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No statistical tests were performed (insufficient strength of evidence) cheap duphalac 100 ml on-line medicine on time. Quality of Life One fair-quality study reported no statistically significant difference in overall quality of life (SF-36) at 18 months in those receiving digoxin versus verapamil or those receiving acute versus 145 routine subsequent electrical cardioversions purchase 100 ml duphalac otc symptoms dehydration. Scores were not provided discount duphalac 100 ml without a prescription medications 563, and no p-values were reported for the overall quality-of-life assessment (insufficient strength of evidence). Stroke One good-quality study reported that one patient receiving metoprolol with electrical 178 cardioversion versus no patients receiving placebo with electrical cardioversion had a stroke (insufficient strength of evidence). Results in Specific Subgroups of Interest No results were reported for outcomes of interest in specific subgroups of interest. Comparison of Pharmacological Agents Thirteen studies with a total of 3,718 patients compared pharmacological agents (Table 180,181,224,230,241,245,249,256,258-261,269 15). One of these studies compared an AAD with a beta-blocker 269 (sotalol vs. Five studies included a placebo arm; 180,181,245,258,260 results of the placebo arm were not included in this review. Studies including comparisons of pharmacological agents Study Sample Drug Comparison Outcomes Assessed Size (N) Kochiadakis, 186 Amiodarone vs. Sotalol Composite (Recurrence of AF or Adverse drug 260 2000 effect): 1 month,12 months, 24 months, mean monthly progression Composite (Maintenance of SR and Free of adverse drug effects): 1 year, 2 years Kochiadakis, 214 Amiodarone vs. Sotalol Composite (Recurrence of AF or Adverse drug 261 2000 vs. Propafenone effect): 12 months, 24 months, mean monthly progression Recurrence of AF: 2 years, and monthly rate Composite (Maintenance of SR and Free of adverse drug effects): 1 year, 2 years 230 Roy, 2000 403 Amiodarone vs. AF hospitalization: 12 months, Sotalol/Propafenone All-cause mortality: mean Control of AF symptoms: 3 months Recurrence of AF at mean followup of 468 days, and time to event Quality of life Stroke 245 Bellandi, 2001 300 Sotalol vs. Propafenone Maintenance of SR: 1 year Recurrence of AF: 12 months, mean time 269 Plewan, 2001 128 Sotalol vs. Bisoprolol Maintenance of SR: 12 months Recurrence of AF: 12 months, mean days to recurrence, monthly rate of recurrence Anonymous, 256 Amiodarone vs. Sotalol All-cause mortality: 5 years 241 2003 Arrhythmic deaths: 5 years Maintenance of SR: 5years Recurrence (prevalence) of AF: 4 months, 1 year 249 De Simone, 2003 324 Amiodarone vs. Flecainide AF-free survival at 90 days (amiodarone/flecainide vs. Flecainide Recurrence of AF: 3 months with Verapamil Maintenance of SR: 3 months 256 Katritsis, 2003 90 Carvedilol vs. Bisoprolol Recurrence of AF: 1 year Kochiadakis, 254 Sotalol vs. Propafenone Composite (Recurrence of AF or Adverse drug 258 2004 effect): 12 months, mean monthly progression; Composite (Maintenance of SR and Free of adverse drug effects): 30 months Kochiadakis, 146 Amiodarone vs. Composite (Recurrence or Adverse drug effect): 259 2004 Propafenone 12 months, 24 months, mean monthly progression Recurrence of AF Composite (Maintenance of SR and Free of adverse drug effects): 1 year, 2 years 180 Singh, 2005 665 Amiodarone vs. Sotalol All-cause mortality at last followup Stroke (per 100 person years) Recurrence of AF: 1 year, median days to recurrence Quality of life Vijayalakshmi, 94 Amiodarone vs. Sotalol All-cause mortality: 6 months 181 2006 Maintenance of SR: 1. Composite (Recurrence or Adverse drug effect), Dronedarone time to event Recurrence of AF: 12 months after conversion to SR All-cause mortality Abbreviations: AF=atrial fibrillation; N=number of participants; SR=sinus rhythm 83 Maintenance of Sinus Rhythm Nine studies comparing primarily pharmacological interventions reported this 181,241,245,249,258-261,269 181,241,260,261 outcome. Four studies compared amiodarone with sotalol, two of which reported a composite outcome of maintenance of sinus rhythm without adverse effects 260,261 from medication. In all four studies maintenance of sinus rhythm was greater with amiodarone than with sotalol, but the differences were statistically significant only in some studies and at some of the assessed time points (see Table 16). One of these studies showed no significant difference in the rate of this 245 outcome, while the other two found that the propafenone groups had rates of maintenance of sinus rhythm that were almost twice that of the sotalol groups, although statistical analyses 258,261 comparing the groups were not reported. Two studies compared amiodarone with propafenone and evaluated a composite outcome of 259,261 maintenance of sinus rhythm free from adverse effects from medication. In both studies, at 1 year amiodarone was better than propafenone for this outcome, but at 2 years propafenone was better. In both studies, investigators described the rate of recurrence of AF as being constant throughout followup for amiodarone, but they described the rate of recurrence of AF on propafenone as being high early on during therapy and then decreasing over time. One study compared bisoprolol with sotalol and found no significant difference in the rate of 269 maintenance of sinus rhythm. The final study found that the addition of verapamil to treatment with either amiodarone or flecainide increased the rate of AF-free survival compared with 249 treatment with either antiarrhythmic agent alone. These studies suggest that amiodarone appears to be better sotalol but no different from propafenone, but given the diversity in comparisons and the imprecision of the findings, the strength of evidence was considered low. Studies assessing maintenance of sinus rhythm with or without adverse effects Study Sample Time Point Results P-Value Size (N) a Kochiadakis, 214 1 year Amiodarone: 70. Studies assessing maintenance of sinus rhythm with or without adverse effects (continued) Study Sample Time Point Results P-Value Size (N) a Kochiadakis, 254 30 months Propafenone: 47% NR 258 2004 Sotalol: 25% a Kochiadakis, 146 12 months Amiodarone: 72% NR 259 2004 Propafenone: 56% a 24 months Amiodarone: 42% NR Propafenone: 51% Vijayalakshmi, 94 1. Abbreviations: AE=adverse event; CI=confidence interval; HR=hazard ratio; N=number of participants; NR=not reported Recurrence of AF Ten studies comparing primarily pharmacological interventions for AF included recurrence 180,224,230,241,245,249,256,259,261,269 (or prevalence) of AF as an outcome (Table 17). Three of these 180,241,261 studies compared amiodarone with sotalol. Of these three studies, one showed no 241 statistically significant difference between treatment arms at 4 months or 1 year; however, the other two studies reported a higher rate of recurrence of AF among those on sotalol compared with amiodarone—68 percent versus 33 percent at 2 years of followup in one study (no statistical 261 180 test reported), and 68 percent versus 48 percent at 1 year in the other study (p=0. The rate of recurrence of AF for sotalol versus propafenone was not statistically significantly different in 1 study at 12 months 245 (23% vs. Another study reported a higher rate with sotalol than with 261 propafenone at 2 years (68% vs. Two studies compared the effects of amiodarone versus propafenone; one found a 261 statistically significantly higher monthly rate of recurrence with propafenone; the other found 259 no significant difference in recurrence between the two drugs. In line with the results of these two studies, another study evaluated the risk of recurrence of AF for amiodarone compared with either sotalol or propafenone over approximately 1 year and found a significantly lower risk 230 among those on amiodarone, with a hazard ratio (HR) of 0. One compared amiodarone versus flecainide, with and without verapamil added to either treatment. The rate of recurrence of AF did not differ at 3 months between amiodarone and flecainide (no statistical test reported). The addition of verapamil to flecainide reduced the rate of recurrence significantly compared with flecainide alone (21% vs. One study compared amiodarone with dronedarone and found a higher rate of recurrence with 224 dronedarone, but the statistical analysis was not reported. Finally, two studies compared the beta-blocker bisoprolol with either another beta-blocker or 256,269 an antiarrhythmic agent. One study showed no significant difference between rates of 256 recurrence at 1 year between bisoprolol and carvedilol; the other showed no significant 269 difference between rates of recurrence of AF with bisoprolol versus sotalol. These findings suggest that amiodarone appears to be better than dronedarone or sotalol, but no different from propafenone (low strength of evidence). Studies assessing recurrence of AF Study Sample Time Point Results P-Value Size (N) Kochiadakis, 214 2 years Amiodarone: 33. Amiodarone + Verapamil: 20% Amiodarone + Flecainide + Verapamil: 21% Verapamil) p=0.
A reporter gene can be different from a therapeutic gene as long as IMAGING REGULATION OF GENE parallel levels of expression are expected by sharing a com- EXPRESSION mon promoter generic duphalac 100 ml overnight delivery medications list template. At the moment discount duphalac medications causing gout, imaging of reporter probes is used to Signal transduction initiated with presynaptic firing does detect expression only of exogenously introduced genes order duphalac 100 ml with mastercard medications prescribed for pain are termed. En- not terminate with the interaction of a transmitter with dogenous gene expression, which is interesting in psychiatric its receptors and consequent second messenger generation. A well-known example is the tation of these techniques in brain imaging is that the widely induction of the protooncogene c-fos by receptor–ligand used reporter probes, the radiolabeled substrates of herpes interactions (80). In fact, oncogenes encoding growth fac- simplex type 1 thymidine kinase, do not show good perme- tors, membrane receptors, cytoplasmic and membrane-asso- ability of the blood–brain barrier. This limitation can be ciated protein kinases, guanosine triphosphate-binding pro- overcome by using dopamine D2 receptor as a reporter gene teins (GTP), and transcription factors play important roles and D2 ligands as reporter probes (86,87). Because the in signal transduction and altered gene expression. These expression of functional D2 receptors may cause unwanted genes and their cognate proteins will be important future effects, further studies are being performed on the use of targets for brain imaging. Much of what we know about D2-receptor mutants, which are not coupled with intracel- these proteins in the central nervous system is derived from lular signaling but still maintain binding affinity for D2 studies of cancer biology. These imaging studies may make it possible to apply therapy of a neuropsychiatric disorder (88). The concept of new findings in molecular biology to the study of patients gene therapy for Parkinson disease has grown directly from with neuropsychiatric disorders in exciting ways. However, the limited availability and ethically controversial nature of the tissue source have re- CONCLUSIONS stricted the utility of fetal grafts in this disorder. As an alter- native, a relatively unlimited supply of homogenous, well- Progress in molecular neurobiology has dramatically characterized viral vectors could theoretically be produced changed our understanding of psychiatric disorders. A sig- to deliver tyrosine hydroxylase, the rate-limiting enzyme in nificant proportion of these findings have been obtained dopamine synthesis. Attempts have also been made in ani- from animal experiments and postmortem human studies. Similar techniques of gene therapy have and to a lesser extent with SPECT, is ideally suited for been investigated in motor neuron degenerative diseases and such in vivo applications because of its extraordinarily high Alzheimer disease. Reporter genes whose probes can cross sensitivity and improving anatomic resolution (now about the blood–brain barrier, such as D2 receptors, can monitor 2 mm). This chapter has reviewed what is arguably the the expression of these transfected genes. On the other hand, most difficult barrier to accomplishing in vivo molecular dopamine release from the grafts could be monitored by a imaging—the development of useful and quantifiable conventional technique utilizing competition of radioligand tracers. The blood–brain barrier is a challenge to both the binding to D2 receptors, as described in the section on delivery of radiolabeled tracers and the quantification of estimation of endogenous neurotransmitter levels. However, many successful this technique of receptor displacement has been used to tracers have been developed to date. These probes have detect dopamine release in patients with embryonic nigral largely been synthesized as analogues of agents active at syn- transplants (89). Rela- imaging with small probes for relevant gene or oncogene tively little progress has been made in measuring protein products, is hampered by the development of useful intracellular signal transduction or gene expression. As described in the section on the two areas are clearly important targets for future ligand de- required properties of an in vivo tracer, it is difficult to fulfill velopment. By bridging new findings in molecular neurosci- all the requirements for a successful brain-imaging agent. Many new anticancer agents are being developed, and a significant number of these agents target signal trans- duction systems, which may also play pathophysiologic roles in psychiatric disorders (90,91). For example, Ras farnesyl- REFERENCES transferase is a target for cancer chemotherapy and poten- 1. Can receptors be imaged tially also for brain imaging. Localized 1H NMR cations, including farnesylation, Ras binds to the cell measurements of gamma-aminobutyric acid in human brain in membrane and transmits signals. Among them, a recently developed agent has tions of metabolites in the adult human brain in vivo: quantifica- a high affinity (93) and may be used as a template from tion of localized proton MR spectra. PET studies of a small molecule ligand for epidermal growth factor receptor binding competition between endogenous dopamine and the D1 11 11 has been labeled with C and has shown brain uptake (94). Rapid developments in molecular biology and the advent 5. In: of gene-targeting techniques have enabled the study of indi- Bendriem B, Townsend DW, eds. The theory and practice of 3D vidual genes in mice by means of in vitro experimental tech- PET. Recently developed animal-dedicated PET devices tion of microPET: a high-resolution lutetium oxyorthosilicate (e. J Nucl Med 1999;40: of about 2 mm and can now image these animalsin vivo 1164–1175. Performance results of a SPECT measurements of amphetamine-induced dopamine re- new DOI detector block for a high resolution PET–LSO research lease in nonhuman primates. Relationship of octanol/water partition coefficient and lated dopamine release competes in vivo for [123I]IBZM binding molecular weight to rat brain capillary permeability. Kinetic properties of the accumulation tein binding on in vivo activity and brain penetration of glycine/ of 3H-raclopride in the mouse brain in vivo. Imaging D2 receptor tween lipophilicity and brain extraction of C-11-labeled radio- occupancy by endogenous dopamine in humans. Regional rat brain distribution ing of amphetamine-induced dopamine release in drug-free of iodinated benzamides. Mapping cocaine binding trations: evidence from a novel positron emission tomography sites in human and baboon brain in vivo. Persistence of haloperi- mine transmission in schizophrenia: confirmation in a second dol in human brain tissue. Removal of en- of the 5-HT1A receptor radioligand, [O-methyl- C]WAY- dogenous dopamine reveals elevation of D2 receptors in schizo- 100635, in rat, monkey and humans plus evaluation of the brain 11 phrenia. Exquisite deline- ligand characteristics and task length for detection of activation. Principles of tracer kinetic modeling in changes with bolus or infusion delivery on neuroreceptor ligands. In: Phelps J Cereb Blood Flow Metab 1998;18:1196–1210. Comparison and autoradiography: principles and applications for the brain and heart.
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FINDINGS FROM THE NATIONAL SURVEYS 45 40 35 30 Year 25 2014 20 2016 15 10 5 0 Managers GPs Other clinicians Lay members excluding GPs FIGURE 8 Influence of managers order generic duphalac pills medicine 773, GPs purchase 100 ml duphalac fast delivery treatment 3rd degree av block, other clinicians and lay members in the redesign of services 100 ml duphalac free shipping medications used for bipolar disorder. Some answers from 2016 were then broken down to show how different kinds of respondents answered this question. It was evident that finance officers tended to see managers as the most influential figures. GP members of governing boards and others (directors of public health and other managers) tended likewise to see managers as influential. Next, we delved deeper into the perceived influence of GPs, as broken down by role of respondent. As the results in Figure 10 show, GP members of the boards were, ironically, the least convinced that they had much influence. Accountable officers, for example, may have wished to reflect the idea that they were the servants of a membership organisation. We also wanted to know in what capacity GPs were acting when they influenced service redesign. Was it as official governing members, as clinical leads who did not have a seat on the governing body, as locality leads, or as leaders of GP federations? Perhaps not a surprise, given the role of many respondents, GPs sitting on the governing bodies were seen as the most influential of the GP categories. Of note also was that the perceived influence of locality-level commissioning GPs declined between 2014 and 2016. A related question concerned who sets the compelling vision. Were GPs and other clinicians making a leadership contribution through envisaging alternative service provision or was this vital leadership role filled by others? In 2014, the results for clinicians were the same (between 25% and 26% of respondents said that GPs set the compelling vision). The main difference between the two time periods was in the proportion of 25% Clinicians Managers Neither 54% Both equally 19% 2% FIGURE 12 Who sets the compelling vision for service redesign? 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 25 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. Figure 13 shows the breakdown by role of respondent to this same question. As shown in Figures 12 and 13, most respondents suggested that it was managers and clinicians equally who set out the compelling vision. These results suggest that the notion that GPs would be the visionaries and architects and that managers would play the role of delivery agents is not an accurate depiction of the reality in most cases. There is also more evidence here of dual leadership occurring – a particular type of distributed leadership. We asked about communication with patients and the public, and the results are shown in Figure 14. For these stakeholders, managers acting alone or acting equally with clinicians account for 87. Once again there was apparent progress between 2014 and 2016. In 2014, nearly one-quarter of respondents said that neither managers nor clinicians from the CCG were in communication with patients and the public, but in 2016 this fell to only 2%. In a related question, we asked who provided the insights into public and patient needs. The results (shown in Figure 15) suggest that the largest part of this is done jointly with managers and clinicians, although 21% of respondents said that managers were mainly responsible for this activity. An increasingly important theme since the formation of CCGs as independent statutory bodies has been the growth of the idea that more collaboration is required – with other CCGs and with other stakeholders, such as social services and voluntary bodies. Building collaborations The building of collaborations with providers and with other commissioners has increasingly become a vital activity for CCGs. 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 27 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. FINDINGS FROM THE NATIONAL SURVEYS 5% Clinicians Managers 51% 43% Neither Both equally 1% FIGURE 17 Collaboration building. The results suggest that half the respondents saw managers and clinicians equally involved in this. However, a very significant proportion (43%) identified managers as leading on this, and only a very small proportion (5%) argued that clinicians led on this work. Qualitative, free-form answers added some depth and flavour to the question of the kind of contribution being made by clinical leaders. A central reason for much of the emphasis on clinical leadership, as we noted in the literature review, relates to the idea that clinicians have the potential to make a difference through a distinctive set of contributions. The answers clustered into eight main categories of types of response, as shown in the first column of Table 3. As these reservations stem from governing board members with a close-up view of proceedings in CCGs, it is especially interesting to note the scepticism about the impact of clinical leadership. 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 29 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. Obstacles to achieving clinical leadership This free-form question elicited many responses. The most commonly cited response was that GPs did not have the time to fulfil the role adequately. Respondents also took the opportunity to use this question to identify what they saw as the source of the failings and difficulties faced by CCGs. Hence, many GP respondents pointed to wider problems of the health service at large (such as fragmentation, complexity, political interference, bias towards the acute sector and the like). Some managerial respondents used the question to highlight shortcomings in the GP contribution (poor attendance, lack of system-wide understanding), whereas some GPs also pointed to managerial shortcomings. Some GP respondents argued that the sources of the problem were deeper – that they extend to intractable system problems, such as fundamental diversity of objectives and lack of autonomy for the CCGs to influence the system because of the power and influence of bodies (such as NHSE, NHS Improvement) and the power of the acute hospitals – all of which impeded the plans of the CCGs. In other words, there was evidence of a perceived vicious circle. Yes, many GPs were reluctant to step forward to commit significant time and energy to the work of the CCGs, but they contended that this was because there was little incentive to do so, and indeed little point in so doing because bigger forces are stacked against this being a rational action.
For example order 100 ml duphalac with mastercard symptoms 7 days past ovulation, Bouton order duphalac once a day symptoms yellow fever, using lick suppression Using fluorodeoxyglucose autoradiography to measure neu- as a measure of fear discount 100 ml duphalac mastercard medicine 003, showed a blockade of extinction when ral activity, Mcintosh and Gonzalez-Lima compared region- rats were given chordiazepoxide during nonreinforced CS specific activity in parallel auditory pathways in two groups presentations and were then tested in the absence of the presented with a tone-light compound (172). However, when chordiazepoxide also was given groups, the tone was a fear-eliciting CS. The groups differed before testing, extinction was still evident. This finding sug- with respect to the significance of the light, which had been gests that the benzodiazepine did not actually block the trained as a conditioned inhibitor in one group and as a learning that was occurring during extinction, but, instead, neutral stimulus in the other. Thus, the experiment allowed the change in drug state between extinction and testing was for an analysis of whether a conditioned inhibitor modulates the factor that produced renewal (36). Interestingly, in only one area, the ventral brook found similar effects on excitatory conditioning. For medial geniculate nucleus, was there a significant difference example, rats given fear conditioning after injection with in activation between the two groups. This structure showed benzodiazepines showed an impairment in conditioned less activation in the conditioned inhibition group, a finding freezing measured 24 hours later in the same context com- suggesting that a conditioned inhibitor may act at this locus pared with rats trained under the drug but tested in a differ- in the auditory pathway to inhibit conditioned fear nor- ent context (111) or rats given a stressor before testing (109). Thus, the benzodiazepines did not actually prevent original We found normal conditioned inhibition of fear-poten- learning, but instead produced a state during conditioning tiated startle, using a visual excitatory stimulus and an audi- that interfered with retrieval during testing. In interfere with either excitatory or inhibitory learning, but, addition, local infusion into the nucleus accumbens of either instead, act on processes that are important for retrieval of amphetamine or glutamate antagonists did not alter the prior learning. However, if extinction is a form of active magnitude of conditioned inhibition, as they alter respond- inhibition, it is possible that GABA may be one of the ing to conditioned reinforcers trained in an operant situa- neurotransmitters necessary for the expression of extinction. In fact, in an elegant set of experiments, Harris and West- In an appetitive learning situation, Holland et al. Amygdala and extended nomenon closely related to conditioned inhibition. Several studies suggested that the lateral septum may play 7. Role of the amygdaloid complexes in the an important role in conditioned inhibition. Using pav- stress-induced release of ACTH in the rat. Neuroendocrinology lovian discriminative fear conditioning, single-unit firing 1974;15:220–230. Amygdalar participation in tonic ACTH presence of a conditioned inhibitor and decreased in the secretion in the rat. Human extrastriate presence of a conditioned excitor (238,254). This finding visual cortex and the perception of faces, words, numbers, and was not seen when recordings were made in the medial colors. Different lateral amygdala reported that stimulation of the same area of dorsolateral outputs mediate reactions and actions elicited by a fear-arousing septal nucleus inhibited restraint stress-induced ulcers stimulus. Using c-fos mRNA as a measured of neuronal activa- gray dissociate-conditioned freezing from conditioned suppres- tion, we found a unique increase in c-fos in a ventral part of sion behavior in rats. Temporally graded when a conditioned inhibitor of fear was presented (53). Expression without recognition: con- liminary pilot studies, although further work certainly is tributions of the human amygdala to emotional communica- required to evaluate the role of the lateral septum, perhaps tion. Impairment of social and moral behavior related to early damage in human One study suggests that the dorsal central gray may play prefrontal cortex. The conditioned emotional response as reported that posttest infusions of 5 ng of picrotoxin (a a function of US intensity. J Comp Physiol Psychol 1961;54: GABA chloride channel blocker) into the dorsal central 428–432. Autonomic and somatomotor effects of amygdala central n. Multiple measures of the orienting is complicated by the finding that neither 2. The GSR of monkeys during orienting and habituation and after ablation of the amyg- releases GABA into the dorsal central gray. Alternatively, dala, hippocampus and inferotemporal cortex. Neuropsychologia because low doses of picrotoxin would be expected to acti- 1965;3:111–119. The NMDA antagonist MK-801 blocks these results could be interpreted as indicating that the dor- the extinction of pavlovian fear conditioning. Behav Neurosci sal central gray is involved in inhibiting an unknown brain 1996;110:618–620. Integrated defence reaction elicted by structure mediating conditioned inhibition (81). Given the excitatory amino acid microinjection in the midbrain periaque- prominent role of the central gray in the expression of fear ductal grey region of the unrestrained cat. Brain Res 1988;439: (162), more work is needed to investigate the role of the 95–106. Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? Control of response REFERENCES selection by reinforcer value requires interaction of amygdala 1. A role for the human amygdala and orbital prefrontal cortex. The human amygdala in nergic system and its relevance to the glucocorticoid delayed social judgment. The functional effects of amygdala lesions in hu- amygdaloid nucleus in the response of adrenocorticotropin se- mans: a comparison with findings from monkeys. In: Aggleton cretion to immobilization stress: opposing roles of the noradren- JP, ed. The amygdala: neurobiological aspects of emotion, memory ergic and dopaminergic systems. Deciding advanta- of the basolateral amygdala prevents inflation of fear condition- geously before knowing the advantageous strategy. Amygdala activity at encoding conditioning and declarative knowledge relative to the amygdala correlated with long-term, free recall of emotional information. Amygdaloid complex lesions differen- ioral responses to cholecystokinin microinjected into rat nucleus tially affect retention of tasks using appetitive and aversive rein- accumbens and amygdala. Neural systems for the expres- lasting declarative memory. Morphine withdrawal syn- nictitating membrane response: implications for potential inter- drome: differential participation of structures located within the actions between hippocampal and cerebellar brain systems. Involvement of the central nucleus and to threat in rats with amygdaloid lesions. J Comp Physiol Psychol basolateral complex of the amygdala in fear conditioning mea- 1972;81:281–290. 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