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If the ischemic insult is sufficiently severe purchase cytotec 200 mcg line, cell death and/or Thus discount cytotec 200mcg with visa, important insights into the basic and applied biology of detachment leads to loss of cells from the epithelium lining the tight junctions are likely to be forthcoming from further analy- kidney tubules effective 200 mcg cytotec. To recover from such a severe insult, cell regen- sis of the ATP depletion-repletion model. Nevertheless, it is like- eration, differentiation, and possibly morphogenesis, are neces- ly that, as in the calcium switch model, tight junction reassem- sary. To a limited extent, the recovery of kidney tubule function bly is regulated by classical signaling pathways that might after such a severe ischemic insult can be viewed as a recapitu- potentially be pharmacologically modulated to enhance recov- lation of various steps in renal development. M any of these involved in kidney development) appears necessary to amelio- (eg, the tight junction protein, occludin, and the adherens junction rate renal recovery after acute ischemic injury [21–30]. The Ischemic Epithelial Cell FIGURE 16-1 Functional renal tubules Ischem ic acute renal failure (ARF). Flow chart illustrates the cellu- lar basis of ischem ic ARF. As described above, renal tubule epithe- Uninjured cells lial cells undergo a variety of biochem ical and structural changes in Ischemic insult response to ischem ic insult. If the duration of the insult is suffi- ciently short, these alterations are readily reversible, but if the Injured cells insult continues it ultim ately leads to cell detachm ent and/or cell death. Interestingly, unlike other organs in which ischem ic injury ↓ATP; ↑[CA2+]; ↑Free radicals; Other changes? Tight junction Apical-basolateral M icrofilament disruption polarity disruption disruption Dysfunctional renal tubular epithelial cells Remove insult Continued insult Cell loss Cellular (detachment repair or death) Cell regenertation, differentiation, and morphogenesis Remove insult Acute Renal Failure: Cellular Features of Injury and Repair 16. Sublethal injury to polarized epithelial cells leads to m ultiple Brush lesions, including loss of the perm eability barrier and apical-basolat- border eral polarity [7–12]. To recover, cells m ust reestablish intercellular junctions and repolarize to form distinct apical and basolateral dom ains characteristic of functional renal epithelial cells. These Tight junction junctions include those necessary for m aintaining the perm eability barrier (ie, tight junctions), m aintaining cell-cell contact (ie, Adherens Terminal web adherens junctions and desm osom es), and those involved in cell-cell junction Actin cortical ring com m unication (ie, gap junctions). In addition, the cell m ust estab- lish and m aintain contact with the basem ent m em brane through its integrin receptors. Thus, to understand how kidney cells recover from sublethal ischem ic injury it is necessary to understand how renal epithelial cells form these junctions. Furtherm ore, after lethal Desmosome Intermediate injury to tubule cells new cells m ay have to replace those lost during filaments the ischem ic insult, and these new cells m ust differentiate into epithelial cells to restore proper function to the tubules. Gap junction Na+, K+, ATPase Integrins Extracellular matrix FIGURE 16-3 Symplekin Occludin The tight junction. The tight junction, the m ost apical com ponent of the junctional com plex of epithelial cells, serves two m ain functions in epithelial cells: 1) It separates the apical and 7H6 p130 basolateral plasm a m em brane dom ains of the cells, allowing for vectorial transport of ions Cingulin ZO–1 and m olecules; 2) it provides the m ajor fram ework for the paracellular perm eability barrier, allowing for generation of chem ical and electrical gradients. These functions are criti- cally im portant to the proper functioning of renal tubules. The tight junction is com prised ZO–2 of a num ber of proteins (cytoplasm ic and transm em brane) that interact with a sim ilar group of proteins between adjacent cells to form the perm eability barrier [16, 32–37]. Actin These proteins include the transm em brane protein occludin [35, 38] and the cytosolic pro- filaments teins zonula occludens 1 (ZO -1), ZO -2, p130,, cingulin [33, 40], 7H 6 antigen and sym plekin, although other as yet unidentified com ponents likely exist. The Fodrin Paracellular tight junction also appears to interact with the actin-based cytoskeleton, probably in part space through ZO -1–fodrin interactions. This model of short-term ATP Intact intercellular Compromised Damaged disassembled junctions intercellular junctions intercellular junctions depletion-repletion is probably most relevant to transient sublethal ischemic injury of renal tubule cells. However, in a model of Short-term Long-term Severe longterm ATP depletion (2. The disruption of the perme- (message and protein) and bioassembly of ability barrier, mediated by the tight junction, is a key lesion in the pathogenesis of tubular new tight junction components. M any of dysfunction after ischemia and reperfusion. Cell culture models employing ATP depletion these components (membrane proteins) are and repletion protocols are a commonly used approach for understanding the molecular assembled in the endoplasmic reticulum. This is dem onstrated control here by indirect im m unofluorescent localization of these two pro- teins in norm al kidney epithelial cells. After 1 hour of ATP deple- tion this association appears to change, occludin can be found in the cell interior, whereas ZO -1 rem ains at the apical border of the ATP depletion (1 hr) plasm a m em brane. Interestingly, the intracellular distribution of the actin-cytoskeletal–associated protein fodrin also changes after ATP depletion. Fodrin m oves from a random , intracellular distrib- ution and appears to becom e co-localized with ZO -1 at the apical ATP repletion (3hrs) border of the plasm a m em brane. These changes are com pletely reversible after ATP repletion. These findings suggest that disrup- tion of the perm eability barrier could be due, at least in part, to altered association of ZO -1 with occludin. In addition, the appar- FIGURE 16-5 ent co-localization of ZO -1 and fodrin at the level of the tight Im m unofluorescent localization of proteins of the tight junction junction suggests that ZO -1 is becom ing intim ately associated after ATP depletion and repletion. FIGURE 16-6 Occludin Occludin ATP depletion causes disruption of tight junctions. Diagram of the ZO–1 Fodrin changes induced in tight junction structure by ATP depletion.

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Emerging technologies for detect- using the process of fluorescence resonance energy transfer ing protein interactions in intact cells are suggesting new (FRET) (77) best cytotec 100mcg. FRET can be detected in living tein interactions in living cells proven cytotec 100mcg. FRET imaging has GPCR function and regulation cytotec 100mcg overnight delivery, we anticipate that the next not yet been used extensively for GPCR research but holds several years will see even greater progress in our understand- great promise for future study of the spatial and temporal ing of the fundamental biology of GPCRs. Indeed, the field dynamics of protein interactions with GPCRs in intact cells of GPCR research is rapidly moving away from a focus on and tissues. Further developments of these experimental meth- SUMMARY AND CONCLUSIONS ods, combined with new in vivo imaging and genomics ap- proaches that have appeared on the horizon, are likely to We have discussed a subset of experimental approaches that fuel continued rapid progress in the field. This exciting have provided powerful new tools for studying GPCR func- progress is fundamentally and directly relevant to the main tion and regulation. These approaches are responsible, in mission of neuropsychopharmacology: to develop and pro- large part, for the vast explosion of new information about vide effective therapies for the complex neuropsychiatric specific mechanisms of GPCR biology that has emerged disorders that affect our patients. In many cases these developments have extended directly from seminal observations made REFERENCES originally through classic pharmacologic approaches, which 1. On nerve endings and on special excitable substances remain of central importance to understanding GPCR func- in cells. New York: Scientific American minergic D2 receptors expressed in different cell types. New York: WH Free- LtK-fibroblasts, hyperpolarization, and cytosolic-free Ca2 con- man, Basingstoke, 1999. Dopamine receptor diversity: molecular for receptor identification. Regulation of G-protein and pharmacological perspectives. Prog Drug Res 1997;48: coupled receptor function and expression. Amino and carboxyl terminal modifications to facili- chemosensory receptors. Molecular characterization location is shared with that of the receptor for platelet-derived of a common binding site for small molecules within the trans- growth factor. Cloning and expres- Toxicol Methods 1995;33:179–185. Pharmacological characteristics of alpha-2 adrener- tion of a functional cDNA encoding the serotonin 1c receptor. Genetic identification of critical residues in four transmem- tor: isolation of a cDNA by expression cloning and pharmacologi- brane helices. GPCRDB: an infor- rhodopsin: a G protein-coupled receptor. Science 2000;289: mation system for G protein-coupled receptors. Visualisation coupled receptors: implications of the high-resolution stucture and integration of G protein-coupled receptor related informa- of rhodopsin for structure-function analysis of rhodopsin-like tion help the modelling: description and applications of the Vi- receptors. Cloning of the gene body motion of transmembrane helices for light activation of for a human dopamine D4 receptor with high affinity for the rhodopsin. Multiple dopamine American Science and Medicine 1994;July/August:14–23. Dopamine D4 receptor Proc Natl Acad Sci USA 1999;96:12322–12327. The phosphorylation of proteins: a major mechanism 18. Fourteenth Sir Frederick Gowland 2C receptor G-protein coupling by RNA editing. Molecular cloning, tissue distribution tory for counterregulatory effects of insulin. J Biol Chem 1995; and chromosomal localization of a novel member of the opioid 270:25305–25308. Orphanin FQ: the intracellular trafficking of G-protein-coupled receptors. Adv a neuropeptide that activates an opioidlike G protein-coupled Pharmacol 1998;42:420–424. Desensitization of G protein-cou- coupled receptors that regulate feeding behavior. Recent Prog Horm Res 1996;51:319–351; discus- 573–585. Mechanisms of beta- is caused by a mutation in the hypocretin (orexin) receptor 2 adrenergic receptor desensitization and resensitization.

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The use of CSF PCR instead of brain biopsy as the diagnostic standard for HSV encephalitis has expanded awareness of mild or atypical cases of HSV encephalitis purchase 200mcg cytotec otc. Adult encephalitis is caused by 2 viral serotypes cheap cytotec 200mcg free shipping, HSV-1 and HSV-2 buy generic cytotec 200mcg on line. Patients with greater than 100 DNA copies/µL HSV in CSF are more likely than those with fewer copies to have a reduced level of consciousness, more significant abnormal findings on neuroimaging, a longer duration of illness, higher mortality, and more sequelae (Domingues 1997). EBV is almost never cultured from CSF during infection, and serological testing is inconclusive, so CSF PCR diagnosis is mandatory. Semiquantitative PCR analysis of EBV DNA suggests that copy numbers are significantly higher in patients with active EBV infection. HHV-6 and -7 can cause exanthema subitum, and appear to be associated with febrile convulsions, even in the absence of signs of exanthema subitum. Almost all children (>90%) with exanthema subitum have HHV-6 or HHV-7 DNA in CSF. Inflammatory primary brain damage like meningitis and encephalitis come from pyogenic infections that reach the intracranial structures in one of two ways - either by hematogenous spread (infected thrombi or emboli of bacteria) or by extension from cranial structures (ears, paranasal sinuses, osteomyelitic foci in the skull, penetrating cranial injuries or 42 | Critical Care in Neurology congenital sinus tracts). In a good number of cases, infection is iatrogenic, being introduced in the course of cerebral or spinal surgery, during the placement of a ventriculoperitoneal shunt or rarely through a lumbar puncture needle. Nowadays, nosocomial infections are as frequent as the non-hospital acquired variety. The reason for altered sensorium in meningitis is postulated to be the spillage of inflammatory cells to the adjacent brain parenchyma and the resultant brain edema (Levin 1998). During tumor growth, cerebral tissues adjacent to the tumor and nearby venules are compressed, which results in elevation of capillary pressure, particularly in the cerebral white matter, and there is a change in cerebral blood flow and consequently intracranial pressure. At that stage the tumor begins to displace tissue, which eventually leads to displacement of tissue at a distance from the tumor, resulting in false localizing signs such as transtentorial herniations, paradoxical corticospinal signs of Kernohan and Woltman, third and sixth nerve palsies and secondary hydrocephalus, originally described in tumor patients. Secondary brain injuries Secondary brain injuries include renal coma, hepatic coma, salt and water imbalance, disturbance of glucose metabolism, other endocrinal causes of coma, disturbances of calcium and magnesium metabolism, drug intoxication and other material intoxication, not only drug toxicity, hypertensive and metabolic encephalopathies, sleep apnea syndromes and other ventilator disturbances. Mechanisms of secondary brain injury include hypoxia, hypoperfusion, reperfusion injury with free radical formations, release of excitatory amino acids and harmful mediators from injured cells, electrolyte and acid base changes from systemic or regional ischemia (Semplicini 2003). The primary goal in managing neurologically compromised patients includes (Stasiukyniene 2009) stabilizing the brain Brain Injuries | 43 through the maintenance of oxygen delivery via the following parameters: 1. Assuring systemic oxygen transport and adequate oxygenation, maintaining hemoglobin level (at approximately 10 g/dl or more) and cardiac output. Many insults are associated with hypertension, which may be a physiologic compensation, so excessive lowering of blood pressure may induce secondary ischemia. In general, systolic pressure should be treated when more than 200 mmHg or MAP when more than 125 mmHg. Cautious reduction in mean arterial pressure by only 25% is recommended (Adams 2007). Avoiding prophylactic or routine hyperventilation - a decrease in extracellular brain pH may produce vasoconstriction in responsive vessels and reduce CBF to already ischemic zones. This applies to patients with head trauma in whom routine hyperventilation is no longer considered desirable; brief hyperventilation may be lifesaving in the patient with herniation, pending the institution of other methods to lower elevated ICP. Hypervolemia may also be helpful when vasoconstriction is suspected, as in the setting of subarachnoid hemorrhage. Consideration should be given to administering intravenous lidocaine 1. Nimodipine should be instituted immediately in patients with SAH and is advocated by some in patients with subarachnoid bleeding after head trauma. Nimodipine probably improves outcome by decreasing calcium- mediated neuronal toxicity. Using normal saline as the primary maintenance fluid; dextrose administration is usually avoided unless the 44 | Critical Care in Neurology patient is hypoglycemic; hypotonic solutions should also be avoided. Sedation and/or neuromuscular blockade after intubation may be required to control harmful agitation. If seizure occurrs, it should be aggressively treated. Titration of the ICP and cerebral perfusion pressure. Management of Special Issues Traumatic brain injury Outcome after traumatic brain injury depends upon the initial severity of the injury, age, the extent of any subsequent complications, and how these are managed. Much of the early management of traumatic brain injury falls upon emergency room staff, primary care and ambulance services prior to hospital admission. Most patients who attend hospital after a traumatic brain injury do not develop life-threatening complications in the acute stage. However, in a small but important subgroup, the outcome is made worse by failure to detect promptly and deal adequately with complications. A traumatic brain injury should be discussed with neurosurgery when a. Persistent coma (GCS <9, no eye opening) after initial resuscitation ii.

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Benzo­ two decades significant progress has been made in under- diazepines differ widely in their pharmacologic half-life cheap cytotec 200mcg without prescription, and standing the pharmacology of alcohol and why some people this has been a factor in the choice of which benzodiazepines become dependent buy generic cytotec 200 mcg on-line. This has led to the development of sev- to use for detoxification cytotec 200mcg free shipping. For example, one popular ap­ eral medications that have been shown in research studies proach is to use a benzodiazepine with a long half-life such to improve treatment outcomes. This chapter reviews some as chlordiazepoxide as a loading dose and let the benzodiaze­ of the possible neurobiological mechanisms involved in al- pine self-taper (8). We introduce precludes problems with patience noncompliance. A second future directions for research such as the use of combina- approach is to use shorter acting benzodiazepines and titrate tions of medications that may have additive or synergistic the dose depending on symptoms. In a recent study, oxaze­ effects on improving treatment, and discuss the role of psy- pam was used as needed depending on the severity of with­ chosocial support to facilitate the effectiveness of pharmaco- drawal symptoms as assessed by the Clinical Institute With- therapy. As needed oxazepam resulted in effective alcohol withdrawal management with a lower total amount of oxazepam over a shorter duration compared to routine dosing (9). Volpicelli: Department of Psychiatry, University of Pennsylva- Anticonvulsants nia, Veterans Affairs Medical Center, Philadelphia, Pennsylvania. Anticonvulsants have the 1446 Neuropsychopharmacology: The Fifth Generation of Progress advantage of no abuse potential and a theoretical advantage drinking (17–33). These studies have consistently demon­ of reducing kindling, a sensitization of withdrawal symp­ strated that alcohol enhances the release of endogenous toms that occurs after multiepisodes of alcohol withdrawal. For example, Gia­ of less hostility in the phenobarbital group (10). Carbamaze­ noulakis and colleagues (34) have found that in humans pine has also been used as an alternative to benzodiazepines peripheral levels of �-endorphin increase in family his­ to attenuate alcohol withdrawal symptoms (11). Although tory–positive subjects following a moderate dose of alcohol, its mechanism of action remains unknown, research gener­ whereas there is no increase in �-endorphin for social drink­ ally shows that carbamazepine is as effective as benzodiaze­ ers without a family history of alcoholism. Disadvantages of carbamazepine include a rather nar­ lich and colleagues (36) have also demonstrated that alco­ row therapeutic window, the need to monitor serum levels, hol-induced �-endorphin responses both prior to and and hepatotoxic effects. For patients with a history of alco­ following alcohol administration are significantly heritable. Nonpreferring (NP) rats exhibit differences in the densities of � opioid receptors in certain brain reward regions compared to alcohol-preferring rats. PHARMACOLOGIC TREATMENTS TO Transgenic mice lacking �-endorphin have been shown to REDUCE ALCOHOL RELAPSE exhibit decreased preference for alcohol compared with wild-type mice (39). Disulfiram Nonspecific and specific opioid antagonists have been The aversive agent disulfiram has been available for the found to reduce alcohol self-administration in rodents and treatment of alcoholism since 1949. Preclinical studies have also inhibiting the liver enzyme that catalyzes the oxidation of evaluated the efficacy of antagonists specific for the � and � acetaldehyde, a toxic by-product of alcohol, resulting in an opioid receptors in reducing alcohol drinking. The � opioid aversive reaction to alcohol consumption. In this way, disul­ receptor antagonist �-funaltrexamine (B-FNA) and the � firam is thought to deter drinking by making the negative opioid receptor antagonists naltrindole (NTI) and naltriben consequences of drinking more certain, immediate, and (NTB) have all been shown to reduce alcohol drinking (17, aversive than they would be otherwise. Recent evidence also suggests a role for the � opioid patient takes the disulfiram, the decision about whether or receptors in mediating the aversive effects of alcohol as indi­ not to drink is probably shifted toward abstinence when cated by an increase in conditioned taste aversion in alcohol faced with opportunities to drink based on the knowledge preferring (P) rats in the presence of the � opioid receptor of the disulfiram-ethanol interaction. With supervi­ ing at least in part because of its effects on enhancing the sion and positive contingencies for taking disulfiram, how- release of endogenous opioids. The use of opioid antagonists ever, the effectiveness of disulfiram appears to be enhanced as an effective agent in the treatment of alcoholism is (14). As an alternative to behavioral methods for enhancing strongly predicted by these preclinical studies. However, these efforts have been unsuc­ Pharmacokinetics, Pharmacodynamics, and cessful perhaps because these implants have not yielded ade­ Safety quate disulfiram blood concentration required to produce a reaction to alcohol (15,16). Naltrexone, an opioid antagonist, was originally developed for use in the prevention of relapse in detoxified opiate addicts. Naltrexone has a half-life of approximately 4 hours, Opioid Antagonists and 6-�-naltrexol, its major metabolite, has a half-life of 12 hours. Rapidly absorbed, naltrexone reaches peak plasma Background levels between 60 and 90 minutes. Naltrexone undergoes The role of the alcohol-induced activation of the endoge­ first-pass hepatic metabolism, and there is some evidence nous opioid system in the reinforcing effects of alcohol has of dose-related hepatotoxicity at doses four to five times been well established in dozens of animal models of alcohol higher than the currently recommended 50-mg daily dos- Chapter 101: Alcoholism Pharmacotherapy 1447 age. In alcohol-dependent patients, adverse events reported riod. Samples have been composed primarily of male sub­ by at least 2% of those participating in an open-label safety jects (ranging from 71% to 100%) without other complicat­ study were nausea (10%), headache (8%), dizziness (4%), ing psychiatric or substance abuse problems, although there nervousness (4%), fatigue (4%), insomnia (3%), vomiting have been smaller studies in specialized populations, includ­ (3%), anxiety (2%), and somnolence (2%) (45). In addition ing those who use cocaine and alcohol (53) and older alco­ to these new-onset adverse events, naltrexone is contraindi­ holics (50). The behavioral interventions provided in con- cated for patients who are currently opioid dependent, are junction with naltrexone include day-hospital treatment, in acute opioid withdrawal, or require opioid analgesics for cognitive behavioral therapy, and supportive therapy.