By O. Xardas. University of Denver.

We determined the appropriateness of a quantitative synthesis (i order allopurinol 100mg overnight delivery. Where at least three comparable studies reported the same outcome buy allopurinol 100 mg overnight delivery, we used random-effects models to synthesize the available evidence quantitatively using Comprehensive Meta-Analysis software (Version 2; Biostat, Englewood, NJ). We tested for heterogeneity using graphical displays and test statistics ES-7 2 (Q and I statistics), while recognizing that the ability of statistical methods to detect heterogeneity may be limited. For comparison, we also performed fixed-effect meta-analyses. We present summary estimates, standard errors, and confidence intervals in our data synthesis. Unless noted otherwise, when we were able to calculate odds ratios (ORs), we assumed that an OR between 0. Strength of the Body of Evidence We rated the strength of evidence for each KQ and outcome using the approach described in 23,28 the Methods Guide. In brief, the approach requires assessment of four domains: risk of bias, consistency, directness, and precision. Additional domains were used when appropriate: strength of association (magnitude of effect) and publication bias (as assessed through a search of ClinicalTrials. These domains were considered qualitatively, and a summary rating of high, moderate, or low strength of evidence was assigned after discussion by two reviewers. In some cases, high, moderate, or low ratings were impossible or imprudent to make—for example, when no evidence was available or when evidence on the outcome was too weak, sparse, or inconsistent to permit any conclusion to be drawn. In these situations, a grade of insufficient was assigned. Applicability We assessed applicability across the KQs using the method described in the Methods 23,29 Guide. In brief, we used the PICOTS format to organize information relevant to applicability. The most important applicability issue is whether the outcomes observed in any individual study, with its specific patient population and method of implementing treatments, can confidently be extrapolated to a broader context. We used these data to evaluate the applicability to clinical practice, paying special attention to study eligibility criteria, demographic features of the enrolled population compared with the target population, characteristics of the intervention used compared with care models currently in use, and clinical relevance and timing of the outcome measures. We summarized issues of applicability qualitatively. Results Figure B depicts the flow of articles through the literature search and screening process. Searches of PubMed, Embase, and CDSR yielded 8,103 unique citations. Manual searching of gray literature databases, bibliographies of key articles, and information received through requests for scientific information packets identified 224 additional citations, for a total of 8,327 citations. After applying inclusion/exclusion criteria at the title-and-abstract level, 505 full-text articles were retrieved and screened. Of these, 323 were excluded at the full-text screening stage, leaving 182 articles for data abstraction. The relationship of studies to the review questions is as follows: 14 studies relevant to KQ 1, 3 ES-8 studies relevant to KQ 2, 6 studies relevant to KQ 3, 42 studies relevant to KQ 4, 83 studies relevant to KQ 5, and 14 studies relevant to KQ 6. The full report provides a detailed list of included articles, along with a complete list of articles excluded at the full-text screening stage, with reasons for exclusion. As described in the Methods chapter of the full report, we searched ClinicalTrials. We acknowledge that this is not an exhaustive strategy, as several other registries also exist with differing geographical focus and varying degrees of overlap in their trial listings; however, in the opinion of the investigators, the large, widely used, U. The sample sizes of the potentially relevant unpublished studies we identified corresponded to 8 percent of the included population for published studies relevant to KQ 1 and 12 percent for KQ 5. Because of the relatively low proportion of unpublished studies identified through our ClinicalTrials. Literature flow diagram aSome studies were relevant to more than one KQ. Note: CRT = cardiac resynchronization therapy; KQ = Key Question; RCT = randomized controlled trial. Rate-Control DrugsKey points from the Results chapter of the full report are as follows: • Based on three studies (two good, one fair quality) involving 271 patients, evidence suggests that amiodarone is comparable to the calcium channel blocker diltiazem for rate control (low strength of evidence). ES-10 • Many outcomes/comparisons were rated to have insufficient strength of evidence. These include improvement of AF symptoms in patients receiving combined treatment with carvedilol plus digoxin compared with digoxin alone, rate control in patients using metoprolol versus diltiazem or sotalol, and the safety of any one pharmacological agent used for ventricular rate control in patients with AF. A total of 14 RCTs involving 1,017 patients were identified that assessed the use of pharmacological agents for ventricular rate control in patients with AF. Six studies were considered to be of good quality, eight of fair quality, and none of poor quality. Only one study included a site in the United States; eight included sites in continental Europe; two included sites in Asia; and one each included sites in Canada, the United Kingdom, and Australia/New Zealand.

For example buy 300 mg allopurinol with visa, the behav- receptor agonists are blocked by the selective 5-HT2A antag- ioral effects of PCP and related compounds are not discount 300mg allopurinol with visa, for the onist M100907, but not by the dopamine blocker haloperi- most part, mediated by increased dopamine transmission dol (74). Furthermore, in keeping with the similarities be- and therefore are not blocked by typical antipsychotics (see tween acute psychotic states and the syndrome induced by below). Similarly, in normal human volunteers, the psy- hallucinogens, latent inhibition is also disrupted by LSD chotomimetic effects of ketamine are not blocked by typical and other serotoninergic hallucinogens (75), as it is in antipsychotics, but they are reduced significantly by the pro- acutely ill schizophrenic patients. These effects can be totypal atypical antipsychotic clozapine (79). Therefore, this blocked by the putative antipsychotic M100907 (75). Thus, model may be especially useful for testing the effectiveness the effects of hallucinogens on habituation, PPI, and latent of atypical and perhaps even novel antischizophrenia drugs. The construct validity of this model is based been based on preclinical PCP models (41,80). Another on compelling evidence that both the symptoms of schizo- attractive aspect of the NMDA antagonist model is that, phrenia and the effects of hallucinogens reflect exaggerated unlike the dopamine-based models, it has strong construct responses to sensory and cognitive stimuli, theoretically re- validity for studying the cognitive and attentional deficits sulting from failures in normal filtering or gating processes in schizophrenia. In laboratory animals, NMDA antagonists such as habituation, PPI, or latent inhibition (1,3,9). Ac- impair working memory, set shifting, and other cognitive cordingly, 5-HT2A antagonism by itself might be effective functions that are related to schizophrenia (31). More im- in the treatment of certain forms of schizophrenia. Indeed, portantly, in clinical studies, direct comparison of schizo- a rather selective 5-HT2A antagonist, M100907, appears phrenic patients with healthy volunteers receiving subanes- to have efficacy as an antipsychotic in some patients with thetic doses of ketamine have indicated no significant schizophrenia, despite having negligible affinity for dopa- difference in scores for thought disorder between the two mine receptors (76). This finding suggests the possibility of groups (81). These drugs produce both locomotor hyperactivity and stereotyped behaviors. Al- Glutamatergic Models though they also increase dopamine neurotransmission in Dysfunctional glutamate neurotransmission has been impli- limbic regions (82), their motor-activating effects appear to cated in schizophrenia, primarily because noncompetitive be dopamine-independent (83). At rather low doses, PCP antagonists of the NMDA subtype of glutamate receptors, retards habituation of the startle response without affecting including PCP and ketamine, produce a behavioral syn- startle reactivity (84), a pattern similar to that seen in paral- drome in healthy humans that closely resembles symptoms lel studies in schizophrenic patients (9). Also as in schizo- of schizophrenia and is frequently misdiagnosed as acute phrenia, PCP-treated rats exhibit marked deficits in social schizophrenia (77,78). Although typical antipsychotics have no reliable symptoms, such as paranoia, agitation, and auditory halluci- effect on the PCP-induced disturbance in social behavior nations; negative symptoms, such as apathy, poverty of in rats, the atypical antipsychotics clozapine, sertindole, and thought, and social withdrawal; and cognitive deficits, such olanzapine appear to reverse the effects partially (22). The remarka- terms of sensorimotor gating measures, PPI is reduced or ble similarity of PCP-precipitated behaviors with the diverse eliminated in rats by psychotomimetic noncompetitive array of symptoms associated with schizophrenia has NMDA antagonists, including PCP, dizocilpine (MK-801), prompted the use of PCP (and its analogue ketamine) in and ketamine (14,15). As with apomorphine and as in schiz- pharmacologic models of schizophrenia in both basic and ophrenia, both intramodal and cross-modal PPI is sensitive clinical studies. Notably, whereas psychotic episodes are to noncompetitive NMDA antagonists (59). In contrast to 696 Neuropsychopharmacology: The Fifth Generation of Progress the effects of dopamine agonists on PPI, but in keeping with Isolation rearing of rats has also been used as a manipula- the results of studies of the subjective effects of ketamine in tion to generate models related to schizophrenia and models humans, the PPI-disruptive effects of NMDA antagonists of depression and attention-deficit/hyperactivity disorder are not reversed by typical antipsychotics such as haloperidol (ADHD). In the context of schizophrenia, the focus has or selective D1 or D2 antagonists. Importantly, these effects been on the disruptions of PPI rather than the locomotor are reversed by the atypical antipsychotics clozapine, olan- hyperactivity observed in isolation-reared rats. Indeed, com- zapine, quetiapine, and remoxipride (14,15). These findings parisons among different strains of rats indicate that both raise the possibility that the PCP-induced disruption of PPI effects are strain-dependent but appear in different strains may be a useful model for identifying compounds with atyp- (91–93). Thus, as with a variety of pharmacologic manipu- ical antipsychotic potential. Although this model lacks some of the impor- to exhibit a neuroleptic-reversible deficiency in PPI in com- tant characteristics of acute models, such as lack of an effect parison with group-reared controls (91,94). This effect of on PPI, it produces an enduring cognitive impairment that isolation rearing appears to be specific to development; simi- is highly relevant to schizophrenic symptomatology. Furthermore, as in the most common form of schizophrenia, the PPI deficits DEVELOPMENTAL MODELS are not evident before puberty but emerge at about that time (96). Converging evidence for an influence of isolation The best-characterized animal model in this class is that rearing on gating mechanisms in adulthood stem from the proposed by Lipska and Weinberger (86,87), which involves observation that the rat analogue of the P50 sensory gating neonatal excitotoxic lesions of the ventral hippocampus. Because these deficits in PPI and P50 gating are not such as increased spontaneous, amphetamine-induced, and associated with concomitant deficits in latent inhibition NMDA antagonist-induced locomotion. They also produce (95), which occurs only in acutely ill schizophrenic patients potentiated apomorphine-induced stereotypies, disruption (19), it would appear that the isolation-rearing model is of PPI, reduced cataleptic response to haloperidol, impaired more relevant to chronic than to acute schizophrenia. In working memory, and hypersensitivity to stressful stimuli. Thus, PPI deficits in isolation-reared rats may be a 1 (EAAT1) and glutamic acid decarboxylase (GAD67).

It is worth noting that discount allopurinol 300 mg with visa, if we exclude from the m ortality analysis patients who died as a result of the original disease buy allopurinol 100 mg overnight delivery, the corrected m ortality due to the ARF episode itself and its com plications, drops to 27%. GI— gastrointestinal; DIC— dissem inated intravascular coagulation. Liaño F, Pascual J the M adrid ARF Study Group: Epidem iology of 9. Lunding M , Steiness I, Thaysen JH : Acute renal failure due to tubular acute renal failure: A prospective, m ulticenter, com m unity-based necrosis. Pascual J, Liaño F, the M adrid ARF Study Group: Causes and prog- 20:5–78. Gerrard JM , Catto GRD, Jones M C: Acute renal failure: An iceberg 46:1–5. Kleinknecht D: Epidem iology of acute renal failure in France today. Acute Renal Failure Conference, In Acute Renal Failure in the Intensive Therapy Unit. Chugh S, Sakhuja V, M alhotra H S, Pereira BJG: Changing trends in of acute renal failure in Kuwait: A 2-year prospective study. J Trop acute renal failure in Third-W orld countries— Chandigarh study. Seedat YK, N athoo BC: Acute renal failure in blacks and Indians in prospective study on incidence and outcom e (Abstract). N ephron 1993, Congress of EDTA-ERA, Paris, 1992, p 54. Sanchez Rodrìguez L, M artÌn Escobar E, Lozano L, et al. Feest TG, Round A, H am ad S: Incidence of severe acute renal failure 17. Br M ed J 1993, com e of hospital-acquired acute renal failure. Lauzurica R, Caralps A: Insuficiencia renal aguda producida en el 29. M ed ClÌn organ failure assessm ent) score to describe organ dysfunction/failure. Liaño F, Solez K, Kleinknecht D: Scoring the patient with ARF. Liaño F, Pascual J: Acute renal failure, critical illness and the artificial Critical Care N ephrology. Doum a CE, Redekop W K, Van der M eulen JH P, et al. Kierdorf H , Sieberth H G: Continuous treatm ent m odalities in acute m ortality in intensive care patients with acute renal failure treated renal failure. Knaus W A, Draper EA, W agner DP, Zim m erm an JE: APACH E II: A 32. Viviand X, Gouvernet J, Granthil C, Francois G: Sim plification of the severity of disease classification system. Crit Care M ed 1985, SAPS by selecting independent variables. Bion JF, Aitchison TC, Edlin SA, Ledingham IM : Sickness scoring and system: Risk prediction of hospital mortality for critically ill hospitalized response to treatm ent as predictors of outcom e from critical illness. Chew SL, Lins RL, Daelem ans R, De Broe M E: O utcom e in acute score for ICU patients. Liaño F: Severity of acute renal failure: The need of m easurem ent. Le Gall, Lem eshow S, Saulnier F: A new Sim plified Acute Phisiology N ephrol D ial Transplant 1994, 9(Suppl. Score (SAPS II) based on a European/N orth Am erican m ulticenter study. Bonom ini V, Stefoni S, Vangelista A: Long-term patient and renal prognosis in acute renal failure. Turney JH : W hy is m ortality persistently high in acute renal failure? Knaus W A, Draper EA, W agner DP, Zim m erm an JE: Prognosis in APACH E II en el fracaso renal agudo de las unidades de cuidados acute organ-system failure. Racusen cute renal failure (ARF) in the transplanted kidney represents a high-stakes area of nephrology and of transplantation practice. AA correct diagnosis can lead to rapid return of renal function; an incorrect diagnosis can lead to loss of the graft and severe sequelae for the patient. In transplant-related ARF percutaneous kidney allograft biopsy is crucial in differentiating such diverse entities as acute rejection (Figs. In the case of acute rejection, standardization of transplant biopsy interpretation and reporting is necessary to guide therapy and to estab- lish an objective endpoint for clinical trials of new immunosuppressive agents. The Banff Classification of Renal Allograft Pathology is an internationally accepted standard for the assessment of renal allograft biopsies sponsored by the International Society of N ephrology Commission of Acute Renal Failure.

Hence discount allopurinol 100mg otc, the relationship between the The VTA receives afferent projections from 5HT-con- monoamine systems purchase allopurinol 100 mg visa, and between monoamines and other taining axon terminals originating in the dorsal and median neurotransmitter systems suspected of playing a role in raphe nuclei (70). Moreover, 5HT neurons innervate both depression biology, is worthy of discussion. Local application (in the VTA) of agonists rons innervate the serotonergic raphe nuclei and the dopa- at 5-HT1A receptors increases the firing of DA neurons in minergic VTA. Both the dorsal and median raphe nuclei the VTA (6,87) and administration of a 5HT1A receptor receive noradrenergic innervation (15,121). In fact, the rat agonist systemically increases DA release in the medial PFC dorsal raphe receives one of the richest noradrenergic inner- (7). Microinfusion of 5HT into the VTA in rats results in vations in the brain (15,89,150). Overall, NE appears to an increased release of DA in the NAC (61). It is tempting be excitatory at serotonergic raphe neurons. For example, to speculate that the firing mode of VTA DA neurons is interruption of noradrenergic transmission by systemic ad- dependent, among other factors, on the activity of seroto- ministration of an -adrenoceptor antagonist or iontopho- nergic terminals originating in the raphe. Because 5HT in- retic application of an -adrenoceptor antagonist in the vi- creases extracellular DA (128), a serotonergic deficit, which cinity of serotonergic neurons completely suppresses their has been suggested as one primary abnormality in depres- spontaneous firing (14). Iontophoretic application of NE sion, would also lead to a DA deficit. Chapter 73: Neurocircuitry of Mood Disorders 1057 High levels of DA are found in the dorsal raphe and LC effects of intracerebroventricularly administered CRF on (89). Moreover, D2 receptors and D2 receptor mRNA are striatal 5HT release are biphasic (140). Lesions of the VTA cause decrease 5HT release in the striatum, whereas high doses LC DA levels to fall by about 50%. Price and associates (140) suggest that is important for the rewarding effects of LC stimulation, CRF has predominantly inhibitory actions at the level of without which such stimulation appears to be aversive (41). Hence, a putative hypersecretion of CRF in major In the dorsal raphe nuclei, a moderate number of DA- depression could contribute to the deficit in serotonergic immunoreactive fibers cover rather homogenously all subdi- transmission at the level of the raphe nuclei. It has been postulated that dopa- The VTA is densely innervated by CRF-positive fibers, minergic neurotransmission to the dorsal raphe inhibits the whereas the substantia nigra receives only scattered CRF activity of dorsal raphe neurons by increasing extracellular innervation (11). Intracerebroventricular administration of concentrations of 5HT in the dorsal raphe and, conse- CRF to mice produces behavioral activation and a 'stress- quently, by increasing somatodendritic 5HT autoreceptor like' increase in DA metabolism in several brain regions. Direct injections of CRF into the VTA produces dose-de- pendent increase in locomotor activity, an affect that is not antagonized by the DA receptor blocker, haloperidol (74). Monoamine Systems and Other Intracerebroventricular or intraperitoneal administration of Neurotransmitters low doses of CRF increases DA and DA metabolite levels in the rat medial prefrontal cortex (84). Together, these CRF findings suggest that CRF exerts an excitatory action in the Much evidence has accumulated implicating a state of CRF VTA. The long-term effects of CRF administration on DA hypersecretion in major depression (112,113,125). The LC receives excita- tory CRF input from several sources, and these afferents Substance P appear to be topographically organized with respect to the type of information conveyed (177). The LC also receives been questions regarding their efficacy (45). Interestingly, CRF input from limbic brain regions, including the central there is a relatively dense network of substance P immunore- nucleus of the amygdala, as well as the bed nucleus of the active fibers in the human LC and surrounding regions (50). These Many of these fibers may originate from the nucleus of limbic CRF neurons project to the peri-cerulea area, and the solitary tract (50,100,145). In addition, there is a high in particular to the rostrolateral peri-LC. CRF terminals density of binding of radiolabeled substance P to neuroki- form direct contacts with noradrenergic dendrites (176). Substance P potently stimu- CRF, injected intracerebroventrically or directly into the lates the firing of LC neurons (62). There is considerable LC, activates LC neurons and enhances release of NE in evidence that substance P plays a role in the central response projection areas (163). Internal and external stressors are to stress (13,65). Interestingly, substance P antagonists (in known to activate the LC via CRF, including colonic disten- particular, selective neurokinin-1 receptor antagonists), sion, hypotensive challenge, and foot shock. The ability of when administered intracerebroventricularly, attenuate re- these stressors to activate the LC is blocked by CRF antago- straint stress-induced biochemical indices of LC activation nists (32,85,104,174). Repeated administration of rats with antidepressant CRF projections to the LC are thought to coordinate cogni- drugs (perhaps not all types) down-regulates substance P in tive and autonomic responses to internal physiologic chal- several brain regions (27,158). Interestingly, administration of a CRF antagonist respectively (12,155). Substance P-containing serotonergic blocks stress-induced increases in LC tyrosine hydroxylase neurons are not randomly located within the raphe nuclei, (104), an effect shared by antidepressant drugs (105). CRF terminals in raphe nuclei originate from local dorsal raphe nuclei also receive innervation from substance and distant cell bodies (148,151).