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Subsequent studies using have been used loosely with inadequate definitions discount 20mg cialis soft otc, the diverse ligands and dosing regimens continued to give varied overall concept that chronic -opioid agonist administra- results purchase cialis soft 20 mg amex, with up-regulation of -opioid receptors, down- tion may cause reduced capacity to bind, or increased capac- regulation of -opioid receptors, and no change of -opi- ity to bind, or to have no effect, but each alternative with oid-receptor density or binding after chronic -opioid-ago- reduced capacity of activated receptors to have an effect nist administration all reported. The prevailing concept for (or 'tolerance'), has persisted, and repeatedly studied, with receptor-agonist ligands and, in this case, specifically ago- conflicting results. The earliest studies to address this issue nists for the -opioid-receptor system, has been that persis- of impact of chronic opioid administration effects on bind- tent activation of receptors would generally lead to down- ing were conducted to elucidate the well-documented and regulation, and conversely, the persistent deprivation of re- accepted phenomenon of tolerance, both in cell systems and ceptors of specific ligands would generally lead to persistent in whole animals. Morphine was the most common opiate lack of activation of receptors and thus to up-regulation. From 1996 to 2000, several intriguing articles appeared Later, the effects of specific opioid antagonists on opioid- concerning the effects of opioid-agonist administration on receptor binding or density were also conducted, primarily receptor internalization (44–52). The binding of opioid antagonists, of relevant studies on signal transduction, primarily through course, does not involve coupling; that is, no Gi/o-pro- G-protein–coupling mechanisms, but also alternative tein–coupled signal transduction mechanisms are involved, mechanisms, appeared and extended our earlier knowledge because the opioid antagonists (according to most current and may ultimately explain some of the apparently conflict- theories) do not activate receptors, but rather prevent activa- ing results concerning receptor binding and density (12–15, tion by endogenous or exogenous opioids. There is now animals was shown to alter, at a cellular level, the function essentially a consensus from many and diverse studies that of neurons, specifically in the locus ceruleus, and also to the chronic administration of opioid antagonists, primarily lead to tolerance and physical dependence (12,18,20,24). There has, how- inhibition by morphine of adenylyl cyclase, as well as result- ever, been some controversy regarding whether opioid an- ant inhibition of the cyclic adenosine monophosphate tagonist treatment and the resultant up-regulation of - (cAMP)–dependent cascade, followed by, during chronic opioid receptors leads to a sensitized state, that is, a state morphine treatment, a compensatory increase of activity of in which an opioid agonist would have a greater than usual adenylyl cyclase, with an increase in the cAMP-dependent effect on any system. This has been addressed both in animal cascade, including increases in protein kinase A and in- models and in humans, with some conflicting results. Nestler and Aghajanian hypothesized that this up- merous studies have used several different opioid agonists, regulation of the entire cAMP pathway in the locus ceruleus primarily morphine, given by different regimens, ranging represents a compensatory change to oppose or offset the from intermittent injections to repeated pellet implantation, initial inhibitory effects of morphine and thus could be con- to a few studies using chronic administration by pump, sidered to be one component of tolerance (18,20). They there have been conflicting study results and no consensus also suggested that these increases in the cAMP pathway on the effects on -opioid-receptor binding or density. The components could contribute to opiate dependence and results reported from studies conducted in living adult ani- thus withdrawal, because these changes could be involved mals, for the most part, have shown no overall net changes in a variety of functions once no longer opposed by mor- in -opioid-receptor–binding capacity, that is, no overall phine (18,20). This concept is of particular relevance be- changes in opioid-receptor density, as measured by quanti- cause this up-regulation of the entire cAMP pathway during tative autoradiography or by classic homogenate binding chronic morphine exposure has been shown to occur pre- assay studies, and, more recently, no overall changes in - dictably in the locus ceruleus of all strains and species of opioid-receptor mRNA levels. Because the locus ceruleus is the ducted in living adult animals by the groups that included major noradrenergic nucleus of the brain, diverse noradren- those who first defined opioid receptors, showed no altera- ergic functions that are known to be activated in opiate Chapter 104: Neurobiology and Pathophysiology of Opiate Addiction 1493 withdrawal could be affected. Nestler and other groups tein–coupled family of seven transmembrane receptors; showed that although these changes occur uniformly in the there has been further documentation of receptor phosphor- locus ceruleus neurons, and in a few other brain regions, ylation, desensitization, and uncoupling from G proteins, particularly in the nucleus accumbens, this type of change as well as new studies documenting internalization (endocy- in the nucleus accumbens is strain dependent, and also such tosis) of opioid receptors (36–52). However, studies in ani- changes do not occur in many other brain regions in any mals continue to produce very conflicting results concerning strain or species (12,18,20,24). They also do not occur in the effects of chronic opiate administration on opioid-recep- the gastrointestinal tract. Nestler and others did not find a tor binding and density or number. Similarly, despite docu- down-regulation of -opioid receptors during chronic mor- mentation by many groups that cellular adaptations may phine treatment in the locus ceruleus (18,20,24). They did, be directly involved in the development of tolerance and however, report an uncoupling of the -opioid receptor dependence, the mechanisms have yet to be fully elucidated. This is intriguing in the context of findings changes in G-protein–coupled signal transduction mecha- of the laboratories of Yu and Kreek, who reported that after nisms and changes in downstream effectors, such as in- binding of the long, 31-residue, endogenous opioid -en- creases in CREB and phosphorylated CREB, and also other dorphin to the variant -opioid receptor coded by the very changes such as increases in and accumulation of chronic common SNP, A118G, there is enhancement of activity FRAs (Fos-related antigens), are all nonspecific. For in- of these G-protein–coupled inwardly rectifying potassium stance, diverse stimuli such as cocaine, opiates, opiate with- channels (58). CREB is of Aghajanian, as well as more recent work of Nestler and one component of the enhanced cAMP response and is a others, have suggested that the locus ceruleus may be pri- transcription factor; chronic FRAs have now been identified marily involved in expression of opioid physical dependence as isoforms of FosB, which is a splice variant of the fosB and thus in opioid withdrawal (20). Each of these enhanced or altered transcription factors al. These increases in CREB and from the locus ceruleus and showed that chronic morphine in chronic FRAs, both results of chronic morphine adminis- treatment decreased the inhibitory G-protein activity in the tration, may yield enhanced or altered gene transcription locus ceruleus and yet did not produce any detectable desen- elements and, in turn, changes in levels of expression of sitization, a finding suggesting a potential adaptation at that specific genes and in specific brain regions. Chronic morphine treatment decreased both in chronic FRAs after long-term morphine administration basal and opioid stimulated guanosine triphosphatase occur exclusively in the striatum, whereas the increases in (GTPase) activity and yet caused no changes in the percent- chronic FRAs seen after stress occur in the prefrontal cortex age of stimulation by an opioid agonist. For 35 were extended by binding assays using [ S]GTP S (40). These increased and accumulated amounts of CREB nist–stimulated [35S]GTP S binding was observed in the and chronic FRAs are tangible examples of neuroplasticity locus ceruleus and in a few related regions during long-term of the brain and document one type of change that may heroin self-administration. These findings were similar to occur and persist with chronic exposure to a drug of abuse. Moreover, the decreased -opi- many such changes and, although related to specific addic- oid-stimulated [35S]GTP S binding was found in two addi- tion related phenomena, are not the sole cause of any of tional regions, the thalamus and the amygdala, which may the three distinct and separable phenomena of tolerance, be of importance for the reinforcing effects of drugs of abuse physical dependence, or addiction. Moreover, all the result- and thus self-administration (42). The opioid receptors involved have all been cloned with respect to the causative agent.

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Although lacking the level of resolution of postmortem The principles of PET and SPECT neurochemical imaging studies and limited by the relatively small number of targets are reviewed elsewhere in this volume purchase cialis soft 20mg. Numerous PET and that can be currently studied in vivo purchase cialis soft 20 mg with mastercard, these imaging tech- SPECT radiotracers are currently available to study key pro- niques provide unique opportunities for elucidation of path- teins in the living brain, such as receptors, transporters, and ophysiology associated with neuropsychiatric conditions. Regarding schizophrenia, the majority of clinical vivo imaging techniques enable studying patients with well- investigations studied various aspects of dopaminergic trans- documented psychopathology, relating biochemical obser- mission. Dopamine (DA) D2 receptors were the first neuro- vations to psychiatric symptoms and cognitive processes, receptors visualized in the living human brain (1). Since and clarifying abnormalities associated with the disease as then, several DA-related radiotracers have been developed, opposed to its treatment. Neurochemical imaging allows allowing the study of many aspects of dopaminergic trans- longitudinal studies to investigate mechanisms of actions mission (DA synthesis, DA release, D1 and D2 receptors, and consequences of treatments, as well as to characterize DA transporters). Given the availability of these tools and neurochemical abnormalities in relation to treatment re- the important role that DA transmission is believed to play sponse and illness outcome. Neurochemical imaging further in schizophrenia, it is not surprising that most of the re- provides insight as to the pathophysiologic bases of altera- search effort focused on this system. Despite marked limita- tions measured with flow and metabolism imaging studies, tions, these studies provide a relatively consistent picture and can provide a direct link with animal models of the suggesting that schizophrenia, at least during periods of clin- illness. These potentialities are dis- cussed in this chapter. Imaging DA Transmission Parameters In Schizophrenia Daniel R. Weinberger: Clinical Brain Disorders Branch, Intramural Re- search Program, National Institute of Mental Health, Bethesda, Maryland. The classic DA hypothesis of schizophrenia, formulated Marc Laruelle: Division of Functional Brain Mapping, New York State Psychiatric Institute; Departments of Psychiatry and Radiology, Columbia over 30 years ago, proposed that a hyperactivity of the dopa- College of Physicians and Surgeons, New York, New York. As D2 receptor blockade is most effective comparing parameters of D2 receptor binding in patients against positive symptoms, the DA hyperactivity model ap- with schizophrenia and healthy controls (n 16 studies) peared to be most relevant to the pathophysiology of posi- are listed in Table 59. The fact that sustained exposure to DA ago- (102 were neuroleptic-naive, and 126 were neuroleptic-free nists such as amphetamine can induce a psychotic state for variable periods of time). These patients were compared characterized by some salient features of positive symptoms to 213 controls, matched for age and sex. Ten studies used of schizophrenia (emergence of paranoid delusions and hal- PET and six studies used SPECT. Radiotracers included lucinations in the context of a clear sensorium) also contrib- 11 11 butyrophenones ([ C]N-methyl-spiperone, [ C]NMSP, uted to the idea that positive symptoms might be due to 76 n 3, and [ Br]bromospiperone, n 3), benzamides sustained excess dopaminergic activity (6,7). A variety of methods establish, a dysregulation of DA systems in schizophrenia. Five studies used deficient, such as the glutamatergic or serotoninergic system model-based methods to measure the binding potential (8,9). Under these conditions, D2 receptor blockade would (BP), which is equal to the product of receptor density reestablish a compromised balance between dopaminergic (Bmax) and affinity (1/Kd). Five studies reported both Bmax and glutamatergic or serotoninergic tone. Indeed, documentation of abnormali- However, metaanalysis of the 16 studies reveals a small (on ties of DA function in postmortem studies in schizophrenia the order of 13%) but significant elevation of D2 receptors has remained elusive (10–12). Because positive symptoms in patients with schizophrenia. If D2 receptor density did are mostly prominent in young patients and their intensity not differ between patients and controls (null hypothesis), decreases with age, the ability to detect their biochemical one would expect approximately 50% of the studies to re- correlates in postmortem studies (generally performed in port lower D2 receptor levels in schizophrenics compared to older subjects) may be limited. Instead, 12 out of 16 studies reported an increase On the other hand, negative and cognitive symptoms (although not significant in 10 out of 12 cases), two re- are generally resistant to treatment by antipsychotic drugs. This distribution is un- toms are associated with prefrontal cortex (PFC) dysfunc- likely (p. Studies in nonhuman primates demonstrated that over, under the null hypothesis, the effect sizes [mean value deficits in DA transmission in PFC induce cognitive impair- in schizophrenic group mean value in control group/ ments reminiscent of those observed in patients with schizo- standard deviation (SD) in control group] should be distrib- phrenia (14), suggesting that a deficit in DA transmission uted around 0. The average effect size of the 16 studies was in the PFC might be implicated in cognitive impairments 0.

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Tis is the purpose of Research for universal health coverage buy 20 mg cialis soft with visa. Tis report is for everyone concerned with understanding how to reach the goal of universal health coverage – those who fund the necessary research generic 20 mg cialis soft fast delivery, those who do research and who would like to do research, and those who use the evidence from research. It shows how research for health in general underpins research for universal health coverage in particular. Understanding how to make progress towards achieving the MDGs is central to this report. As the 2015 deadline draws closer, we are looking for ways to improve all aspects of health, working within and beyond the MDG framework. And we are investigating how better health can contribute to the larger goal of human development. In this broad context, I invite you to read Research for universal health coverage. Dr Margaret Chan Director-General World Health Organization v Contents Message from the Director-General iv Executive summary xi 1. The role of research for universal health coverage 5 Developing the concept of universal health coverage 6 Investigating fnancial risk protection 11 Investigating the coverage of health services 15 Equity and universal health coverage 19 Coverage of health services: quality as well as quantity 20 Conclusions: research needed for universal health coverage 21 2. The growth of research for universal health coverage 31 Creativity everywhere 35 Research ascending 35 Growing unevenly 42 The value of health research 46 Conclusions: building on the foundations 47 3. How research contributes to universal health coverage 57 Case-study 1 61 Insecticide-treated mosquito nets to reduce childhood mortality Case-study 2 63 Antiretroviral therapy to prevent sexual transmission of HIV Case-study 3 65 Zinc supplements to reduce pneumonia and diarrhoea in young children vii Case-study 4 67 Telemedicine to improve the quality of paediatric care Case-study 5 69 New diagnostics for tuberculosis Case-study 6 71 The “polypill” to reduce deaths from cardiovascular disease Case-study 7 73 Combination treatment with sodium stibogluconate (SSG) and paromomycin compared to SSG monotherapy for visceral leishmaniasis Case-study 8 75 Task shifting in the scale-up of interventions to improve child survival Case-study 9 77 Improving access to emergency obstetric care Case-study 10 79 Conditional cash transfers to improve the use of health services and health outcomes Case-study 11 81 Insurance in the provision of accessible and afordable health services Case-study 12 82 Afordable health care in ageing populations Conclusions: general lessons drawn from specifc examples 84 4. Building research systems for universal health coverage 95 Setting research priorities 96 Strengthening research capacity 98 A framework for strengthening capacity 99 Creating and retaining a skilled research workforce 103 Ensuring transparency and accountability in research funding 105 Building research institutions and networks 107 Defning and implementing norms and standards 110 Ethics and ethical review 110 Reporting and sharing research data, tools and materials 110 Registering clinical trials 110 Using evidence to develop policy, practice and products 113 viiiviii Translating evidence into policy and practice 113 Monitoring and coordinating research, nationally and internationally 116 Financing research for universal health coverage 117 National and international governance of health research 118 Conclusions: building efective research systems 118 5. Research has the power to address a wide range of questions about how we can reach universal coverage, providing answers to improve human health, well-being and development. The creativity and skills of researchers should be used to strengthen investigations not only in academic centres but also in public health programmes, close to the supply of and demand for health services. To make the best use of limited resources, systems are needed to develop national research agendas, to raise funds, to strengthen research capacity, and to make appropriate and effective use of research findings. In 2005, all WHO Member States made the commitment to achieve universal health coverage. Te commitment was a collective expression of the belief that all people should have access to the health services they need without risk of fnancial ruin or impoverishment. Working towards universal health coverage is a powerful mechanism for achieving better health and well-being, and for pro- moting human development. Chapter 1 explains how the resolution adopted by all WHO Member States embraces the two facets of universal health coverage: the provision of, and access to, high-quality health services; and fnancial risk protection for people who need to use these services. Te term includes ways of taking action on social and environmental determinants both within and beyond the health sector. Financial risk protection is part of the package of measures that provides overall social protection. Scientifc research has been fundamental to the improvement of human health. Research is vital in developing the technology, systems and services needed to achieve universal health coverage. On the road to universal coverage, taking a methodical approach to formulating and answering questions is not a luxury but a necessity. When WHO Member States made the pledge to achieve universal coverage they took a signifcant step forward for public health. As described in Chapter 1, taking that step efectively launched an agenda for research. In this report, research is the set of formal methods that turns promising ideas into practical solutions for improving health services, and consequently for improving health. Te goal of the report is to identify the research questions that open the way to universal health coverage and to discuss how these questions can be answered. Many recent advances have been made in health service coverage and in fnan- cial risk protection as shown, for example, by progress towards the United Nations Millennium Development Goals (MDGs).

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Age–sex differences in response to antidepressant gender in identifying subtypes of schizophrenia—a latent class drugs order cialis soft 20mg with amex. Magnetic reso- of imipramine plasma levels for depressive illness discount cialis soft 20 mg on-line. Arch Gen nance imaging of the brain in schizophrenia—the pathophysio- Psychiatry 1977;34:197–204. Structural and without attempted potentiation by liothyronine. Arch Gen Psy- functional characteristics of the corpus callosum in schizophren- chiatry 1972;26:234–241. Forms of atypical depression and their nance imaging and neuropsychological evaluation. Antidepressant response ences in schizophrenia on MRIbrain scans. Gender differences in pharmacokinetics magnetic resonance imaging study of corpus callosum morphol- and pharmacodynamics of psychotropics: focus on women. Schizophr Bull 1984;10:430– in pharmacokinetics and pharmacodynamics of psychotropic 459. Plasma levels of imipramine tive, schizoaffective, and schizophrenic disorders. Schizophr Bull and desmethylimipramine during therapy. Plasma levels of amitriptyline: effects course of schizophrenia: differences in treated outcomes. Gender differences in affective, ine metabolism: model-based analysis of variability factors from schizoaffective and schizophrenic disorders. Am J Psychiatry 1984;141:206– netics: effects of age, gender, and obesity. Clinical implications of the pharmacology of Compr Psychiatry 1983;24:125–128. A controlled clinical trial of fluspirilene, a long-acting injectable neuroleptic, in schizo- 118. Antidepressant- phrenic patients with acute exacerbation. J Clin Psychopharmacol induced mania and cycle acceleration: a controversy revisited. Suicide attempts in pa- admitted schizophrenic patients. Psychopharmacology 1982;76: tients with panic disorder. Gender differences in psychiatry: epidemiology and men. No gender effect on age therapy in the aftercare of acute schizophrenics. Am J Psychiatry 1992;149: chiatry 1978;35:1169–1177. Sex differences in dexes in first-episode schizophrenic patients. Am J Psychiatry the functional organization of the brain for language. Gender and the onset of schizophrenia: neurohu- 147. Neural sexual mosaicism: sexual differentiation of 126. Sex differences in brain morphology, and schizophrenia. Schizophr Bull 1990;16: patterns of hemispheric cerebral metabolism—a multiple 195–203. Two sexually dimorphic cell J Psychiatry 1996;153:799–805. Gender differences in 1176 Neuropsychopharmacology: The Fifth Generation of Progress regional cerebral blood flow during transient self-induced sad- relationship to the premenstrual syndrome.

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