By A. Rhobar. Golden State Baptist College. 2019.

The study described how the early evaluated in monetary terms (90) generic cipro 250mg without a prescription. Te assess- intervention services buy cipro 500mg, contributing to the Irish ment included 28 trials carried out at a total cost mental health service purchase cipro 1000mg on line, could reduce the dura- of US$ 335 million. By valuing a quality-adjusted tion of untreated psychosis, the severity of life year (QALY) as the same as gross domestic symptoms, suicidal behaviour and the rate of product (GDP) per capita, the projected net ben- relapse and subsequent hospitalization. The eft to society afer 10 years was US$ 15·2 billion, study suggested that early detection reduces indicating a yearly return on investment of 46%. For instance, public-sector ing from the wider economic efects of public and research institutions in the USA do more applied charitable research spending, including the stim- research than has sometimes been thought. Te yearly one domain, they contributed to the discovery of rate of return with respect to the health gain was 9–21% of all drugs involved in new-drug applica- 9% for cardiovascular disease research, and 7% for tions that were approved between 1990 and 2007 mental health research. Publicly funded research in the USA also terms of GDP was 30% for all medical research in tends to discover drugs that are expected to have the United Kingdom. Putting these together gave disproportionately large clinical efects. A key con- should be, measured in monetary terms (91). To cern, therefore, is how far such countries can rely capture the diversity of benefts from research, on medical research carried out elsewhere (91). Tis model of assessment has Research for universal health coverage is not a logical appeal because, while acknowledging luxury; rather, it is fundamental to the discov- complexities and feedback loops, it tracks the ery, development and delivery of interventions evolution of a research idea from its inception, that people need to maintain good health (100). It parallels the research research also lie ahead (101). Te report generated a wide appreciation and weaknesses of research for health, country of the shortfall in research investment and of the by country, worldwide. When public money is fragility of health research in low- and middle- being spent on research, there should be mecha- income countries. More than 20 years later, it nisms for debating research priorities, for devel- is clear that research for health is on the rise oping the capacity to carry out research, for worldwide. Health problems are better defned setting standards, and for translating the results than they were two decades ago. In judging the priorities funds and greater research capacity to address for spending, there should be a consensus on the key questions about health. Investigations are balance of activities related to the research cycle: increasingly following best practice in design, measuring the size of the health problem; under- ethics and the reporting of results. Tere are standing its cause; devising solutions; translating more research institutions and networks, and the evidence into policy, practice and products; there is more national and international col- and evaluating the efectiveness of interventions laboration, “south to south” as well as “north to afer implementation. Te review of the research land- studied in any given setting, there should be scape in this chapter is not yet a story of research discussion on the methods of investigation, the potential fulflled but it shows the strengthen- signifcance of the fndings, and the inferences to ing foundations on which better research pro- be drawn from them. Te means of creating a healthy research Creativity and imagination are central to environment and of judging its performance the research enterprise. A premise of this report are described in greater detail in Chapter 4. Health research - essential link to equity in development. London, Higher Education Funding Council for England, 2005. Scientifc evidence alone is not sufcient basis for health policy. Paris, Organisation for Economic Co-operation and Development, 2012. Implementation science and its application to population health. Seattle, Institute of Translational Health Sciences, 2012 (www. Health research classifcation systems: current approaches and future recommendations. Translating research into action: WHO evidence-informed guidelines for safe and efective micronutri- ent interventions. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Developing evidence-based immunization recommendations and GRADE. Addis Ababa, United Nations Economic Commission for Africa and the African Innovation Foundation, 2011 (www. Priority-setting in health: building institutions for smarter public spending. Washington, DC, Center for Global Development, 2012. Innovation in healthcare delivery systems: a conceptual framework. The Innovation Journal: The Public Sector Innovation Journal, 2010,15(1). Report of the Ad Hoc Committee on Health Research Relating to Future Intervention Options. Macroeconomics and health: Investing in health for economic development. Report of the Commission on Macroeconomics and Health. Informed choices for attaining the Millennium Development Goals: towards an international cooperative agenda for health-systems research. World report on knowledge for better health − strengthening health systems. The emergence of global attention to health systems strengthening. Climate for evidence-informed health systems: a profle of systematic review production in 41 low- and mid- dle-income countries, 1996–2008. Journal of Health Services Research & Policy, 2012,17:4-10. GBD 2010: a multi-investigator collaboration for global comparative descriptive epidemiology. Setting priorities for health interventions in developing countries: a review of empirical studies. Tropical Medicine & International Health, 2009,14:930-939. A checklist for health research priority setting: nine common themes of good practice.

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Does self-monitoring by means of Ineligible intervention symptom diaries improve asthma control in children? J Asthma 2014;51:299–305 Asarnow JR purchase cipro 500 mg without a prescription, Jaycox LH buy 750 mg cipro fast delivery, Duan N cheap 250 mg cipro free shipping, LaBorde AP, Rea MM, Murray P, et al. Effectiveness Ineligible intervention of a quality improvement intervention for adolescent depression in primary care clinics: a randomized controlled trial. JAMA 2005;293:311–19 Asarnow JR, Jaycox LH, Tang L, Duan N, LaBorde AP, Zeledon LR, et al. Long-term benefits Ineligible intervention of short-term quality improvement interventions for depressed youths in primary care. Am J Psychiatry 2009;166:1002–10 Au A, Lau K-M, Wong AH-C, Lam C, Leung C, Lau J, et al. The efficacy of a group Triple P No eligible economic (positive parenting program) for Chinese parents with a child diagnosed with ADHD in outcomes Hong Kong: a pilot randomised controlled study. Aust Psychol 2014;49:151–62 Bartholomew LK, Sockrider M, Abramson S, Swank PR, Czyzewski D, Tortolero SR, et al. No clinical diagnosis, Partners in school asthma management: evaluation of a self-management program for ineligible intervention children with asthma. J Sch Health 2006;76:283–90 Beebe A, Gelfand EW, Bender B. A randomized trial to test the effectiveness of art therapy No eligible economic for children with asthma. J Allergy Clin Immunol 2010;126:263–6 outcomes Bhaumik U, Norris K, Charron G, Walker SP, Sommer SJ, Chan E, et al. A cost analysis for a No eligible health outcomes community-based case management intervention program for pediatric asthma. J Asthma 2013;50:310–17 Bodden DHM, Dirksen CD, Bogels SM, Nauta MH, De Haan E, Ringrose J, et al. Costs and Absent/ineligible comparator cost-effectiveness of family CBT versus individual CBT in clinically anxious children. Clin Child Psychol Psychiatry 2008;13:543–64 Boogerd EA, Noordam C, Kremer JA, Prins JB, Verhaak CM. Teaming up: feasibility of an No eligible economic online treatment environment for adolescents with type 1 diabetes. Asthma education and health outcomes of children aged 8 to 12 years. Clin Nurs No eligible economic Res 2013;22:172–85 outcomes Brandao HV, Cruz CM, Santos Ida S Jr, Ponte EV, Guimaraes A, Augusto Filho A. Ineligible population, Hospitalizations for asthma: impact of a program for the control of asthma and allergic adult/child data mixed rhinitis in Feira de Santana, Brazil. J Bras Pneumol 2009;35:723–9 Brandt S, Gale S, Tager I. The value of health interventions: evaluating asthma case No eligible health outcomes management using matching. Appl Econ 2012;44:2245–63 Brandt S, Gale S, Tager I. Estimation of Treatment Effect of Asthma Case Management No eligible health outcomes Using Propensity Score Methods. Amherst, MA: University of Massachusetts, Department of Resource Economics; 2009 Bratton DL, Price M, Gavin L, Glenn K, Brenner M, Gelfand EW, et al. Impact of a Absent/ineligible comparator multidisciplinary day program on disease and healthcare costs in children and adolescents with severe asthma: a two-year follow-up study. 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 103 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. APPENDIX 4 Study ID Reason for exclusion Brent DA, Holder D, Kolko D, Birmaher B, Baugher M, Roth C, et al. A clinical No eligible economic psychotherapy trial for adolescent depression comparing cognitive, family and supportive outcomes therapy. Arch Gen Psychiatry 1997;54:877–85 Brent DA, Kolko DJ, Birmaher B, Baugher M, Bridge J. A clinical trial for adolescent No eligible economic depression: predictors of additional treatment in the acute and follow-up phases of the outcomes trial. J Am Acad Child Adolesc Psychiatry 1999;38:263–70 Brent DA, Holder D, Kolko D, Birmaher B, Baugher M, Roth C, et al. A clinical No eligible economic psychotherapy trial for adolescent depression comparing cognitive, family and supportive outcomes therapy. Arch Gen Psychiatry 1997;54:877–85 Britto MT, Vockell AL, Munafo JK, Schoettker PJ, Wimberg JA, Pruett R, et al. Improving Absent/ineligible comparator outcomes for underserved adolescents with asthma. Pediatrics 2014;133:e418–27 Broquet Ducret C, Verga ME, Stoky-Hess A, Verga J, Gehri M. Randomized trial of a comprehensive No eligible health outcomes asthma education program after an emergency department visit. Ann Allergy Asthma Immunol 2006;97:44–51 Bruzzese JM, Markman LB, Appel D, Webber M. An evaluation of open airways for schools: Absent/ineligible comparator using college students as instructors. J Asthma 2001;38:337–42 Bruzzese JM, Evans D, Wiesemann S, Pinkett-Heller M, Levison MJ, Du YL, et al. J Sch Health 2006;76:307–12 Bruzzese JM, Unikel L, Gallagher R, Evans D, Colland V. Feasibility and impact of No eligible economic a school-based intervention for families of urban adolescents with asthma: results from a outcomes randomized pilot trial. Fam Process 2008;47:95–113 Buchner DA, Butt LT, De Stefano A, Edgren B, Suarez A, Evans RM. Effects of an asthma No comparator; adult/child management program on the asthmatic member: patient-centered results of a 2-year study mixed data in a managed care organization. Am J Manag Care 1998;4:1288–97 Buelow JM, Johnson CS, Perkins SM, Austin JK, Dunn DW. Creating Avenues for Parent No eligible economic Partnership (CAPP): an intervention for parents of children with epilepsy and learning outcomes problems. Epilepsy Behav 2013;27:64–9 Butz AM, Malveaux FJ, Eggleston P, Thompson L, Schneider S, Weeks K, et al. Use of Absent/ineligible comparator community health workers with inner-city children who have asthma. Clin Pediatr 1994;33:135–41 Bynum A, Hopkins D, Thomas A, Copeland N, Irwin C. The effect of telepharmacy No eligible economic counseling on metered-dose inhaler technique among adolescents with asthma in rural outcomes Arkansas.

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Unfortunately discount 750 mg cipro otc, although this has Understanding of the capacities of persons with mental become the focus of political and media attention generic 500mg cipro with amex, there is illnesses to consent to research has historically relied on data often a lack of understanding of what informed consent gathered from studies looking at competence to consent is best cipro 750mg, and what the literature shows regarding the capacity of to treatment. Recent years have seen an expansion of the mentally ill subjects to give informed consent. Gen­ With regard to the ability to communicate a choice, al­ erally, informed consent, whether to research or treatment, though sometimes taken for granted, studies have shown is broken down into three parts: voluntariness, disclosure, and that a proportion of patients will have difficulties in this competence (51). In a study by Appelbaum, Mirkin, and Bateman, 9% must be acting of their own free will when they agree to of community mental health center patients who were con­ participate in research. Disclosure provides information on tacted to participate in a study were found to be mute or the basis of which potential subjects may make an informed catatonic (53). In research settings, disclosures must generally in­ patients were unable to make a decision in vignettes that clude such details as the nature and purpose of the study, required some problem solving (54). The risk of simply as well as the potential risks and benefits involved in the excluding these persons from studies is that their inability study. Other information provided includes disclosure of to communicate a choice may reflect a degree of illness that the right to discontinue participation in the study, who will is worthy of study, and their exclusion might skew the re­ have access to the data, the differences between participation sults of research based on altered group composition. There- in research and routine treatment, and the availability of fore, there may be value in considering whether proxy deci­ compensation should harm ensue as a result of the study. First, who are unable to express a consistent choice. The choice need not be expressed verbally, understand information. For example, Grossman and Sum­ but subjects must be able to communicate their preference mers (55) found that patients with schizophrenia under- in some way. The degree of psycho- Additionally, subjects must have a factual understanding pathology may affect learning of new information in schizo­ of the information that has been presented to them. Kleinman and colleagues (57) suggested that degree of factual understanding required for competence a formalized informing process increased schizophrenic pa­ is unclear, and there is no threshold value of how much tient understanding of tardive dyskinesia. In a frequently information must be understood in order to be considered cited study of 41 patients with affective disorders who were to have 'enough' factual understanding. Furthermore, ac­ potential subjects of a sleep EEG study, Roth and colleagues ceptable levels of understanding may vary depending on the (58) found that only about 50% of the subjects understood risks involved in a proposed research study. Benson and associates (59) showed that tia were noted not to perform as well as nondemented el­ patients with schizophrenia demonstrated greater impair­ derly subjects in providing logical reasons for their decisions ment in understanding specific psychiatric research pur­ to participate in hypothetical research protocols. Comparing the to make treatment decisions was reported by Grisso and capacity of stable patients with schizophrenia and healthy Appelbaum (68,69) from the MacArthur Treatment Com­ volunteers to understand a low-risk study involving a mag­ petence Study. This study utilized standardized instruments netic resonance imaging test for research purposes, Pinals designed to assess capacities to make treatment decisions, and co-workers (60) found no difference in understanding and involved the assessment of multiple components of of consent forms between groups. Of note, neither group competence (understanding, appreciation, and reasoning) on average was able to correctly answer 100% of the ques­ and the use of several subject groups. Deficits were most tions on a brief questionnaire related to information on the pronounced in patients with schizophrenia, and slightly consent form. Another study using a questionnaire relating more patients with depression were likely to have deficits to research protocols found that out of 49 patients with than controls. Because the majority of all subjects performed schizophrenia, 53% required a second trial at the question­ well on measures of competence, the study underscored the naire after re-education about the protocols to achieve a notion that subjects cannot be presumed incompetent by score of 100%, and 37% of subjects required three or more virtue of mental illness alone. The authors concluded that with an adequate Carpenter and associates (70) recently reported their informed consent process, research subjects with schizo­ findings examining how psychopathology and cognition af­ phrenia were able to comprehend consent form informa­ fect decisional capacity. In a classic report, Soskis perform as well as healthy controls in decision making, and (62) found that 68% of schizophrenic subjects did not rec­ performance was strongly related to cognitive impairments ognize the reason they were receiving treatment compared and somewhat related to symptomatology. In an earlier study looking study found that a weeklong educational intervention that at patient appreciation of their participation in research, provided information regarding the hypothetical study led Appelbaum and associates (63) showed that more than half to improved decisional capacity such that scores of schizo­ of the psychiatric patients interviewed failed to comprehend phrenic subjects were not significantly different from the the research nature of some component of the methodology well control group. In another recently published study, of the research in which they were participating. In this study, female outpatients with major to the subject at all, the 'therapeutic misconception. This study further demon­ tionally manipulate information pertaining to research, strated the utility of instruments such as the MacCAT-CR Stanley and colleagues (64) reported that the degree of psy­ as a means of assessing decisional capacity as part of the chopathology in patients with mental illness did not appear broader informed consent process in an actual research to influence their willingness to participate in hypothetical study. In that study, patients tended to agree to low-risk/high-benefit hy­ pothetical studies more than high-risk/low-benefit studies. COMMENTARY In a subsequent study, Stanley and associates (65) found that approximately one-third of patients with mixed psychi­ Although ethics in human subject research has long been atric diagnoses refused low-risk/high-benefit hypothetical the focus of attention, awareness of the ethical dilemmas study enrollment, whereas about 40% of patients agreed to has been heightened in recent years. Despite calls for a mora­ participate in a hypothetical study of high risk/low benefit. What can be gleaned from the estimates of the likelihood of an adverse event compared to current debate is that researchers must attend to the con­ nondelusional psychiatric patients and normal controls. In cerns raised, both to maintain public trust and ensure the 480 Neuropsychopharmacology: The Fifth Generation of Progress ethical integrity of research itself. As Bonnie (74) noted, 'Exit criteria' should be established a priori to determine the challenge is to create generally accepted guidelines on when patients will be restarted on their medications (41). Patients at known risk of The research community has made several efforts to tac­ catastrophic responses to relapse should be excluded from kle these issues. The American College of Neuropsycho­ the subject pool. Finally, study subjects must be given the pharmacology (ACNP) has developed guidelines on ethical opportunity to provide informed consent, pose questions, practices related to neuropsychopharmacologic research. Those Highlighted are the needs to: (a) ensure appropriateness of patients with initial decision-making deficits and those who the study and its design; (b) minimize risk to subjects and may become decisionally impaired during the study will maximize benefit to subjects or to the population of patients require special measures of protection, addressed in the fol­ with the illnesses under study; (c) ensure informed consent, lowing. Several suggestions have been made that may offer new rules for 'high-risk' studies, including the creation protections to subjects. For example, Tishler and Gordon of a special Human Subject Research Workgroup of the (46) have suggested a careful recruitment process that would National Advisory Mental Health Council (NAMHC), include detailed disclosure of the inherent risks, review of which will review study protocols involving challenge meth­ compensation for participation, and screening prospective odology or drug withdrawal studies (76). After several meet­ normal subjects for the presence of or vulnerability to de­ ings with representatives of the NIMH, in 1995 the Na­ velop psychiatric illness. Miller and Rosenstein (49) indi­ tional Alliance for the Mentally Ill (NAMI) adopted cated that: (a) the study should have clear scientific merit, 'Policies on Strengthened Standards for Protection of Indi­ (b) subjects with specific clinical vulnerabilities may need to vidual with Severe Mental Illnesses who Participate in be excluded from participation, (c) selected methods should Human Subjects Research' (77). Among these policies are minimize risks, (d) subjects should have access to careful a recognition of the 'critical necessity' of human subject monitoring and follow-up, and (e) informed consent disclo­ research, and recommendations for protection of persons sure should make clear that the challenge study is distinct with cognitive impairments, clearer standards for consent from other studies in which the subject may be enrolled protocols, and specialized training for members of IRBs that (80). Mea­ With regard to the consent process and the potential sures to ensure that ethical issues are addressed have been for decision-making impairments of mentally ill research developed, including the Research Protocol Ethics Assess­ subjects, existing literature provides only rudimentary guid­ ment Tool (RePEAT), which may assist in the planning of ance in identifying groups at high risk of impairment. It has been suggested that not pursuing placebo shown that many of these persons will retain abilities to and drug withdrawal studies would be unethical, given all make decisions that affect their lives, and thus it is mislead­ there is to learn from them regarding the pathophysiology, ing to presume them incompetent by virtue of their diag­ natural course, and treatment of severe mental illness (79). That said, it also is clear that specific approaches can be Although policies will need to offer protection for those utilized in order to ensure that this research is conducted who may have decision-making impairments, excessive bur- safely and ethically. For example, there may be some studies dens must be avoided if advancement of knowledge is to of pathophysiology in which subjects may be maintained continue. By thwarting attempts to conduct bold and novel on a low but effective neuroleptic dose, without interfering studies, society runs the risk of limiting knowledge of the with the acquisition of valid data (38). For neuroleptic with­ very populations who may be most in need of such research. Drug-free phases may tial for benefit is low, testify to the desperation that some best be conducted while subjects are in an inpatient setting, of these patients may feel regarding their illnesses.

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The best known of these is -catenin purchase cipro 250mg free shipping, and both - transgenic mice purchase 750mg cipro visa. Immunohistochemical analysis has shown and its homologue cheap 500 mg cipro, -catenin, have been shown to interact that cholinergic markers accumulate in swollen abnormal with PS1 (23). The effect of PS1 mutations on -catenin neurites around amyloid deposits in the cortex (4), and our stability and hence its downstream effects are controversial. Significantly, this finding correlates with re- and mutant PS1 protein (25–27). Quite how PS1 muta- duced cholinergic neurotransmitter activity (unpublished tions may lead to AD through a -catenin pathway is un- data). Further work to assess how cholinergic neurons in clear, although in addition to the effect on A 42, one action all areas of the brain respond to increasing amyloid burden maybe on the action of GSK- and hence tau phosphoryla- and age is under way because cholinesterase inhibitors are tion (for a review, see Alzheimer forum panel discussion at currently considered to be valid therapeutic agents for AD. Cognitive Impairments and Neurodegeneration Neurodegeneration Human AD brain shows extensive neurodegeneration, both Recreating human cognitive impairment is perhaps the in cholinergic neurons of the nucleus basalis (28) and in greatest challenge facing genetic engineers working on Chapter 84:Transgenic Mouse Models of Alzheimer Disease 1217 transgenic models of human dementia. Mice are genetically is not detrimental to tau or differences between mouse and less suitable to behavioral testing than rats because perfor- human brain preclude the formation of pathogenic tau, as mance data on normal mice from different strains are often suggested by Geula et al. Despite these reservations, most of the countered by reports that mouse tau is capable of forming transgenic mice that form amyloid deposits have been tested PHF-like structures in vitro (44). The PDAPP mouse (35,36), the transgenic mice that overexpress all isoforms of human tau Tg2576 mouse (3), and the Tg2576/PS1 cross-mouse (12) under the control of the human tau promoter (45), in an have all shown a deficit in tests of hippocampal dysfunction effort to 'humanize' the tau environment in amyloid- before amyloid deposits form, a finding that strongly sug- depositing mice by cross-breeding the different lines. Unfor- gests that overt amyloid accumulation or deposition is not tunately, even in the presence of extensive amyloid, the mice responsible for this early cognitive impairment. Deficits in do not form neurofibrillary pathology (unpublished data), water maze performance that correlate with increasing age a finding suggesting that the mice are either still deficient and amyloid burden and with decreasing long-term poten- in another human component or that A accumulation tiation have been reported for Tg2576 mice (3,37). Mutations in tau have been shown to cause frontal tem- poral lobe dementia (FTD-17) (46–48), which, in some cases, appears to result from an imbalance in tau isoform Tau Pathology ratios (47). Transgenic mice that overexpress normal human One of the major deficits in the current AD mice is the tau isoforms and recreate this imbalance show a partly unex- lack of tau pathology. In humans, tau pathology takes the pected phenotype in that the mice develop hind limb weak- form of intracellular tangles of an abnormally phosphory- ness mainly resulting from spheroid accumulations com- lated form of the tau protein, which associates into paired posed of tau and neurofilament form, which are particularly helical filaments (PHFs). Both amyloid plaques and tau tan- prevalent in the axons of motor neurons (45,49,50). Al- gles are pathognomic features of human AD, and their rela- though the tau does appear to be in an abnormal conforma- tive contribution to the disease has long been disputed. The tion, the relevance of the axopathy to human FTD-17 or identification of AD-causing mutations in APP and the pre- the tauopathies is unclear. Mutant tau transgenic mice have senilin genes, however, adds weight to the amyloid-based been created, but their phenotype has not yet been de- scribed. It is likely that the creation of a battery of tau hypothesis of pathogenesis, which assumes that tau abnor- transgenic mice will provide long-awaited resources for the malities are a secondary lesion that form in response to study of the normal and abnormal biology of this important amyloid accumulation. This work showed that amyloid deposits in transgenic mice are ringed by dystrophic neurites that are immunoreactive ACKNOWLEDGMENT for markers of phosphotau epitopes such as phosphoserine This work is supported by National Institute of Health 202 (4,38). These epitopes are phosphorylated to some de- grants AG146133, AG10485, AG17585, and AG17216. In the mice, it is not yet clear whether the immu- noreactivity around deposits reflects local hyperphosphory- lation of tau or simple elevation of tau protein levels in REFERENCES response to neuritic damage. Alzheimer-type neuro- both tyrosine phosphotau and the signaling protein fyn, pathology in transgenic mice overexpressing V717F -amyloid which is an src, nonreceptor tyrosine kinase (39). Correlative memory defi- of fyn interact directly, a finding suggesting that tau may be cits, A elevation and amyloid plaques in transgenic mice. Science involved in signal transduction pathways (40). Two amyloid fyn binds another signaling protein, FAK (41), which is precursor protein transgenic mouse models with Alzheimer dis- itself up-regulated by A (42). Proc Natl Acad Sci USA 1997;94:13287– study of how FAK, fyn, tau, and A interact in transgenic 13292. Nalbantoglu J, Tirado-Santiago G, Lahsaini A, et al. Impaired learning and LTP in mice expressing the carboxy terminus of It is clear, however, that tau pathology does not develop the Alzheimer amyloid precursor protein. Nature 1997;387: further in the mutant APP and PS transgenic animals, a 500–505. Increased amyloid-A 42(43) associated with Alzheimer disease cause defective intracellular in brains of mice expressing mutant presenilin 1. Nature 1996; trafficking of beta-catenin, a component of the presenilin protein 383:710—713. Proc Natl Acad Sci USA protein in both transfected cells and transgenic mice. Immunization with amy- associated with neuropil changes, but not with overt neuronal loid-beta attenuates Alzheimer-disease–like pathology in the loss in the human amyloid precursor protein V717F (PDAPP) PDAPP mouse. APPSw deposition in the brains of transgenic mice co-expressing mutant transgenic mice develop age-related A deposits and neuropil presenilin 1 and amyloid precursor proteins. Neuron 1997;4: abnormalities, but no neuronal loss in CA1. Neuron mer-type phenotype in transgenic mice carrying both mutant loss in APP transgenic mice. Reorganization of cholinergic amyloid precursor protein and mutant presenilin 1 transgenes. Society for Neurosciences, transgenic mouse: effect on an age-dependent increase of amyloid New Orleans, 1997. Two transmembrane transgenic Alzheimer mice [Abstract 636. The protein tyrosine kinase, fyn, in Alzhei- pressing FAD-linked presenilin 1. Functional phenotype in non-receptor tyrosine kinases. Presenilin 1 is required for tyrosine kinase, pp125FAK. Notch1 and DII1 expression in the paraxial mesoderm. Notch1 is required for the able to amyloid -protein neurotoxicity. Presenilin 1 interaction helical filaments from mouse tau: implications for the neurofibril- in the brain with a novel member of the Armadillo family. Characterization of pathol- catenin by mutations in presenilin-1 potentiates neuronal ogy in transgenic mice over-expressing human genomic and apoptosis. Association of missense Chapter 84:Transgenic Mouse Models of Alzheimer Disease 1219 and 5′-splice-site mutations in tau with the inherited dementia and progression of a tauopathy in transgenic mice overexpressing FTDP-17.

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Several knock- gression) order cipro 750 mg amex, the construct validity is as yet largely unknown order cipro 1000 mg mastercard. In the resident-intruder paradigm buy cipro 1000mg low price, a male rat is One has to be careful to consider the hyperaggression ob- housed with a female, a situation resembling the natural tained after the mutation directly caused by the absence situation in which animals establish and defend territories of the gene. When resident or territorial males meet an unfamiliar interpretation, whereas adaptational processes over time male intruder in their territory, heavy fighting may ensue, may also influence the outcome. Most studies reported do considered natural fighting (39,40). The attacking male per- not use extensive description of the behavioral phenotype, forms a complete agonistic repertoire including both appeti- and conclusions whether the observed 'aggressive' pheno- tive and consummatory behaviors Aggressive behavior in type of the mutant is directly caused by the absence of the this situation may consist of searching (patrolling), ap- gene or results from maladaptation of the mutant to external proach, investigation, threats fighting, chasing, and domi- stimuli have to be investigated before a mutant can be con- nant posturing The nature of such interactions between an sidered as a putative model for a certain kind of aggression. The types of behaviors displayed by ing novel mechanisms involved in aggression and provide the resident toward the intruder are not random but follow useful models for development of novel drug intervention certain rules (15), a strong indicator of the neural substrates targets. The 5-HT1B-receptor knockout mouse (27) has been The resident-intruder model differs both from isolation- evaluated most extensively on different aspects of its hyper- induced aggression in mice and intermale aggression in rats, aggressiveness and has been proposed as an animal model of because there is no isolation, which may lead to behavioral impulsivity (32,33). The latter study investigated territorial abnormalities (8). Moreover, resident-intruder paradigms aggression in 5-HT1B knockout males and corresponding have a very wide species generality (41), including humans wild types (in a 129SV background) while equipped with (42). Isolation-induced aggression, in contrast, is far more telemetric senders to record heart rate and body temperature restricted to certain species (10). Ethologic analysis of the behavior effectively the quality and behavioral mechanisms of action 1702 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 118. ANIMAL BEHAVIOR ANALYSIS Frequency Duration Behavior Wild-Type Knockout Wild-Type Knockout Nonsocial activity Attention 28 (19–33) 22. Mice were subjected to a 10-min encounter with a group-housed male intruder, and the behavior of the resident was scored, using an ethologic method. Data are given as median (using twenty-fifth to seventy-fifth percentiles) frequencies and duration (seconds) per 10 min. Mann-Whit- ney U test: the asterisk means significantly different from wild-type mice (p. Vasopressin receptor antagonists injected into 44), whereas at higher doses they clearly cause ataxia, which this area are potent inhibitors of aggression. Fluoxetine, a interferes with the behavioral performance. Alcohol, as in selective serotonin uptake inhibitor, decreases offensive ag- mice, enhances aggression in some rats, but not in others gression in male hamsters and prevents vasopressin-induced (14,18). Interestingly, this increased aggression in a sub- aggression. This finding has led to the hypothesis that there population of the resident males was observed both after is an interaction between vasopressinergic and serotonergic experimenter-administered ethanol and after self-adminis- systems in the regulation of offensive aggression. Understanding the underlying neuro- subjected to social subjugation as juveniles displayed ele- chemical mechanisms responsible for the individual differ- vated levels of aggression toward smaller hamsters as adults ences in behavioral response to ethanol in these two (46). As adults, these subjugated hamsters had altered levels subpopulations of rats or mice should prove valuable for of both vasopressin and serotonin in the anterior hypothala- understanding the factors resulting in pathologic aggression mus, a finding providing a potential mechanism by which in humans. Interestingly, elevated levels agonistic behavior (15), although in different ways (25). This with indices of aggression in personality-disordered patients effect is caused by the activation of postsynaptic 5-HT1B (47). This model provides an example in which discovering receptors because ligands affecting other 5-HT receptors the neural mechanisms underlying aggression could poten- have quite different antiaggressive profiles. Hamsters, which are territorial, tive validity toward human aggression. The neuropeptide vasopressin has (alcohol and benzodiazepines) and antiaggressive effects of Chapter 118: Animal Models of Aggression 1703 psychoactive drugs are highly similar in rodents and hu- 2 g/kg, had no effects on any parameter, a finding suggesting mans. Because of the species generality of this type of aggres- that the proaggressive actions of alcohol and also the benzo- sion, the model also has considerable face validity. Con- diazepines seen in the territorial and isolated male paradigms struct validity is as yet less clear, but the brain mechanisms are probably related to variables (anxiety? As such, this Haloperidol enhanced aggression thresholds simultane- paradigm seems an excellent choice in screening for poten- ously with locomotion, again indicative of nonspecific ef- tial antiaggressive compounds (serenics), but it also indicates fects on aggression. Because thresholds for teeth chatter, other drug effects such as sedation and sensory and motor which accompanies normal aggression, were not affected, impairment (15). D-Amphetamine had no effect on aggression and teeth chattering, but it decreased the locomotor threshold, Behavior largely similar to that of offensive territorial males a finding illustrating its stimulatory action without having can be elicited by electrical stimulation in the medial-lateral specific effects on aggression. Scopolamine, a (muscarinic) hypothalamus of male and female rats (48–50). Hypotha- anticholinergic drug, had effects similar to those of D-am- lamic aggression in male rats is sensitive to manipulations phetamine, again illustrating that activation of substrates of androgen levels (51), and it can be induced in an area for locomotor activity is independent from activation or (52) roughly coinciding with the areas where levels of circu- inhibition of aggression substrates in the brain. Moreover, stimulation an opiate antagonist, did not influence any aspect of the of this area is accompanied by elevated levels of stress hor- brain stimulation–induced behaviors, in line with its ab- mones (adrenocorticotropic hormone, corticosterone, and sence on spontaneous aggression (11,15). Manipulation of prolactin) resulting from activation of the area itself and various serotonergic mechanisms showed that activation of not caused by the stress of fighting (53). In female rats, the 5-HT1B receptor, by eltoprazine, fluprazine, meta-chlo- aggression can be elicited in this same area (54,55). This rophenylpiperazine, DL-propranolol and other phenylpiper- behavior is readily reproduced under controlled circum- azines (25,26), induces a highly specific effect on aggression. The aggressive behavior induced although aggression still could be evoked, but locomotor by the stimulation can be explosive. Depending on the stim- activity was not affected or was even somewhat decreased. The attack ceptors, including 5-HT1A, 5-HT3, and the serotonin trans- behavior is not purely driven by internal stimulation of the porter, demonstrate the specificity of the 5-HT1B receptor hypothalamic substrate. In addition to aggressive behavior, stimulation in this HT-receptor mechanisms. By directly stimulating neural substrates in the brain in- In this paradigm, the effects of drugs are measured by the volved in offensive aggression, this model has great potential changes in the current thresholds required to evoke the re- spective behavior (56). Increases in the current thresholds to predict violent, pathologic aggression in humans. In con- for aggression indicate antiaggressive effects, considered spe- trast to the more natural models (isolation-induced, resi- cific if simultaneously the drug does not affect thresholds dent-intruder, maternal aggression), this model is not sensi- for locomotion. Several drugs have been analyzed in this tive to certain intervening variables present in the other model, including benzodiazepines, neuroleptics, psycho- paradigms (anxiety, fear, sedation, and motor and sensory stimulants, alcohol, 5-HT -receptor agonists, serenics (5- disturbances) and directly reflects antiaggressive properties 1A HT1A/1B-receptor agonists) and selective serotonin reuptake of drugs. In addition, this model is not completely artificial inhibitors (56–59). For example, such animals do not attack rats on aggression and teeth-chattering thresholds at lower doses that previously have defeated them or females in estrus.

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