By P. Benito. Cumberland University. 2019.

The three lead CCGs work in partnership order 160 mg super avana overnight delivery, but also retain a high degree of autonomy within the wider programme order 160mg super avana free shipping. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed buy super avana no prescription, the full report) may be included in professional journals 65 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. FINDINGS FROM THE CASE STUDIES mature of the partners, particularly in terms of the emphasis placed on clinical leadership. CCG informants reported that they felt constrained by the slower pace of change in the other two areas. Clinical leadership across different arenas The chairperson of the CCG, the lead for the GP network, the local medical committee representative and the named CCG integrated care lead were widely seen as each having a particularly important role in advocating for integrated care not only in strategic arenas, but also to their colleagues involved in delivering primary care. However, there was evidence of a disconnect between the clinical leadership and institutional work of advocating and resourcing integrated care in strategic arenas and the level of engagement of many of the front-line clinical staff with delivering the various aspects of the programme. There was one clinically led fundamental challenge to the integrated care programme, when a respected GP questioned the evidence base for focusing on unplanned hospital admissions. This can be seen as an instance of counter-implementation leadership, whereby a provider clinician actively opposes implementation of the new service model. The GP complained that if reducing unplanned admissions to hospital was a key rationale for the programme (which at a national level it is) then, on the basis of past evidence, the programme was probably doomed to failure. Instead, he felt that the CCG should be focusing on evidence-based, disease-focused interventions to manage the rising demand for hospital care, specifically by greater use of statins to reduce cholesterol and more effective management of atrial fibrillation. The GP arranged a meeting of key clinicians to discuss the issue and he gained some support from colleagues, although not enough to derail the wider integrated care programme. Case E2: urgent care The urgent care work in this case aimed to produce a single point of access for patients rather than the current array, which included a hospital A&E department, two walk-in centres, NHS 111 as an urgent telephone consultation and triage service, a GP out-of-hours service, a number of minor injuries centres and an urgent care centre. The ends or break clauses of the contracts for these commissioned services were aligned by the CCG in a way that enabled a system-level review of provision, its overlaps and its variation in per head/per visit cost. The plan was to use this to retender all urgent care services and achieve a more coherent and cost-effective result. This review involved a number of different partners, including the clinical leads of these services, A&E staff, the lead for extended GP hours (which is being funded nationally), and also a number of staff from the local CSU and a senior CCG manager responsible for urgent care. The review was carried out through a series of workshops facilitated by the CSU. In terms of Figure 24, the review can be seen as taking place in an operational commissioning arena, with commissioners and providers coming together to consider the future pattern of services. It remained in progress at the end of our fieldwork period. There were a number of important local contextual factors affecting this urgent care review. First, and the biggest issue for the CCG, was the rapid increase in the population and the potential impact of this increase on future demand for urgent care services. A second factor was the co-location in the local acute hospital of traditional A&E services alongside some of the newer community-led services. This arrangement carried the potential for novel ideas in the way services were provided. Third, the distribution of urgent care services across the CCG area was at the time asymmetrical, and the desire to distribute all kinds of urgent care services evenly across this geography created logistical, estates and financial challenges for the CCG. This initiative raised the profile of urgent care redesign led by GPs, many of whom had been arguing that general practice should be the first port of call for patients requiring urgent care services. Others complained of a lack of clarity about how differing costs between the various existing out-of-hours or urgent care providers would be rationalised and how the pressure on the local A&E service would be solved. As the review progressed there was a growing consensus that a single point of access using a telephone or online service was desirable, with patients triaged to the most appropriate service for their needs. Clearly, in this case, clinical leadership in the operational commissioning arena took the form of combining advocacy for more integrated and patient-centred services with arguing for the preservation of existing clinical services and the capabilities they had developed. The relatively early stage of service redesign in this case meant that there was no opportunity for us to study clinical leadership in operational delivery arenas – the initiative was not yet entering the stage of implementation. Features of clinical leadership from these two cases These two cases illustrate a well-developed pattern of clinical leadership in strategic and operational commissioning arenas, with mechanisms put in place to engage with clinicians in operational delivery roles. Although the latter mechanisms appear to have been problematic, this CCG illustrates some key features of clinical leadership in commissioning. Collaboration between clinical and non-clinical leaders The working relationships between clinicians and managers working within both strategic and operational commissioning arenas in this case study were built on high levels of trust and mutual respect. Clinical leadership was seen as not just desirable but a core defining characteristic of what made the CCG successful. A strong emphasis was placed on face-to-face meetings, and the conversational style in these meetings was informal and friendly. This enabled significant challenges and passionate debates to be voiced in ways that were usually not perceived to be threatening. And actually, bring an added level of vigour and rigour in relation to that process. Senior manager They also spoke explicitly about the ways in which clinical leaders had more traction with their colleagues than non-clinical managers. They tended to be effective at turning what might be perceived to be a managerial issue (such as a budget overspend) into a clinical one. Challenging established assumptions Many of the GPs in leadership roles in strategic and operational commissioning roles in this CCG had a long history of anti-establishment radicalism. They used this identity to differentiate themselves and thereby to create a strong ethos of common cause based on consistent principles. It appeared that they actually enjoyed challenging governmental authority and NHS bureaucracy. There was some evidence that clinicians were encouraging their managerial colleagues to also push back on directives from NHSE, empowering them to do what they thought was right rather than what they were told they must do. 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 67 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. FINDINGS FROM THE CASE STUDIES They had started to question the medicalisation of the health service and were beginning to have discussions about how they might influence the broader determinants of health. The clinical leaders in the locality were much less interested in defining detailed care processes than they perceived non-clinical managers had been in the past, placing a strong emphasis on outcomes and leaving clinical teams to determine how to deliver them. Both the clinical and non-clinical leaders saw merit in the development of local networks of practices as ways to engage clinicians. Radical changes in ways of managing unacceptable performance and incentivising collective behaviours were introduced: You cannot federate unless you really seriously tackle the very poor performance. GP In another example of professionally led challenge, clinicians countered the threatened withdrawal of the Minimum Practice Income Guarantee funding for struggling practices, launching a high-profile public campaign to highlight the problems of government policy in this area, and this appeared to have been successful in securing additional resources. Indeed, the number of partnership-related initiatives in the CCG suggested a strong commitment to looking outside the boundaries of the CCG and of primary care. Much of this approach was driven by a strong clinical voice, supported by a robust strategy developed in partnership with non-clinical managers: I think what would be very powerful.

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Priorities in operational research to improve tuberculosis care and control order super avana visa. The malERA Consultative Group on Health Systems and Operational Research cheap 160 mg super avana free shipping. A research agenda for malaria eradica- tion: health systems and operational research cheap super avana. Leishmaniasis: Middle East and North Africa research and development priorities. Vaccines for the leishmaniases: proposals for a research agenda. Research priorities for Chagas disease, human African trypanosomiasis and leishmaniasis. Research priorities for neglected infectious diseases in Latin America and the Caribbean region. Research priorities for zoonoses and marginalized infections. Prioritized research agenda for prevention and control of noncommunicable diseases. Priorities for research into human resources for health in low- and middle-income countries. Bulletin of the World Health Organization, 2010,88:435-443. Establishing health systems fnancing research priorities in developing countries using a participatory methodology. Setting priorities for research and development in the NHS: a case study on the inter- face between primary and secondary care. Priorities for research on equity and health: towards an equity-focused health research agenda. Transforming biomedical research to develop efective TB vaccines: the next ten years. Fulfllment of the Brazilian agenda of priorities in health research. Revista Panamericana de Salud Pública, 2009,26:447-457. Développement du système de recherche en santé: analyse et établissement des priorités en Tunisie [Development of health research system: analysis and defning priorities in Tunsia]. A review of selected research priority setting processes at national level in low and middle income countries: towards fair and legitimate priority setting. Where there is no health research: what can be done to fll the global gaps in health research? The Paris Declaration on Aid Efectiveness and the Accra Agenda for Action. Paris, Organisation for Economic Co-operation and Development, 2005. Busan, Global Partnership for Efective Development Cooperation, 2011. The emergence and current performance of a health research system: lessons from Guinea Bissau. Building capacity in health research in the developing world. Bulletin of the World Health Organization, 2004,82:764-770. Building the feld of health policy and systems research: an agenda for action. A review of conceptual barriers and opportunities facing health systems research to inform a strategy from the World Health Organization. Strengthening capacity for health research in Africa. South African Medical Journal/Suid-Afrikaanse tydskrif vir geneeskunde, 2012, 102:228–233. What must be done to enhance capacity for health systems research? Improving implementation: building research capacity in maternal, neo- natal, and child health in Africa. Defning organizational capacity for public health services and systems research. Journal of Public Health Management and Practice, 2012,18:535-544. Developing ANDI: a novel approach to health product R&D in Africa. The world health report 2006 − working together for health. Guidelines for research in partnership with developing countries: 11 principles. Bern, Swiss Commission for Research Partnership with Developing Countries, (KFPE), 1998. Research and capacity building for control of neglected tropical diseases: the need for a diferent approach. Applying DOTS principles for operational research capacity building. How much longer will Africa have to depend on western nations for support of its capacity-building eforts for biomedical research? Tropical Medicine & International Health, 2011,16:258-262. UK investments in global infectious disease research 1997–2010: a case study. Mapping global health research investments, time for new thinking - a Babel Fish for research data. Transforming the fght towards elimination of tuberculosis. Tuberculosis Research and Development: 2011 report on tuberculosis research funding trends, 2005–2010. Tropical Medicine & International Health, 2012,17:1409-1411. Operational research for improved tuberculosis control: the scope, the needs and the way forward. The International Journal of Tuberculosis and Lung Disease, 2011,15:6-13. Five keys to improving research costing in low- and middle-income countries.

Thus purchase super avana australia, not all clinically led innovations – even those that brought in extra funding – were necessarily welcomed and celebrated buy super avana with american express. There has been talk by the local acute provider about moving into primary care services purchase 160 mg super avana visa. There is a plan to put in a bid around urgent care which will be provider driven. Again we need to assess how all this fits within our own wider plan. CCG chairperson These observations from the chairperson of one of the more influential CCGs in the county raises questions about the difficulties in aligning the plurality of initiatives being encouraged and launched in different arenas. Hence, once again we see the complexities of leadership in practice when the context is given proper consideration. I suspect it will sort of be a natural move in one direction or the other. 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 61 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. FINDINGS FROM THE CASE STUDIES This quotation is very revealing. The admissions from the CCGs that they lack the wherewithal to tackle the fundamental redesign of health-care systems which the Vanguards are seeking to deliver was made apparent by the individual CCGs in this case. More than 3 years into the CCG experiment, it indicates the extent and nature of CCG ambitions. We can elaborate on this important point by providing an illustration of just such a bottom-up, GP-led service redesign that was initially supported and then unsupported. We were informed of a new dementia service which located more care in GP practices and which therefore allowed patients to be treated locally rather than having to travel to the mental health trust. The redesign involved employment of care facilitators. Funding came jointly from the CCG and the mental health trust. However, despite apparent success and positive feedback, the initiative was ended and dementia services were taken away from primary care and returned solely into the hands of the acute sector, the mental health trust. Some GPs claimed that this resulted from pressure from the mental health trust which the CCG was unable to resist given its parlous financial state and the power of the trust. As interviewees noted, the federation had, so far, remained on the periphery of the core GP business of the General Medical Services and Personal Medical Services contracts. However, he noted that the access to extended hours work could catalyse a change as it creates a new workforce which would share information and patients across practices. Activity and clinical leadership at a neighbouring CCG were even less developed. Practice in this particular CCG reflected that found in many others which we encountered at the scoping phase of the study where little advantage was being taken of the CCG institution as a platform for change. Instead, it was treated as just another administrative unit. Thus, even the accountable officer made the assessment that: The function of the CCG to date, by and large, has been to fulfil statutory duties. In the early days of the CCG there were a large number of high-level strategies written around a number of things. So everything for the last year has been driven by the financial position in the CCG. Accountable officer This CCG is now in the hands of a managerial team which also manages two other CCGs. CCG chairperson Thus, in these instances, the work of the agents – managers and clinical leaders – in these new bodies was focused primarily on institution building. This included appointing chairpersons, accountable officers and other key figures plus the wider representation for the governing body. A practice nurse representative on this CCG likewise confirmed that assessment. Lack of resources and continued assertive intervention from the national centre had, in these cases, crowded out the hoped-for local leadership. The prime arena of the CCG, despite its statutory backing, was not enough in these cases to prompt the emergence of effective clinical leadership. In response to this increasingly evident lacuna, the national-level authority, in the shape of NHSE, initially encouraged much more cross-CCG collaboration and then moved more radically to offer firmer guidance in the shape of the models of collaboration outlined in the Five Year Forward View12 and then even more forthrightly with the creation (indeed imposition) of the STPs. However, not all of the six CCGS in the county were quite so passive and reactive. Despite the financial and other challenges, some local leaders were able to use the new institutions as a means of devising local solutions. He said he wanted to re-engineer the use of their two community hospitals. However, one of the hybrid clinical managers working across three of the CCGs reported: There is a definite lack of clinical leadership and engagement in practices in [this CCG]. Hybrid manager across three CCGs Thus, overall, the picture that emerged from the CCG level (the apex of Figure 24) in case D was that, in a number of CCGs, the senior teams (managers, clinicians and hybrids) had failed to utilise the privileged statutory positon, resources and power of the CCG board-level arena as a means to bring about a redesign of local services in the way that had been hoped by the national policy-makers. However, other teams had used the same arena to make a difference both in reforming primary care and in reimagining the roles of acute and community services. Increasingly, these more innovative teams were given power by NHSE to take over the agenda-setting for the more passive CCGs. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 63 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. FINDINGS FROM THE CASE STUDIES Sustainability and transformation plan level As momentum built behind STPs from mid-2016, all actors involved in any significant service redesign attempts had to consider how these would align with the emerging STP systems architecture. This process – occurring over a relatively short period of less than 12 months – revealed a great deal about the multilevel power dynamics in service redesign. They represented a spectrum offering varying degrees of integration across the system: from a loose association of providers and commissioners at one end, to a unified ACO at the other. The hubs would offer co-ordinated out-of-hours primary care services. The middling options were essentially variants of a new service architecture based on between one and three overarching MCPs catering for populations of approximately 500,000 with a set of localities/hubs or primary care homes sitting beneath them looking after populations of around 30,000 to 50,000. Notably, most of the options assumed the continuing separation of acute hospital services on the one hand and primary/community care on the other. The subvariants essentially amounted to options relating to the number (and hence size) of the constituent MCPs and hubs. Our informants (clinical leaders and managers at CCG level) reported that they felt this exercise was taking place to a large extent beyond their sphere of influence. Nonetheless, a number of clinical leaders interviewed were keen to work within the templates offered by MCPs and the primary care home locality/hub models.

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Reduction in hippo- planum temporale in patients with schizophrenia: three-dimen- campal formation volume is caused mainly by its shortening in sional cortical morphometry with MRI super avana 160mg lowest price. Br J Psychiatry 1995;166: chronic schizophrenia: assessment by MRI cheap 160mg super avana amex. Superior temporal gyrus Gunther W generic super avana 160mg amex, Petsch R, Steinberg R, et al. Brain dysfunction during volume in schizophrenia: a study using MRI morphometry assisted motor activation and corpus callosum alterations in schizophrenia by surface rendering. MRI study of cavum septi Biol Psychiatry 1991;29:535–555. Am J Psychiatry Kwon JS, McCarley RW, Hirayasu Y, et al. Arch Gen Psychiatry 1999;56: Gur RE, Cowell P, Turetsky BI, et al. Similar extent of brain changes to clinical and neurobehavioral measures. Arch Gen Psy- dysmorphology in severely ill women and men with schizophrenia. Abnormalities of auditory Lewine RR, Gulleu LR, Risch SC, et al. Sexual dimorphism, brain evoked magnetic fields and structural changes in the left hemi- morphology, and schizophrenia. Cortical gray matter volume netic resonance imaging study. Medial temporal lobe struc- in schizophrenia on magnetic resonance imaging. Psychol Med tures in schizophrenia: relationship of size to duration of illness. Corpus callosum di- Marsh L, Harris D, Lim KO, et al. Structural magnetic resonance mensions measured by magnetic resonance imaging in bipolar imaging abnormalities in men with severe chronic schizophrenia affective disorder and schizophrenia. Biol Psychiatry 1989;26: and an early age at clinical onset. Lower left temporal Menon RR, Barta PE, Aylward EH, et al. Posterior superior temporal lobe MRI volumes in patients with first-episode schizophrenia gyrus in schizophrenia: grey matter changes and clinical correlates compared with psychotic patients with first-episode affective disor- Schizophr Res 1995;16:127–135. Gender differences in corpus Nopoulos P, Torres I, Flaum M, et al. Brain morphology in first- callosum size in first-episode schizophrenics. Pattern of brain morphology Hokama H, Shenton ME, Nestor PG, et al. Caudate, putamen, and in patients with schizophrenia and large cavum septi pellucidi. J globus pallidus volume in schizophrenia: a quantitative MRI Neuropsychiatry Clin Neurosci 1996;8:147–152. Cavum septi pellucidi in Jernigan TL, Zisook S, Heaton RK, et al. Magnetic resonance imaging normals and patients with schizophrenia as detected by magnetic abnormalities in lenticular nuclei and cerebral cortex in schizo- resonance imaging. A magnetic resonance Johnstone EC, Owens DGC, Crow TJ, et al. Temporal lobe structure imaging study in first episode disorganized-type patients with as determined by nuclear magnetic resonance in schizophrenia and schizophrenia. J Neurol Neurosurg Psychiatry 1989;52: Petty RG, Barta PE, Pearlson GD, et al. Am J Psychiatry 1995; Jurjus GJ, Nasrallah HA, Olson SC, et al. Volumetric evaluation netic resonance imaging study. Chapter 55: Structural MRI Studies in Schizophrenia 773 Raine A, Harrison GN, Reynolds GP, et al. Structural and functional Shioiri T, Oshitani Y, Kato T, et al. Prevalence of cavum septum characteristics of the corpus callosum in schizophrenics. Arch Gen pellucidum detected by MRI in patients with bipolar disorder, Psychiatry 1990;47:1060–1064. Psychol Med 1996;26: Raine A, Lencz T, Reynolds GP, et al. Psychiatry Res Neuroimag 1992;45: schizophrenia: a preliminary magnetic resonance imaging study. Magnetic source imaging evidence Suddath RL, Casanova MF, Goldberg TE, et al. Temporal lobe pa- of sex differences in cerebral lateralization in schizophrenia. Arch thology in schizophrenia: a quantitative magnetic resonance imag- Gen Psychiatry 1997;54:433–440. Standardized magnetic resonance Suddath RL, Christison GW, Torrey EF, et al. Anatomical abnormali- image intensity study in schizophrenia. Psychiatry Res 1988;25: ties in the brains of monozygotic twins discordant for schizophre- 223–231. Quantification of corpus callosum Sullivan EV, Mathalon DH, Lim KO, et al. Patterns of regional and ventricles in schizophrenics with nuclear magnetic resonance cortical dysmorphology distinguishing schizophrenia and chronic imaging: a pilot study. Reduced temporal lobe area Swayze II VW, Andreasen NC, Alliger RJ, et al. Subcortical and in schizophrenia by magnetic resonance imaging: preliminary evi- temporal structures in affective disorder and schizophrenia: a mag- dence. Reduced temporal lobe areas Tune L, Barta P, Wong D, et al. Striatal dopamine D2 receptor in schizophrenia: preliminary evidences from a controlled mul- quantification and superior temporal gyrus: volume determination tiplanar magnetic resonance imaging study. Biol Psychiatry 1990b; in 14 chronic schizophrenic subjects. The morphology of the corpus callosum in magnetic resonance in bipolar affective disorders and schizophre- schizophrenia: an MRI study. Midsagittal cortical pathomorphology of schiz- Rossi A, Stratta P, Mattei P, et al.

It seems that only if the drugs are given in a (233 discount super avana online american express,254–256) order super avana 160 mg visa. The regimen that causes decreases in SERT binding can changes investigators speculated that positive results with long-term in its mRNA be observed purchase super avana 160mg mastercard, and even then only if one looks citalopram administration might be obtained if the adminis- at the proper times (i. This was achieved by giving the ied the effect of long-term treatment of rats with NE uptake drug subcutaneously by minipump at a dose of 20 mg/kg inhibitors on NET binding sites. This regimen produced stable plasma nisoxetine, a radioligand that binds specifically to the NET, citalopram levels of about 300 nM. In the study of Bauer and Tejani- out, when analytic experiments were carried out, plasma Butt (275), 21 days of treatment with desipramine (10 mg/ levels of citalopram had dropped to levels that were not kg intraperitoneally once daily) caused modest (20% to pharmacologically active. At this time, evidence for marked 40%) but significant decreases in 3H-nisoxetine binding in subsensitivity of somatodendritic 5-HT1A receptors was ob- some areas of brain, but not in others. Their conclusion was that if a proper, pharmacoki- widespread changes were obtained when desipramine was netically validated, long-term regimen with citalopram is given by osmotic minipump for 21 days (272). We think used, 5-HT1A-autoreceptor desensitization can be observed. It does seem likely that long- obtained evidence of decreases in SERT function (246, term desipramine treatment can down-regulate the NET; 257–259). Inconsistent results have been obtained in studies of ing, with a maximum effect occurring after 3 days of expo- the effects of long-term administration of this drug on sure (276). In this study, measurements were up study in which cells transfected with hNET were used, made after 7 days of drug washout. Similar results were similar results were obtained with desipramine; in addition, obtained by Dean et al. Interestingly, desipramine did not cause any change for either 10 or 28 days. By contrast, in the study of Durand in mRNA for the NET in these cells. For this reason, Zavosh binding of phosphate groups to substrate proteins, or by et al. Most often, these enzymes are the primary Szot et al. Importantly, many kinases can regulate once daily) increased mRNA for the NET in the locus ceru- different and independent functions within a cell, presum- leus. This implies that drug effects on translocation of (and presumably also NET binding sites) may have impor- kinases, in addition to direct effects on their activity, may tant functional consequences relevant to the behavioral im- have important functional consequences. The changes The long-term administration of either fluoxetine or de- that acute local administration of an SSRI has on the clear- sipramine decreases the basal activity of both soluble and ance of 5-HT in vivo, measured by chronoamperometry, particulate PKC in cerebral cortex and hippocampus (281). Variable and quite small effects Because PKC may be involved in the desensitization of are produced on the peakamplitude of the electrochemical 5-HT receptors (282) and cell surface expression of the 2A signal caused by 5-HT, and clearance of the indolalkylamine SERT (283), antidepressant-induced effects on PKC activ- is inhibited by 30% to 40% (246). However, when antide- ity may cause changes in 5-HT -receptor sensitivity or 2A pressant treatment causes a marked reduction in SERT SERT expression (246,257). Similar effects on the 5-HT chrono- namely PKA in the microtubule fraction and calcium/cal- amperometric signal were also observed in rats treated with modulin-dependent protein kinase II (CaMKII) in the syn- a serotoninergic neurotoxin to cause more than a 70% loss aptic vesicle fraction. Such activation results in phosphate of SERT binding sites (279). Thus, acute blockade of the incorporation into selected substrates (284,285). With re- SERT by SSRIs may not produce the same enhancement spect to PKA, Nestler et al. They found that long-term antide- sertraline treatment has been found to cause a marked loss pressant administration decreases the activity of PKA in the of SERT binding sites only after 10 to 15 days of treatment cytosol but increases enzyme activity in the nuclear fraction. Interestingly, long-term desipramine sary to obtain marked enhancement of serotoninergic trans- treatment increases the phosphorylation of MAP-2, a sub- mission and consequent behavioral improvement. The effects Signal Transduction on PKA may be caused when long-term treatment with In recent years, there has been considerable speculation that antidepressants increases the binding of cAMP to the regula- the beneficial behavioral effects of antidepressants are a con- tory II subunit of PKA in brain homogenates (287,289). In other ment may be cAMP-dependent phosphorylation, mediated words, behavioral improvement is not a direct consequence by PKA, in microtubules. It may be speculated that such of antidepressant-induced receptor activation (which may phosphorylation causes cytoskeletal changes that result in a occur quickly); rather, it results when such receptor activa- modification of neurotransmission and antidepressant- tion alters signaling pathways to cause more slowly develop- induced changes in gene expression (see below), as PKA ing changes in gene expression. Two major areas have been translocation to the nucleus is microtubule-dependent studied. One deals with effects of antidepressants on second (290). Antidepressant-induced activation of PKA is interest- messenger-regulated protein kinases in brain. The other ing in light of findings of decreased PKA activity in cultured deals with changes in activities of protein kinases that result fibroblasts of melancholic patients with major depression in changes in gene expression and perhaps even neurogene- (291), perhaps a consequence of reduced binding of cAMP sis. Given the estab- lished facilitative function of CaMKII on neurotransmitter Protein Kinases release (293), the effect of long-term antidepressant treat- Phosphorylation of proteins may well be the primary regula- ment on CMKII, with increased phosphorylation of sub- tory mechanism for intracellular events. Such phosphoryla- strates such as synapsin 1 and synaptotagmin, may underlie Chapter 79: Mechanism of Action of Antidepressants and Mood Stabilizers 1155 the facilitation of monoamine transmitter release produced increase in BDNF can oppose and perhaps overcome the by these drugs. Indeed, long-term anti- depressant treatment has been shown recently to increase neurogenesis of dentate gyrus granule cells (312). Gene Expression/Neuroplasticity Although the precise mechanism is not understood, long- term but not acute treatment with antidepressants has ef- CONCLUSION fects on the expression of specific genes that may be a conse- quence of the activation of protein kinases, particularly Our understanding of the mechanism of action of drugs PKA. It is known, for example, that PKA can phosphorylate that treat mood disorders such as depression and manic- the transcription factor CREB. CREB binds to specific pro- depressive illness derives for the most part from their inter- moter sites (cAMP response elements) to produce changes action with known signaling systems within the brain. It is in the expression of specific genes, such as those for brain- evident that intracellular effects initiated by antidepressant derived neurotrophic factor (BDNF) and its receptor, trkB. Al- of antidepressants increases the mRNA for CREB in addi- though much more research is needed to test this hypothesis tion to CREB protein in brain (294; see 221,295). More and establish whether and how such long-term changes are recently, it was shown that such treatments increase CREB of physiologic significance, current evidence suggests that expression and CREB phosphorylation, indicative of func- such changes in brain may be quite important for the now tional activation of CREB (296). Furthermore, long-term well-established prophylactic effects of mood stabilizers and antidepressant treatment increases BDNF and trkB expres- antidepressants in the treatment of recurrent mood disor- sion in hippocampus (294,297). Finally, exogenous BDNF has that use gene expression arrays, we have the opportunity been shown to have antidepressant-like activity in behav- to examine multiple targets in the brain, both known and ioral tests sensitive to antidepressant treatment (301). Within this chapter, Such results are viewed as evidence that long-term antide- we have tried to identify the most promising of the candi- pressant treatment causes sustained activation of the cAMP date targets of mood stabilizers and antidepressants. The noradren- ever, research to determine which current and future targets ergic and serotoninergic receptors producing increases in constitute a profile that is most relevant to the therapeutic cAMP are -adrenoceptors and 5-HT4, 5-HT6, and 5-HT7 action of these agents will continue to be hampered by a receptors. If such intracellular effects are responsible for clin- lackof animal models for these complex behavioral disor- ical improvement, then these receptors may be the impor- ders that have strong construct and predictive validity. The hypothesis which new mood stabilizers can be discovered has proved is fundamentally different from earlier views of antidepres- more challenging. We suggest that the creation of models sant action, in which depression was a problem of synaptic with both construct and predictive validity to permit the transmission and drugs acted within the synapse to improve discovery of novel targets directly related to therapeutic effi- behavior directly (301,302). The new view is more morpho- cacy will be significantly enhanced by the identification of logic in nature. It posits that depression may be caused by susceptibility and protective genes for these illnesses.

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It is primarily medullary in most cases except in dystrophic calcification associated with inflammatory cheap super avana 160 mg free shipping, toxic buy cheapest super avana and super avana, or ischemic disease purchase super avana 160mg visa. The spectrum of causes of nephrocalcinosis is described by W rong. The numbers represent Distal renal tubular acidosis 19. It is likely that the case mix Medullary sponge kidney 11. As in other studies, the most important causes of Milk-alkali syndrome 3. The primary factor predisposing patients Hypomagnesemia-hypercalciuria 1. Causes of cortical nephrocalcinosis in this study included acute cortical necrosis, chronic glomerulonephritis, and chronic pyelonephritis. Impaired urinary acidification Alkaline urine The high urine pH favors precipitation of calcium phosphate (CaPO 4). Thus, RTA-1 should be suspected in any patient with Systemic acidosisHypercalciuria pure calcium phosphate stones. System ic acidosis also prom otes hypercal- ciuria, although not all patients with RTA-1 have excessive urinary calcium Hypokalemia Decreased urinary Resorption of excretion. H ypercalciuria results from citrate excretion bone mineral resorption of bone m ineral and the conse- quent increased filtered load of calcium as Reduced renal tubular calcium Hypercalciuria acidosis leads to consum ption of bone reabsorption buffers. Acidosis also has a direct effect of inhibiting renal tubular calcium reabsorp- CaPO precipitation tion. Conversely, nephrocalcinosis from 4 other causes can im pair urinary acidifica- tion and lead to RTA in som e patients. FIGURE 11-4 The m ainstay of therapy for RTA-1 is N ephrocalcinosis in type I (distal) renal tubular acidosis. N ephrocalcinosis and potassium citrate, which corrects acidosis, nephrolithiasis are com m on com plications in distal renal tubular acidosis (RTA-1). The m ost im portant of these factors rate excretion, and reduces urinary loss of are a reduction in urinary excretion of citrate and a persistently alkaline urine. In this nephron segm ent, sodium chloride limb of the loop of Henle is transported into the cell together with potassium by the bum et- Lumen Blood am ide-inhibitible sodium -potassium -2 chloride cotransporter (N KCC2). Recycling of potassium back to the lum en through an Na+ apical potassium channel (RO M K) allows an adequate supply of ClC-Kb NKCC2 2Cl– potassium for optim al activity of the N KCC2. Chloride exits the K+ basolateral side of the cell through a voltage-gated chloride channel (ClC-Kb), and sodium is expelled separately by the sodium -potassi- + Na+ um adenosine triphosphatase cotransporter. Inactivating m utations ROM K K ATP in N KCC2, RO M K, and ClC-Kb have been identified in patients K+ with Bartter syndrom e [6–8]. Approxim ately 20% of filtered calcium is reabsorbed in the thick ascending lim b, and inactivation of any of these three trans- port proteins can lead to hypercalciuria. N ephrocalcinosis occurs in alm ost all patients with m utations in N KCC2 or RO M K, but it FIGURE 11-5 is less com m on in patients with a m utation in the basolateral chlo- Bartter syndrom e. Bartter syndrom e is a hereditary renal functional ride channel ClC-Kb, even though patients with chloride-channel disorder characterized by hypokalem ic m etabolic alkalosis, renal m utations currently m ake up the largest reported group. This salt wasting with norm al or low blood pressure, polyuria, and interesting observation is unexplained at present. O ther features include juxtaglom erular hyperplasia, nificant num ber of patients with Bartter syndrom e have been found secondary hyperreninem ia and hyperaldosteronism , and excessive to have norm al coding sequences for all three of these genes, indi- urinary excretion of prostaglandin E. It often has been noted that cating that m utations in other gene(s) m ay explain Bartter patients with Bartter syndrom e appear as if they were chronically syndrom e in som e patients. Bartter syndrom e often presents with growth with hypocalciuria. In this respect these patients resem ble people retardation in children, and nephrocalcinosis is com m on. In fact, m utations have been found syndrom e is inherited as an autosom al recessive trait. H ypom agnesem ia is com m on and often severe, and im paired reabsorption in the loop of H enle has now been confirm ed patients with Gitelm an syndrom e do not develop nephrocalcinosis. The patient had recurrent calcium nephrolithiasis beginning in child- hood and developed end-stage renal disease requiring dialysis at 40 years of age. Ultrasound im age of right kidney in a patient with prim ary hyperparathyroidism. Echogenicity of the renal cortex is com parable to that of the adjacent liver. In a few families, all affected males have phatem ic rickets in Italy and France, and a syndrom e of had rickets. In other families, rickets is present in only low m olecular weight (LM W ) proteinuria with hyper- one of several males sharing the same mutation. At pre- calciuria and nephrocalcinosis in Japanese schoolchild- sent, the variability of this feature and other features of ren. M utations in a gene encoding a voltage-gated chlo- the disease is unexplained and may reflect dietary or envi- ride channel (ClC-5) are present in all of these syn- ronmental factors or the participation of other genes in drom es, establishing that they represent variants of one the expression of the phenotype. The disease occurs m ost often in boys, Fem ales who are carriers often have m ild to m oder- with m icroscopic hem aturia, proteinuria, and hypercal- ate LM W proteinuria. M any but not all have recurrent nephrolithiasis clinically as a screening test, but LM W protein excre- from an early age. Affected m ales excrete extrem ely tion will not be abnorm al in all heterozygous fem ales. O ther defects hypercalciuria, but other biochem ical abnorm alities are of proxim al tubular function, including hypophos- rare. Although sym ptom atic nephrolithiasis and even phatem ia, am inoaciduria, glycosuria, or hypokalem ia, renal insufficiency have been reported in fem ale carri- occur variably and often interm ittently. N ephrocalcinosis is com m on by the endosomal function would explain the LM W proteinuria. Renal failure is com m on The mechanism of hypercalcinuria remains unexplained and often progresses to end-stage renal disease by the at present. This gene belongs to the family of voltage- fourth or fifth decade, although som e patients escape it. Thus, the organism is highly dependent on urinary excretion, doxine deficiency. N orm ally, dietary sources of oxalate account for which involves net secretion. Normal urine is supersaturated with only approxim ately 10% of urinary oxalate. Crystallization is prevented by a number of oxalate can be effective in som e patients with kidney stones who endogenous inhibitors, including citrate. A mild excess of oxalate load, are hyperoxaluric, but even conscientious adherence to dietary as occurs with excessive dietary intake, contributes to nephrolithiasis. Intestinal absorption of oxalate can be enhanced and possibly through the toxic effects of glyoxalate. PH1 In this setting, several mechanisms have been described including a) results from absolute or functional deficiency of the liver-specific enhanced oxalate solubility as a consequence of binding of calcium enzyme alanine:glyoxalate aminotransferase (AGT).