By I. Sancho. Saybrook Graduate School and Research Center. 2018.

Genetic correlation fascia dentata: identification of target structures on granule cells of inhibitory gating of hippocampal auditory evoked response by combining choline acetyltransferase immunocytochemistry and alpha-bungarotoxin-binding nicotinic cholinergic receptors and Golgi impregnation discount 50 mg nitrofurantoin overnight delivery. Mechanisms of action of acetyl- inhibitory interneurons purchase nitrofurantoin 50 mg with amex. AGHAJANIAN AND ELAINE SANDERS-BUSH Serotonin, or 5-hydroxytryptamine (5-HT), has been impli- cellular aspects of individual 5-HT receptor subtypes and cated in almost every conceivable physiologic or behavioral their transduction mechanism, in addition to interactions function—affect, aggression, appetite, cognition, emesis, between different receptor subtypes within a single neuron endocrine function, gastrointestinal function, motor func- or region. The implications of this work in understanding tion, neurotrophism, perception, sensory function, sex, the global functions of the 5-HT system are discussed. Moreover, most drugs that are currently used for the treatment of psychiatric disorders (e. How is it possible for 5-HT to be involved in so many different processes? One answer lies in In the first half of the last decade, the cloning of the major the anatomy of the serotoninergic system, in which 5-HT known families of 5-HT receptors was accomplished. More cell bodies clustered in the brainstem raphe nuclei are posi- recently, attention has turned to issues of transcriptional tioned through their vast projections to influence all regions and post-transcriptional regulation. Another answer lies in the molecular diver- sity and differential cellular distribution of the many 5- RNA Processing HT receptor subtypes that are expressed in brain and other tissues. The 5′-flanking region of several 5-HT-receptor genes has During the past decade, molecular cloning techniques been cloned, and consensus sequences for transcription fac- have confirmed that putative 5-HT receptor subtypes, pre- tors have been identified in the promoter region (2–4). The dicted from radioligand binding and functional studies identification of these potential regulatory sites sets the stage (e. This knowledge has revolution- tion of gene transcription in vivo (5). A prominent form of ized contemporary research on the serotoninergic system. Alter- ization and immunocytochemical maps, studies of previ- native splicing is common and occurs for a number of 5- ously recognized 5-HT receptors could be directed more HT receptors, including the 5-HT2C, 5-HT4, and 5-HT7 precisely toward neurons and model cell lines that express receptors. The two splice variants of the 5-HT2C receptor these specific 5-HT receptor subtypes. Moreover, by the described in the literature encode severely truncated pro- use of cloning techniques, investigations could be initiated teins with no obvious function (6–8). In contrast, the splice to determine the functional role of previously unrecognized variants of the 5-HT4 receptor (5-HT4(a)–5-HT4(f)) and 5-HT receptors (e. Concur- 5-HT7 receptor (5-HT7(a)–5-HT7(d)) differ in length and rently, much progress has been made in delineating the composition in the carboxyl terminus (see refs. Marked species differences and perhaps regional subtypes. The focus of this review is on the molecular and differences lead to different patterns of splicing. Aghajanian: Departments of Psychiatry and Pharmacology, molecule. Splice variants of the 5-HT receptor have no 7 Yale University School of Medicine, New Haven, Connecticut. Elaine Sanders-Bush: Department of Pharmacology, Vanderbilt Univer- known functional differences. In contrast, a second form sity School of Medicine, Nashville, Tennessee. It is not known whether other ing properties of this ligand-gated ion channel (see ref. It seems likely that the RNA editing in mammalian systems was discovered 5-HT2C receptor would not be unique. However, screening about a decade ago and is defined as any modification, other methods for reliably detecting RNA editing are not avail- than alternative splicing, that occurs at the level of mRNA. Conse- editing generally involves the conversion of adenosine resi- quently, new edited substrates are slow to emerge. Such editing events have the potential to alter the genetic code at the level of RNA; the resulting is the Post-translational Regulation formation of multiple protein isoforms with altered func- tion. The discovery of RNA editing of the 5-HT receptor Receptor desensitization and down-regulation are common 2C provided the first, and so far only, example of editing of a adaptive responses to sustained agonist exposure. Editing of the human 5- widely accepted model of desensitization of G protein-cou- HT receptor mRNA involves five sites, A through E, pled receptors is based on extensive studies of the -adrener- 2C where adenosine is converted to inosine; inosine substitutes gic receptor, a G -linked receptor. In a simplified renditions for guanosine in the genetic code, thus generating different of the model, agonist binding to a cell surface receptor leads protein isoforms.

M ost laboratories now have the HLA phenotype capability of reporting at least low-resolution molecular class II types buy discount nitrofurantoin 50 mg line. Patient cells tested with known antisera The sera of patients awaiting cadaveric donor kidney transplantation are tested for the HLA antibody screen degree of alloim m unization by determ ining the percentage of panel reactive antibodies (PRAs) purchase 50 mg nitrofurantoin free shipping. Current federal regulations require that the serum screening test use lym phocytes Known cells tested with patient sera as targets; however, because these sam e regulations no longer m andate m onthly screening, HLA crossmatch assays using soluble antigens m ay be used as adjuncts to the classic lym phocytotoxic assays. W hen present, the antibodies indicate that the im m une system of the recipient has been sensitized to the donor antigens. The various test methods differ in sensitivity, including the multiple variations of the lym phocytotoxicity text, flow cytom etry, and enzym e-linked im m unosorbent assay (ELISA). The degree of acceptable risk is one factor to be considered in selecting a m ethod of appropriate sensitivity. For exam ple, when the only risk considered unacceptable is that of hyperacute rejection, a technique having lower sensitivity is adequate. A second approach m ay be to consider the degree to which an individual patient or type of patient is at risk for graft rejection. The patient having a repeat graft is at higher risk for graft rejection than is the patient receiving a prim ary graft. Because patients differ in their degree of risk, it is appropriate to use different techniques to offset that risk. FIGURE 8-4 M HC I AND II CHARACTERISTICS H um an leukocyte antigens (H LAs) are heterodim eric cell-surface glycoproteins. H LAs are divided into two classes, according to their biochemical structure and respective functions. Class I antigens Class I Class II (A, B, and C) have a m olecular weight of approxim ately 56,000 D and consist of two chains: a glycoprotein heavy chain (a) and a Composed of HLA-A, -B, and -C Composed of HLA-DR, -DQ, and -DP light chain (b -m icroglobulin). The a chain is attached to the cell 2 Ubiquitous distribution Restricted distribution m em brane, whereas b2-m icroglobulin is associated with the a Autosomal codominant Autosomal codominant chain but is not covalently bonded. The H LA class I m olecules are Target for immune effector mechanism Major role in immune response found on alm ost all cells; however, only vestigial am ounts rem ain Serologic and molecular detection induction on m ature erythrocytes. Class II antigens (H LA-DR, DQ , and DP) Heterodimer noncovalently linked Serologic, molecular, and cellular have a m olecular weight of approxim ately 63,000 D and consist of Heavy chain (a): detection two dissim ilar glycoprotein chains, designated a and b, both of Contains variable regions Heterodimer noncovalently linked which are attached to the m em brane. Each chain consists of two Confers human leukocyte antigen a Chain: extram em branous am ino acid dom ains, and the outer dom ains of specificity Nonvariable in HLA-DR each m olecule contain the variable regions corresponding to class II Light chain (b2-microglobulin): Contains variable regions in HLA-DQ alleles. Although class I antigens are expressed on all nucleated cells Invariant and -DP of the body, the expression of class II antigens is more restricted. Class b Chain: II antigens are found on B lymphocytes, activated T lymphocytes, Contains variable regions m onocyte-m acrophages, dendritic cells, and early hem atopoietic Confers most of HLA-DR specificity cells, and of im portance in transplantation, endothelial cells. A, The biologic function of M H C antigens is to present antigenic peptides α chain to T lym phocytes. In fact, it is an absolute requirem ent of T-lym - phocyte activation for the T cells to “see” the antigenic peptide bound to an M H C m olecule. This M H C restriction has been defined on a m olecular basis with the elucidation of the crystalline structures of classes I and II M H C m olecules. B, The N -term inal Processed β chain dom ains of the M H C m olecules are form ed by the folding of por- antigen tions of their com ponent chains in b-pleated sheets and a helices. C, The sheet portions form a floor, and the helices form the sides of a peptide-binding groove. A α1 α2 β2m α3 B C FIGURE 8-6 Peptide The structure of class I and II m olecules. Peptide Com parison of the crystalline structures of classes I and II molecules has revealed overall structural sim ilarity, with a few significant differences. A, Class I m olecules have a groove with deep anchor pockets at each end (a “pita pocket”). These pockets restrict the binding of peptides to those of eight to nine am ino acid residues in length. B, The peptide-binding groove of class II m olecules Heavy β2m subunit α subunit β subunit is m ore flexible and relatively open at one subunit end, m ore like a “hotdog bun,” perm itting larger peptides from 13 to 25 am ino acid residues in length to bind. Allelic polym orphism is a hallmark of the human leukocyte antigen (HLA) system. The extreme polymorphism of A B B C DR DQ DP the HLA system is seen in the large numbers of different alleles that exist for the m ultiple A1 B5 B51(5) Cw1 DR1 DQ1 DPw1 m ajor histocom patibility com plex (M H C) A2 B7 B5102 Cw2 DR103 DQ2 DPw2 loci. At any given locus, one of several A203 B703 B5103 Cw3 DR2 DQ3 DPw3 alternative form s or alleles of a gene can A210 B8 B52(5) Cw4 DR3 DQ4 DPw4 exist. Because so m any alleles are possible A3 B12 B53 Cw5 DR4 DQ5(1) DPw5 for each H LA locus, the system is extrem ely A9 B13 B54(22) Cw6 DR5 DQ6(1) DPw6 polym orphic. The currently accepted W orld A10 B14 B55(22) Cw7 DR6 DQ7(3) H ealth O rganization serologically defined A11 B15 B56(22) Cw8 DR7 DQ8(3) alleles are shown here. Established H LA A19 B16 B57(17) Cw9(w3) DR8 DQ9(3) antigens are designated by a number following A23(9) B17 B58(17) Cw10(w3) DR9 the letter that denotes the H LA locus (eg, A24(9) B18 B59 DR10 H LA-A1 and H LA-B8). For exam ple, by A2403 B21 B60(40) DR11(5) serologic techniques, 28 distinct antigens A25(10) B22 B61(40) DR12(5) are recognized at the HLA-A locus, and A26(10) B27 B62(15) DR13(6) 59 defined antigens at the H LA-B locus.

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This diagram from the US Renal Data System Coordinating Center 1994 report indicates that 29% of calendar year 12% 1991 incident patients entered ESRD programs because of “hypertension (HBP) nitrofurantoin 50mg overnight delivery. Crude estimates of the percentage of patients entering DM ESRD programs because of ASO-RAD range from 1 purchase 50mg nitrofurantoin. Precise bases for making 5% these estimates are both unclear and confounded by the high likelihood of coexisting arterio- Urology 29% lar nephrosclerosis, type II diabetic nephropathy, and atheroembolic renal disease. ASO-RAD High blood as a major contributor to the ESRD population is probably small on a percentage basis, occu- 3% pressure Cyst pying some portion of the ESRD diagnosis “hypertension (HBP). Treatment of Renovascular Hypertension and Ischemic Nephropathy FIGURE 3-39 TREATM ENT OPTIONS FOR RENOVASCULAR Treatment options for renovascular hypertension and ischemic HYPERTENSION AND ISCHEM IC NEPHROPATHY nephropathy. The main goals in the treatment of renovascular hyper- tension or ischemic nephropathy are to control the blood pressure, to prevent target organ complications, and to avoid the loss of renal Pharmacologic antihypertensive therapy function. Although the issue of renal function may be viewed as PTRA mutually exclusive from the issue of blood pressure control, uncon- trolled hypertension may hasten a decline in renal function, and Renal artery stents renal insufficiency may produce worsening hypertension. Even in the Surgical renal revascularization presence of excellent blood pressure control, progressive arterial stenosis might worsen renal ischemia and promote renal atrophy and fibrosis. Therapeutic options include pharmacologic antihypertensive therapy, percutaneous transluminal renal angioplasty (PTRA), renal artery stents, and surgical renal revascularization. Pharmacologic anti- hypertensive therapy is covered in more detail separately in this Atlas. FIGURE 3-40 INCREASING COM ORBIDITY IN PATIENTS Com orbidity in patients undergoing renovascular surgery. Patients UNDERGOING RENOVASCULAR SURGERY presenting for renovascular surgery or endovascular renal revascu- larization are at high-risk for com plications during intervention because of age, and frequently associated coronary, cerebrovascular, Comorbidity, % or peripheral vascular disease. As the population ages, the percentage of patients being considered for interventive m aneuvers on the Condition 1970–1980 1980–1993 renal artery has increased significantly. Congestive heart failure, cerebrovascular disease (eg, carotid Cerebrovascular disease 11. REVASCULARIZATION FOR ATHEROSCLEROTIC RENOVASCULAR DISEASE Severe atherosclerosis of the abdom inal aorta m ay render an aortorenal bypass or renal endarterectom y technically difficult Preoperative screening and correction of coronary and carotid artery disease and potentially hazardous to perform. Avoidance of operation on severely diseased aorta Effective alternate bypass techniques include Unilateral revascularization in patients with bilateral renovascular disease splenorenal bypass for left renal revascular- ization, hepatorenal bypass for right renal revascularization, ileorenal bypass, bench surgery with autotransplantation, and use FIGURE 3-41 of the supraceliac or lower thoracic aorta Dim inished operative m orbidity and m ortality following surgical revascularization for (usually less ravaged by atherosclerosis). O perative m orbidity and m ortality in patients under- Sim ultaneous aortic replacem ent and renal going surgical revascularization have been m inim ized by selective screening and/or correc- revascularization are associated with an tion of significant coexisting coronary and/or carotid artery disease before undertaking increased risk of operative m ortality in elective surgical renal revascularization for atherosclerotic renal artery disease. Screening com parison to renal revascularization alone. Som e surgeons advocate unilateral renal Screening tests for coronary artery disease include thallium stress testing, dipyridam ole revascularization in patients with bilateral stress testing, dobutam ine echocardiography, and coronary arteriography. FIGURE 3-42 Schem atic diagram of alternate bypass procedures. A B C D Renovascular Hypertension and Ischemic Nephropathy 3. PTRA of the renal artery has em erged as an im portant inter- A, High-grade (more than 75% ) nonostial atherosclerotic stenosis of the ventional m odality in the m anagem ent of patients with renal left main renal artery in a patient with a solitary functioning kidney (right artery stenosis. PTRA is m ost successful and should be the initial renal artery totally occluded). Note gradient of 170 mm Hg across the interventive therapeutic m aneuver for patients with the m edial stenotic lesion. B, Balloon angioplasty of the left main renal artery was fibroplasia type of fibrous renal artery disease (eg, Fig. Repeat nonostial atherosclerotic lesions of the m ain renal artery, as aortogram 3 years later demonstrated patency of the left renal artery. FIGURE 3-44 H igh-grade athero- sclerotic renal artery stenosis at the ostium of the right m ain renal artery in a 68-year-old m an with a totally occluded left m ain FIGURE 3-45 renal artery. Because percutaneous transluminal renal attem pts at balloon angioplasty (PTRA) has suboptimal long-term benefits for athero- dilatation were sclerotic ostial renal artery stenosis, endovascular stenting has gained unsuccessful. From a technical standpoint, indications oped (serum creati- for renal artery stenting include 1) as a primary procedure for ostial nine increasing from atherosclerotic renal artery disease (ASO-RAD), 2) technical difficul- 2. Renal function never It is unclear what the long-term patency and restenosis rates will be im proved and the for renal artery stenting for ostial disease. Preliminary observations patient rem ained suggest that the 1-year patency rate for stents is approximately twice on dialysis. SURGICAL REVASCULARIZATION VERSUS FOR ATHEROSCLEROTIC RENAL ARTERY DISEASE PTRA FOR FIBROUS RENAL ARTERY DISEASE Successful surgical Successful surgical Lesion Successful PTRA, % revascularization, % Lesion Successful PTRA, % revascularization, % Nonostial 80–90 90 Main 80–90 90 (20%) (50%) Ostial 25–30 90 Branch NA 90 (80%) (50%) FIGURE 3-47 Surgical revascularization vs percutaneous translum inal renal The “percent success” for PTRA and surgical revascularization angioplasty (PTRA) for renal artery disease. A, Success rates for depicted above are estimates, and reflect primarily “technical” success atherosclerotic renal artery disease (ASO -RAD). B, Success rates for both nonostial and ostial lesions in ASO-RAD. Success of either PTRA or surgi- rates for surgical revascularization are high, approxim ating 90% , cal renal revascularization is viewed in term s of “technical” suc- with little difference in the technical success rates between ostial cess and “clinical” success. For PTRA, technical success reflects and nonostial lesions.

In com parison best nitrofurantoin 50 mg, a group of relatively rare disorders exists generic nitrofurantoin 50mg overnight delivery, each of which is m etabolic pathway result in hyperoxaluria, transmitted as a M endelian trait and causes a variety of different crystal nephropathies. The oxalate stone form ation, and consequent most common of these disorders is cystinuria, which involves defective cystine and dibasic loss of renal function. Am J Physiol 1992, m onem ia in congenital lysinuria. Sm ith A, Strang L: An inborn error of m etabolism with the urinary 2. H ediger M , Coady M , Ikeda T, W right E: Expression cloning and excretion of -hydroxybutric acid and phenyl-pyruvic acid. Arch D is cDN A sequencing of the N a/glucose co-transporter. Rosenberg LE, Downing S, Durant JL, Segal S: Cystinuria: biochem i- 3. W oolf L, Goodwin B, Phelps C: Tm -lim ited renal tubular reabsorption cal evidence for three genetically distinct diseases. J Clin Invest 1966, and the genetics of renal glycosuria. M orris JR, Ives H E: Inherited disorders of the renal tubule. Philadelphia: W B Saunders, m utations in rBAT, a gene involved in the transport of cystine. Kanai Y, H ediger M : Prim ary structure and functional characteriza- 12. N ature 1992, cystinuria: the SLC3A1 gene is linked to type I but not to type III 360:467–471. Perazella M , Buller G: Successful treatment of cystinuria with captopril. Grieff M : N ew insights into X-linked hypophosphatem ia. Curr O pin the epithelial sodium channel cause salt wasting with hyperkalem ic N ephrol H ypertens 1997, 6:15–19. Robertson GL: Vasopressin in osm otic regulation in m an. Kuhle U: Pseudohypoaldosteronism : m utation found, problem solved? Econs M , Drezner M : Tum or-induced osteom alacia: unveiling a new M ol Cell Endocrinol 1997, 133:77–80. Gordon R: Syndrom e of hypertension and hyperkalem ia with norm al 19. The H YP Consortium : A gene (PEX) with hom ologies to endopepti- glom erular filtration rate. Bergeron M , Gougoux A, Vinay P: The renal Fanconi syndrom e. N ature G enet 1997, The M etabolic and M olecular Bases of Inherited D iseases. Robertson GL, et al: Developm ent and clinical application of a new 1995:3691–3704. Sly W , H u P: The carbonic anhydrase II deficiency syndrom e: osteo- plasm a. Bichet D, O sche A, Rosenthal W : Congenital nephrogenic diabetes M etabolic and M olecular Bases of Inherited D iseases. Bastani B, Gluck S: N ew insights into the pathogenesis of distal renal in the aquaporin 2 water channel gene. Coe F, Parks J, Asplin J: The pathogenesis and treatm ent of kidney tal renal tubular acidosis is associated in three fam ilies with heterozy- stones. In The M etabolic and M olecular Bases of exchanger. Edited by Scriver CH , Beaudet AL, Sly W S, Valle 25. Guay-W oodford L: Bartter syndrom e: unraveling the pathophysiologic D. Polinsky M S, Kaiser BA, Baluarte H J: Urolithiasis in childhood. In The M etabolic Pediatr Clin N orth Am 1987, 34:683–710.

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