By O. Lee. Manhattanville College. 2018.
Each polypeptide chain possesses both a conserved constant Its size and large number of antigen-binding sites provide region and a variable region purchase 100mcg entocort with mastercard, where considerable amino acid the molecule with an excellent capacity for agglutination buy entocort 100 mcg without prescription, sequence heterogeneity is found even within a single anti- the ability to clump particulate antigens purchase entocort 100 mcg line, such as bacteria body class order 100mcg entocort amex. Clumped antigens are efficiently and widely diverse antigen-binding ability of antibody molecules, quickly removed by fixed phagocytic cells of the mono- for it is the variable region that actually combines with the cyte-macrophage system. These The amino terminal portions of the variable regions, the cells are heavily granulated. The granules contain histamine, antigen-binding sites, are known as the Fab regions. Each leukotrienes, and other biologically active agents that in- antibody unit possesses two identical antigen-binding sites, crease vascular permeability, dilate blood vessels (and, one at each end of the “Y. The granules are released when IgE, consisting of Fc and Fab regions of antibody molecules can bound to mast cells at the Fc region, binds its specific anti- TABLE 11. The ensuing allergic responses range from hay fever, openings in blood vessels. The aggregates form a physical hives, and bronchial asthma (induced by local or inhaled al- barrier that begins to limit blood loss soon after the open- lergens) to systemic anaphylaxis, a potentially fatal response ing occurs. Second, phospholipids on the platelet plasma triggered when antigen is given systemically. Platelet activation results in the sequential responses of ad- HEMOSTASIS herence, aggregation, and secretion. Adherence is initiated when one or more substances, released from cells or activated Circulating in a high-pressure, closed system that communi- in plasma at the site of a hemorrhage, bind to receptors in the cates with all tissues and cells in the body, blood exchanges platelet plasma membrane. Receptor binding results, via sec- oxygen, nutrients, and wastes and provides necessary compo- ond messengers, in adherence (to other platelets and the in- nents for host defense. This communication takes place largely ner, endothelial surface of blood vessels) and secretion. Endothelial cells also rapidly de- fragile capillaries may result from minor tissue injury associ- ploy cellular adherence antigens known as integrins on the ated with normal physical activity or from massive tissue outer surface of their plasma membranes during wound trauma as a result of serious injury or infection, and may healing. These adherence antigens are deployed to the cell quickly lead to death. Any opening in the vascular network membrane by cellular processes set in motion by factors may lead to massive bruising or blood loss if left unrepaired. In turn, activated endothelial cells injury, components of the hemostatic system are activated. They may be activated on exposure to for- forming a bridge between cell surface receptors and colla- eign surfaces during bleeding, or by torn tissue at the site of gen in the subendothelial matrix. The protein thrombin, injury, or by products released from the interior of dam- which is generated by the plasma coagulation cascade, is a aged cells. Hemostasis can be viewed as four separate but potent activator of platelet adherence and secretion. Rup- interrelated events: tured cells at the site of tissue injury release adenosine • Compression and vasoconstriction, which act immedi- diphosphate (ADP), which causes platelets to aggregate at ately to stop the flow of blood the damaged site. These aggregates effectively stop the • Formation of a platelet plug flow of blood from the ruptured vessels. The fibrin network traps red cells, leuko- exerted by the tissue around the injured area, and vasocon- cytes, platelets, and serum at sites of vascular damage, striction. The degree of compression varies in different tis- thereby forming a blood clot. The stable, fibrin-based sues; for example, bleeding below the eye is not readily de- blood clot eventually replaces the unstable platelet ag- terred because the skin in this area is easily distensible. Fibrin is Back-pressure increases as blood which leaks out of the dis- an insoluble polymer of proteolytic products of the rupted capillaries accumulates. Fibrin molecules are cleaved uterus after childbirth, contraction of underlying muscles from fibrinogen by thrombin, which is generated in compresses blood vessels supplying the tissue and mini- plasma during clotting. Damaged cells at the site of tissue injury mation, thrombin cleaves four small peptides (fib- release potent substances that directly cause blood vessels rinopeptides) from each molecule of fibrinogen. The fib- to constrict, including serotonin, thromboxane A2, epi- rinogen molecule devoid of these fibrinopeptides is nephrine, and fibrinopeptide B. The fibrin monomers sponta- neously assemble into ordered fibrous arrays of fibrin, resulting in an insoluble matrix of fibrous strands. At this Platelets Form a Hemostatic Plug stage, the clot is held together by noncovalent forces.
Total body water averages about 60% of body gram is for an average young adult man weigh- weight in young adult men and about 50% of body weight ing 70 kg proven entocort 100 mcg. In an average young adult woman discount 100 mcg entocort overnight delivery, total body water is in young adult women (Table 24 buy discount entocort 100 mcg. The percentage of 50% of body weight generic entocort 100 mcg, intracellular water is 30% of body weight, body weight water occupies depends on the amount of adi- and extracellular water is 20% of body weight. A lean person has a high per- centage and an obese individual a low percentage of body weight that is water because adipose tissue contains a low ter is in the ICF, and one third is in the ECF (Fig. Newborns have a low percent- (osmolalities) are normally equal, because of the high water age of body weight as water because of a relatively large permeability of most cell membranes, so that an osmotic dif- ECF volume and little fat (see Table 24. As compartments, which are separated from each other by the people age, they tend to lose muscle and add adipose tissue; endothelium of blood vessels. Body Water Is Distributed in The blood plasma water comprises about one fourth of the Several Fluid Compartments ECF or about 3. The interstitial fluid and lymph are considered together be- Total body water can be divided into two compartments or cause they cannot be easily separated. The water of the in- spaces: intracellular fluid (ICF) and extracellular fluid terstitial fluid and lymph comprises three fourths of the (ECF). The interstitial fluid directly bathes most body cells, of cells in our body. The ECF is comprised of fluid outside and the lymph is the fluid within lymphatic vessels. In a young adult man, two thirds of the body wa- blood plasma, interstitial fluid, and lymph are nearly iden- tical in composition, except for the higher protein concen- tration in the plasma. Age Men Both Sexes Women Transcellular fluids include cerebrospinal fluid, aqueous hu- mor of the eye, secretions of the digestive tract and associated 0–1 month 76 organs (saliva, bile, pancreatic juice), renal tubular fluid and 1–12 months 65 bladder urine, synovial fluid, and sweat. In these cases, the 1–10 years 62 fluid is separated from the blood plasma by an epithelial cell 10–16 years 59 57 17–39 years 61 50 layer in addition to a capillary endothelium. The epithelial 40–59 years 55 52 layer modifies the electrolyte composition of the fluid, so that 60 years and older 52 46 transcellular fluids are not plasma ultrafiltrates (as is intersti- tial fluid and lymph); they have a distinct ionic composition. There is a constant turnover of transcellular fluids; they are continuously formed and absorbed or removed. Impaired for- CHAPTER 24 The Regulation of Fluid and Electrolyte Balance 405 mation, abnormal loss from the body, or blockage of fluid re- Cellular water cannot be determined directly with any moval can have serious consequences. It can, however, be calculated from the differ- ence between measurements of total body water and extra- cellular water. The Indicator Dilution Method Measures Plasma water is determined by using Evans blue dye, Fluid Compartment Size which avidly binds serum albumin or radioiodinated serum The indicator dilution method can be used to determine albumin (RISA), and by collecting and analyzing a blood the size of body fluid compartments (see Chapter 14). In effect, the plasma volume is measured known amount of a substance (the indicator), which should from the distribution volume of serum albumin. The as- be confined to the compartment of interest, is adminis- sumption is that serum albumin is completely confined to tered. After allowing sufficient time for uniform distribu- the vascular compartment, but this is not entirely true. In- tion of the indicator throughout the compartment, a plasma deed, serum albumin is slowly (3 to 4% per hour) lost from sample is collected. The concentration of the indicator in the blood by diffusive and convective transport through the plasma at equilibrium is measured, and the distribution capillary walls. To correct for this loss, repeated blood sam- volume is calculated from this formula ples can be collected at timed intervals, and the concentra- tion of albumin at time zero (the time at which no loss Volume Amount of indicator/ would have occurred) can be determined by extrapolation. Concentration of indicator (1) Alternatively, the plasma concentration of indicator 10 If there was loss of indicator from the fluid compart- minutes after injection can be used; this value is usually ment, the amount lost is subtracted from the amount ad- close to the extrapolated value. For example, suppose we want to measure total tween ECF and plasma volumes. We inject 30 mL of deu- terium oxide (D2O) as an isotonic saline solution into an arm vein. After a 2-hr equilibration period, a blood sample Body Fluids Differ in Electrolyte Composition is withdrawn, and the plasma is separated and analyzed for Body fluids contain many uncharged molecules (e. Suppose during the equilibration period, urinary, (ionized substances) contribute most to the total solute respiratory, and cutaneous losses of D2O are 0. Osmolality is stituting these values into the indicator dilution equation, of prime importance in determining the distribution of wa- we get ter between intracellular and ECF compartments.
However buy cheap entocort 100mcg online, it has been clear for some time that the majority of 5-HT is metabolised in the cytoplasm by MAO before it is released from 5-HT nerve terminals cheap entocort 100 mcg on-line. Consequently cheap entocort 100 mcg without a prescription, the reliability of the 5-HIAA:5-HT ratio as an index of transmitter release is rather dubious discount entocort 100mcg overnight delivery, although it could be used as an acceptable measure of MAO activity. In any case, the development of in vivo microdialysis means that changes in the concentration of extracellular 5-HT can now be monitored directly which, under drug- free conditions, provides a far more reliable indication of any changes in the rate of release of 5-HT. RECEPTORS Over the last 20 years, the development of receptor-selective ligands, coupled with advances in molecular biology, has resulted in the number of 5-HT receptors increasing from a modest two (identified by Gaddum and Picarelli in 1957) to the 14 recognised to date (Table 9. These form seven distinct families which, with the exception of the 5-HT3 receptor, are all G protein-coupled with seven transmembrane-spanning domains. Apart from 5-ht1E, 5-ht1F, 5-ht5 and 5-ht6 subtypes, for which genes have been identified, even though the native receptor protein remains elusive (hence their lower- case nomenclature), all are expressed in the CNS. All the native 5-HT receptors characterised so far are found postsynaptically, with respect to 5-HT terminals, and some are located presynaptically where they regulate the firing rate of 5-HT neurons and/or release of transmitter from their terminals. There is also evidence that some regulate the release of other transmitters in the terminal field and so could act as 5-HT heteroceptors. For instance, 5-HT1B receptor agonists inhibit K-evoked release from synaptosomes preloaded with either [3H]dopamine, [3H]nor- adrenaline, [3H]prolactin or [3H]glutamate. Apart from regulating neuronal firing and transmitter release, activation of certain 5-HT receptors with selective ligands causes specific behavioural or physiological changes (Table 9. There is also some evidence that 5-HT1A receptors, at least, might influence gene expression and neurogenesis and so they could have far-reaching effects on brain function. Essential features of the different receptor subtypes are highlighted here and, except where indicated, references to specific points can be found in the definitive review of this subject by Barnes and Sharp (1999). They are negatively coupled, via Gi/o/z proteins, to adenylyl cyclase such that their activation reduces production of cAMP. In turn, this leads to an increase in K conductance and hyperpolarisation of 198 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION 5-HYDROXYTRYPTAMINE 199 Table 9. The importance of this action, as a possible explanation for the delay in the therapeutic effects of those antidepressants that increase the concentration of extracellular 5-HT, is discussed in Chapter 20. There is some evidence that pre- and postsynaptic receptors do not respond in exactly the same way to drug challenges and it has even been suggested that they are not identical. For instance, the drug BMY 7378 behaves as an agonist at presynaptic 5-HT1A receptors but has a low intrinsic activity at the postsynaptic site where it acts as an antagonist. However, there is as yet insufficient evidence to claim that there are subtypes of this receptor and, in any case, differences in the receptor reserve at pre- and postsynaptic sites could well explain some of the apparently conflicting findings. Given that the firing rate, and hence the release of 5-HT, is greater in awake animals than in those that are asleep (see Chapter 22), it is not surprising that the effects of 5-HT1A antagonists on neuronal firing and 5-HT release are more evident in behaving, conscious subjects than in those that are anaesthetised. Indeed, this should be borne in mind when perusing the literature on this subject. However, in terms of their gross physiological effects in awake animals, consistent findings are that 5-HT1A receptor agonists induce hypothermia and increase food intake. They also reduce anxiety and, so far, this is the only action to be exploited clinically. Even so, only one such compound, buspirone, is licensed for use in the clinic and it is still not known whether its anti- anxiety effect is mediated by activation of pre- or postsynaptic 5-HT1A receptors (see Chapter 19). Another well-known agonist at these receptors is lysergic acid diethylamide (LSD) and, for several years it was thought that this explained its hallucinogenic effects. However, this drug is a non-selective ligand that also binds to 5-HT2A/2C receptors. Although activation of 5-HT1A receptors by LSD seems to have some effects on motor activity, this site can be ruled out as being responsible for its hallucinogenic effects. This is not least because neither buspirone, which is also an agonist of these receptors, nor reserpine, which diminishes 5-HT transmission, have any hallucinogenic actions in humans. In fact, experimental preclinical models strongly indicate that 5-HT1A agonists could be beneficial in treatment of both the positive and negative symptoms of schizophrenia. For instance, they increase the concentration of extracellular dopamine in the frontal cortex but diminish apomorphine-induced stereotypy in rats.
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