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Awareness and understanding of the Predictive RIsk Stratification Model Awareness of the PRISM tool among community health staff and managers at baseline was generally high purchase micardis 40 mg on line hypertension young women, largely because respondents had already come across it generic micardis 40mg otc hypertension 1 symptoms, and in some cases worked directly with it micardis 80mg with mastercard blood pressure procedure. It had been an intrinsic component of a pilot virtual ward development in part of the ABM UHB area generic micardis 20mg free shipping arrhythmia consultants of connecticut, when piloted prior to the PRISMATIC study. Many of the respondents indicated a generally high level of understanding of the details of PRISM in terms of its technical functioning, though there were still some uncertainties about, for example, the differences between relative and absolute risk. A minority of respondents, despite feeling generally positive about the potential benefits of PRISM, reported some specific concerns. Respondents also identified a potential problem with the PRISM approach of identifying relative risk, practice by practice – and as practice lists vary widely, this could produce inequity as patients in the highest category of risk in one practice might actually be at much less risk than patients in another practice, who were further down in the stratification: Well, how do we make – how do we manage need across a whole population, not just at a practice level? Respondent 5, focus group E Respondents described their understanding of how PRISM could be used as a resource by practitioners in order to support case finding of patients who might benefit from case management. But, actually, you can keep select – you can select however many you want. Respondent 1, focus group E 76 NIHR Journals Library www. Another community nurse, working across four different practices, was concerned about another practical challenge. As PRISM rolled out, she would have to visit each practice to access PRISM separately, and would need to enter four different access codes. How do we make sure we target our resources to the most effective area, and how do we ensure that people come out of service as well as come in? One respondent suggested that, for those GP practices that had not signed up to the PRISMATIC study, there was a list of anxieties that were still current:. As one health service manager with responsibility for service redesign said: Clearly the PRISMATIC tool is of great interest to me in terms of how that can support redesign in the community. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 77 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. STAKEHOLDER VIEWS: THE PREDICTIVE RISK STRATIFICATION MODEL IMPLEMENTATION AND USE Respondents identified scope for PRISM to support strategic service development and management in further ways. The first way was to measure the effectiveness of service change – instead of waiting to see impact on admissions, see what change there is in risk scores. A second way would be to support workforce modelling as part of service redesign. Third, respondents talked about the potential for using PRISM as a way of benchmarking within a network: [If] you can start to see maybe some networks, maybe some practices, have got these much higher risks then – and then you try and work out why. Respondent 1, focus group E There was an acknowledgement, though, that if the tool were seen as part of a performance management regime, this could create resistance to its adoption in practices. In terms of the work of putting PRISM into practice, respondents felt that practices were likely to vary greatly in their enthusiasm, and that peer-to-peer influence would be helpful, particularly through the practice networks. Views of general practitioners and practice staff on the Predictive RIsk Stratification Model risk prediction tool We now present the views of GPs and practice staff from data collected both before they had access to the PRISM tool and while it was available for use in their practices (mid-trial and end-of-trial fieldwork). To understand how these potential users perceived the technology and implemented it within their health-care practice, we present findings in line with the theoretical framework offered by NPT. Table 38 presents a summary of key findings in relation to the four components of NPT, which we then expand on in the text which follows. TABLE 38 Summary of findings from interviews with general practice staff Questions to consider within the Findings from interviews with GPs using NPT component NPT framework PRISMATIC Coherence (i. GPs found the PRISM tool easy to understand sense-making by participants) because they recognised the principles of risk prediction Is it clearly distinct from other PRISM predicted risk resulting from health and interventions? Are target user groups likely to think GPs found that PRISM was very relevant in commitment and engagement it is relevant and usable? Competing demands on time and resources and technical problems limited their willingness to use PRISM Collective action (i. Ideas about how to use the data intervention function) in patient care came from focus groups, their own aims or QOF How will the intervention affect the GPs felt that PRISM helped them complete the work of user groups? Other use was infrequent and inconsistent across GPs Will it promote or impede their PRISM was easy to use, but technical problems work? Will it be clear what effects the GPs were unsure of effects on emergency participants reflect on or intervention has had? It was difficult to fit use of PRISM into the reactive structure of practices How are users likely to perceive the PRISM was not used in practices after the intervention once it has been in use completion of the QOF process for a while? Can users/staff contribute feedback Lack of time and treatment options for about the intervention once it is in high-risk patients limited use of PRISM use? Can the intervention be adapted or Respondents identified technical changes to improved on the basis of experience? Normalisation process theory: a framework for developing, evaluating and implementing complex interventions. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 79 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. STAKEHOLDER VIEWS: THE PREDICTIVE RISK STRATIFICATION MODEL IMPLEMENTATION AND USE Understandings and expectations of the Predictive RIsk Stratification Model tool In this section, we describe how respondents discussed what they understood PRISM to be before they started to use it, and how it offered something distinct from existing practice. These views relate to the first component of the NPT framework – coherence or making sense of the intervention and are drawn from the interviews and focus groups conducted at baseline. The PRISM tool was not seen as something entirely new. Most agreed that risk scores needed to be interpreted by GPs, informed by their knowledge of individual patient situations. GP09base, interview However, a range of reservations was expressed by many of the respondents. We felt that the chance of this churning out unexpected patients was probably pretty low. I mean, it assumes first of all that you can predict it, but secondly it presumes that some of these things are modifiable. GP15base, interview There were also concerns that resources might not be available to meet any identified needs. If these were not available, then the scope for PRISM to make a difference would be limited: We have to have a system in place, where there is an alternative. GP11base, interview Respondents described how being unable to respond to identified needs would be likely to create frustration among clinicians and disappointment among patients. There were also, among a minority of respondents, anxieties about implications in terms of performance management, if practices were to identify needs but then fail to respond to them: So, if your patient has a certain level of risk, in the top 5%. GP12base, focus group C Though the function of PRISM was generally identified as being individual case finding, a minority of respondents recognised a potential role in service planning.

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The GDG also noted that adequate iron in the diet is important in CKD and restricting protein intake may adversely influence iron intake generic micardis 20mg line prehypertension blood pressure values. The GDG agreed that the studies combined in the meta-analysis by Pedrini et al buy cheap micardis 40 mg on-line blood pressure higher in right arm. It was also noted that some of the studies were carried out at a time when the pharmacological management purchase 40 mg micardis fast delivery heart attack lyrics one direction, particularly the use of ACE inhibitors generic micardis 40 mg fast delivery heart attack warnings, was likely to be different. The individual studies were examined and the GDG agreed that there was limited evidence that there may be a benefit of protein restriction in patients with stage 4 and 5 CKD, but the evidence did not point to an optimal protein intake. R37 Where dietary intervention is agreed this should occur within the context of education, detailed dietary assessment and supervision to ensure malnutrition is prevented. R38 Offer dietary advice to people with progressive CKD concerning potassium, phosphate, protein, calorie and salt intake when indicated. The optimal treatment target remains poorly defined and considerable confusion has occurred because there is a lack of conformity between recommended treatment targets in different disease guidelines and in the Quality and Outcomes Framework. The objective of this section was both to consider the evidence and to rationalise treatment targets with those recommended by the NICE guidelines for management of type 2 diabetes and hypertension. Although the hypertension guideline did not recommend home monitoring recent data shows that self-measurement leads to less medication use than clinic blood pressure measurement without leading to significant differences in outpatient values of blood pressure. Antihypertensive therapy should be adjusted to achieve blood pressure <130/80, or <125/75 mmHg for those with a PCR >100 mg/mmol. The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines35 recommend achieving blood pressure <130/80 mmHg and the SIGN guidelines32 recommend a target maximum systolic blood pressure of 130 mmHg in those with 1 g/day of proteinuria. CARI guidelines are more proscriptive, recommending a target blood pressure of <125/75 mmHg in those with proteinuria >1 g/day but acknowledging that the precise goal below 130/80 mmHg is not clear. The British Hypertension Society guidelines define optimal blood pressure control in people with kidney disease as <130/80 mmHg and suggest reducing blood pressure to <125/75 mmHg in those with proteinuria ≥1 g/24 h. All post-hoc analyses of RCTs were downgraded to level two evidence. A case series (N=860, follow-up 10 years) investigated the association of systolic blood pressures <133 mmHg and mortality in a cohort of men (mean age 68±10 years) with stages 3 to 5 CKD. Two post-hoc analyses of the Irbesartan in Diabetic Nephropathy Trial (IDNT) RCT (N=1590, median follow-up 2. Diastolic blood pressure was not significantly associated with all-cause mortality, cardiovascular mortality, or congestive heart failure. There was a significantly higher risk of cardiovascular mortality for people with an achieved SBP <120 mmHg compared with SBP >120 mmHg. People with an achieved SBP ≤120 mmHg had a significantly greater risk of congestive heart failure compared to people with an achieved SBP >120 mmHg. For people with baseline urinary protein excretion >3 g/day (N=32), there was a benefit of intense control (GFR decline 5. There was NS risk for the combined renal endpoint 104 9 Blood pressure control between people with achieved SBP 130–139 mmHg (N=401) compared to people with achieved SBP <130 mmHg (N=278). People with an achieved DBP <70 mmHg (N=365) had a significantly lower risk of reaching the combined renal endpoint compared with those with an achieved DBP of 90–99 mmHg (N=152). People with an achieved DBP of 90–99 mmHg (N=144) had a significantly higher risk of reaching ESRD or death compared to people with achieved DBP <70 mmHg (N=377). People with achieved SBP 140–159 mmHg (N=518) had a significantly higher risk of reaching ESRD or death compared with people with achieved SBP <130 mmHg (N=286). Achieved SBP 140–159 mmHg (N=518) was associated with a significantly higher risk of reaching ESRD compared with achieved SBP <130 mmHg (N=286). Achieved DBP of 90–99 mmHg (N=144) was associated with a significantly higher risk of reaching ESRD compared to achieved DBP <70 mmHg (N=377). For people with urine protein excretion ≥1 g/day, there was NS risk for renal disease progression when SBP was 120–129 mmHg compared with SBP 110–119 mmHg. For people with urine protein excretion ≥1 g/day, there was a significantly increased risk for renal disease progression when SBP was 130–139 mmHg (RR 4. This was seen in people with baseline proteinuria >0. In a cohort of type 1 diabetic patients with nephropathy (N=301), more people with a lower follow-up MAP achieved remission. Stratified by MAP: MAP 93 mmHg (58% remission), MAP 99 mmHg (33% remission), MAP 103 mmHg (25% remission), MAP 107 mmHg (20% remission), MAP 113 mmHg (17% remission). In a cohort of type 1 diabetic patients with nephropathy (N=301), more people with a lower follow-up MAP achieved regression. Stratified by MAP: MAP 93 mmHg (42% regression), MAP 99 mmHg (32% regression), MAP 103 mmHg (11% regression), MAP 107 mmHg (20% regression), MAP 113 mmHg (17% regression). The adjusted odds ratio for regression associated with a 10 mmHg decline in MAP was 2. SBP >120 mmHg (IDNT*) continued 106 9 Blood pressure control Table 9. Intense MAP control – – creatinine clearance usual MAP control (MDRD) (GFR decline 5. SBP <130 mmHg (RENAAL*) ESRD or death NS risk intense vs. SBP <130 mmHg (RENAAL*) Doubling serum NS risk SBP <110 to NS risk SBP 120–129 – – creatinine or ESRD >160 mmHg (Jafar vs. DBP <65 mmHg (US vet) Cardiovascular – – – DBP not predictive mortality (IDNT*) Congestive heart – – – DBP not predictive failure (IDNT*) Myocardial infarction – – – ↑ Risk DBP <70 mmHg vs. DBP <70 mmHg (RENAAL*) ESRD or death – – – NS risk DBP 70–-89 mmHg vs. DBP <70 mmHg (RENAAL*) ESRD – – – NS risk DBP 70–89 mmHg vs. DBP <70 mmHg (RENAAL*) Doubling serum DBP not predictive DBP not predictive – – creatinine or ESRD (Jafar meta-analysis) (Jafar meta-analysis) *Post-hoc analysis. Evidence relating to lifestyle advice (such as salt restriction) in blood pressure control can be found in the NICE clinical guideline 34 on hypertension. The evidence presented suggests that there are optimal ranges, with increased risk of adverse outcomes both above and below the optimal range, for both systolic and diastolic blood pressure. In practice, when treatment is given to maintain the systolic blood pressure in the optimal range, this results in the diastolic blood pressure falling below its optimal range. Recommendations were therefore made for a systolic range and a diastolic threshold. In people with CKD without diabetes, there is some evidence to suggest lower blood pressure targets in those with a threshold level of proteinuria equivalent to an ACR of ≥70 mg/mmol, or PCR ≥100 mg/mmol (approximately equivalent to urinary protein excretion of ≥1 g/day). In order to be consistent with the available evidence on ACEI/ARB therapy a threshold level of proteinuria at which ACEI/ARBs should also be recommended for blood pressure control in people without diabetes was set at an ACR of ≥30mg/mmol, or PCR ≥50 mg/mmol (approximately equivalent to a urinary protein excretion of 0. R40 In people with diabetes and CKD or when the ACR is ≥70 mg/mmol, or PCR ≥100 mg/mmol (approximately equivalent to PCR ≥100 mg/mmol, or urinary protein excretion ≥1. Danger zones: systolic blood pressure 120 130 140 150 160 Increased risk of: Increased risk of: Increased risk of: • mortality • 2 x SCr or ESRD* • 2 x SCr, ESRD or death • CV mortality • ESRD or death • stroke • ESRD • congestive heart failure *When proteinuria >1 g/24 h Danger zones: diastolic blood pressure 60 70 80 90 100 Increased risk of: Increased risk of: • mortality • 2 x SCr, ESRD or death • myocardial infarction • ESRD or death • decline in GFR • ESRD Figure 9. Hypertension is extremely common in people with CKD and the mean number of antihypertensive agents prescribed is associated with the stage of CKD, increasing as GFR falls. The UK CKD guidelines15 recommend that ACEI/ARBs should be used as first line therapy only for people with diabetic kidney disease and for those with proteinuria (urine PCR >100 mg/mmol) and this was endorsed by the UK consensus conference.

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Most studies conducted thus far sug- with OCDwho would not even have presented for treat- gest that OCDis chronic and lifelong generic 80 mg micardis overnight delivery pulse pressure 46. Previous studies have been hampered by a also expanded significantly in the last 10 years discount 40mg micardis with visa arrhythmia practice strips. Treatment number of methodologic limitations purchase micardis 20mg without a prescription hypertension young age, including a lack of centers specializing in OCDhave succeeded in enrolling standardized assessments 80mg micardis for sale hypertension 8 weeks pregnant, small numbers of subjects, and a large cohorts of patients, so that a more sophisticated analy- sample bias toward more severely ill patients. The introduc- sis of the heterogeneity and comorbidity of OCDand the tion of effective treatments for OCDin the last 10 years relationship of these variables to treatment outcome has also raises the question of the relevance of course studies been possible. Prospective observational studies of the longi- conducted in a pretreatment era. It has into the clinical characteristics and prognosis of the illness been described in children as young as age 2 (7) and also (3). Improvements in methodology, including the develop- in the very elderly (8). Evidence supports the hypothesis ment of structured interviews with proven reliability and that OCDis a heterogeneous disorder with multiple causes validity, the application of survival analysis and other statis- (9). Neurobiologic studies have demonstrated abnormalities tical techniques to assess longitudinal variables, and more in frontostriatal–basal ganglia circuitry (10). Like any organ sophisticated database management systems, have been in- system, these neural circuits are susceptible to a variety of strumental in these advances. Identifying homogeneous subgroups of patients with OCDshould help in unraveling its neurobiologic pathogen- Steven A. Rasmussen: Brown University, Butler Hospital, Providence, esis and developing more specific and effective treatment Rhode Island. Eisen: Department of Psychiatry and Human Behavior, Brown strategies. This chapter reviews data related to the clinical features 1594 Neuropsychopharmacology: The Fifth Generation of Progress and course of OCDduring the lifespan. It focuses on the dren of parents with OCDfor subsequent development of heterogeneity and comorbidity of the disorder in relation the disorder is poorly defined. No data are available that to its course, and points to a new wave of studies that should would make it possible to predict this transition. Similarly, complement neurobiologic and genetic studies of the patho- almost no data are available relating the effect of continuing genesis of OCD, lead to fuller recognition of its impact on subthreshold symptoms during a period of remission to the society, and help to measure the effectiveness of behavioral likelihood of relapse in adults. Prospective quantitative lon- and pharmacologic treatment strategies that have been de- gitudinal assessment of probands with subthreshold symp- veloped during the past two decades. SUBTHRESHOLD SYMPTOMS DEVELOPMENTAL PSYCHOPATHOLOGY It is generally agreed that it is the frequency of obsessions Little systematic study of the developmental antecedents of and compulsions, in addition to the degree with which they OCDhas been carried out since Janet. In his Obsessions interfere with function, that distinguishes normal from ab- and Psychasthenia, Janet (19) postulated that obsessions and normal. A patient must have had an hour of obsessive-com- compulsions are the most severe stage of an underlying pro- pulsive symptoms daily for a period of 6 months that inter- dromal state that he called psychasthenia, a syndrome charac- fere with social or occupational function to meet DSM-IV terized by feelings of incompleteness and imperfection. This requirement has tradi- hypothesized that all patients in whom obsessions and com- tionally been thought to translate to a score of 16 or higher pulsions develop pass through a prodromal stage of psychas- on the Yale–Brown Obsessive-Compulsive Scale (Y- thenia. His clinical descriptions of the temperamental fea- BOCS). Like symptoms of anxiety, obsessive-compulsive tures of psychasthenics coincide remarkably well with our symptoms are present to some degree in most people. Rach- preliminary findings of the prodromal symptoms of patients man and Hodgson (12) found that a high percentage of the with OCD. His description of the patient who 'finds on normal population report some obsessions and compul- the stairway the word that needed to be said in the parlor' sions. Similarly, after screening 861 Israeli military recruits is an astute clinical description and close analogue of the at 16 years of age, Apter et al. It is worth noting that Janet included three of the toms and severe impairment on the other. The receiver op- five elements of DSM-III compulsive personality disorder in erating characteristics that would best distinguish the clini- his description of the psychasthenic state: perfectionism, cal from the subthreshold syndrome of OCDhave yet to restricted emotional expression, and indecisiveness. Goodman (15) screened 958 college students and pean diagnostic schema for anacastic personality is more identified 23 subjects with subclinical OCD. Deter- A retrospective study of 90 of our OC probands in which mining where the clinical syndrome begins and ends is im- a semistructured format was used was designed to elicit pro- portant for pharmacologic and genetic studies. For example, dromal personality traits or temperamental factors com- the multicenter collaborative studies of the selective seroto- monly found in OCD(22). During this study, we identified nin reuptake inhibitors (SSRIs) in OCDnoted a higher 10 factors commonly found in our adult OC probands as rate of response to placebo in patients with Y-BOCS scores children (Table 111. These traits tended to vary mini- between 16 and 20, a finding that prompting some investi- mally during the childhood and adolescent years. Family genetic cantly with the behavioral inhibition syndrome in children studies have shown a higher risk for both subthreshold and that Kagan et al. Four of the developmental clinical OCDin OCDprobands (18). The clini- tance to change or novelty, risk aversion, and submissive- cal significance of subthreshold symptoms in childhood ness. Four of the traits are more specific to OCD: perfec- continues to be poorly understood. The risk carried by chil- tionism, ambivalence, excess devotion to work, and Chapter 111: Obsessive-Compulsive Disorder 1595 TABLE 111. BEHAVIORAL INHIBITION Brown OC Study Separation anxiety Age of onset in Obsessive Compulsive Disorder Resistance to change or novelty Risk aversion 50 Submissiveness (compliance) Female Sensitivity Anacastic Male Perfectionism Hypermorality 40 Ambivalence Excess devotion to work 30 excessive morality. The relationship of adult personality characteris- 10 tics and clinical subtypes to developmental antecedents awaits further analysis. It appears that some traits are more commonly seen in particular phenomenologic presentations (e. It is probable that temperamental factors such as behavioral inhibition increase the risk for the develop- FIGURE 111. Age at onset in obsessive-compulsive disorder in ment of a number of psychiatric syndromes. An informative to determine the relative risk for development overviewof obsessive-compulsive disorder. Obsessive-compulsive disorders practical of each of the major anxiety syndromes by following a group management, third ed. Louis: Mosby, 1998;3–11, with permis- of children with behavioral inhibition longitudinally. It is also worth noting that a significant mi- nority of patients with OCDdo not manifest risk-aversive in fewer than 15% of obsessional patients (Fig. Further prospective study of the de- significant increase in incidence appeared at puberty. Most velopmental antecedents of OCDand prospective longitu- adult patients remembered having minor obsessive-compul- dinal evaluation of children at risk should be an important sive symptoms that did not significantly interfere with their area for future research. Although male patients noticed minor AGE AT ONSET symptoms earlier than female patients, the difference did not reach statistical significance.

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Development of selective purino- the P2X7 receptor Neuropharmacology 1997;36:1277–1283 discount 40mg micardis amex blood pressure goes down when standing. Allosteric enhancement of adenosine A1 re- gated cation channels change their ion selectivity in seconds buy micardis 80mg cheap arrhythmia signs. Nat ceptor binding and function by 2-amino-3-benzothophenes buy micardis 20mg on line arrhythmia while sleeping. Adenosine A3receptors: novel ligands and paradox- phosphates buy micardis 40 mg free shipping arrhythmia recognition chart, extracellular function and catabolism. Cloned adenosine A3 receptors: pharmacological prop- 55. Mitochondrial disorders: clinical and ge- approaches in experimental therapeutics. P2 Purine and pyrimidine receptors: neuromodulation: a historical perspective. In: Jacobson KA, Jarvis emerging superfamilies of G-protein coupled and ligand gated MF, eds. Aggressiveness, zation of recombinant human and rat P2X receptor subtypes. Reduced vas defer- multiple ATP subtypes during the differentiation and inflamma- ens contraction and male infertility in mice lacking P2X1 recep- tory activation of myeloid leukocytes. Curr Opin Neuro- display urinary bladder hyporeflexia and reduced nocifensive be- biol 1997;7:346–357. Decreased platelet aggrega- and P2X5receptor subunits reveals a novel ATP-gated ion chan- tion, increased bleeding time and resistance to thromboembolism nel. Effect of loss of Annu Rev Pharmacol Toxicol 2000;40:563–580. P2Y2receptor gene expression on nucleotide regulation of murine 40. How should P2X receptors be classified phar- epithelial Cl transport. Lack of specificity of [35S]- ing regulates radical-mediated bacterial killing mechanism in ATP S and [35S]-ADP S as radioligands for inotropic and meta- macrophages through a P2X -independent mechanism. Modulators of adenosine substituted nucleotides are potent antagonists selective for P2X1, uptake, release, and inactivation. In: Jacobson KA, Jarvis MF, P2X3, and heteromeric P2X2/3 receptors. Pathobiology of ischae- is a potent antagonist at recombinant rat P2X receptors. Anti-inflammatory effects of adenosine kinase in- tent antagonist of the P2Z-receptor of human lymphocytes. In: 206 Neuropsychopharmacology: The Fifth Generation of Progress Jacobson KA, Jarvis MF, eds. Purinergic approaches in experimen- accumbens modulate prepulse inhibition of the startle response. Adenosine agonists reduce con- seizure arrest and postictal refractoriness. Ann Neurol 1992;32: ditioned avoidance responding in the rat. Promotion of sleep extracellular nucleotides and nucleosides on glial and neuronal mediated by the A -adenosine receptor and possible involvement 2a cells. Trophic effects Proc Natl Acad Sci USA 1996;93:5980–5984. A unifying purinergic hypothesis for the initiation 663–690. Curr Opin CPNS Invest chemistry and function of striatal adenosine A2A receptors. Purinergic and pyrimi- Trends Pharmacol Sci 1997;18:338–344. Adenosine A2Aantagonist: function handbook of experimental pharmacology, vol 151/I. Hei- a novel antiparkinsonian agent that does not provoke dyskinesia delberg: Springer-Verlag, 2001:371–401. New York: coffee and caffeine intake with the risk of Parkinson disease. Adenosine A2A receptors in the nucleus Syst 2000;81:285–288. DUMAN A clear limitation of treating diseases of the central nervous time in development to support the survival of a particular system arises from the loss of regenerative potential of the neuronal population. Although several variations and exten- brain at a very early age. Improper development of neural sions of these principles have been delineated, the basics of circuits or injury of neurons appears to be permanently fixed defining a neurotrophic factor remain the same. This is most clearly true of the spectrum of neurologic the realization that neurotrophic factors play important diseases, such as neurodegenerative diseases (e. In addition, breakthrough tion in the adult nervous system, as well as during develop- disorders such as epilepsy or myoclonus reflect inappro- ment (2–4). It has also become apparent that some differentiation, and modeling of the nervous system. Later psychiatric diseases represent similar fixed deficits or lack the levels generally drop, but they do not subside com- of appropriate functional adaptation. In fact, in most cases in which it has been explored, neuroanatomic deficits have been documented in affective the continued presence of these factors is substantial and is diseases, schizophrenia, and anxiety disorders. Neuronal recreate the early restorative potential of the brain would populations continue to depend on these factors for survival have great potential for significantly, and possibly perma- and optimal functioning. The first identified some cases, specific neurotrophic factors have been found neurotrophic factor, nerve growth factor (NGF), was identi- to be necessary and sufficient for these changes to occur, fied and characterized in the pivotal studies of Levi-Montal- from hippocampal plasticity and long-term potentiation cini (1). The general properties of NGF now essentially (8–11) to the acquisition of new songs by songbirds define what neuroscientists consider a neurotrophic factor. Models of neuronal now often incorporate com- A neurotrophic factor is capable of supporting the survival ponents of neurotrophic factor signaling to explain synaptic of at least one population of neurons in culture. Contrary to the original by a target tissue (either neuronal or nonneuronal) and acts models, these signaling events have been found not only to on the neurons that innervate that tissue to support their be retrograde signals from target neurons or other tissues, survival or differentiation. Finally, a neurotrophic factor is but also to be anterograde or autocrine signals. Furthermore, expressed in the appropriate region and at the appropriate numerous studies have demonstrated that the expression of at least some of these factors can be rapidly regulated in the adult, a finding supporting a dynamic role in mediating David S. Duman: Laboratory of Molecular Psy- chiatry, Departments of Psychiatry and Pharmacology, Yale University School responses to the environment.

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