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Our secondary analyses thus focused on hospital admissions and ED use 160mg kamagra super. Hospital use represents a significant driver of total costs in most health-care systems kamagra super 160mg. However kamagra super 160 mg, focusing on a single source of utilisation leaves the analysis vulnerable to cost shifting 160 mg kamagra super, where any benefits found in terms of reduced hospital use may mask increased costs elsewhere in the health-care system (such as in community care) . Our primary analysis thus remained focused on total costs . Data presentation We present the results of included studies according to a permutation plot (see Chapter 1 , Figure 2) . The permutation plot presents data from all studies reporting both outcomes (i . QoL and total costs , QoL and hospital admissions, and QoL and emergency care). Each plot shows the pattern of results at the level of the individual study and gives a visual impression of the distribution of studies across the cost-effectiveness plane. The plot distinguishes between studies in the appropriate quadrant (i. We analysed data for included studies as a whole and then conducted meaningful subgroup analyses. A priori subgroup analyses were conducted for level of evidence quality (defined as the adequacy of allocation concealment) and the age of the children and young people. Subgroup analyses for age classified studies according to whether they delivered self-care support to children (aged < 13 years), adolescents (aged ≥ 13 years) or a mixed child–adolescent age group. Additional subgroup analyses were conducted for the type of LTC and the setting and type of self-care support intervention that was evaluated (i. The subgroups that we used for these preplanned analyses were determined post hoc, based on the nature and distribution of the evidence. Post hoc classification by long-term condition We grouped different LTCs post hoc into four conceptually and clinically relevant categories. These categories were asthma, other (non-asthma) physical health conditions, behavioural disorders and mental health. Post hoc classification by intervention type Existing typologies of self-care support for children and young people with LTCs highlight the importance of considering different aspects and characteristics of the intervention, including its target, location, facilitation and delivery methods. 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 provided that 13 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. REVIEW METHODS We conducted subgroup analyses based on intervention target (child and/or young person, adult or both), format (individual, group or mixed) and delivery method (face to face, remote or mixed model). We also conducted subgroup analyses on intervention setting, defined as inpatient, outpatient/clinic, school or community, home or mixed location. In line with our previous review of self-care support for adults with LTCs,26 we included interventions across the spectrum of care and distinguished post hoc between the different intensities and types of self-care support that were provided. We used a similar approach to classify intervention intensity as we used in our previous review, with post hoc amendments to accommodate the level and type of intervention descriptions provided in our primary studies. Our final classification system was informed and approved by our PPI advisory panels and distinguished between four different categories of self-care support: 1. Facilitated self-care support for interventions providing fewer than four sessions or < 2 hours of face-to-face or remote self-care support. Support is provided by a designated self-care agent (e. The support provided will often be (but is not limited to) self-care education, feedback or care plan review. Support is provided by a designated self-care agent health professional or peer and often targets multiple groups (e. Case management for interventions providing more than four sessions or 2 hours of additional support from a designated agent, with additional support from a multidisciplinary team and explicit referrals or care co-ordination as part of the intervention protocol. Two authors independently assessed the type, and content, of each self-care support intervention. Disagreements were identified and resolved via team discussion. Changes to the review protocol The review protocol is available as part of the PROSPERO database: A Rapid Evidence synthesis of Outcomes and Care Utilisation following Self-care support for children and adolescents with long-term conditions (REfOCUS): reducing care utilisation without compromising health outcomes (registration number CRD42014015452). We have been explicit about any deviations from the published protocol in the relevant sections of this report. Deviations of the review from the protocol published in PROSPERO are summarised in Box 5. YoungMinds, Asthma UK, Diabetes UK), allied organisations (e. All lay members were reimbursed for their time and travel expenses. We will structure our synthesis according to the LTCs prioritised by previous reviews (i. We will include other LTCs in our synthesis where we identify eligible economic evidence (e. We grouped studies in a way that was conceptually and clinically relevant. We will repeat this analysis for all major types of costs (e. We only conducted secondary analyses where data allowed and where the costs were sufficiently similar to make meta-analyses appropriate and interpretable. Our secondary analysis focused on hospital admissions and urgent care. We will extract data to assist in the quality assessment of primary studies according to the Cochrane risk-of-bias tool criteria for RCT and nRCT designs. We intend to aggregate data at several different levels (i. Data did not allow for meaningful aggregation at the level of condition clusters. We will distinguish between groups of interventions differing in content (e. Insufficient data were available to enable meaningful analysis at the level that was originally specified. Four panel meetings were held for 1–2 hours on each occasion throughout the course of the review. Meetings took place on university premises and were attended by members of the research team. The initial meeting for both panels was focused on establishing relationships, orientating panel members to the project, and developing and agreeing terms of reference for participation. The second meeting was led by the children and young people and was, at their own request, focused on developing a patient-centred logo and tagline for the project. 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 provided that 15 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. REVIEW METHODS The third meeting was dedicated to developing the frameworks and priorities for the review. This process included PPI approval of the taxonomies used to classify self-care support interventions and the clusters of LTCs that fed through into the analyses. In collaboration with members of the research team, PPI panel members participated in an interactive discussion designed to explore lay interpretations of a systematic review simultaneously assessing patient outcomes and health-care costs. PPI panel members developed a framework depicting the impact of living with a LTC from the perspective of children, young people and their families (Figure 3). This was used to select meaningful patient-centred outcomes for extraction and analysis in the review and may be used to contextualise the remit and scope of this report within a broader sphere of the potential costs incurred by LTC management. At the fourth and final meeting, advisory panel members discussed the findings of the review and interpreted their meaning for services and for children, young people and their families. Panel members assisted in formulating and prioritising evidence-based recommendations for service commissioners and research funding bodies, ensuring that these remained relevant to stakeholder priorities. All recommendations arising from this review are detailed in Chapter 4. All resource utilisation NHS/publicly Societal/ funded health costs non-NHS costs Hospital admission Inpatient care Missed school days Emergency Acute care CYP education Alternative treatment provision Educational Frequency resources Length Type Outpatient care Family/parental costs Specialist equipment/food GP Supplementary Primary costs Nurse medicines Specialist Family transport and parking Missed appointments Holiday insurance Medication Missed work days Home visits Community care Secondary costs Additional childcare Non-pharmacological treatment Loss of career FIGURE 3 Key determinants of resource utilisation in children and young people with long-term physical and mental health conditions: a PPI perspective. CYP, children and young people; GP, general practitioner. Figure 4 presents the flow of studies through the review. A full list of the included studies and their study reference details is provided in Appendix 3. Excluded studies and the reasons for their exclusion are provided in Appendix 4. Records identified through database Additional records identified searching, duplicates removed through other sources (n=36,493) (n=0) Title and abstract screening of 36,493 records based on the following criteria: • RCT, nRCT, CBA, ITS • <18 years of age • long-term physical or mental health condition • potential self-care support intervention Records excluded (n=32,835) Records eligible for full-text screening (n=3658) Full-text screening of records (n=3658) Based on the following criteria: • RCT, nRCT, CBA, ITS • <18 years of age • LTC • Self-care support • CYP QoL or symptom data • Health-care utilisation or cost data Records excluded (n=3412) Potentially eligible studies re-examined (n=246) • 16 had ineligible populations • 39 had an ineligible or unclear intervention • 25 did not report economic outcomes • 45 did not report eligible health outcomes • 24 were the wrong design/did not report comparison data Records excluded (n=149) Eligible studies (n=97) • Reported data not amenable to analysis, n=19 Studies contributed to one or more meta-analyses (n=78) • QoL: 66 studies, 77 comparisons • Admissions: 56 studies, 65 comparisons • Emergency visits: 50 studies, 57 comparisons • Total costs: 8 studies, 10 comparisons QoL and total costs QoL and admissions QoL and emergency visits n=10 comparisons n=53 comparisons n=47 comparisons FIGURE 4 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram: flow of studies through the review. 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 provided that 17 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. RESULTS The included studies comprised 77 RCTs, 10 cluster RCTs, four nRCTs and six quasi-experimental (CBA) designs. Thirty-seven trials (38%) were rated as high quality (i. Full details of the data extracted from individual studies (i. Formal economic analyses were reported by a subset of studies (n = 35, 36%). This subset is listed in Appendix 9, which provides detailed information on the design and quality of the economic analyses. The vast majority of included studies recruited children and young people with physical health conditions (n = 77, 76%), predominantly asthma (n = 66, 68%). Long-term mental health conditions were also represented (n = 18, 19%), split between depression and anxiety (n = 6), psychosis or schizophrenia (n = 3), self-harm or suicide (n = 6) and eating disorders (n = 3). Most studies (n = 42, 43%) recruited across a broad age continuum (e. The majority of the interventions that were evaluated were intensively facilitated self-care support or case management, requiring more than four sessions or 2 hours of total contact from a health professional and/or other self-care agent. As might be expected in this population, the majority of interventions targeted adult caregivers, either together or in parallel with children and young people. Most studies delivered self-care support in addition to usual care and compared its effects with usual care alone. TABLE 1 Basic descriptive data on the studies Category Characteristic n (%) or mean (SD) Study context UK 14 (14. Overall pattern of the results Sixty-four studies, reporting on 77 comparisons, provided QoL outcome data in a form suitable for meta- analysis. The number of studies contributing data to a meta-analysis of health service costs was limited (n = 10 comparisons), restricting the utility of our primary analysis. A greater number of studies contributed data on hospital admissions (65 comparisons) and ED visits (57 comparisons), facilitating more meaningful interpretation of these outcomes (Table 2). The meta-analysis of all study data demonstrated that self-care support was associated with statistically significant but minimal improvements in QoL [ES –0. Self-care support was associated with minimal but statistically significant reductions in ED use (ES –0. Meta-analyses showed minimal, statistically non-significant reductions in hospital admissions (ES –0. 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 provided that 19 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. RESULTS Study ID ES (95% CI) % weight Atherly et al. CBT, cognitive–behavioural therapy; CBTpA, Cognitive Behavioural Therapy for Adolescents with Psychosis; CC, care co-ordination; CIT, conventional insulin therapy; FACI, Facilitated Asthma Communication Initiative; FipA, family intervention in adolescent inpatients with psychosis; IIT, intensive insulin therapy; IVR, interactive voice response; PST, problem-solving skills training; ST, Sweet Talk. CC, care co-ordination; CIT, conventional insulin therapy; FACI, Facilitated Asthma Communication Initiative; IIT, intensive insulin therapy; IVR, interactive voice response; PST, problem-solving skills training; ST, Sweet Talk. Pooled estimates for total health service costs were based on a small number of comparisons with high variation across trials. Subgroup analyses were used to explore the different characteristics of self-care support that may be associated with each of these outcomes (these are detailed in Analyses of different types of self-care support, Table 9). 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 provided that 21 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. RESULTS Study ID ES (95% CI) % weight Atherly et al. CC, care co-ordination; FACI, Facilitated Asthma Communication Initiative; IVR, interactive voice response; PST, problem-solving skills training. Primary analysis: quality of life and total health service costs Total health service costs were infrequently reported. Only eight studies reporting 10 comparisons were eligible for inclusion in a permutation plot that simultaneously charted the effects of self-care support on children and young people QoL and total health-care costs (Figure 9). Six of these comparisons were rated as being at a low risk of bias. When effects were plotted against each other, the comparisons were primarily distributed across the left-hand quadrants of the plot, suggesting that self-care support interventions currently demonstrate high variability in terms of economic effect, but typically confer minimal to small improvements for QoL.

A spatio-temporal dipole¨ multiple stages of processing: evidence from human and monkey model of the readiness potential in humans 160 mg kamagra super. The new cognitive neu- Electroencephalogr Clin Neurophysiol 1994;91:286–294 160mg kamagra super. Cortico-limbic circuits and novelty: a movement-related brain potentials kamagra super 160 mg. Brain Res 1980;202: review of EEG and blood flow data kamagra super 160mg. Mental chro- processing streams in verbal working memory: evidence from nometry and the study of human information processing . Electrophysiology of mind: event- Res 1997;6:95–113 . Neural correlates of encoding nary L , Bernston G , eds . Electroencephalogr Clin Neu- bridge: Cambridge University Press , 2000:53–84. Recall and stem-completion priming have different tion and movement-related cortical potentials in Parkinsonism. Bereitschafts- Trans R Soc Lond B Biol Sci 1999;354:1307–1324. Task-related and item- Electroencephalogr Clin Neurophysiol 1993;89:95–103. Performance monitoring in a confus- USA 1999;96:1794–1799. J Exp Psychol Hum Percept Perform In: Tulving E, Craik FIM, eds. Boston: Birkhauser, monitoring: negative affect and emotionality in relation to fron- 1994:149–168. Is the P300 component a manifesta- brain potentials and positron emission tomography. Event-related potentials and cognition: a critique priming vs explicit remembering during the repetition of visual of the context updating hypothesis and an alternative interpreta- word-form. The P300 wave of the human event-related poten- potential investigation of source and item memory. An event-related potential study of Science 1997;6:163–169. Sources of dual-task interference: evidence from 1996;119:889–905. Memory and meta- Chapter 32: Event-Related Potentials and Magnetic Fields 439 memory: comparisons between patients with frontal lobe lesions 97. Bridging the gap: evidence from ERPs and amnesic patients. Reading senseless sentences: brain poten- 1993;5:196–214. Influences of semantic and syntactic to comprehension. In: Caci- Exp Psychol Learn Mem Cogn 1999;25:394–417. Semantic integration in sentences and discourse: evidence from the N400. Right words and left words: electro- conceptual order. Electrophysiological estimates¨ hension in aphasia: event-related potential evidence for a lexical of the time course of semantic and phonological encoding dur- integration deficit. Event-related brain potentials elic- evidence on the time course of semantic and phonological pro- ited by syntactic anomaly. Handbook of with syntactic incongruencies in words and pseudo-words. Spatio-temporal activ- related brain response to morphosyntactic violations. Lang Cogn ity of a cortical network for processing visual motion revealed Proc 1998;13:21–58. Functionally indepen- steps in syntactic analysis: early automatic and late controlled dent components of the late positive event-related potential dur- processes. For these more mechanis- Another evolutionary change in neuroimaging has been tic questions, images become simply measurements for test- the continued shift from positron emission tomography ing hypotheses and are not an end in themselves. However, as described by Fujita and Innis, imaging (MRI) is a good example of a field that is no longer PET and single photon emission computed tomography restricted to simple localization of pathology in psychiatric (SPECT) remain the only viable techniques for studying disease. Indeed, there are few psychiatric cases that are char- ligand binding in the brain, and the resolution of PET is acterized by clear pathology that is visible in MRI pictures. Fujita By contrast, the new analytic approaches to measuring the and Innis review the status of radiotracer development in size of structures in MRI images described by Evans in this PET and SPECT and describe new tracers for measuring section allow one to track small changes in structures over postreceptor signal transduction and even gene expression. Recently, for ex- tion and concentration of specific molecules in the brain ample, these techniques have been used to track the distribu- is magnetic resonance spectroscopy (MRS), described by tion of gray and white matter during development in child- Rothman et al. The focus of this chapter is onset schizophrenia, which is characterized by an abnormal on measurements of metabolites involved in neuroenergetics and amino acid neurotransmission, especially the flux time course of gray matter reductions in several different through glutamate/glutamine and -aminobutyric acid (GABA)/glutamine cycles during neural activity. GABA metabolism, in particular, appears to be sensitive to both Robert Desimone: National Institute of Mental Health, Intramural Re- psychiatric disorders, such as depression, and to pharmaco- search Program, National Institutes of Health, Bethesda, Maryland. For example, there are characteristic signals found in have been in the time domain. Bandettini describes new visual tasks for the arrival of visual information in a cortical methods for improving the temporal resolution of fMRI, region, for the modulation of this signal by attention, and in particular event-related designs. In more traditional for the decoding of the visual information into semantic blocked-trial designs, the BOLD signal is averaged for many information. With the appropriate task design and with the seconds, typically for several trials of a behavioral task. How- large base of information acquired on the timing of these ever, with event-related designs, one can measure BOLD cognitive operations in normal subjects, one can then begin changes for events lasting less than 2 seconds, which allows to ask how these operations differ in schizophrenia, for ex- one to distinguish activity changes in one part of a trial ample. One new, direct approach to functional connectivity is an ana- chapter by Davidson. The brain systems important for the lytic technique known as effective connectivity mapping, regulation and expression of mood and emotion are highly described by Buchel and Friston. Davidson also can quantify the contribution of activity in one brain struc- describes how basic behavioral research lays the necessary ture to the activity in another. An even more direct approach groundwork for studying mood and anxiety disorders, and to measuring connectivity is through the combined use of he gives specific examples of basic research into fear and transcranial magnetic stimulation (TMS) and fMRI, de- anxiety and its implications for understanding disorders scribed by George and Bohning. As described by Hillyard and Kutas, The chapters in this section describe an impressive arma- new analytic techniques have improved the spatial resolu- mentarium of techniques now available to brain imaging tion of ERPs, and there has been considerable progress in researchers, and they outline some promising new directions combining the spatial resolution of fMRI with the temporal in the application of these techniques to mental illness. Perhaps even more important than these gether, the chapters show that the key to progess in brain technologic advances, there have been conceptual advances imaging studies of pathophysiology will be to see beyond in understanding the functional components of ERP signals the images. EVANS In recent years, the study of gross neuroanatomy and its nomenon. It is still difficult to identify reliably in any single relationship to behavior and brain function has been reener- brain the anatomic landmarks, boundaries, and other delim- gized by the advent of imaging techniques and the powerful iting features necessary for any subsequent analysis. Thus, computational tools with which to analyze high-resolution we face a new problem posed by this newfound technology three-dimensional (3D) brain images (10,11,22,52,53). The tools exist scientific questions be restated and made more amenable to to image large numbers of brains noninvasively with MRI, quantitative analysis. Tradi- assumption that the borders of individual structures can be tional brain atlases identify brain regions only by pointing specified accurately in any brain. In the past, basic questions to the middle of the region or surface feature, leaving the of functional neuroanatomy were difficult to address in a interfaces between regions unspecified. We have learned much debate the exact boundary of even relatively simple struc- from anecdotal reporting of individual patients with various tures such as the thalamus or caudate nucleus. With this forms of brain lesion or from direct cortical stimulation context, new initiatives at various laboratories are attempt- during brain surgery, but the generalization of individual ing to standardize and codify the partitioning of the human observation to the wider population has been confounded brain into named regions, not without controversy. Tradi- by the normal variation in brain structure itself. There is tional neuroanatomists debate among themselves about then a fundamental interest in understanding the nature of what parcellation scheme and nomenclature to use. Com- anatomic variability in the population, both for its relation- puter scientists argue among themselves about whether to ship to functional variability and for the potential of using use hierarchical, relational, object-oriented, or some other structural abnormality as a measure of development, normal form of database structure to organize the brain parcellation. Neurobiologists or physicians are not used sulci become more open and the ventricles become enlarged. Some sophisticated analytic approaches for quantifying ana- tomic variability assume that a particular landmark can be Alan C. Evans: Department of Neurology, McGill University, Montreal perfectly identified in any brain when the reality is that Neurological Institute, Montreal, Quebec, Canada. The atlas template is matched sets in 3D is a labor-intensive effort that is not likely to be to the new MRI volume through a variety of nonlinear de- widely adopted. Fully automated techniques that produce formation techniques, the most successful of which use accurate neuroanatomic segmentation in large numbers of image similarity criteria to deform one image into another. MRI data sets are essential if questions of normal cross- Once delineated in their native space it is possible to sectional variability, normal longitudinal development, and map the regional labels into stereotaxic space in much the detection of abnormality in single subjects or in groups are same way as tissue class maps and to conduct voxel mor- to be answered definitively. Many groups are now engaged phometry among groups using the random field statistical in the field of MRI-based quantitative neuroanatomy, and analysis (3,4,6,12,18,18,21,26,32,34,36,39–41,50,68). A representative sampling of activity by other tion is generally quite successful at labeling relatively well- groups in the field, categorized into the four forms of seg- defined 3D brain regions, such as the thalamus, but is mentation discussed in the subsequent Methods section, typically less successful in identifying cortical gyri. In- include the following: deed, the cortex as such is sufficiently important to merit special analytic treatment. In normal brain, the tissue classes are typically partial effects, some groups have targeted the internal gray matter, white matter, and CSF, although there is cortical margin at the interface between gray and white no reason in principle to restrict to these three tissue matter. Obtaining a measure of the two surfaces simul- types. In these approaches, one or more co-registered taneously allows for a measure of cortical thickness at MRI images of the same neuroanatomy, obtained using each location over the cortical surface. At each voxel the MRI intensity surface as a means of studying functional neuroanatomy for each of the N input images provides an N-dimensional on a two-dimensional (2D) plane. In practice, many confounding cortical folding in three dimensions. Many different multivariate statistical of area, direction, distance etc. Recent interest has cen- 3D data sets from different individuals. All of the ma- tered upon extracting not just the surface trace of the chinery of random field statistical analysis developed for sulcus as a line but rather the depth of the sulcus as a functional imaging then becomes available for structural ribbon. The latter approach provides more information analysis (1,5,30,31,35,54,56,57,81–83). Some form of prior information techniques, hardware, and algorithms to neuroscience at all on neuroanatomic boundaries is needed, usually in the spatial scales. We are involved in one of these applications form of a computerized brain atlas, to assist in 3D brain operating at the gross morphology level. Regions can be identified by vector Consortium for Brain Mapping (ICBM) (52), seeks to cre- boundaries or by labeling of all internal voxels. The atlas ate a so-called probabilistic human brain atlas (see below). The pipeline concept has also been implemented for clinical trial analysis of MRI data from multiple sites. All data sets, across pa- tients, time points, and pulse sequences, are mapped into a standardized 3D coordinate space for automatic segmenta- tion and statistical analysis. Once the MRI image has been segmented, each voxel in the 3D image space carries an anatomic label and a measure FIGURE 24. Brain Imaging Centre (BIC) pipeline environment of the confidence in that label. This information can be for magnetic resonance imaging (MRI) processing: major compo- nents of pipeline analysis of large ensembles of MRI multispectral used in a variety of ways to detect subtle neuroanatomic or data sets. Eachmultispectral data set yields labeled maps of tissue neuropathologic changes: type, three-dimensional (3D) brain region, and cortical topology. MRI simulator for validation of segmentation algorithms Illustrative example applications of some of these capabil- (MRISIM). Correction for coil-dependent 3D intensity nonuniform- ities are described at the end of the chapter. Within-subject registration of different sequence volumes (MINCTRACC). Fully automated 3D classification of gray/white/CSF tis- Within the BIC image analysis pipeline, MRI data are pro- sue classes (INSECT). To manage the flow Fully automated 3D extraction of gray/CSF and gray/ of MRI data through the pipeline, we have developed PCS white cortical interfaces (MSD, ASP). Each processing stage in the pipeline is performed by a single command. PCS allows the user to specify this command with its options, input Stereotaxic Image Format—MINC and output files, and dependencies on other stages in the A fundamental aspect of this pipeline environment and its pipeline using a simple script language. Efficient coarse- interaction with other sites within ICBM is the MINC grain parallelism is achieved by distributing the individual image format for intersite data communication. PCS monitors the sta- (Medical Image Net CDF), developed at the MNI by Peter tus of each job and submits a new job when the prerequisites Neelin, is a multidimensional, multimodality image file for- for submission have been satisfied (typically the completion mat that supports stereotaxic coordinate representation.

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J Consulting and Clinical chiatry Allied Disc 1996;37:445–452 160 mg kamagra super. Chapter 61: Genetic and Other Vulnerability Factors for Anxiety and Stress Disorders 881 90 160mg kamagra super. Heritability of anxiety sensitiv- development of posttraumatic stress disorder kamagra super 160mg. Are different parts of the extended amygdala involved attacks in adolescents kamagra super 160 mg. J Am Acad Child Adolesc Psychiatry 2000; in fear versus anxiety? Factors associated with the sition to childhood aggression at age 11 years . Arch Gen Psychia- development of substance use disorder in depressed adolescents . J Am Acad Child Adolesc Psychiatry 1999;38:1109–1117 . Depression , anxiety , and stria terminals: differential roles in the fear and anxiety measured smoking initiation: a prospective study over 3 years . Philos Trans R Soc Lond 1997; Health 1998;88:1518–1522. 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Biologic findings in and their relation to anxiety and depressive disorders. J Abnorm panic disorder: neuroendocrine and sleep-related abnormalities. Reactivity to a 35% CO2 challenge in of stressful life events. Life events and panic disorder/ Psychiatry 2000;47:830–835. Arch Gen Psychiatry 1995;47: antecedent stressful life events to childhood and family history 21–26. Smoking and panic attacks: an epidemio- Gen Psychiatry 2000;51:960–962. Parental representa- in children with anxiety disorders. Am J Psychiatry 2000;157: tions of patients with panic disorder and generalised anxiety 1236–1242. Vulnerability factors in the anxiety disor- adolescent depression: a review of the past 10 years, part II. Lactate infusions: The ogy, parenting styles and the risk of social phobia in offspring: a role of baseline anxiety. Philos Trans R Soc on brain systems involved in the pathophysiology of anxiety Lond [B] 1997;352:1755–1759. Fear and the brain: where have we been, and where 169. The emotional Stroop section with anxiety disorders. Biol Psychiatry 1999;1999: task and psychopathology. The adolescent brain and age-related behavioral mani- and its amelioration by effective treatment with SSRis. KALIN ANIMAL MODELS OF PSYCHIATRIC fore, it is difficult to come up with an animal model for an ILLNESS illness that meets the aforementioned criteria and also models the pathologic syndrome in its entirety. An alterna- Animal Models: Types Of Validity tive approach that has been used involves the modeling of An important criterion for developing animal models to discrete symptom clusters and physiologic alterations rather study psychopathology involves establishing the validity of than the whole syndrome, with the assumption that what the model as a true representation of the process being stud- causes the symptoms contributes mechanistically to the ill- ied. Generally, three types of validity are applied to animal ness. This general approach has involved the use of endo- models: face validity, construct validity, and predictive va- phenotypes that may be related to a particular psychiatric lidity (1–3). Face validity refers to the outward similarity disorder. The term endophenotype refers to a set of behavioral in appearance between the model and the illness. Construct and/or physiologic characteristics that accompany a basic validity, on the other hand, does not exclusively involve process that is altered in relation to the illness that is being outward tangible signs of the modeled illness. It is important to note that this more narrowly refers to the internal mechanism or state that underlies the defined endophenotype approach does not necessarily have illness. Finally, predictive validity refers to the ability of to capture specific symptoms that are a part of the clinical the animal model to identify therapeutic treatments for the diagnosis, but rather may focus on a core process or function illness. It should be noted that the different types of validity that is abnormal in the clinical population under study and can be independent of each other; an animal model can that is thought to be related to the manifestation of the possess predictive and construct validity without possessing illness. For example, in the case of anxiety-related disorders, face validity. Ideally, an animal model should possess both investigators have focused on studying the genetic, physio- construct and predictive validity so that it may be used to logic, and neurochemical correlates of fearful or anxious understand the mechanisms and etiology of the disorder endophenotypes because a core aspect of anxiety-related dis- and also to identify promising treatments for the disorder. Thus, by identify- Endophenotype Approach ing animals that display fearful endophenotypes, it is possi- ble to study the neural substrates that contribute to this Species differences in the manifestation of a particular inter- basic process that may underlie the development and expres- nal state can cloud the usefulness of face validity in animal sion of anxiety-related psychopathology. In addition, when considering a complex psychiat- Using endophenotypes that are based on core and basic ric illness, it is likely that several different symptom clusters processes rather than the entire illness offers certain advan- contribute to the final pathologic condition; these different tages. Because the whole illness is not being modeled, the sets of symptoms may have different underlying substrates endophenotype approach affords greater possibility for con- and thus may be ameliorated by different treatments. There- struct and predictive validity in the model, and can incorpo- rate species-specific manifestations of the core process being modeled. This approach may also make screening for ge- VaishaliP. Kalin: DepartmentofPsychiatry,Univer- sity of Wisconsin at Madison, Wisconsin Psychiatric Institute and Clinics, netic abnormalities associated with the disorder more fruit- Madison, Wisconsin. Moreover, heterogeneity among other variables, the nature of the perceived threat within a diagnostic category could potentially dilute the (14,15). Studies of defensive behaviors in rhesus monkeys strength of a sample population (i. Ideally, one might be able to generate occur in dispositionally fearful humans who have an in- several different endophenotypes for a particular disorder, creased risk to develop psychopathology (16). In other words, pathologic anxiety could be concep- definition and use of endophenotypes in animal models of tualized as the inappropriate expression of defensive or fear- psychiatric illness is a developing area. This chapter presents related behaviors, consisting of either an exaggerated or some promising candidates of animal models of fearful and overly fearful response to an appropriate context, or a fearful anxious endophenotypes, and outlines some of the prelimi- response to an inappropriate or neutral context. Although nary genetic factors that have been identified to contribute appropriate levels of defensive behaviors in response to envi- to the manifestation of these endophenotypes. Thus, in- FEARFUL TEMPERAMENT appropriate or exaggerated expression of defensive behaviors may represent an important animal endophenotype of anxi- Defensive Behaviors ety. An understanding of the specific neural substrates un- In an attempt to understand the basic neural mechanisms derlying the expression and regulation of defensive behav- underlying psychiatric conditions involving fear and anxi- iors may therefore ultimately shed insight into the processes ety, several groups have focused on identifying the neural that become dysregulated in stress-related psychopathology. Defensive be- In defining animal endophenotypes relevant to anxiety, spe- haviors are exhibited by a wide array of species including cific symptoms of a particular type of anxiety disorder are rats, nonhuman primates, and humans in response to per- not being modeled, but rather the general phenomenon of ceived threats from the environment, and are essential com- hyperreactivity to mildly stressful stimuli is studied. Because organisms display defen- iors in animals has been described previously for rodent sive behaviors in reaction to threat, it is thought that the models (17,18). In the following sections, both primate and aberrant expression of defensive behaviors may represent a rodent analogues of stress hyperresponsiveness are de- good example of a fearful endophenotype that would have scribed, with a particular emphasis on models of either the relevance to stress and anxiety-related disorders. Although overly intense but context-appropriate expression of defen- the specific behavioral responses that compose defensive be- sive behaviors or the normal but context inappropriate haviors are dependent on the environmental context and expression of defensive behaviors. Because specific examples of fearful endophenotypes that have been defensive behaviors are expressed in response to an immedi- identified using these tests are discussed. One defensive response pattern Paradigm expressed by many species is to inhibit all body movements and assume an immobile or freezing posture. In the cial relevance for understanding psychopathology. A human in- paradigms including the elevated plus maze (composed of truder then enters the test area, representing a potential safer closed, dark arms versus riskier open bright arms), the predatorial threat to the animal (14,15,19). The test session open field (consisting of a darker wall-bordered peripheral consists of three consecutive brief conditions: alone ('A,' portion versus a brighter open center section), a light-dark animal left alone in cage); no eye contact ('NEC,' animal transition box (consisting of an exploratorium divided into presented with the facial profile of a human standing 2. The NEC condition causes a reduction in cooing Conditioned Fear and an increase in behavioral inhibition, which functions to help the monkey remain inconspicuous in the face of a Behavioral tests that measure conditioned fear utilize basic predator and is often manifested as hiding behind the food principles of Skinnerian conditioning. The ST condition elicits aggressive (open- paradigms to assess fear conditioning are conditioned freez- mouth threats, lunges, cage shaking, barking vocalizations) ing and fear-potentiated startle. Conditioned freezing is eval- and submissive (lip smacking, fear-grimacing) behaviors uated using a two-step procedure. First, during the training that represent adaptive responses to the perceived threat of or conditioning phase, a stressful unconditioned stimulus the staring experimenter. The different test conditions (A, (UCS, such as a foot shock) that elicits freezing is paired NEC, ST) reliably elicit responses in young or adult labora- with a neutral stimulus that subsequently becomes a condi- tory-reared monkeys or in feral animals (14,19). On the test day, the amount of freez- these context-specific defensive responses are not dependent ing in response to the CS is assessed; animals that have on the gender of the intruder, and can also be elicited by not undergone the CS-UCS pairing do not normally freeze showing the animal a videotape of the intruder (Kalin et when the CS is presented, but animals that have learned to al. The Endophenotype in Rodents level of conditioned freezing is thought to correspond to To identify fearful endophenotypes in rodents, a variety the level of fear or anxiety that the animal is experiencing of behavioral paradigms have been employed. The behavioral tests measure one of four general cate- previously with shock. The startle response is markedly in- gories of stress-related behavior: approach-avoidance con- creased when the startling stimulus occurs in the presence flicts, conditioned fear, aggression, and punished of the CS; this relative increase in startle magnitude is quan- responding conflicts. Detailed descriptions and protocols tified, and serves as an index of the level of fear (thought for these tests can be found in a recent review by File and to be elicited by a discrete cue as the CS) or anxiety (thought colleagues (22). The study of defensive aggressive behaviors ment that seems novel but risky (usually bright, wide open, has been summarized and reviewed by a number of investi- large spaces). The entries into and amount of time spent gators (26–28). A number of flight, freezing) of a male intruder are measured. Other 886 Neuropsychopharmacology: The Fifth Generation of Progress stress-related paradigms involve the study of affiliative be- specific defensive responses. These defensive responses have haviors and include the social interaction test in which ap- been characterized using the HIP (see previous section). For proach toward and contact between two rats is measured example, some monkeys tend to coo frequently during the (e. A condition (in which the animal is isolated), whereas other same-aged animals engage in little or no cooing.

A circuitry model of the expression of clear that there is a distinction between the effects of acute behavioral sensitization to amphetamine-like psychostimulants kamagra super 160mg. In the analysis of the literature outlined in the of ventral tegmental area dopaminergic neurons by nicotine 160 mg kamagra super. Morphine-induced activation of A10 dent on cortical glutamate transmission kamagra super 160 mg. Brain Res 1983;277: an oversimplification based on too few experiments using 119–127 160mg kamagra super. Autoradiographic localization of mu- too few classes of drugs of abuse , it is similar to the physio- opioid and neurotensin receptors within the mesolimbic dopa- logic neuroadaptive processes associated with the develop- mine system . Regulation by nicotine motivationally relevant natural stimuli (Fig . Prog Brain Res 1989;79: over , involvement of cortical and allocortical brain regions 173–185 . Autoradiographic evidence for nicotine in addiction imparts a mandate that future researchers to receptors on nigrostriatal and mesolimbic dopaminergic neu- consider the neurobiology of learning and memory as an rons . Synapse speed chronoamperometric study in freely behaving rats. Feeding-evoked dopamine release in nels: past, present and future. Increased extracellular dopamine roadaptation to neurodegeneration. Progr Neurobiol 1998;56: in the nucleus accumbens and striatum of the female rat during 385–431. Different effects of repeated stress- and systemic ethanol effects on extracellular dopamine concen- ful experiences on mesocortical and mesolimbic dopamine me- tration in rat nucleus accumbens by microdialysis. Cocaine potentiates ethanol- bens modulate stress-induced dopamine release in nucleus ac- induced excitation of dopaminergic reward neurons in the ven- cumbens and ventral tegmental area. Behavior-relevant changes in nu- cessation of withdrawal hyperexcitability. Brain Res 1998;803(1, cleus accumbens dopamine transmission elicited by food rein- 2):144–152. Dynamic changes in sensitivity occur during sium current (sK) potentiates the excitatory effect of ethanol the acute response to cocaine and methylphenidate. Psychophar- on ventral tegmental area dopamine neurons. Suppression of ethanol-reinforced be- modulation of dopamine release in the three ascending pathways havior by naltrexone is associated with attenuation of the studied by in vivo microdialysis: comparison of naive and ethanol-induced increase in dialysate dopamine levels in the chronic nicotine-treated rats. Non-competitive N-methyl-D-aspartate activation of mesolimbic dopamine transmission by a common antagonists are potent activators of ventral tegmental A10 dopa- m1 opioid receptor mechanism. Characterization of substan- J Physiol 1998;80:1–27. Footshock and conditioned retically applied GABA and flurazepam. Life Sci 1993;53: stress increase in 3,4-dihydroxyphenylacetic acid (DOPAC) in 1911–1919. Reinforcing effects of morphine in the nucleus ac- 1985;333:143–146. Heroin and cocaine caine alters subsequent cocaine-induced increase of extracellular intravenous self-administration in rats: mediation by separate dopamine in the medial prefrontal cortex. The basal ganglia and chunking of action reper- are localized to extrasynaptic plasma membranes of GABAergic toires. Molecular, cellular and of the rewarding effect elicited by microinjections of morphine anatomical substrates of place learning. Neurobiol Learning into the nucleus accumbens of mice. Brain Cogn 1999;41: accumbens-pedunculopontine nucleus circuitries involved in 1–8. The hippocampus and mechanisms of declara- bic motor circuits and neuropsychiatry. The circuitry mediat- campal and catecholaminergic terminals converge on spiny neu- ing the translation of motivational stimuli into adaptive motor rons and are in apposition to each other. Opioid modulation and sensitization in the nucleus accumbens septi and on dopamine neurons in of dopamine release elicited by sexually relevant stimuli: a high- the ventral tegmental area. The role of excitatory amino acids in behavioral repeated administration of cocaine or amphetamine is transient sensitization to psychomotor stimulants. Progr Neurobiol 1998; and selectively involves AMPA receptors. Self-administered nico- glutamatergic signaling in the induction and expression of be- tine activates the mesolimbic dopamine system through the ven- havioral sensitization. Adaptive responses of circuits during cue-elicited cocaine craving. Proc Natl Acad Sci -aminobutyric acid neurons in the ventral tegmental area to USA 1996;93:12040–12045. 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Reproducibility of repeated amine- and K -mediated dopamine release in rat striatum after measures of endogenous dopamine competition with repeated amphetamine: differential requirements for Ca2 - [11C]reclopride in the human brain in response to methylphen- and calmodulin-dependent phosphorylation and synaptic vesi- idate. Molecular and cellular basis of ad- and nicotine predisposes rats to self-administer a low dose of diction. Effects of cocaine, nicotine, dizocilpine BTB protein that can prevent behavioral sensitization in rat. J and alcohol on mice locomotor activity: cocaine-alcohol cross- Neurosci 2000,20:6210–6217. Molecular alterations in the neostria- porter binding sites. Expression of the tran- lar actions of chronic morphine and cocaine in dopaminergic scription factor dFosB in the brain controls sensitivity to co- brain reward regions. Homer: a protein York Academy of Sciences, Volume 654). New York: New York that selectively binds metabotropic glutamate receptors. AMPA receptors by the extracellular immediate early gene prod- 72. Prior expe- phencyclidine exposure: involvement in frontostriatal cognitive rience of morphine application alters the c-fos response to deficits. Dopamine depletion in the medial pre- Res 2000;77(1):55–64. Stress-induced cross-sensitiza- ical responses to cocaine. Blockade of D-1 dopa- short- and long-term withdrawal. Psychopharmacology 1998; mine receptors in the medial prefrontal cortex produces delayed 136:24–33. Facilitation of sexual behaviors in the in the nucleus accumbens. Supersensitivity to the macol Biochem Behav 1990;35:643–650. Animal models of stimulant-induced sions to the medial prefrontal cortex in rats. Animal models of drug dysfunction in drug abuse: implications for the control of behav- craving. Time-depen- 1366 Neuropsychopharmacology: The Fifth Generation of Progress dent changes in cocaine-seeking behavior and extracellular dopa- 108. Repeated cocaine augments mine levels in the amygdala during cocaine withdrawal. Neuro- excitatory amino acid transmission in the nucleus accumbens psychopharmacology 1998;19:48–59. Dissociation of primary and secondary reward- on the involvement of dopamine. Repeated cocaine administration alters psychpharmacology 2000;22(5):473–479. Evidence for conditional neuronal activation following exposure to a cocaine-paired envi- 2000;20:RC89. Fos protein expres- phetamine- and cocaine-induced behavioral sensitization. Cereb sion and cocaine seeking behavior in rats after exposure to a Cortex 2000;10:488–498. Differential effects of excitotoxic lesions 20(2):798–805. Developing a neuronal model and conditioned place preference. Psychopharmacology 1993; for the pathology of schizophrenia based on the nature of elec- 113:123–130. Modulation of memory neurobiological aspects of emotion, memory and mental dysfunction. Cortical regulation of subcortical dorsal nucleus of the thalamus and the ventromedial prefrontal dopamine release: mediation via the ventral tegmental area. J cortex in stimulus-reward associative learning in the monkey. Persistent structural modifications in the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem 1996;66: nucleus accumbens and prefrontal cortex neurons produced by 589–598. Morphine alters the structure of neurons adult rats with neonatal excitotoxic lesions to the medial pre- in the nucleus accumbens and neocortex of rats. HYMAN Addiction to alcohol, tobacco, and illegal drugs represents cludes understanding the molecular processes that lead to a substantial burden to societies worldwide. In terms of compulsive use and the long-term risk of relapse. Both addictive and be responsible for 450,000 deaths yearly in the United many nonaddictive drugs may produce tolerance and de- States), and disability. Tolerance refers to the diminishing effect of a diction results in crime, negative impacts on families, de- drug after repeated administration at the same dose, or to railed lives, and personal suffering. The major categories of the need for an increase in dose to produce the same effect. De- pendence is typically unmasked when drug taking stops, nicotine, marijuana, and phencyclidine-like drugs. Withdrawal symptoms standing the molecular and cellular actions of addictive may even emerge during active drug use as a result of toler- drugs is obligatory if we are to better understand pathophys- ance, helping to drive increasing dosages or shorter intervals iology and develop potent pharmacotherapies to treat addic- between doses. Of course, the molecular and cellular information pre- Among the addictive drugs, ethanol and opiates produce sented in this chapter cannot be applied directly to the dependence that has a somatic component, manifested by behavioral expression of addiction without putting it into somatic symptoms during withdrawal, such as hyperten- the context of systems level neuroscience described in other sion, tremor or seizures for ethanol, and hypertension, lacri- chapters. All addictive Acutely, addictive drugs are both rewarding (i. The central feature of ad- when produced by addictive drugs, tolerance and with- diction is compulsive drug use—the loss of control over drawal symptoms tend to resolve within days to weeks and the apparently voluntary acts of drug seeking and drug tak- therefore cannot account for the persistence of drug addic- ing. Once it has taken hold, addiction tends to follow a tion (as manifest by the tendency to relapse)for many years. Even after extended periods of drug abstinence, the risk inhaled for asthma, many antihypertensive drugs, and of relapse remains high. From the point of view of develop- shorter-acting serotonin selective reuptake inhibitors may ing treatments, a central problem in addiction research in- produce dependence and withdrawal symptoms on cessa- tion, but do not produce compulsive drug seeking and drug taking. Based on these considerations, the molecular mecha- nisms underlying tolerance and dependence, and those re- Kathy L. Hyman: National Institutes of Health, sponsible for addiction may overlap, but cannot be iden- Bethesda, Maryland. Mesocorticolimbic dopamine peated administration of a drug elicits escalating effects of projections originate in the ventral tegmental area (VTA) a given dose. Because clude the nucleus accumbens (NAc)(a complex structure behavioral sensitization to drugs in animal models can be within the ventral striatum that is the best-established sub- quite long-lived, it has been considered by some to be a strate for reinforcement), and the prefrontal cerebral cortex. In vivo microdialysis studies have indicated that most if Not every individual who experiments with drugs be- not all addictive drugs, including cocaine, amphetamines, comes addicted. Indeed, the likelihood that a person will opiates, nicotine, and ethanol, cause selective elevation of experiment with drugs, use them repetitively, and progress extracellular dopamine levels in the NAc, and blockade of to addiction, appear to be the product of complex dopamine neurotransmission in this region attenuates most gene–gene and gene–environment interactions, acting to- measurable reinforcing and rewarding effects of addictive gether with contextual variables, such as drug availability.

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