By T. Agenak. Kentucky Christian College. 2018.
O xford: O xford University Press; the 2q13 region are a m ajor cause of juvenile nephronophthisis generic exforge 80mg with amex. Pirson Y 80 mg exforge visa, Chauveau D: Intracranial aneurysm s in autosom al dom inant 44 generic exforge 80mg mastercard. Edited by I: An unusual cause of hereditary cystic kidney disease cheap exforge 80mg with amex. O xford:O xford University Press; Transplant 1997, 12:1247–1250. Feather SA, W inyard PJD, Dodd S, W oolf AS: O ral-facial-digital syn- 28. Pirson Y, Christophe JL, Goffin E: O utcom e of renal replacem ent therapy in autosom al dom inant polycystic kidney diseases. Scheinman variety of m etabolic conditions produce disease of the renal interstitium and tubular epithelium. In m any cases, disease Areflects the unique functional features of the nephron, in which the ionic com position, pH , and concentration of both the tubular and interstitial fluid range widely beyond the narrow con- fines seen in other tissues. Recent genetic discoveries have offered new insights into the m olecular basis of som e of these conditions, and have raised new questions. This chapter discusses nephrocalcinosis, the relatively nonspecific result of a variety of hypercalcem ic and hypercalciuric states, as well as the renal consequences of hyperox- aluria, hypokalem ia, and hyperuricem ia. In the parathyroid gland the calcium-sensing recep- tor allows the cell to sense extracellular levels of calcium and transduce that signal to regu- late parathyroid hormone production and release. In the nephron, expression of the calcium receptor can be detected on the api- cal surface of cells of the papillary collecting Hypercalcemia duct, where calcium inhibits antidiuretic inhibits reabsorption hormone action. Thus, hypercalcemia impairs of NaCl, Ca, and M g urinary concentration and leads to isotonic polyuria. The most intense expression of the calcium receptor is in the thick ascending limb of the loop of Henle, particularly the cortical portion, where the calcium receptor protein is located on the basolateral side of the cells; this explains the known effects of hypercalcemia in inhibiting reabsorption of calcium, magnesium, and sodium chloride in the thick ascending limb. In addition, Hypercalcemia inhibits hypercalcemia causes hypercalciuria through reabsorption an increased filtered calcium load and of water suppression of parathyroid hormone release with a consequent reduction in calcium reabsorption. Ca— calcium; M g— magne- sium; NaCl— sodium chloride. FIGURE 11-2 RENAL EFFECTS OF CALCIUM H ypercalcem ia leads to renal vasoconstriction and a reduction in the glom erular filtration rate. H owever, no expression of the calci- um -sensing receptor has been reported so far in renal vascular or Hypercalcemia glom erular tissue. Calcium receptor expression is present in the Collecting duct proxim al convoluted tubule, on the basolateral side of cells of the distal convoluted tubule, and on the basolateral side of m acula Resistance to vasopressin, leading to isotonic polyuria densa cells. Functional correlates of calcium receptor expression Thick ascending limb of the loop of Henle at these sites are not yet clear. Impaired sodium chloride reabsorption, leading to modest salt wasting H ypercalciuria leads to m icroscopic hem aturia and, in fact, is Inhibition of calcium transport, leading to hypercalciuria the m ost com m on cause of m icroscopic hem aturia in children. The Inhibition of magnesium transport, leading to hypomagnesemia m echanism is presum ed to involve m icrocrystallization of calcium Renal vasculature salts in the tubular lum en. Conflicting effects of calcium on urinary Arteriolar vasoconstriction acidification have been reported in clinical settings in which other Reduction in ultrafiltration coefficient factors, such as parathyroid horm one levels, m ay explain the obser- Hypercalciuria vations. Impaired urinary acidification M etabolic Causes of Tubulointerstitial Disease 11. It is primarily medullary in most cases except in dystrophic calcification associated with inflammatory, toxic, or ischemic disease. The spectrum of causes of nephrocalcinosis is described by W rong. The numbers represent Distal renal tubular acidosis 19. It is likely that the case mix Medullary sponge kidney 11. As in other studies, the most important causes of Milk-alkali syndrome 3. The primary factor predisposing patients Hypomagnesemia-hypercalciuria 1. Causes of cortical nephrocalcinosis in this study included acute cortical necrosis, chronic glomerulonephritis, and chronic pyelonephritis. Impaired urinary acidification Alkaline urine The high urine pH favors precipitation of calcium phosphate (CaPO 4). Thus, RTA-1 should be suspected in any patient with Systemic acidosisHypercalciuria pure calcium phosphate stones. System ic acidosis also prom otes hypercal- ciuria, although not all patients with RTA-1 have excessive urinary calcium Hypokalemia Decreased urinary Resorption of excretion. H ypercalciuria results from citrate excretion bone mineral resorption of bone m ineral and the conse- quent increased filtered load of calcium as Reduced renal tubular calcium Hypercalciuria acidosis leads to consum ption of bone reabsorption buffers. Acidosis also has a direct effect of inhibiting renal tubular calcium reabsorp- CaPO precipitation tion. Conversely, nephrocalcinosis from 4 other causes can im pair urinary acidifica- tion and lead to RTA in som e patients. FIGURE 11-4 The m ainstay of therapy for RTA-1 is N ephrocalcinosis in type I (distal) renal tubular acidosis. N ephrocalcinosis and potassium citrate, which corrects acidosis, nephrolithiasis are com m on com plications in distal renal tubular acidosis (RTA-1). The m ost im portant of these factors rate excretion, and reduces urinary loss of are a reduction in urinary excretion of citrate and a persistently alkaline urine. In this nephron segm ent, sodium chloride limb of the loop of Henle is transported into the cell together with potassium by the bum et- Lumen Blood am ide-inhibitible sodium -potassium -2 chloride cotransporter (N KCC2). Recycling of potassium back to the lum en through an Na+ apical potassium channel (RO M K) allows an adequate supply of ClC-Kb NKCC2 2Cl– potassium for optim al activity of the N KCC2. Chloride exits the K+ basolateral side of the cell through a voltage-gated chloride channel (ClC-Kb), and sodium is expelled separately by the sodium -potassi- + Na+ um adenosine triphosphatase cotransporter. Inactivating m utations ROM K K ATP in N KCC2, RO M K, and ClC-Kb have been identified in patients K+ with Bartter syndrom e [6–8]. Approxim ately 20% of filtered calcium is reabsorbed in the thick ascending lim b, and inactivation of any of these three trans- port proteins can lead to hypercalciuria. N ephrocalcinosis occurs in alm ost all patients with m utations in N KCC2 or RO M K, but it FIGURE 11-5 is less com m on in patients with a m utation in the basolateral chlo- Bartter syndrom e. Bartter syndrom e is a hereditary renal functional ride channel ClC-Kb, even though patients with chloride-channel disorder characterized by hypokalem ic m etabolic alkalosis, renal m utations currently m ake up the largest reported group. This salt wasting with norm al or low blood pressure, polyuria, and interesting observation is unexplained at present.
Presentation at Fourth Banff analysis using the Banff grading schem a cheap exforge 80 mg with visa. Transplantation 1996 discount exforge 80mg overnight delivery, Conference on Allograft Pathology buy exforge 80mg on-line, M arch 7–12 safe 80 mg exforge, 1997. Frem GJ, Rennke H G, Sayegh M H : Late renal allograft failure 4. Salyer W R, Keren D:O xalosis as a com plication of chronic renal secondary to throm botic m icroangiopathy— hum an im m unodeficiency failure. Strom EH , Epper R, M ihatsch M J: Cyclosporin-associated arteri- 14. M azzucco G, M otta M , Segoloni G, M onga G: Intertubular capillary lym phocytic infiltrate: Acute rejection, post-transplantation lym pho- changes in the cortex and m edulla of transplanted kidneys and their proliferative disorder, neither, or both entities? Kelly umans are exposed intentionally and unintentionally to a variety of diverse chemicals that harm the kidney. As the list H of drugs, natural products, industrial chemicals and environ- mental pollutants that cause nephrotoxicity has increased, it has become clear that chemicals with very diverse chemical structures pro- duce nephrotoxicity. For example, the heavy metal H gCl2, the myco- toxin fumonisin B1, the immunosuppresant cyclosporin A, and the aminoglycoside antibiotics all produce acute renal failure but are not structurally related. Thus, it is not surprising that the cellular targets within the kidney and the mechanisms of cellular injury vary with dif- ferent toxicants. Nevertheless, there are similarities between chemical- induced acute tubular injury and ischemia/reperfusion injury. The tubular cells of the kidney are particularly vulnerable to toxi- cant-mediated injury due to their disproportionate exposure to circu- lating chemicals and transport processes that result in high intracellu- lar concentrations. It is generally thought that the parent chemical or a metabolite initiates toxicity through its covalent or noncovalent binding to cellular macromolecules or through their ability to produce reactive oxygen species. In either case the activity of the macromole- cule(s) is altered resulting in cell injury. For example, proteins and lipids in the plasma membrane, nucleus, lysosome, mitochondrion and C H A P T ER cytosol are all targets of toxicants. If the toxicant causes oxidative stress both lipid peroxidation and protein oxidation have been shown to contribute to cell injury. In many cases mitochondria are a critical target and the lack of adenosine triphosphate (ATP) leads to cell injury due to the depen- dence of renal function on aerobic metabolism. Increased cytosolic free Ca2+ concentrations can occur in Clinically, a vast number of nephrotoxicants can produce a the early or late phase of cell injury and plays a critical role lead- variety of clinical syndromes-acute renal failure, chronic renal ing to cell death. The increase in Ca2+ can activate calcium acti- failure, nephrotic syndrome, hypertension and renal tubular vated neutral proteases (calpains) that appear to contribute to defects. The evolving understanding of the pathophysiology of the cell injury that occurs by a variety of toxicants. During the toxicant-mediated renal injury has implications for potential late phase of cell injury, there is an increase in Cl- influx, fol- therapies and preventive measures. This chapter outlines some lowed by the influx of increasing larger molecules that leads to of the mechanisms thought to be important in toxicant-mediat- cell lysis. Two additional enzymes appear to play an important ed renal cell injury and death that leads to the loss of tubular role in cell injury, particularly oxidative injury. Phospholipase A2 epithelial cells, tubular obstruction, “backleak” of the glomeru- consists of a family of enzymes in which the activity of the lar filtrate and a decreased glomerular filtration rate. The recov- cytosolic form increases during oxidative injury and contributes ery from the structural and functional damage following chemi- to cell death. Caspases are a family of cysteine proteases that are cal exposures is dependent on the repair of sublethally-injured activated following oxidative injury and contribute to cell death. Sensitive to vasoactive compounds Nephrotoxic renal injury often occurs in conjunction with ischemic acute renal failure. Concentrates toxicants through reabsorptive and secretive processes Acute renal failure may occur in 2% to 5% of hospitalized patients and 10% to 15% of Many transporters result in high intracellular concentrations patients in intensive care units. Large luminal membrane surface area The mortality of acute renal failure is approximatley 50% which has not changed Large biotransformation capacity significantly in the last 40 years. Baseline medullary hypoxia Radiocontrast media and aminoglycosides are the most common agents associated with nephrotoxic injury in hospitalized patients. Aminoglycoside nephrotoxicity occurs in 5% to 15% of patients treated with these drugs. FIGURE 15-1 Clinical significance of toxicant-m ediated renal failure. FIGURE 15-3 FACTORS THAT PREDISPOSE THE Factors that predispose the kidney to toxicant injury. KIDNEY TO TOXICANT INJURY Preexisting renal dysfunction Dehydration Diabetes mellitus Exposure to multiple nephrotoxins Pathophysiology of Nephrotoxic Acute Renal Failure 15. FIGURE 15-5 Proximal convoluted tubule N ephrotoxicants m ay act at different sites in the kidney, resulting (S1/S2 segments) in altered renal function. The sites of injury by selected nephrotoxi- Aminoglycosides cants are shown. N onsteroidal anti-inflam m atory drugs (N SAIDs), Cephaloridine Glomeruli angiotensin-converting enzym e (ACE) inhibitors, cyclosporin A, Cadmium chloride Interferon–α and radiographic contrast m edia cause vasoconstriction. Gold, Potassium dichromate Gold interferon-alpha, and penicillam ine can alter glom erular function Penicillamine and result in proteinuria and decreased renal function. M any Proximal straight tubule nephrotoxicants dam age tubular epithelial cells directly. Renal vessels (S3 segment) Am inoglycosides, cephaloridine, cadm ium chloride, and potassium NSAIDs Cisplatin dichrom ate affect the S1 and S2 segm ents of the proxim al tubule, ACE inhibitors M ercuric chloride whereas cisplatin, m ercuric chloride, and dichlorovinyl-L-cysteine Cyclosporin A Dichlorovinyl–L–cysteine affect the S3 segm ent of the proxim al tubule. Cephalosporins, cad- m ium chloride, and N SAIDs cause interstitial nephritis whereas phenacetin causes renal papillary necrosis. Interstitium Papillae Cephalosporins Phenacetin Cadmium NSAIDs 15. Cyclosporin A is one FIGURE 15-6 exam ple of a toxicant that acts at several sites within the kidney. M echanism s that contribute to decreased glom erular filtration rate It can injure both endothelial and tubular cells. After exposure to a nephrotoxicant, results in increased vascular perm eability and hypovolem ia, which one or m ore m echanism s m ay contribute to a reduction in the activates the sym pathetic nervous system. These include renal vasoconstriction resulting in prerenal um also results in increases in endothelin and throm boxane A2 azotem ia (eg, cyclosporin A) and obstruction due to precipitation and decreases in nitric oxide and vasodilatory prostaglandins. Intrarenal factors include direct tubular ture to vasoconstrictors, activate the renin-angiotensin system , and obstruction and dysfunction resulting in tubular backleak and increase angiotensin II levels. All of these changes lead to vasocon- increased tubular pressure.
Medicalization/psychiatricization of daily life Medicalization is the defining of non-medical problems in medical terms buy exforge 80mg on line, usually as an illness or disorder generic 80 mg exforge with amex, and usually with the implication that a medical intervention or treatment is appropriate (Zola exforge 80mg amex, 1972) buy exforge 80mg with visa. Medicalization leads to “normal” human behaviour and experience being “re-badged” as medical conditions (van Praag, 2000). An early claim of medicalization (too sweeping, in the opinion of many) was the book, The Manufacture of Madness, by Thomas Szasz (1970). Double, (2002) more recently stated, “Mental health care may function as a panacea for many different personal and social problems”. It is claimed both birth (Shaw, 2012) and death (Goh, 2012) have been medicalized. Initially, the medical profession was held solely responsible for the phenomenon of medicalization, and the term “medical imperialism” was coined. For example, on the rebadging “deviance” as a series of medical disorders, sociologist Ian Robertson (1987) writes, “They have become so only because physicians – and particularly psychiatrists – have successfully claimed authority over them”. While this has been and continues to be part of the explanation, the complete answer includes broader community factors (Scott, 1990). The current “engines driving medicalization” have been identified as biotechnology (especially the pharmaceutical industry and genetics), consumers, and managed care (Conrad, 2005; Iriart et al, 2011). Dr Juan Garcia of New Zealand (personal communication) has pointed out that in literature (which is a fair proxy for the real world) medicalization may have nothing to do with doctors, and in fact, doctors may dispute the presence of any disorder. He points to two example in Macbeth by William Shakespeare (circa, 1607). The first is when Macbeth sees a ghost and his guests respond, “Gentlemen, rise, his highness is not well. The second occurs when Lady Macbeth walks and talks in her sleep. A physician is called who states “More needs she the divine than the physician”. The majority of psychiatrists working in public general hospitals lament the emergence of medicalization/psychiatricization, which has allowed the community (citizens, police, courts, and welfare agencies) to force clinical psychiatrists to accept responsibility for situations/problems over which they have no real influence. A good case can be made for the validity of psychiatric disorders such as schizophrenia, major depressive disorder, bipolar disorder and obsessive compulsive disorder. And, using “evidence based” protocols, the psychiatrist is capable of providing the best possible management for people suffering these disorders. Disorders of interest Critics raise doubts about the validity of some recently described “disorders”, many spawned by the medicalization of the difficulties of everyday life (distress). The following table lists some behaviours and potentially matching diagnoses. The intention is not to discredit these diagnostic categories, but to illustrate the potential for normal behaviour to be cast as a mental disorder. Behaviour Diagnosis Shyness Social anxiety disorder Naughtiness Conduct disorder, Childhood onset Conduct disorder, Adolescent onset Delayed language Expressive language disorder Active Hyperactivity disorder Promiscuity Sexual addiction (Schaeffer, 1997) Sexually disinterested Hypoactive sexual desire disorder Unsatisfactory erections Male erectile disorder Unsuccessful gambling Pathological gambling Amorality Antisocial personality disorder Violence Intermittent explosive disorder Apprehension Agoraphobia (specific places) Specific phobia (except places) Social phobia (social anxiety disorder) Worried Generalized Anxiety Disorder Stress at work Work stress (Wainwright & Calnan, 2002) Stress Acute stress disorder Dependent Dependent personality disorder Narcissistic Narcissistic personality disorder Attention seeking Histrionic personality disorder Factitious disorder Avoidant Avoidant personality disorder Isolative Schizoid personality disorder Excessive coffee use Caffeine intoxication Caffeine induced sleep disorder Caffeine induced anxiety disorder Smoking Nicotine dependence Excessive alcohol use Alcohol intoxication Alcohol abuse Excessive cannabis use Cannabis intoxication Cannabis abuse Pridmore S. Distress is frequently misclassified as Major depressive disorder or PTSD. Nevertheless, it is frequently medicalized by rd commentators, thus becoming a 3 topic of interest. Depression (Major depressive disorder) See Chapter 8 for additional details. Clinicians who work in psychiatric wards do not doubt the existence of Major depressive disorder. Episodes last months, but may be shortened by treatment. Early episodes may be triggered by undesired events (loss). Later episodes may occur spontaneously, without detected triggering events. Depressed (sad, unhappy) mood is one, but only one, of the symptoms of Major depressive disorder (and related psychiatrically recognised conditions such as bipolar disorder), but depressed mood alone, is not sufficient to justify the diagnosis. Other symptoms include vegetative symptoms such as changes in sleep, ability to concentrate, energy and appetite (food, sexual intimacy). A psychiatric diagnosis can only be made safely when a recognized constellation of symptoms has been present for a sufficient length of time. Medicalization and Major depressive disorder As The Buddha pointed out, many life experiences are painful (or sad, unhappy or distressing). The mistaken belief is now held by many (citizens, police, courts, and welfare agencies), that sadness/distress automatically indicates a psychiatric disorder, the need for psychiatric treatment, and the need for psychiatric services to “take responsibility” for the individual. AGE ADMIT UR DIAGNOSIS 30 15-Feb 224691 Mania 20 1-Mar 281297 Situational Crisis 1 35 26-Feb 279575 Schizophrenia 39 27-Feb 233388 Schizophrenia 30 1-Mar 327579 Situational Crisis 2 19 28-Feb 414102 Situational Crisis 3 49 27-Feb 655614 Mania 18 20-Feb 235999 Schizophrenia 56 1-Feb 209051 Schizophrenia 40 25-Feb 348912 Drug Psychosis 30 21-Feb 226554 MDD Poly sub 33 5-Mar 353365 MDD 21 30-Jan 371426 Mania 28 20-Feb 379737 Schizoaffective d/o Pridmore S. This is the “bed status” from a 36 bed psychiatric ward of an Australian teaching hospital one day in early March, 2007. Eight people had been admitted with the “diagnosis” of “situational crisis”. The DSM-IV (the system in use at the time) did not have a “diagnosis” of “situational crisis”, but was the term used in this particular hospital when patients were admitted because of complaints of distress in the absence of evidence of a psychiatric disorder, or threats by the individual that if they are not given a bed, they will self-injure. The diagnosis of “situational crisis” is a form of medicalization – in some instances because staff find it difficult to make a judgement, in other cases because the presenting individual resorts to black-mail. Other hospitals use other “diagnoses” in the same circumstances including, Depression NOS (not otherwise specified; meaning not meeting criteria of Major depressive disorder, or other depressive disorders), and Personality disorder NOS (not otherwise specified). Medicalization of distress into Major depressive disorder has been facilitated by well- meaning attempts to increase public awareness of this disorder. Non-psychiatrists have been handed puny checklists and invited to make diagnoses. They have happily co-operated, with disastrous over diagnosis of mood disorders. The World Health Organization (1996) claims there is a world-wide epidemic of depression (Ustun et al, 2004), and experts claim Major depressive disorder is frequently missed by general practitioners. A recent cross sectional study in Australia found depression and dysthymia (a mild form of depression) in 5. Arguments against the epidemiological studies which underpin the “epidemic” story include that the symptom checklists which have been used do not take into account the circumstances and the meaning of those circumstances to the individuals being examined (Jacob, 2006; Summerfield 2006a). Differentiating distress from Major depressive disorder can be difficult (Pilgrim & Bentall, 1999) and, distress is part of normal reaction to stress, a common feature of people facing the demands of life (Jacob, 2006). Progressive medicalization of distress has lowered the threshold of individuals to tolerate mild symptoms and encouraged the seeking of medical attention (Barsky and Borus, 1995). The social supports available to the individual have been reducing over the last century, and the mental health team in now providing the psychological and social support which was previously provided by the family and local community (Jacob, 2006). Antidepressants have become the panacea for loneliness, relationship difficulties, interpersonal conflicts, inability to cope with day to day stress.
The qual- tic and postsynaptic dopamine abnormalities discount 80 mg exforge fast delivery, related to ex- ity of future clinicopathologic correlations will be enhanced trapyramidal dysfunction buy generic exforge 80mg online, including sensitivity to neurolep- by the prospective acquisition of clinical data in longitudinal tic medication cheap 80 mg exforge with amex. The recognition of DLB is clinically studies with the use of standardized and validated instru- important in view of the high incidence (60%) of adverse ments buy cheap exforge 80 mg online. For example, levodopa-induced 'on/off' responses and have not been described in DLB to any extent, but some dyskinesias have not been reported in DLB, as they have show promise as potential markers to differentiate DLB in PD. This may be because parkinsonism is generally less from AD. These include relative preservation of temporal severe and may take longer to develop than DLB or because lobe structures on MRI and loss of presynaptic and post- distinct striatal pathology (e. Novel therapies aimed at relieving parkinsonism DLB respond positively to cholinesterase inhibitors with that do not exacerbate neuropsychiatric features are needed. In relation to ACKNOWLEDGMENTS neuropsychopharmacology, the disease provides a unique opportunity to understand mechanisms underlying symp- The secretarial assistance of Maureen Middlemist and Lor- toms such as hallucinations and disturbances in conscious- raine Hood is gratefully acknowledged. In terms of understanding the core pathologic mecha- 1. Diffuse intracytoplasmic nisms, however, as in AD and PD, the objective of disease inclusions (Lewy type) associated with progressive dementia and prevention still appears to be a long way off. Diffuse type of Lewy tive inclusions in cortex and substantia nigra and decreased body disease: progressive dementia with abundant cortical Lewy dopamine levels in basal ganglia (113). It is interesting that bodies and senile changes of varying degree—a new disease? Operational criteria ologically distinct form of dementia in the elderly. Lancet 1989; for senile dementia of Lewy body type (SDLT). Neuroleptic sensitivity correlative neuropathology using anti-ubiquitin immunocyto- in patients with senile dementia of Lewy body type. J Neurol Neurosurg Psychiatry 1989;52:1236– 1992;305:673–678. Neuropathological and biochemical studies of six pa- Psychiatry 1993;162:385–392. The Lewy body variant pathological findings in Lewy body dementias. Psychiatric features in diffuse ical aspects of differential diagnosis. Neurobiol Aging 1998; Lewy body disease: findings in 28 pathologically diagnosed 19:S4. J Neurol Neurosurg Psychiatry 1996;60:531– 1999;96:13450–13455. Acta Neuropathol 1996;91: Int J Geriatr Psychiatry 2000;15:267–273. Neu- (A beta) deposition in dementia with Lewy bodies: predomi- rology 1998;51:351–357. Simple standardised neuro- amyloid subtypes 40 and 42 differentiates dementia with Lewy psychological assessments aid in the differential diagnosis of bodies from Alzheimer disease. Lewy body type and Alzheimer type are biochemically distinct 35. REM sleep behavior in terms of paired helical filaments and hyperphosphorylated disorder and degenerative dementia: an association likely reflect- tau protein. Prevalence of par- disease is usually the Lewy body variant, and vice versa. J Neuro- kinsonian signs and associated mortality in a community popu- pathol Exp Neurol 1993;52:648–654. A clinically and neuropathologically distinct form Ageing 1999;28:401–409. Comparison of extrapyrami- robiol Aging 1997;18:S1–S2. J Neurol Neurosurg Psychiatry 1989; Lewy bodies: reliability and validity of clinical and pathologic 52:709–717. A detailed phenomeno- and sporadic and familial dementia with Lewy bodies. Neuro- logical comparison of complex visual hallucinations in dementia report 1998;9:3925–3927. Report of the second demen- Ann Neurol 1995;37:110–112. Clin Neuropharmacol 1994;17: tion of diagnostic criteria for dementia with Lewy bodies. Apolipoprotein E epsilon4 disorder and dementia: cognitive differences when compared is associated with neuronal loss in the substantia nigra in Alzhei- with AD. The apolipo- tivities in Lewy body dementia: relation to hallucinosis and protein E epsilon 4 allele increases the risk of drug-induced extrapyramidal features. The CCTTT polymorphism in Neural Transm 1999;106:525–535. Failure to find an associa- muscarinic receptors in dementia of Alzheimer, Parkinson and tion between an intronic polymorphism in the presenilin 1 gene Lewy body types. J Neurol Neurosurg Psychiatry alpha-1 anti-chymotrypsin polymorphism genotyping in Alz- 1999;67:209–213. Butyrylcholinesterase otoxin and nicotine binding in the thalamus. J Neurochem 1999; K: an association with dementia with Lewy bodies. Correlation neuropathology, cholinergic dysfunction and synapse density. What is the neuropathological Neurobiol Aging 1998;19:S207. Striatal dopami- 'prefrontal' and 'limbic' functions. Delayed emergence nergic activities in dementia with Lewy bodies in relation to of a parkinsonian disorder in 38% of 29 older men initially 1314 Neuropsychopharmacology: The Fifth Generation of Progress diagnosed with idiopathic rapid eye movement sleep behavior of the Alzheimer-type and diffuse Lewy body disease. Psychol Med 1999;29: dopaminergic degeneration in dementia with Lewy bodies. Dementia with Lewy atrophy on MRI in dementia with Lewy bodies. Neurology 1999; bodies: a study of post-synaptic dopaminergic receptors with 52:1153–1158. MR-based hippo- of dementia with Lewy bodies: a case series of nine patients. Neuroleptic sensitivity from normal ageing, depression, vascular dementia and other to clozapine in dementia with Lewy bodies. Diagnostico clinico with Lewy bodies: a clinical study.
Serotonin also inhibits locomotion quality 80 mg exforge, appar- anesthetics have not been conclusively identified exforge 80mg without a prescription. In princi- ently by inhibiting neurotransmitter release from excitatory ple cheap exforge 80 mg, this problem appears ideally suited to attack by a pheno- motor neurons (32 exforge 80mg sale,33). The signal transduction mecha- type-driven genetic approach; by identifying mutants that nisms that mediate both of these actions of serotonin have are resistant or hypersensitive to anesthetics and cloning been analyzed genetically, and in both cases the phospholi- and sequencing the mutant genes, it should be possible to pase C (PLC) homologue egl-8 is required for serotonin identify anesthetic targets that are essential for anesthesia response. In the egg-laying muscles, the effects of PLC ap- in vivo. In fact, such screens have been conducted in both pear to be mediated through the protein kinase C homo- Drosophila and C. At present, none of tant mediator appears to be the diacylglycerol-binding the Drosophila anesthetic response genes have been cloned; synaptic protein UNC-13. The involvement of the phos- thus, molecular information about their gene products is phoinositide signaling pathway in serotonin signal transduc- not available. At lower concentrations (similar to the alveolar con- ways mediating serotonin response in C. Although this effect is behaviorally quite dissimilar netic analysis in C. As noted previously, the allevia- from anesthesia, it is similar to the effect of many mutations tion of depression by serotonin-potentiating antidepressants that affect synaptic transmission in C. In fact, treat- is thought to involve adaptive signaling pathways that are ment with volatile anesthetics confers resistance to the be- activated by prolonged elevation of serotoninergic neuro- havioral effects of cholinesterase inhibitors (38), a hallmark transmission. Thus, at these con- has been shown to lead to adaptive down-regulation of egg- centrations, volatile anesthetics appear to act presynaptically laying behavior and recovery from serotonin-induced paral- to interfere with synaptic transmission in C. Genes encoding possible components of serotonin ber of mutants with altered sensitivity to these low-concen- adaptation pathways have been identified on the basis of tration effects of volatile anesthetics have been identified. Future nents of the SNARE complex, the presynaptic machinery analysis of serotonin adaptation genes may provide insight that mediates synaptic vesicle fusion. Recessive mutations into the molecular mechanisms underlying long-term re- in at least three SNARE genes, unc-64 [encoding C. Furthermore, a novel mutation Volatile Anesthetics in unc-64, which affects a spice receptor site and conse- A variety of volatile molecules, including diethyl ether, halo- quently leads to the production of truncated syntaxin pep- thane, and isoflurane, are capable of inducing general anes- tides, confers strong resistance to the effects of volatile anes- thesia, a behavioral state involving loss of consciousness, thetics on both coordinated movement and cholinesterase analgesia, amnesia, and loss of motor activity. These results suggest that volatile anes- these agents have been widely used in surgery for over a thetics interfere with synaptic transmission through direct century, their mechanism of action remains poorly under- interaction with one or more members of the SNARE com- stood. General anesthesia appears to result from defects in plex. Interest- ber of receptors and channels, including the N-methyl-D- ingly, none of the synaptic mutations affecting the low- aspartate (NMDA), serotonin, and -aminobutyric acid concentration effects on coordinated movements affect this (GABA) receptors and various voltage-gated ion channels, high-concentration paralytic response. However, a different, appear to be modulated by the presence of ethanol (45). Several of these genes have been cloned, in- choactive effects of ethanol; however, a variety of experi- cluding unc-1, which encodes a homologue of stomatin ments in cultured cells suggest that a critical short-term (41), and unc-8, which encodes a subunit of the degenerin/ effect of ethanol is to enhance receptor-mediated synthesis ENaC family of passive sodium channels (42,43). Both unc- of the second messenger 3′,5′-cyclic adenosine monophos- 1 and unc-8 are expressed in neurons, and both genes can phate (cAMP). Conversely, long-term ethanol exposure ap- be mutated to confer either resistance or hypersensitivity to pears to decrease intracellular cAMP levels. Allele-specific genetic interactions between and chronic effects of ethanol have also been linked to unc-1, unc-8, and the yet uncloned unc-79 and unc-80 genes changes in dopaminergic neurotransmission (46). In partic- suggest that their products may physically interact in a mul- ular, ethanol has been shown to promote release of dopa- timeric channel complex specifically involved in anesthetic mine in the mesolimbic pathways of the brain, in particular responses. Since stomatin has been shown to function as the so-called reward pathway synapses between the ventral a negative regulator of cation channels in erythrocytes, a tegmental area (VTA) and the nucleus accumbens (NAc). Homologues of both stomatins remains to be determined. Moreover, although sensitivity and ENaC channels have been identified in mammals, and to both the acute and chronic effects of ethanol are clearly are known to be expressed in the central nervous system; affected by genetic factors, the nature of the genes affecting thus, in principle stomatin-regulated ENaC channels could human ethanol sensitivity are not known. Recent work in Drosophila has provided support for both In summary, there are two distinct sets of genes that the dopamine and cAMP hypotheses of ethanol action. At present, it is not clear which of and ultimately immobilization. Using an instrument called the two (or whether both) might encode homologues of an inebriometer (47), lines of mutant flies have been identi- biologically relevant human anesthetic targets. Although the fied that exhibit abnormal sensitivity to volatilized ethanol. Conversely, although the stomatin/de- lian pituitary adenylyl cyclase activating peptide (PACAP) generin genes affect a paralytic response that closely resem- (48,49). Consistent with the implications of this homology, bles anesthesia, the response also has a relatively long time the effects of amnesiac on ethanol response appeared to delay and occurs at concentrations well above those clini- involve the adenylyl cyclase pathway, since the adenylyl cy- cally relevant in humans. Given the effective drug concen- clase activator foskolin blocks the ethanol sensitivity associ- trations for these two behavioral responses, it is possible that the synaptic genes might encode targets relevant to ated with amnesiac loss-of-function mutations. Moreover, anesthesia, while the stomatin/degenerin genes might en- several other loss-of-function mutations affecting cAMP code targets relevant for side effects of anesthetics. Alterna- pathway components, including the adenylyl cyclase gene tively, it is possible that genes affecting high-concentration rutabaga and the cAMP-dependent protein kinase gene anesthetic responses do define molecules involved in anes- DCO, also conferred ethanol sensitivity. Although one thesia, especially since the nematode cuticle is relatively im- might suppose based on these results that the response to permeant and presents a significant barrier for the entry of ethanol is simply a function of the level of cAMP signaling many drugs. Since well-defined mammalian homologues in the relevant neuronal targets (with increased ethanol re- exist for both classes of anesthetic response genes, it should sponse corresponding to low cAMP signaling), a variety of be possible in the future to examine these issues directly in data are inconsistent with this simple model. Nonetheless, these ge- Drugs of Abuse netic data provide the first conclusive link between the activ- ity of the cAMP pathway and the behavioral effects of Ethanol ethanol in an intact organism; the precise nature of that Unlike many neuroactive substances, ethanol is not believed link remains to be determined, but should be accessible to to have a single molecular target in neurons; rather, a num- further genetic analysis. During the first 7 to 10 minutes of Genetic analysis in C. When flies are depleted of dopamine through traction of body wall muscles, stimulation of egg laying, ingestion of a tyrosine hydroxylase inhibitor, they become and increased pharyngeal pumping. The effects of nicotine significantly less susceptible to this stimulation of motor on the body and egg-laying muscles are mediated through activity by ethanol. However, these dopamine-depleted flies a nicotinic receptor known as the levamisole receptor (57, exhibited no abnormalities in their sensitivities to ethanol- 58). The antihelminthic drug [and ganglionic nAChR ago- induced uncoordination or immobilization. Thus, the stim- nist (59)] levamisole is a potent agonist of this receptor; like ulation of motor activity by ethanol may involve ethanol- nicotine, levamisole causes body muscle hypercontraction induced enhancement of dopaminergic transmission in and (at high doses) spastic paralysis. Although the levamisole brain areas controlling locomotion, whereas the other be- receptor is found on nematode muscle, its pharmacologic havioral effects of ethanol are likely to involve other neuro- profile generally resembles that of ganglionic nicotinic re- transmitter systems. By screening for levamisole-resistant The genetic analysis of ethanol response mechanisms in mutants, it has been possible to identify genes affecting the Drosophila is still in its early stages. However, it is already function of the levamisole receptor (60).
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