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The dynamic interactions between dopaminergic and In 1974 discount panmycin 500mg mastercard, Fuxe showed that methylxanthines such as caf- purinergic systems in striatum suggest that dopaminergic feine could stimulate rotational behavior and could poten- dysfunction may be indirectly ameliorated by adenosine re- tiate the effects of dopamine agonists in rats with unilateral ceptor modulation discount panmycin 250 mg mastercard. Selective adenosine A2A receptor antag- striatal lesions Conversely, adenosine agonists blocked the onists such as KF 17837 and KW 6002 (Fig. Anatomic links be- shown positive effects in 1-methyl-4-[henyl-1,2,3,6-tetra- tween central dopamine and adenosine systems are well es- hydropyridine–lesioned marmosets and cynomolgus mon- tablished; adenosine A2A receptors are highly localized in keys, well characterized animal models of PD, enhancing striatum, nucleus accumbens, and olfactory tubercle, brain the effects of L-dopa (73,74). KW-6002 has successfully regions that also have high densities of dopamine D1 and completed human phase I trials. In men who drank no coffee, the incidence to the globus pallidus that originates from striatal GABA- of PD was 10. Through GABAergic relays, this 10,000 person-years in men drinking at least 28 oz of coffee pathway interacts with a glutaminergic pathway from the per day (75). Dopamine–adenosine (ADO) interactions in the substantia nigra. An indirect path- way dopaminergic pathway arises from the striatal GABA-enkephalinergic dopaminergic neurons on which both dopamine D1 and adenosine A2A receptors are co-localized. Through a GABAergic interneuron originating in the external globus pallidus, the indirect pathway connects to a gluta- minergic pathway arising in the subthalamic nucleus. This, in turn, can activate the internal seg- ment of the pars reticulata and, through another GABA pathway, inhibit ascending glutaminegic neurons arising from the thalamus that innervate the cortex. The direct pathway arises from striatal GABA–substance P–dynorphinergic neurons that, through a GABAergic relay, inhibit the internal segment of the pars reticulata to disinhibit the ascending thalamic-cortical glutaminergic pathway. The balance between the direct (activating) and indirect (inhibitory) striatal dopami- nergic pathways can then tonically regulate normal motor activity. Dopaminergic inputs arising from the substantia nigra pars compacta can facilitate motor activity, inhibiting the indirect path- way by activation of D2 receptors and activating the direct pathway by D1 receptor activation. Distribution, biochemistry and function of striatal adenosine A2A receptors. Prog Neurobiol 1999;59:355–396; and Richardson PJ, Kase H, Jenner PG. CGS 21680, like typical and atypical neu- also produce catalepsy at the same dose levels effective in roleptics, can reverse apomorphine-induced loss of prepulse attenuating conditioned avoidance response, a property inhibition (76). These actions involve a decrease in dopami- shared by typical neuroleptic agents such as haloperidol. CI- nergic neurotransmission, with adenosine receptor agonists 936, an A2A agonist (Fig. Adenosine ago- mid 1970s as a novel antipsychotic agent, but its develop- nists have a behavioral profile similar to that of dopamine ment was discontinued for unstated reasons. Chapter 15: Purinergic Neurotransmission 203 Sleep sine antagonists. Adenosine A1-receptor agonists modulate acutely evoked and inflammation-evoked responses of The hypnotic and sedative effects of adenosine are well spinal cord dorsal horn nociceptive neurons and can also known, as are the central stimulant activities of the various inhibit pain behaviors elicited by spinal injection of sub- xanthine adenosine antagonists including caffeine (18). Di- stance P and the glutamate agonist, N-methyl-D-aspartate rect adenosine administration into the brain elicits an EEG (NMDA). Glutamate is a key mediator of the abnormal profile similar to that observed in deep sleep, an increase hyperexcitability of spinal cord dorsal horn neurons (central in rapid eye movement (REM) sleep with a reduction in sensitization) associated with clinical pain states. A1 agonists REM sleep latency resulting in an increase in total sleep. Microdialysis studies have shown that extra- another key mediator of nociceptive responses. Adenosine cellular adenosine concentrations are increased in basal fore- has both presynaptic and postsynaptic effects on transmis- brain in direct proportion to periods of sustained wakeful- sion from primary afferent fibers to neurons of the substan- ness and decline during sleep, a finding indicating that tia gelatinosa of the spinal dorsal horn (12,80,81), and it adenosine functions as a endogenous sleep regulator (19). Infusion of the A2A agonist, CGS 21680, into the subarach- Adenosine agonists such as CHA and NECA, were 10- to noid space associated with the ventral surface of the rostral 1,000-fold more potent in inhibiting acetylcholine-induced basal forebrain, an area designated the prostaglandin writhing in mice when these agents were administered intra- D2–sensitive sleep-promoting zone, increased slow-wave cerebroventricularly than orally, a finding indicating a su- and paradoxical sleep, effects that were blocked by the A2A praspinal site of action. The ability of adenosine to inhibit antagonist, KF 17837 (78). The A1-selective agonist, CHA, peripheral neurotransmitter (12), and inflammatory pro- suppressed slow-wave and paradoxical sleep before eliciting cesses (67), may block peripheral sensitization, a key feature an increase in low-wave sleep.

Agnosia limited to finger identification may be found in left parietal lesions (in right handed people) panmycin 250mg line, while anosognosia is associated with right parietal lesions buy panmycin 250 mg visa. Dressing and constructional apraxia As mentioned above, these problems should perhaps be included under the heading of Agnosia. Neuropsychiatric aspects of aphasia and related language impairments. Services are poorly developed, even in countries with advanced health care systems such as Australia (Australian Pain Society, 2010). Treatment/management is complex, but not impossible; and may involve doctors (pain specialists), physiotherapists and psychologists/psychiatrists. As some analgesic medicines have addictive potential, risk assessment is indicated. Pain Pain is “an unpleasant sensory and emotional experience associated with actual tissue damage or is described in terms of such damage” (Merskey, 1979). At least two separate components of pain can be identified, 1) a motivational/affective component, which identifies pain as negative and something to be avoided, and 2) a sensory/discriminative component which localizes the pain and forms an appropriate response. Acute Pain Acute pain is a warning system which halts certain actions (or inactions) and teaches us not to perform such actions (or inactions) in the future. The full details of the pain system can not be pursued in detail. However, “nociceptors” are specific primary afferent nerves which respond to potentially tissue-damaging stimuli. They pick up sensations in the skin and other organs and terminate in the dorsal horn of the spinal cord, a complex site where pathology may develop and therapy may be attempted. Ascending fibers (second order cells) cross the cord and travel north, (predominantly) in the spinoreticular and spinothalamic tracts. The spinoreticular tract terminates in the mid brain, connecting with the periaquiductal gray matter (PAG) and other reticular structures, and (importantly) the locus coeruleus (the seat of the sympathetic system). The PAG is a major component of a descending pain inhibitory system, which impacts at the dorsal horn of the spinal cord. The spinothalamic tract terminates at the posterior and medial thalamic nuclei (the central switching station). The thalamus (Th) projects fibers to the primary somatosensory cortex (SI; believed to provide for the localization of pain), secondary somatosensory cortex (SII; Brodmann area 40, supramarginal gyrus, at the posterior end of the lateral fissure), the anterior cingulate cortex (ACC), and the insular cortex (IC). There are also projections to the prefrontal cortex (PFC), but this region is probably less important in acute than other forms of pain (Akparian et al, 2005). Adapted from Pridmore, 2002 Chronic pain is defined as pain which persists for longer than 3 months, or past the usual healing time. The pain of rheumatoid arthritis (for example) persists beyond 3 months. While such pain can be classed as “chronic”, there is ongoing inflammation, and such conditions can be considered “chronic nociceptive pain”. Psychogenic pain has been described as pain which arises from the emotional life of the individual, in the absence of any physical pathology. In the current era, such pain (in the complete absence of physical pathology) is very rarely encountered. However, mental disorders make physical pain more difficult to tolerate. There is also potential for circularity: pain can caused emotional distress, which in turn, makes pain worse. Neuropathic pain is caused by a “lesion or dysfunction of the nervous system” (Merskey & Bogduk, 1994). A lesion of a peripheral nerve by trauma or herpes zoster (for example) may result in various mechanisms which contribute to chronic pain. Peripheral sensitization: describes changes in damaged peripheral nerves, including painful spontaneous firing and abnormal excitability. Central sensitization: describes changes in the spinal cord, and supra spinal structures which are associated with chronic pain. Loss or dysfunction of peripheral nerves leads to dysfunction of the second order ascending cells of the spinothalamic tract (for example). When an insulted peripheral nerve dies, there is a loss of afferent input, leading to “deafferent hypersensitivity” in second order cells.

In case F generic 500 mg panmycin with amex, provider staff had little contact with buy panmycin 500mg free shipping, or even knowledge of, the ACO concept that was being developed within an innovative and highly collaborative strategic arena. 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 77 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. CROSS-CASE FINDINGS AND COMPARISONS Factors shaping clinical leadership Tables 6–8 summarise what was has been achieved through the exercise of clinical leadership across the three arenas in our eight cases, dividing them into the same two groups as above. The tables summarise the factors that were found to help or hinder forms of clinical leadership capable of bringing about service innovations. We have already seen that the coherence of implementation of service redesign was greater in the four cases in Table 5, and this is reflected in the specificity of the achievements documented. The achievements shown emphasise service outcomes, whereas those in Table 6 mostly emphasise service arrangements that have yet to deliver improved outcomes. However, Tables 5 and 6 emphasise that both groups of four cases involved clinicians grappling with both favourable and unfavourable conditions as they engaged with the challenges of service redesign. TABLE 6 Cases demonstrating less consistent relationships between arenas of clinical leadership Case study: clinical leadership activities Case F: towards an Case D: system and Case E1: redesigning Case E2: redesigning accountable managed Arena multilevel redesign integrated care urgent care care organisation Strategic Six CCGs working GPs in formal lead roles CCG establishes review Devolved locality plans commissioning together across a shape aspirations for of urgent-care services, for city-wide integration and budget county to address integrated care service given inconsistent of health and social care holding existing poor redesign across a formal facilities and services under development, performance and collaboration between across its area and with the LA and CCG financial shortfalls. In four CCGs and LAs increasing demand discussing the form of a parallel, finance-led health and social care CCG-level initiatives, ACO with strong influence from NHSE Operational GP federation supports GPs in formal lead roles Clinical leads of a GP Specific collaborative commissioning, establishment of a local shape nature and out-of-hours centre, an projects between CCG monitoring and pilot integrating primary objectives of integrated urgent-care centre, a and LA (e. BCF and evaluation care across practices care programme, and walk-in centre, A&E and Warm Homes scheme), with community communicate these to GP extended hours where health funds services, with support GP community explore models for contribute to improving from NHSE rather than consistent access to homes and advising the CCGs urgent care residents Operational GP practice-led GPs in practice Working party of GPs GPs and acute providers delivery and initiatives for sharing networks call for more and acute A&E clinicians involved in specific and shaping of capacity across a locality focus on operational agree on telephone relatively narrow scope practice and integrating with detail and education of access as first point of improvements to existing community services and different staff groups. As yet, little community hospitals Community services working party designs engagement or run by primary care struggle to understand protocols. Some GPs involvement in the staff, supported by GP the new models of continue to advocate conception of the ACO federation and to an integrated care extended-hour GP extent by CCGs services as first port of call 78 NIHR Journals Library www. The first key enabler concerns the nature of the clinical leadership itself – in the sense of what it is that clinicians see themselves as providing leadership about. Throughout all of our cases, clinical leadership can be seen as closely bound to aspirations to improve health outcomes and the experience of patients. Variously the benefits being sought include: l improving the quality and consistency of primary care, thereby decreasing the burden on acute care l improving understanding of patient preferences and needs, and communication between service providers and patients l achieving simpler patient journeys and better integration of care both within the health service and with other partners l improving efficiency and reducing wasted resources l improving system resilience and delivery. 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 79 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. CROSS-CASE FINDINGS AND COMPARISONS TABLE 8 Factors affecting the exercise of clinical leadership in less integrated cases Case study: clinical leadership activities Achievements, facilitating Case F: towards an factors and Case D: system and Case E1: redesigning Case E2: redesigning accountable managed challenges multilevel redesign integrated care urgent care care organisation Key Primary care networks, Large-scale programme Principle of first-line Productive relationship achievements integrating GP practices for integrated care, with access to urgent care by with LA, including 800 with some specialist services to support telephone agreed homes benefiting from clinics, have emerged in self-care, care Warm Homes scheme, a few localities co-ordination and attracting £1M external appropriate discharge investment; well from hospital. Clearly positioned in reputation argued and widely and relationship terms disseminated strategic for the emerging new rationale for this structures at regional level Factors Some GPs have history Shared history among Clinicians in various Established partnership facilitating of collaborating to GPs of collaborating to services have previous at senior level between clinical lead address issues arising improve health of a experience of defending GP chairperson and from poor performance disadvantaged locality; the future of their strategic manager; of local acute sector culture of independence services while responding established collaboration from national NHS to the need for between CCG, LA and direction; good relations rationalisation and other public agencies between GPs and acute integration sector clinicians Challenges CCG clinical leads Lack of understanding Some providers involved Clarifying the scope, facing clinical experience at practice level of how are reluctant to move a boundaries and leadership disempowerment in new models of care service model where governance mechanisms terms of influencing should function; some their service would no for an ACO covering emerging service confusion as a result of longer be first point of primary care and models, squeezed multiple initiatives call. Concerns for the community services; between initiatives coming from highly future viability of some bringing operational emerging from GP committed and services are not fully clinical leadership into practice grouping and ambitious strategic addressed implementation of the larger-scale STPs leaders ACO Such benefits provide the core of a set of values that clinicians in both commissioning and providing roles have used to spread awareness of and commitment to new models of service provision. When this happens, it is also more likely to be influential within the operational delivery arenas. More generally, a convincing moral ethos can itself serve as a mechanism for binding together the inter-related leadership work that needs to take place within each of the three arenas we have identified. A second key feature of effective leadership for service innovation was a recognition, by those involved, that there are likely to be successive rounds of defining the nature of the new services and the skills involved. This defining work often involves rethinking the interfaces between previously overdefined and separate services that have become established under a contract-driven and somewhat adversarial model of commissioning. It also requires an interplay over time between the arenas of operational commissioning and operational delivery, as the requirements and performance potential of new service models become clearer. This sort of progressive defining and refining of service models, with clinical input on both the commissioning and provider side, is more likely to occur effectively under pilot arrangements, where competitive, market-driven aspects of commissioning are put in abeyance for a period or where system-driven co-production is emphasised (as in case F). More generally, our cases suggest that achieving effective clinical input requires commissioners to find ways of providing reassurance that they understand 80 NIHR Journals Library www. Issues of continued viability of particular provider organisations may need to be faced, but this is more likely to be done effectively if commissioners join providers in thinking through what a viable future might look like for them.