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By D. Marus. Texas Christian University.

Synthesis logic problems inherent in postmortem tissue that may ac- includes an initial conversion to 5-hydroxytryptophan (5 count for differences among studies discount mildronate 250 mg amex, including accuracy of HTP) via the enzyme purchase 250 mg mildronate amex, tryptophan hydroxylase order mildronate 500 mg with amex. This system has been 123I- -CIT), that bind selectively to the transporter has al- studied in the brains of suicide victims. In one study, a significant ates reported [3H] phorbol dibutyrate binding to protein difference in binding using SPECT was observed between kinase C in prefrontal cortex was lower in teenage suicide depressed patients and controls (50). More recently they observed that both phos- cant differences were not observed in platelet binding to pholipase C activity and the 1 isozyme protein level were 3H-paroxetine, raising questions regarding whether the decreased of teenage suicide victims (63). Depression per transporter is regulated differently in the two tissues. In contrast Hrdina and associates (64) reported unaltered protein kinase C activity in antidepres- Receptors sant free depressives who suicided, and Coull and colleagues Presynaptic and postsynaptic 5HT receptors have also been (65) reported that phorbol dibutyrate binding sites were studied in depressed patients. Over a dozen serotonin recep- increased in the prefrontal cortex of adults with similar his- tors have been identified, although the possible roles for tories. Age, diagnosis of depression, antidepressant use, and many have not. Two that have attracted most study for the time to collection of brain may play a role in these disparate longest periods are the 5HT1A and 5HT2a types. As with the transporter, multiple studies have ple groups have explored the potential use of pindolol, a investigated 5HT2a binding sites in the platelets of depressed 5HT1a antagonist, to hasten response to antidepressants or patients. An increase in binding sites (B-max) has been re- bring out responses in refractory patients. These studies ported in depressed and suicidal patients with some sugges- have yielded mixed results suggesting that pindolol may tion that increased binding in suicidal patients may be inde- hasten response to antidepressants in milder or first-episode pendent of a diagnosis of major depression (51–53). As with the serotonin transporter, results here activity in suicide victims (66–68). GeneticStudies 5HT2a receptors are found in frontal cortex suggesting a A number of studies have explored the possible role of ge- role in the cognitive aspects of depression. PET ligands have been developed to study 5HT2a activity 18 Long and short forms of the transporter gene appear to be in brain. One study employed [ F]- altanserin and reported relatively common in the general population. An early study a reduction in activity in right posterolateral frontal, orbito- indicated a relationship of the short form with an increased frontal, and anterior cingulate regions in depressives (58). In another study, no differences were found between nonsu- 18 Allelic variation has also been applied to predicting drug icidal depressives and controls using [ F-] setoperone (59). In three studies in Europe and the United States, The exclusion of patients with recent suicidal ideation may homozygotes or heterozygotes for the S-form were reported have played a role in not finding differences between pa- to show sluggish responses to SSRIs (70–72). Studies on effects of antidepressants on was found in a Korean study (73). Clearly, further work is 5HT2a binding using PET have also yielded mix results. More recently, Mann perone binding (60), whereas another recently reported that and colleagues (69) reported that the short form genotype 3 to 4 weeks of desipramine treatment resulted in a signifi- was associated with a diagnosis of major depression but not cant decrease in 5HT2 activity in multiple areas, particularly with suicide or 5HT-transporter binding in postmortem in frontal cortex (61). Depletion Studies 5HT2A receptors are coupled to the phosphoinositide second messenger system. When 5HT2a receptors are acti- Brain concentrations of serotonin are highly dependent on vated by agonists, phosphatidyl inositol 4,5 bisphosphate is circulating levels of tryptophan, which competes with other Chapter 72: Molecular and Cellular Mechanisms in Depression 1043 amino acids for transport into the brain. Charney and Del- theories of depression, DA has been emphasized far less in gado have pioneered in the use of an amino acid cocktail depression in spite of its being widely distributed in brain. In these lite, are decreased in depressives (2,85,86), although some studies, the drink was first administered to subjects who had studies have reported elevated CSF DA, but not HVA levels responded to various antidepressants and who were being (87). Urinary DOPAC levels are decreased in depressives maintained on medication. Diphenhydramine has been compared with controls (88); in one study, DOPAC levels commonly used as the comparison cocktail. Euthymic pa- appeared associated with suicidal behavior (85). Dopami- tients on SSRIs but not TCAs rapidly experienced depres- nergic agents such as psychostimulants, nomifensine, and sive symptoms when depleted of L-tryptophan, suggesting the dopamine agonist pramipexole all have antidepressant the need for maintaining adequate serotonin levels to ensure effects in nondelusional patients. Parallel decreases in glu- In contrast, elevated mesolimbic DA activity has been cose utilization in frontal and thalamic regions using PET hypothesized to play a role in delusional depression (89). In contrast, there are multiple chotic symptoms and agitation in major depression (89), reports of depletion not causing a clear recurrence of symp- and increased plasma DA and HVA levels have also been toms in patients treated with bupropion or electroconvul- reported in delusional depression (90,91). Studies have used a variety of dif- limbic DA activity has been postulated to occur secondary ferent methods (e. Recent studies in rats, nonhuman primates, and differences may account for the discrepant findings. The psychotic depressives suggest elevated glucocorticoid activ- degree and duration of response observed before the deple- ity could also result in altered or decreased prefrontal corti- tion challenge is administered may be of particular impor- cal dopamine metabolism and to alterations in attention tance (79). Patients who are in remission or have shown a and response inhibition (92,93). These data suggest in- prolonged response are unlikely to demonstrate significant creased HPA axis activity could affect DA turnover differ- worsening of moods (79). These data suggest recent re- ently in specific brain regions—alterations that have been sponders are those who are susceptible to experiencing re- suggested in schizophrenia. Antipsychotic drugs appear to lapse with depletion strategies. Depletion of unmedicated play a key role in treatment of delusional depression and euthymic depressives does not appear to induce recurrence, glucocorticoid receptor antagonists are being actively stud- indicating maintaining serotonin tone is important primar- ied in the disorder. Of interest is a recent report that women controls show GABA much lower rates of 5HT synthesis and a greater decrease in response to depletion than men do (80). This gender- GABA has become a focus of greater study over the past based difference is consistent with a recent observation that several years with the increasing use of anticonvulsants in chronically depressed women are more responsive to an mood disorders. GABA is a major inhibitory neurotransmit- SSRIthan men are (81). There are two types of Fenfluramine Challenge GABA receptors. GABAA receptors have been studied in anxiolysis because of their location within a benzodiaze- Fenfluramine, previously marketed as an appetite suppres- pine–GABA receptor complex that is coupled to chloride sant, causes a release of serotonin from presynaptic neurons 2 channels. Prolactin responses In rats, antidepressants and mood stabilizers appear to up- to fenfluramine challenge are blunted in depressed patients regulate frontal-cortical GABAB, but not GABAA, receptors (82,83) and there are some data to suggest this may be a (94,95). GABAB agonists may enhance cAMP responses to trait marker (84). However, bipolar manic and axis II pa- norepinephrine and -adrenergic down-regulation in re- tients may also demonstrate blunted prolactin responses, sponse to tricyclic antidepressants, suggesting a facilitative raising questions regarding the specificity of the test. GABA levels have DOPAMINE been reported to be decreased in the CSF of depressed pa- tients in some but not all studies (96,97). Plasma GABA As indicated, dopamine (DA) is a precursor for norepineph- levels have also been reported to be lower in unipolar depres- rine. Although NE has played a central role in etiologic sives (98,99), and this may not normalize with treatment 1044 Neuropsychopharmacology: The Fifth Generation of Progress (100).

J Am Acad Child Adolesc Psychiatry 1998;37:512–18 Byford S buy mildronate 500mg on-line, Barrett B buy cheap mildronate 500 mg, Roberts C order 250 mg mildronate mastercard, Wilkinson P, Dubicka B, Kelvin R, et al. Cost-effectiveness of selective 89 serotonin reuptake inhibitors and routine specialist care with and without cognitive-behavioural therapy in adolescents with major depression. Br J Psychiatry 2007;191:521–7 Goodyer I, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al. Selective serotonin reuptake 90 inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: randomised controlled trial. BMJ 2007;335:142 Byford S, Barrett B, Roberts C, Clark A, Edwards V, Smethurst N, et al. Economic evaluation of a randomised 91 controlled trial for anorexia nervosa in adolescents. Br J Psychiatry 2007;191:436–40 Gowers SG, Clark A, Roberts C, Griffiths A, Edwards V, Bryan C, et al. Clinical effectiveness of treatments 92 for anorexia nervosa in adolescents: randomised controlled trial. Br J Psychiatry 2007;191:427–35 Gowers SG, Clark AF, Roberts C, Byford S, Barrett B, Griffiths A, et al. A randomised controlled 93 multicentre trial of treatments for adolescent anorexia nervosa including assessment of cost-effectiveness and patient acceptability – the TOuCAN trial. 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 95 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 3 Reference Study number Calvo A, Moreno M, Ruiz-Sancho A, Rapado-Castro M, Moreno C, Sánchez-Gutiérrez T, et al. Intervention 94 for adolescents with early-onset psychosis and their families: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry 2014;53:688–96 Cano-Garcinuño A, Díaz-Vázquez C, Carvajal-Urueña I, Praena-Crespo M, Gatti-Viñoly A, García-Guerra I. J Invest Allerg Clin 2007;17:216–26 Carswell F, Robinson EJ, Hek G, Shenton T. Bristol Med Chir J 1989;104:11–12 Celano MP, Holsey CN, Kobrynski LJ. Home-based family intervention for low-income children with asthma: 97 a randomized controlled pilot study. J Fam Psychol 2012;26:171–8 Chan DS, Callahan CW, Sheets SJ, Moreno CN, Malone FJ. An Internet-based store-and-forward video home 98 telehealth system for improving asthma outcomes in children. Am J Health Syst Pharm 2003;60:1976–81 Chan DS, Callahan CW, Hatch-Pigott VB, Lawless A, Proffitt HL, Manning NE, et al. Internet-based home 99 monitoring and education of children with asthma is comparable to ideal office-based care: results of a 1-year asthma in-home monitoring trial. Pediatrics 2007;119:569–78 Christie D, Thompson R, Sawtell M, Allen E, Cairns J, Smith F, et al. Structured, intensive education 100 maximising engagement, motivation and long-term change for children and young people with diabetes: a cluster randomised controlled trial with integral process and economic evaluation – the CASCADE study. A randomized controlled trial of a public health nurse-delivered asthma program 102 to elementary schools. J School Health 2013;83:876–84 Clark NM, Gong M, Kaciroti N, Yu J, Wu G, Zeng Z, et al. A trial of asthma self-management in Beijing 103 schools. Chronic Illn 2005;1:31–8 Cowie RL, Underwood MF, Little CB, Mitchell I, Spier S, Ford GT. Asthma in adolescents: a randomized, 104 controlled trial of an asthma program for adolescents and young adults with severe asthma. Can Respir J 2002;9:253–9 Domino ME, Burns BJ, Silva SG, Kratochvil CJ, Vitiello B, Reinecke MA, et al. Cost-effectiveness of treatments 105 for adolescent depression: results from TADS. Am J Psychiatry 2008;165:588–96 Domino ME, Foster EM, Vitiello B, Kratochvil CJ, Burns BJ, Silva SG, et al. Relative cost-effectiveness of 106 treatments for adolescent depression: 36-week results from the TADS randomized trial. J Am Acad Child Adolesc Psychiatry 2009;48:711–20 March J, Silva S, Vitiello B, TADS Team. The Treatment for Adolescents with Depression Study (TADS): 107 methods and message at 12 weeks. J Am Acad Child Adolesc Psychiatry 2006;45:1393–403 March JS, Vitiello B. Clinical messages from the Treatment for Adolescents With Depression Study (TADS). The Treatment for Adolescents with 109 Depression Study (TADS): demographic and clinical characteristics. J Am Acad Child Psy 2005;44:28–40 Donaldson D, Spirito A, Esposito-Smythers C. Treatment for adolescents following a suicide attempt: results 110 of a pilot trial. J Am Acad Child Adolesc Psychiatry 2005;44:113–20 Dougherty GE, Soderstrom L, Schiffrin A. An economic evaluation of home care for children with newly 111 diagnosed diabetes: results from a randomized controlled trial. Med Care 1998;36:586–98 Dougherty G, Schiffrin A, White D, Soderstrom L, Sufrategui M. Home-based management can achieve 112 intensification cost-effectively in type I diabetes. Pediatrics 1999;103:122–8 Eakin MN, Rand CS, Bilderback A, Bollinger ME, Butz A, Kandasamy V, et al. Asthma in Head Start children: 113 effects of the Breathmobile program and family communication on asthma outcomes. J Allergy Clin Immunol 2012;129:664–70 Edwards RT, Céilleachair A, Bywater T, Hughes DA, Hutchings J. Parenting programme for parents of children 114 at risk of developing conduct disorder: cost effectiveness analysis. Parenting intervention in Sure 115 Start services for children at risk of developing conduct disorder: pragmatic randomised controlled trial.

This is a nice example of how an indirect control discount mildronate on line, During sham feeding buy cheap mildronate 250 mg online, liquid food drains from open gastric cannu- las withoutsignificant accumulation inthe stomach orsmall intes- learning buy discount mildronate online, requires connections between the forebrain and tine, so that learned controls based on gastrointestinal food stim- hindbrain in order to affect eating. In this experiment 13 rats were offered a sweet examples. During week 1, rats fed normally (real feeding, RF); There is evidence that D1receptor mechanisms are neces- during weeks 2 to 7, sham-feeding (SF) tests alternated with real- sary for the acquisition of a CTA as well as a conditioned feeding tests, and during weeks 8 to 11, rats were only sham fed. Injection of a D antagonist into the lateral hy- The figure shows the average real and sham meal sizes in each 1 week. During the first sham-feeding test, rats still ate well-de- pothalamus blocked the acquisition of a CTA (38). Like dicating that after this short period of food deprivation, pregas- conditioned preference of the flavor–postingestive type, it tric food stimuli can elicit satiety. However, meal size nearly doubled during this test, because of the absence of direct, uncon- depends on the association between orosensory stimuli and ditioned gastric and postgastric controls of eating. Unlike conditioned preferences size doubled during weeks 3 to 7, when sham- and real-feeding and aversions, conditioned satiation is hedonically neutral. It can be ac- These further increases during the last 4 weeks reflect the extinc- quired or extinguished within one or two meals. Increases of plasma glucose are not a sufficient liams & Wilkins, 2000:209–218, with permission of the publisher. Chapter 115: The Behavioral Neuroscience of Eating 1671 vant to the abnormally large meals that occur with repetitive sumably this synergism is a central action of estrogen chang- bingeing followed by vomiting or purging. The role of CCK in this effect has not been investi- Estrogen has two inhibitory effects on eating. The decrease in food intake is owing to a decrease in nervosa and circulating estrogen is low adds a further disin- meal size (43). The combination of feedback potencies hibition to the central network that controls eating in these (Table 115. The increased negative feedback is the result tonic inhibition of meal size that acts throughout the ovar- of estrogen increasing the potency of endogenous CCK re- ian cycle in rats. Release from this inhibition by ovariectomy leased from the small intestine (Fig. Pre- causes a sustained increase in meal size and obesity. This effect of estrogen, however, does not appear to be mediated by a change in the satiating potency of CCK. Both effects of estrogen depend on binding to the estro- gen receptor because mice with this receptor knocked out do not show either effect (52). There are sex differences in the incidence or clinical course of many diseases associated with anorexia as well as in the anorectic response to many immune-system mediators, such as IL-1 and -TNF. Some of these sex differences appear to be related to estrogenic function. Crohn disease, an inflammatory bowel disease in which anorexia is an early sign (53), is one such. Anorexia caused by Gram-negative bacterial infection is also estradiol-sensitive. The effect of estradiol to increase the anorexia produced in rats by intraperitoneal administra- tion of bacterial lipopolysaccharide is expressed by a decrease in meal frequency without a change in meal size (56), indi- cating that this effect of estrogen is separate from the effects on meal size. Furthermore, endogenous CCK does not appear to contribute to Our understanding of the controls of eating in rodents has the tonic inhibitory effect of estradiol on meal size because deva- been transformed in the past 5 years. Although the relation- zepide did not increase meal size during diestrus. Data are mean ship of eating to nutritional and energetic homeostasis con- meal sizes per 3-hour quartile of the nocturnal phase. More attention to behavioral analysis not an artifact of the cyclic differences in meal size. It has meal size after devazepide larger than after vehicle, P. Re- revealed the operation of a cpg as the final common path produced from Eckel LA, Geary N. The satiating effect of cholecystokinin and The recognition that the size of a meal is under positive bombesin-like peptides. Satiation: from gut to and negative feedback controls has been exploited. Inhibition of food strated to be involved in these feedbacks. The afferent nerves intake in response to intestinal lipid is mediated by cholecystoki- that carry the peripheral information generated along the nin in humans. Cholecystokinin decreases sucrose intake in preabsorptive surface of the gut from the tip of the tongue chronic decerebrate rats. In: Bray of these peripheral mechanisms are activated in every meal, GA, Ryan DH, eds. Baton Rouge, all controls of eating not related to the food being ingested LA: Louisiana State University Press, 1999:227–245. Identification of rat brainstem multisynaptic a new theory of the controls of eating that is more biological, connections to the oral motor nuclei using pseudorabies virus. In: Adelman G, Smith The widely distributed processing of information rele- BH, eds. Systemic factors in the control of food tance and complexity of eating in omnivores such as rodents intake. Patterns of body pressing questions for rodents as well as humans. The ability temperature during feeding in rats under varying ambient tem- peratures. Recognition of this fact increasingly affects re- of food intake after 2-deoxy-D-glucose and nicotinic acid injec- search on eating. The paradigm shift that the study of eating has under- 16. Analysis of the microstructure of the rhythmic tongue movements of rats ingesting maltose and sucrose gone, that is, from viewing eating as serving only nutrient solutions. A model for the control of ingestion, 20 years later. Progress in psychobiology and ioral neuroscience (1), makes the basic science more useful physiologic psychology. Caudal brainstem participates in the distrib- uted neural control of feeding. Using the similarity in eating behavior, gastroin- of behavioral neurobiology.

Transcription occurs when particular activator proteins displace nucleosomes buy discount mildronate online. This permits a complex of proteins (described later)called general transcription factors order mildronate canada, to bind DNA at a particular type of element generic 500mg mildronate free shipping, called a core promoter, and to recruit RNA polymerase. The construction of this protein complex at the transcription start site and the syn- thesis of the first phosphodiester bond between nucleotides Eric J. Nestler: Department of Psychiatry, The University of Texas South- are referred to as transcription initiation (3). The RNA poly- western Medical Center, Dallas, Texas. Hyman: National Institute of Mental Health, Bethesda, Mary- merase must successfully transcribe an appropriate length land. Pre- 218 Neuropsychopharmacology: The Fifth Generation of Progress mature termination appears to be a regulated mechanism Core Promoters: Setting the Start Site that controls expression of a small number of genes. Tran- and Direction of Transcription scription of the RNA must also terminate appropriately (ter- In eukaryotes, transcription is carried out by three distinct mination). RNA polymerases: RNA polymerases I, II, and III (4). These three polymerases interact with different classes of Transcription Initiation: A Critical genes, each of which contains distinct promoter elements. Polymerase I (pol I)promoters are used by genes that encode Biological Control Point large rRNAs (ribosomal RNAs). Polymerase II (pol II) pro- As described in the preceding section, transcription can be moters are used by genes that are transcribed to yield divided into three discrete steps: initiation, mRNA chain mRNAs and hence proteins. Pol II promoters are also used elongation, and chain termination. Although biologically by a subset of the genes that encode snRNAs that are in- significant regulation may occur at any step in the process, volved in RNA splicing. Polymerase III (pol III)promoters transcription initiation appears to be one of the most signifi- are used by genes that encode other small RNAs, including cant control points that gates the flow of information out of the remaining snRNAs, small rRNAs, and tRNAs (transfer the genome. Certainly, as far as we know now, transcription RNAs). The core promoters for each of the three polymer- positioning of the appropriate RNA polymerase at the cor- ases contain distinct elements on which different types of rect start sites of transcription and controlling the efficiency basal transcription complexes are assembled, each using dif- of initiations to produce the appropriate transcriptional rate ferent transcription factors. Because the main focus of this for the circumstances of the cell. These control functions chapter is regulated expression of protein-encoding genes, depend on regulatory elements that recruit appropriate tran- only transcription by pol II is described. Many transcrip- The core promoters of genes transcribed by pol II are tion factors bind DNA directly; others interact indirectly surprisingly diverse, but they share certain key features. By through protein–protein interactions with factors that do far the most common core promoter element for pol II bind DNA themselves. Those regulatory elements that set promoters is the TATA box (Fig. Other regulatory elements tether additional upstream of the transcription start site. In TATA box–con- activator and repressor proteins to the DNA. The figure shows two regulatory elements (open rectangles) along the stretch of DNA (thin black line). These include the TATA element and a hypothetic activator or response element. The TATA element is shown binding the TATA-binding protein, TBP. Multiple general transcription factors and RNA polymerase II (pol II) associate with TBP. The general transcription factors are referred to with the nomenclature of TFII(x), for transcription factors of a pol II promoter. TBP and its associated proteins are collectively called TFIID. This basal tran- scription apparatus recruits RNA polymerase II. It also forms the substrate for interactions with various activator proteins that bind to activator elements such as the one shown. Typical activator proteins contain DNA-binding domains, dimerization domains, and transcription activation do- mains. The latter interact with the basal transcription apparatus and may be modified by phos- phorylation. Chapter 17: Regulation of Gene Expression 219 scription initiation or make it inaccurate. In addition to basally and in response to physiologic and environmental setting the start site of transcription, the TATA box sets signals (7). Many pol II promoters (including those for many shown in Fig. Each of the tran- multimers and heteromultimers with other transcription scription factors represented in Fig. The modularity of these proteins is emphasized by identified as a chromatographic fraction derived from cell the finding that particular binding domains, activation do- nuclei, and it is a mixture of proteins. Thus, TBP together mains, and interaction domains are used in different combi- with its TAFs was originally identified as a fraction called nations in many naturally occurring proteins. Experimen- TFIID, where TFII is a nomenclature identifying general tally, domains can be swapped from different activators to transcription factors associated with pol II, and the final produce novel hybrid proteins that are functionally active. TFIID, but not TBP by itself, Many transcription factors are active only as dimers or is required to build a basal transcription complex from higher-order complexes. Multimerization domains are di- TATA-less promoters. Within transcription factor dimers, whether they Transcription Factors: Key Regulators of are homodimers or heterodimers, both partners commonly Gene Expression contribute jointly to both the DNA binding domain and to the activation domain. In some cases, dimerization can The basal transcription apparatus is not adequate to initiate be a mechanism of negative control of transcription. To achieve significant illustrated by the CREB (cyclic adenosine monophosphate levels of transcription, this multiprotein assembly requires [cAMP]–response element binding protein)family of tran- help from additional transcriptional activators that recog- scription factors discussed later. Other Fos-related proteins, such as Fra1 (Fos- within several hundred bases of the start site of the gene to related antigen–1), bind DNA as heterodimers with c-Jun, which they are linked, but they can occasionally be found and they may still activate transcription, but at lower levels many thousands of base pairs (bp)away, either upstream than c-Fos (11). Overall, the ability of transcription factors or downstream of the start site.

Applications for commercial reproduction should be addressed to: NIHR Journals Library purchase mildronate overnight delivery, National Institute for Health Research order mildronate 500mg line, Evaluation discount mildronate 500mg on-line, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. CONCLUSIONS encouraged experimentation; but, conversely, the relative lack of stability and the pace of change (in diverse directions) meant that the agents we studied had to cope with the extra uncertainty surrounding priorities, funding flows and patient flows. The research findings reveal the many attempts to reform general practice and primary care. This involved larger practices or groups of practices, extended services and extended teams with mixed skills, and a shift in emphasis from commissioning to new forms of leadership and governance of provider organisations. The examples of more far-reaching local action were normally those prompted by and legitimated by higher-level policy shifts. However, notably, even such national-level sponsorship was not enough to ensure a smooth passage for local reforms. Yet, even this piece of collaboration building was not enough to overcome local opposition. Limitations The research underpinning this report included a vast array of investigative activities across a very large number of CCGs. The six CCG cases are not necessarily reflective of the 2009 CCGs in England. That said, the detailed cases were not intended to be a representative sample of all CCGs. Indeed, as mentioned, they were selected through theoretical sampling and there was a bias towards CGGs where there was some evidence of meaningful activity. The wider survey, which covered all CCGs, allows a broader picture and much of the evidence from that source pointed to numerous instances where there has been much less activity than we record in our cases. So our casework is not statistically representative of CCGs, but it does help reveal the pattern of activities and factors which allow GPs to make a substantive difference – if they are minded to do so. Implications for practising clinicians, managers and other local actors The main practical implications to be drawn from this research project are as follows. Past assumptions about power and influence may not be valid. Major new initiatives emanating from national level, such as STPs, Vanguards and the promotion of ACOs, signal that the role of CCGs has been diminished. The lessons will be useful in new contexts even if CCGs do not survive or become much reduced in their role. Learning from the cases suggests that initiatives work best when there is commensurate supportive activity under way in operational planning and practice delivery arenas. Most crucially, clinical leaders on the commissioning side of programme boards need to make sure they engage creatively with influential GPs and acute provider clinical leads who are involved in creating the operational detail of new or improved services. Service redesign is not an end in itself; rather, it should be a response to identified problems and opportunities for service improvement. Actors in the current system are under time pressure and so it is especially important that they are able to direct their energies in effective ways. Exercises in establishing common purpose and reanalyses of the state of the system can be useful but they can also be excessive. Launching reviews and initiatives was experienced by some as too easy and too frequent. The early stages of projects and programmes are the easy part; follow-through and the realisation of effective impacts are the difficult parts. The problem of the plethora of initiatives is not resolved simply by producing documents claiming alignment with other ongoing programmes and projects. Implications for future research When writing the proposal for this research project we stated that even if CCGs did not survive there was merit in studying how managers and clinicians would behave under these kinds of regime. We regarded it then, as we do now, as a valuable opportunity to take advantage of a bold, large-scale, natural experiment. No other system has given GPs such extensive commissioning powers. There was potential for radical change and we wanted to explore how these newly privileged actors would undertake the institutional work of disruption and rebuilding that lay in prospect. In practice, we found that action, in the main, did not match initial expectations or plans. Institutional stickiness in the wider system alongside competing logics and forces meant that attempts at radical change were often blocked. Yet, as shown, we did identify and classify many rich instances of clinical leadership in three main arenas: the strategic, the operational level of programme boards and the practice level of service delivery. The research agenda emerging from this work relates most obviously to how the newly emergent bodies such as the STPs and the extended primary care formations and ACOs, will operate, and with what impact. However, in addition, the other implication for future research is to delve deeper into the forms of clinical leadership which we identified. These operated in different arenas and they seem capable of recurring with, or without, altered forms of commissioning and collaborative planning in health care in the future. Whatever institutional form health-care governance and management may take in the future, many of the processes we uncovered and the capabilities inherent within them will resurface. Future research therefore can usefully focus on these enduring elements: how normative commitment is constructed; how front-line clinicians are engaged; how alliances across professional groups and organisations are built; how existing provider identities are handled while encouraging greater professional exchange in the interests of patients and public. Another theme for future research that emerges from this work is how the established institutional hierarchies (most notably the acute hospitals, especially when they are foundation trusts with budgets to defend and targets to meet, plus also the general practices) will meet on the common ground of shared population-based health and well-being as the supposed priorities, when they continue to feel the tug of professional identity, professional jurisdictions, institutional survival and shortage of resources. The bases of negotiated order, whether or not contractual and/or relational, will need exploring. 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 95 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. Our sincere thanks are also due to our international panel of experts who helped us think through the wider meaning of the findings in relation to similar issues in other health systems and other countries. In particular, we acknowledge the help of John Ovretveit, Stockholm, Sweden; Hub Wollersheim, the Netherlands; Frede Olesen, Peter Vedsted, Flemming Bro and Mogens Vestergaard from Denmark; Michel Wensing, Heidelberg University Hospital, Germany; Charles Heckscher and Susan Jackson, Rutgers University, New York, NY, USA; Jean-Louis Denis, Montreal, QC, Canada; Tom Kochan, Massachusetts Institute of Technology, Cambridge, MA, USA; and Barbara Kellerman, Harvard University, Cambridge, MA, USA. We are also grateful to the many individuals and groups who helped make this research possible. This includes the hundreds of respondents from CCG governing boards who completed the national surveys, which produced the data for the charts and tables in Chapter 3. We are grateful also to the clinicians and managers who agreed to be interviewed about their work, which produced the data for the case study analyses in Chapters 4 and 5. In addition, acknowledgement is due to informants from outside CCGs, including patients and public representatives, ambulance service staff, LA officials and elected members, doctors and managers from the acute sector, and persons from all relevant surrounding bodies such as CSUs, STPs and regulatory bodies. Contributions of authors John Storey (Professor of Management) conceived and designed the study, conducted interviews, designed the national surveys, synthesised the results and authored the final report.

Patients with symptomatic hyperparathyroidism or uncontrolled hypercalcem ia should be considered for parathy- roidectomy before transplantation mildronate 500 mg fast delivery. M edications that interfere with the metabolism of immunosuppressive agents such as cyclosporine should be substituted with appropriate alternatives order mildronate 250mg, if possible cheap mildronate 500mg line, before transplantation. Patients without signs and symp- Signs or toms of bladder dysfunction generally do not Yes symptoms of No bladder need additional urologic testing. Such patients can be screened initially with voiding cystourethrography Yes (VCUG). No Consider ureteral Indications for No No diversion or native kidney intermittent nephrectomy? No Yes Severe diverticular Yes Endoscopic or Yes Consider partial radiographic No disease on barium colectomy enema? No No Adequate response No Consider to medical pretransplantation management? Yes No Delay transplantation History of Yes until evaluation and Proceed with Defer transplantation pancreatitis? Patients with a history of symptomatic diverticulitis must be evaluated for partial colectomy before transplantation. Inflam m atory bowel disease generally FIGURE 12-24 should be quiescent at the tim e of transplantation. Patients with PUD and coworkers; with perm ission. Both conditions m ay be exacerbated by corticos- teroids used after transplantation. Generally, Consider transplantation donors and recipients m ust have com patible blood Potential living No cadaveric groups. Tissue typing is also carried out, and the degree of hum an donor? A positive cross- m atch (X-m atch) generally precludes transplantation from that donor. Yes Assess T-cell CDC No likelihood of X-match negative? Yes No Consider other Transplantation donor Proceed with evaluation Evaluation of Prospective Donors and Recipients 12. Transplantation No 40 0 0 1-5 6-10 >10 0 1-5 6-10 >10 FIGURE 12-26 Donor-specific transfusion (DST). Unfortunately, donor-spe- FIGURE 12-27 cific transfusions may induce the formation of antibodies against the Effects of random blood transfusions on first cadaveric renal allo- donor that will preclude the transplantation. Blood transfusions before transplantation had a abandoned the use of random blood transfusions as part of the sm all but statistically significant beneficial effect on 1-year graft preparation of recipients for cadaveric transplantation. H owever, a sm all reduction occurred in 5-year graft sur- cross-match. Donors and recipients m ust have com patible blood groups. Tissue typing is car- No living ried out, and the degree of m atching is used in the allocation of donor cadaveric organs. Som e data suggest that the presence of hum an leukocyte antigen (H LA) m ism atches that were also m ism atched in a previous graft (especially at the DR locus) m ay lead to early graft First No Review typing from loss. Autoreactive antibodies No Autologous Yes PRA after DTT or m ay not increase the risk for graft loss as do alloreactive antibodies. The presence of high titers of alloreactive antibodies usually is due adsorption Yes No to previous pregnancies, transplantations, and blood transfusions. Determ ining antibody specificities m ay be useful in avoiding certain Identify HLA H LA antigens. In the highly sensitized patient (PRA > 50% ) it m ay W aiting list specificities be difficult to find a com plem ent-dependent cytotoxicity (CDC) Yes cross-m atched (X-m atch) negative donor. Avoiding blood transfu- Periodic sions m ay help the titer decrease over tim e. The best graft survival was seen in recipients of hum an leukocyte antigen (H LA)–identical sibling Years after transplantation donors. Grafts from spouses and other living unrelated donors, however, survived just as well as did grafts from parental donors FIGURE 12-30 and better than grafts from cadaveric donors. These data have Effects of human leukocyte antigen (HLA) matching on living related encouraged centers to use em otionally related donors to avoid graft survival. Graft survival is best for HLA-identical grafts from sib- the long waiting tim es for cadaveric kidneys. This information can be used along with other factors to select the most suitable among two or more living prospective donors. A suitable living donor is better than a cadaveric donor because graft survival is better and preemptive transplantation Candidate for renal transplantation is possible. Psychosocial and biological factors m ust be taken into account when choosing am ong two or m ore living prospective donors. Every effort m ust be m ade to ensure that the donation is truly voluntary. Caregivers W illing to Yes should tell prospective donors that if they do not wish to donate, accept living then friends and relatives will be told “the donor was not m edically donor? No Evaluate for cadaveric No Cross-match Yes transplantation negative? W illing and available No ABO-compatible Yes emotionally related donor? Proceed with evaluation Evaluation of Prospective Donors and Recipients 12. Yes No Voluntarism reasonably No Surgical risk certain? Yes Yes Yes No Preliminary No Yes Financial Long-term risk medical incentive? No donor Yes CM V titer Yes Risk positive or Risk of acceptable? No Yes Proceed with No No Screening for Yes Proceed with evaluation diabetes evaluation negative? FIGURE 12-32 Prelim inary evaluation of a living prospective donor. The FIGURE 12-33 prospective donor m ust be m ade aware of the possible costs Assessing risks. O lder age m ay place the living prospective donor at associated with donation, including travel to and from the greater surgical risk and m ay be associated with reduced graft sur- transplantation center and tim e away from work. The prospective donor m ust be inform ed of donor m ust undergo a psychological evaluation to ensure the both the short-term surgical risks (very low in the absence of car- donation is voluntary. A prelim inary m edical evaluation should diovascular disease and other risk factors) and the long-term conse- assess the risks of transm itting infectious diseases with the kid- quences of having only one kidney.

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