mg line allergy treatment and medicare. Wave of pressure that travels along arteries as ventricles (1) Brachiocephalic artery—branches to arm and contract head on right 2 discount 15 mg aristocort amex allergy symptoms black mold. Rate affected by size, age, gender, activity, and other (2) Left common carotid artery—supplies left side factors of neck and the head D. Blood pressure (3) Left subclavian artery—supplies left arm 1. Factors (1) Thoracic aorta—branches to chest wall, esopha- a. Cardiac output—stroke volume x heart rate gus, bronchi b. Resistance to blood flow—vessel diameter, vessel (2) Abdominal aorta—supplies abdominal viscera elasticity, blood viscosity, blood volume B. Branch to pelvis and legs (1) Occurs during heart contraction C. Arteries that branch to the arm and head—common (2) Averages 120 mmHg carotid, subclavian, brachial b. Anastomoses—communications between vessels (1) Occurs during heart relaxation (2) Averages 80 mmHg III. Deep—usually parallel to arteries with same names as cor- b. Hypertension—high blood pressure responding arteries (1) Essential hypertension—has no apparent med- 1. Superior vena cava—drains upper part of body (2) May involve renin, enzyme released from kidneys (i) Jugular veins drain head and neck (3) May lead to aneurysm, stroke, stress on heart (ii) Brachiocephalic veins empty into superior vena and kidneys, atherosclerosis cava 5. Treatment of hypertension—diuretics, reduction of b. Inferior vena cava—drains lower part of body renin, relaxation of blood vessels 2. Hepatic portal system—carries blood from abdominal V. Arterial degeneration and other blood organs to liver, where it is processed before returning to vessel disorders 15 heart A. Arteriosclerosis—hardening of arteries with scar tissue, cal- cium salts, or fatty deposits IV. Atherosclerosis—deposits of fatty material (plaque) in A. Possible results—pain, breathing problems, angina 2. Medium—tissue fluid pectoris, thrombosis (blood clot), tissue necrosis, gan- 3. Aneurysm—weakness and bulging of a vessel; may burst B. Vasodilation—increase in diameter of blood vessel b. First aid measures: direct pressure, elevation of limb, b. Vasoconstriction—decrease in diameter of blood vessel pressure on artery c. Vasomotor center—in medulla; controls contraction 2. Shock—inadequate blood flow to tissues and relaxation of smooth muscle in vessel wall 3. Precapillary sphincter—regulates blood flow into capillary C.

IONIZING RADIATION polyunsaturated lipids of the endoplasmic Cosmic rays that continuously bombard the earth generic aristocort 4mg otc allergy medicine not working for child, radioactive chemicals aristocort 4mg overnight delivery allergy testing queens ny, and x- reticulum. These reactions spread into the rays are forms of ionizing radiation. Ionizing radiation has a high enough energy plasma membrane and to proteins, eventually level that it can split water into the hydroxyl and hydrogen radicals, thus leading resulting in cell swelling, accumulation of to radiation damage to the skin, mutations, cancer, and cell death (Fig. Monoamine oxidase is a copper- Production of ROS by xanthine oxidase in endothelial cells may be enhanced containing enzyme that inactivates dopamine during ischemia–reperfusion in Cora Nari’s heart. In undamaged tissues, xan- in neurons, producing H2O2. The drug was thine oxidase exists as a dehydrogenase that uses NAD rather than O as an originally administered to inhibit dopamine 2 electron acceptor in the pathway for degradation of purines (hypoxanthine 4 xanthine degradation. However, current theory sug- 4 uric acid (see Chapter 41). When O2 levels decrease, phosphorylation of ADP to ATP gests that the effectiveness of the drug is also decreases, and degradation of ADP and adenine through xanthine oxidase increases. In related to decrease of free radical formation the process, xanthine dehydrogenase is converted to an oxidase. As long as O2 levels are within the cells of the basal ganglia. The below the high Km of the enzyme for O2, little damage is done. However, during reperfu- dopaminergic neurons involved are particu- sion when O levels return to normal, xanthine oxidase generates H O and O at the larly susceptible to the cytotoxic effects of 2 2 2 2 site of injury. OXYGEN RADICAL REACTIONS WITH CELLULAR COMPONENTS Ionizing hv radiation Oxygen radicals produce cellular dysfunction by reacting with lipids, proteins, car- bohydrates, and DNA to extract electrons (summarized in Fig. Evidence of •OH + H• free radical damage has been described in over 100 disease states. In some of these Hydroxyl Hydrogen diseases, free radical damage is the primary cause of the disease; in others, it radical atom enhances complications of the disease. Membrane Attack: Formation of Lipid and Lipid radiation. Peroxy Radicals Chain reactions that form lipid free radicals and lipid peroxides in membranes make a major contribution to ROS-induced injury (Fig. An initiator (such as a hydroxyl radical produced locally in the Fenton reaction) begins the chain reaction. It extracts a hydrogen atom, preferably from the double bond of a polyunsaturated fatty acid in a membrane lipid. The chain reaction is propagated when O2 adds to form lipid peroxyl radicals and lipid peroxides. Eventually lipid degradation occurs, forming such products as malondialdehyde (from fatty acids with three or more double bonds), and ethane and pentane (from the -terminal carbons of 3 and 6 fatty acids, respectively). Malondialdehyde appears in the blood and urine and is used as an indicator of free radical damage. Peroxidation of lipid molecules invariably changes or damages lipid molecular structure. In addition to the self-destructive nature of membrane lipid peroxidation, the aldehydes that are formed can cross-link proteins. When the damaged lipids are The appearance of lipofuscin gran- the constituents of biologic membranes, the cohesive lipid bilayer arrangement and ules in many tissues increases dur- stable structural organization is disrupted (see Fig. The pigment lipofuscin drial membrane integrity may result in further free radical production. These cross-linked products are prob- Protein enzymes ably derived from peroxidatively damaged damage cell organelles that were autophagocytized Mitochondrial by lysosomes but could not be digested. In Les Dopaman and other patients with Parkinson’s disease, lipo- OH• H O 2 fuscin appears as Lewy bodies in degenerat- DNA + Cell swelling NucleusNucleus Na ing neurons. In patients with cataracts, pro- teins in the lens of the eye exhibit free radi- Massive influx cal damage and contain methionine sulfox- of Ca2+ ide residues and tryptophan degradation products. Superoxide and the hydroxyl radical initiate lipid peroxidation in the cellular, mitochondrial, nuclear, and endoplasmic reticulum membranes.

Determining the concentration of the hormone in the sample involves incubat- be certain that the patient has not eaten for ing the plasma or urine sample with the antibody and then quantifying the level of anti- 6–8 hours 4mg aristocort fast delivery allergy medicine holistic, has not done vigorous exercise for at least 4 hours order 4 mg aristocort overnight delivery allergy forecast irvine ca, remains fully awake dur- gen–antibody complex formed during the incubation by one of several techniques. A standard curve is prepared, using a set amount of the antibody and vari- GH secretion for at least 1 week. In addition to Under these carefully controlled circum- a known concentration of the unlabeled hormone, each tube contains the same stances, if both the basal and postsuppres- small, carefully measured amount of radiolabeled hormone. The labeled hormone sion serum levels of the suspect hormone and the unlabeled hormone compete for binding to the antibody. The higher the are elevated, one can conclude that amount of unlabeled hormone in the sample, the less radiolabeled hormone is autonomous hypersecretion is probably bound. At this point, localization proce- patient’s blood or urine, containing the unlabeled hormone to be measured, is incu- dures (such as an MRI of the pituitary gland in an acromegalic suspect) are performed to bated with the immobilized antibody in the presence of the same small, carefully further confirm the diagnosis. The amount of radiolabeled hormone bound to the antibody is determined, and the standard curve is used to quantitate the amount of unlabeled hormone in the patient sample. CHAPTER 43 / ACTIONS OF HORMONES THAT REGULATE FUEL METABOLISM 803 The same principle is used in immunoradiometric assays (IRMAs), but with this technique the antibody, rather than the antigen to be measured, is radiola- beled. The first antibody, attached to a 30 solid support matrix such as a plastic culture dish, binds the hormone to be assayed. The sandwich technique can be improved even further if the second antibody is Fig. Standard curve for a radioim- attached to an enzyme, such as alkaline phosphatase. A constant amount of radioactive an added colorless substrate into a colored product, or a nonfluorescent substrate T4 is added to a series of tubes, each of which into a highly fluorescent product. These changes can be quantitated if the degree of contains a different amount of nonradioactive change in color or fluorescence is proportional to the amount of hormone present in T4. The amount of radioactive hormone that 9 binds to an antibody specific for the hormone the patient sample. Less than a nanogram (10 g) of a protein can be measured by is measured and plotted against the nonra- such an enzyme-linked immunosorbent assay (ELISA). When more nonradioactive T4 is present in the tube, less radioactive T4 binds to the antibody. Fat metabolism and diabetes: 2003 American Diabetes Association Postgraduate Course. Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and I kappa B-. Effect of epinephrine on muscle glycogenolysis and insulin- stimulated muscle glycogen synthesis in humans. In: Larsen PF, Kronenberg HM, Melmed S, Polon- sky KS, eds. Effect of 6-week course of glucagon-like peptide one on glycemic conrol, insulin sensitivity, and beta cell function in type 2 diabetes. As a third-year medical student, you examine your first patient. You find that he is 52 years old, has a round face, acne, and a large hump of fat on the back of his neck. His fasting blood glucose level is 170 mg/dL (reference range = 80–100 mg/dL). Plasma cortisol levels are 62 g/mL (reference range = 3–31 g/mL). Plasma ACTH levels are 0 pg/mL (reference range = 0–100 pg/mL). Based on the information given above, if the patient’s problem is attributable to a single cause, the most likely diagnosis is which of the following?

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