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By F. Bengerd. Saginaw Valley State University.

It is glutamate receptors have been implicated in epileptogenesis therefore conceivable that neuropeptide Y buy cheap femara 2.5mg line, portrayed here and chronic epilepsy (44 buy 2.5mg femara overnight delivery,48,50,58,61,62). Its physiologic pendency and allows channel opening at central neurons actions, as well as its chemical and anatomic changes in even at normal, hyperpolarized membrane potentials. The MTLE, are not confined to the hippocampus but also affect result is spontaneous epileptiform activity (72). Examples include growth factors occur in MTLE as well as in relevant animal models and are and cytokines, which have been shown to be neuroactive seen both in the hippocampus, so far the most thoroughly in various test systems. Thus, various members of the neuro- investigated brain region, and in extrahippocampal areas trophin family, including nerve growth factor, brain-derived such as the entorhinal cortex (56). These although their effects vary widely in both qualitative and receptors, which mediate most fast excitatory neurotrans- quantitative terms (80). All reports of these neuroactive ef- mission, are also composed of an array of subunits, which fects are so far based on exogenously applied neurotrophins; assemble to form distinct receptor subtypes (73). Receptor that is, the results could be compromised by the finding 1850 Neuropsychopharmacology: The Fifth Generation of Progress that the concentrations used for experimentation exceeded ologic properties and the histochemical staining pattern of physiologic levels. Still, it is certainly of interest that the astrocytes in area CA1of the hippocampus differ from those brain concentration of some neurotrophins, such as BDNF, in area CA3 (88). Similar differences are likely to exist in increases dramatically after seizures, whereas others, such as other brain areas as well, adding another layer of complexity neurotrophin 3, decrease. The high-affinity trk receptors to the study of neuron-glia interactions as they pertain to and low-affinity p75 receptors for neurotrophins also appear mechanisms of epileptogenesis and chronic epilepsy. Because normal expres- Expression sion and seizure-induced changes of these putative neuro- Prolonged seizure activity, especially episodes of status epi- modulators occur throughout the limbic system, critical lepticus, often has dramatic effects on gene expression, in- seizure-related effects may not only take place in the hippo- ducing a bewildering array of new genes in the brain. The campus, where most studies have been performed to date. A popular hypothesis to explain these changes is of the immune system. However, some of these compounds, that seizures induce, or influence the expression of, genes for example, interleukin 1(IL-1), IL-6, and tumor necrosis that are normally expressed during development. Sequelae factor- , are expressed in the brain, influence neuronal ac- of seizures may therefore mimic or, to use a more teleologic tivity, and therefore have potential links to seizure mecha- term, recapitulate development. In particular, the mRNA for IL-1 and IL-6, as well zure-induced up-regulation of growth factors and proteins as IL receptors, is increased by seizures (82). Moreover, IL- that are involved in synaptogenesis (89). Other investigators 1 is elevated in tissue from patients with epilepsy (83). This implies the up-regulation Neuron-Glia Interactions of systems that inhibit neuronal activity. Indeed, seizures lead to changed expression of glutamate decarboxylase, the The importance of glia to neuronal function has been appre- enzyme responsible for GABA synthesis, and GABA recep- ciated since the early period of neuroscience research. Besides other roles in brain physiology, glial may be part of the development of the epileptic state. Thus, cells may play a significant role in the modulation of seizure a first seizure may induce gene expression of substances that phenomena. Thus, both astrocytes and microglial cells, the will contribute to further hyperexcitability. One example is two major glial cell types in the brain, are rapidly activated the neurotrophin BDNF, which is normally expressed in by seizure activity in the limbic system (84). It is currently dentate gyrus granule cells and, to a lesser extent, other areas unclear, however, whether this cellular reaction has procon- of the hippocampus and other brain regions (91). Astrocytes have the ability single seizure, BDNF message, protein, and the high-affin- to buffer extracellular potassium and can avidly accumulate ity trkB receptor all increase in granule cells (92,93). Moreover, astro- cause BDNF enhances neuronal activity in the hippocam- cytes increase the production and release of the endogenous pus, the increase in expression could have functional neuroinhibitory and anticonvulsant compound kynurenate, consequences; that is, it could lead to a reduction in seizure possibly as an early defensive response to seizures (85). BDNF also has effects on neuronal structure and These and many conceptually related data indicate a protec- could thus contribute to structural changes occurring after tive function of astrocytes in epileptogenesis and, perhaps, seizures that, in turn, increase susceptibility to seizures (81, in chronic epilepsy. Because BDNF, and other neurotrophins and neuro- croglia also synthesize endogenous proconvulsive agents modulators, are expressed in extrahippocampal regions, this such as quinolinate (86) and cytokines (87), which may hyperexcitability may also occur in these areas. Synaptic Reorganization Of possible relevance to their role in epilepsy, glial cells in limbic brain areas are heterogeneous with regard to both As mentioned above, seizures induce many genes in the structure and function. These genes express a variety of different proteins, Chapter 127: Temporal Lobe Epilepsy 1851 which often closely resemble or duplicate those that are product. This selectivity is particularly important in the preferentially expressed during brain development. It is study of epileptic phenomena, which are associated with therefore hardly surprising that growth and synaptic reorga- many concurrent molecular and cellular changes. In experi- Transgenics may be engineered to overexpress or delete a mental animals, this phenomenon has been studied in great given gene product, and recent techniques have made it detail in the hippocampus, although it can also be observed possible to modify gene expression conditionally, that is, in in extrahippocampal areas such as the entorhinal cortex (65) a brain region– or age-specific fashion (105).

Thus cheap femara 2.5mg online,the lack of CRF1 recep- tor expression in these nuclei suggests that CRF2 receptors may solely mediate the postsynaptic actions of CRF inputs to this region and strongly suggests a role for CRF2 receptors in modulating limbic circuitry at the level of septal activity buy femara 2.5 mg without prescription. In addition,the selective expression of CRF2 receptor mRNA within hypothalamic nuclei indicates that the anxio- genic and anorexic actions of CRF in these nuclei may likely be CRF2 receptor-mediated. In contrast,within the pitui- tary,there is a predominance of CRF1 receptor expression with little or no CRF2 expression in either the intermediate and anterior lobes,indicating that it is the CRF1 receptor that is primarily responsible for CRF regulation of the HPA axis. In addition to the differences in distribution between the CRF1 and CRF2 receptor subtypes,there exists a distinct pattern of distribution between the CRF2 isoforms (CRF2 and CRF2 ) as well. The CRF2 isoform is primarily ex- pressed within the CNS,whereas the CRF2 form is found both centrally and peripherally. Digitized, color-coded images of CRF1 (Panel A) and CRF form is the predominant one,whereas the CRF CRF (Panel B) receptor mRNA expression and receptor autoradi- 2 2 2 ography in adjacent horizontal sections of rat brain. The highest form is localized primarily to non-neuronal structures,the levels of mRNA expression are coded in red, whereas the lowest choroid plexus of the ventricular system,and cerebral arteri- concentrations are coded in blue. The identification of the CRF form in cere- of receptors labeled with either [125I]oCRF (CRF only; Panel C)or 2 1 [125I]sauvagine (CRF and CRF ; Panel D) are coded in red. There bral arterioles suggests a mechanism through which CRF 1 2 was a good correspondence between the message for a particular may directly modulate cerebral blood flow. Peripherally,the receptor subtype and its protein localization; the pharmacologic highest detectable levels of mRNA were found in heart and selectivity was retained for the two radioligands. Taken together, the results of these studies demonstrating a distinct heterogeneous distribution pattern of CRF receptor subtypes in brain and peripheral tissues, strongly suggest that these receptor subtypes subserve very erally corresponded to the previously reported distribution specific physiological roles in CRF related function both of [125I]oCRF binding sites (Fig. Using the radioligand [125I]sauvagine described, Receptors CRF2 receptors could be localized to areas of high CRF2 Radioligand binding studies have demonstrated that CRF message. In addition,because [125I]sauvagine has equal af- receptors in the brain-endocrine-immune axis are coupled finity for both receptor subtypes (34),the autoradiography to a guanine nucleotide regulatory protein. In all of these revealed the localization of both the CRF1 and CRF2 recep- tissues,the primary second messenger system involved in tor subtypes,demonstrating the utility of this novel radioli- transducing the actions of CRF is stimulation of cAMP Chapter 7: Corticotropin-Releasing Factor 99 production (29,31–33,40). CRF initiates a cascade of enzy- cDNA and Amino Acid Sequences matic reactions in the pituitary gland beginning with the The CRF-BP was first isolated and purified to near homoge- receptor-mediated stimulation of adenylate cyclase,which neity for sequencing and generation of oligonucleotide ultimately regulates POMC-peptide secretion and possibly probes (47). Screening a human liver cDNA library using synthesis. POMC-derived peptide secretion mediated by the probes generated from the original amino acid sequence activation of adenylate cyclase in the anterior and neuroin- revealed a full-length cDNA containing a 1. Similarly in the brain and putative N-linked glycosylation site was found at amino spleen,the pharmacologic rank order profile of CRF-related acid 203,which agrees with the previous observation of the peptides for stimulation of adenylate cyclase is analogous presence of asparagine-linked sugar moieties on the native to the profile seen in pituitary and in keeping with the protein (49). Subsequent screening of a rat cerebral cortical affinities of these compounds for receptor binding. In addi- cDNA library,revealed the presence of a single clone con- tion,the putative CRF receptor antagonist -hel ovine taining a 1. The transduction mechanisms may be involved in the actions of pharmacology of these proteins appears to be similar with CRF. For example,CRF has been shown to increase protein both the rat and human binding proteins having high affin- carboxyl methylation,and phospholipid methylation in ity for the rat/human CRF (Kd 0. Preliminary evidence suggests that CRF affinity for the ovine form of CRF (Kd 250 nM). Al- may regulate cellular responses through products of arachi- though there may be some similarities in the binding do- donic acid metabolism (42). Furthermore,although the evi- mains of the binding protein and the CRF receptor (as dence in anterior pituitary cells suggests that CRF does not evidenced by the equal affinity of r/hCRF),these are distinct directly regulate phosphatidylinositol turnover or protein proteins,each with unique characteristics and distributions. Thus, the effects of CRF on anterior pituitary cells and possibly Although the human and rat forms of the CRF-BP are ho- in neurons and other cell types expressing CRF receptors mologous (as indicated),there is a somewhat different ana- are likely to involve complex interactions among several in- tomic distribution pattern in the two species. Peripheral expres- sion of the binding protein may have its greatest utility in CRF and Its Binding Protein in Human the modulation and control of the elevated levels of CRF Plasma in circulating plasma induced by various normal physiologic Under normal conditions,the plasma levels of CRF remain conditions (see the preceding). In addition,expression of low; however,CRF levels are markedly elevated in plasma this binding protein in the brain and pituitary offers addi- during the late gestational stages of pregnancy (43–45). The tional mechanisms by which CRF-related neuronal or neu- source of the pregnancy-associated CRF is most likely the roendocrine actions may be modulated. The CRF in brain regions including neocortex,hippocampus (primarily the maternal plasma is bioactive in releasing ACTH from in the dentate gyrus),and olfactory bulb. In spite of the high levels of brain,mRNA is localized to the amygdaloid complex with CRF in the maternal plasma,there is no evidence of mark- a distinct lack of immunostained cells in the medial nucleus. A plausible explanation for this paradoxic the brainstem particularly in the auditory,vestibular,and situation could be the presence of a binding protein in the trigeminal systems,raphe nuclei of the midbrain and pons, plasma of pregnant women that could specifically inhibit and reticular formation (50). In addition,high expression the biological actions of CRF (44,45). This hypothesis was levels of binding protein mRNA are seen in the anterior validated by the isolation of a CRF-binding protein (CRF- pituitary,predominantly restricted to the corticotrope cells. BP) from human plasma and its subsequent cloning and Expression of this protein in the corticotropes strongly sug- expression (see the following).

Patients with atherosclerotic renal artery Atherosclerosis Nephrosclerosis disease (ASO-RAD) often have coexisting renal parenchymal disease with varying degrees of nephrosclerosis (small vessel disease) or atheroembolic renal disease discount femara 2.5 mg with mastercard. W hether or not the renal insufficiency is solely attributable to renal artery stenosis cheap femara 2.5mg without prescription, nephrosclerosis, or atheroembolic renal disease is difficult to determine. The term “ischemic nephropathy” is more complex than being simply due to atherosclerotic renal artery stenosis. In addition, in the azotemic patient with ASO- Atheroembolism RAD, one should exclude other potential or contributing causes of renal insufficiency such as obstructive uropathy, primary glomerular disease (suggested by heavy proteinuria), drug-related renal insufficiency (eg, nonsteroidal anti-inflammatory drugs), and uncontrolled blood pressure. Renovascular Hypertension and Ischemic Nephropathy 3. Atherosclerotic renal artery disease (ASO- 11% Other RAD) has been claimed to contribute to the ESRD population. 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). Crude estimates of the percentage of patients entering DM ESRD programs because of ASO-RAD range from 1. 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.