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Frequently order cialis soft 20mg with visa, a fam ily history of am yloidosis was not 1 1 1 2 1 1 3 4 obtained until after am yloidosis was diagnosed discount cialis soft 20mg overnight delivery. M ore than 50 3 2 transthyretin m utations have been recognized cialis soft 20 mg low cost. Late onset may CLASSIFICATION OF FAM ILIAL AM YLOIDOSIS occur with the development of symptoms in the seventh or eighth decade of life. The nephropathic form is most often caused by familial M editerranean fever. This form affects persons of M editerranean descent and is characterized by recurrent episodes of fever and abdomi- Classification Major protein component nal pain that begin in childhood. Neuropathic: Portugal, Japan, Sweden, Transthyretin (prealbumin) Familial amyloidosis involving the kidneys has been reported by and other countries Ostertag and others [20–22]. Families with apolipoprotein A1 Cardiopathic: Denmark and Appalachia Transthyretin (prealbumin) mutation, as well as mutations in the fibrinogen -chain gene, have in the United States been recognized. On presentation, patients with renal involvement Nephropathic: familial Mediterranean Protein A exhibit hypertension and mild renal insufficiency that progresses to end- fever stage renal failure. The amyloid deposits have mutations in the fibrino- gen -chain gene. No peripheral neuropathy develops, and the onset of renal disease occurs in the fifth to seventh decades of life. The mutation consists of the substi- FIGURE 3-47 tution of glutamic acid for valine at position 526 of the fibrinogen Classification of familial amyloidosis. A mutation in fibrinogen has been described at position 554 can be classified most easily as neuropathic, cardiopathic, or nephro- [23,24]. A rare form of inherited secondary amyloidosis produces pathic. The neuropathic form is characterized by a sensorimotor nephropathy, deafness, and urticaria. This form has been referred to as peripheral neuropathy beginning in the lower extremities. The duration of dialy- with dialysis-associated am yloidosis. Long-term hem odialysis sis is directly associated with the incidence of amyloidosis. Dialysis- often results in carpal tunnel syndrom e with pain involving associated amyloidosis will develop in more than 80% of patients the shoulders, hands, wrists, hips, and knees. It occurs with both hemodialysis and peri- cies are com m on in the carpal bones. Sherman ince its inception, hemodialysis has been bedeviled by problems of vascular access. Vascular access complications remain the single leading cause of hos- pitalization and expense for dialysis patients. Some, such as infected access sites, are potentially life threatening. Despite the advances made in hemodialysis technology, the same vascular access problems that plagued dialysis pioneers continue today to confound patient care teams. The creation of optimal vascular access requires an integrated approach among patient, nephrologist, and surgeon. The preoperative evaluation includes a thorough history History Physical examination and physical examination. A history of arterial and venous line place- ments should be sought. The upper extremities are examined for Surgical cutdown Asymmetry of pulse edema and asymmetry of pulse and blood pressure. Access should be Multiple peripheral catheters Asymmetry of blood pressure placed at the wrist only after it is verified that the radial artery is not Peripherally inserted central catheter Abnormal capillary refill the dominant arterial conduit to the hand. The classic study is the line placement Abnormal Allen test Allen test, in which an observer compresses both the radial and ulnar Transvenous pacemaker Presence of surgical or other scars arteries, has the patient exercise the hand by opening and closing to Axillary dissection cause blanching, then releases one vessel to be certain that the fingers Intravenous drug use become perfused. An alternative, and perhaps more precise, test is to Obesity verify by Doppler imaging that flow to all digits is maintained despite Peripheral vascular disease occlusion of the radial artery. If indicated, vascular imaging studies should be used to delineate the vascular anatomy and rule out arterial Atherosclerotic disease or venous disease. Clinically silent stenosis involving the central veins is becoming increasingly common with the improved survival of criti- cally ill patients for whom central vein catheters are commonplace. FIGURE 5-2 Creation of a Brescia-Cim ino (radial-cephalic) fistula. The native vein arteriovenous fistula is the preferred choice for hem odialysis access. This sim ple and effective procedure, in which an artery is connected to an adjacent vein to provide a large volum e of blood flow into the superficial venous system , has becom e less com m on in recent years. The ideal artery has m inim al wall calcification, so that dilation can occur with tim e and allow unim peded flow. In addition, the artery should not be affected by proxim al stenosis, the m ost com m on site being an ostial lesion in the subclavian artery. Ideally, the outflow vein is subjected to m inim al dissection or m anipulation during the surgical procedure. Forcible distension of veins and rough handling of arteries leads to form ation of neointim al fibrous hyperplasia and localized stenosis. The first autogenous access site described was radial-cephalic at the level of the radial styloid process. These can be constructed end- vein to side-artery, A and B, or side-to-side, C, between the two ves- sels. The exposure is conveniently obtained using a transverse inci- sion at the wrist, just proxim al to the radial styloid process, where the artery and cephalic vein lie close to one another. In general, the two vessels are just far enough apart so that an end-to-side tech- nique is best. W hen the vessels overlie each other, som e surgeons prefer the side-to-side technique, which allows reversal of blood flow into the dorsum of the hand and then via collaterals into the forearm , theoretically leading to better flow volum e over tim e. Additionally, such accesses have low rates of throm bosis and infection. The photograph shows a m ature Brescia-Cim ino fistula in a patient with longstanding diabetes. They do, however, becom e obvious targets for the dialysis technical staff, who have a tendency to puncture them repeatedly rather than to utilize new needle insertion sites. The patients arm also dem on- strates m arked m uscle atrophy secondary to advanced diabetic neu- ropathy, which particularly involves the thenar em inence and the FIGURE 5-3 interosseus m uscle groups. Com plaints of weakness and loss of The Brescia-Cim ino (radial-cephalic) fistula. The radial-cephalic fis- grip strength in the arm are com m on and m ay represent sym ptom s tula offers m any advantages. In this case, however, the sym ptom s are due to the intrin- m ore proxim al vessels for future access construction. The lower sic loss of m uscle m ass, rather than to steal. If a radial-cephalic vein fistula cannot be constructed, the next best choice for vascular access is the brachial-cephalic vein fistula. Accesses that utilize the brachial artery have the advantage of higher blood flow rates than those that use the radial artery. Although this m ay im prove the efficiency of hem odialysis, it is also associated with increased risk of arm edem a and steal. A, The native anatom y of the ante- cubital veins som ewhat resem bles the letter M. The m edial volar venous flow enters the basilic system ; lateral volar flow enters the cephalic system ; and the central connector, which includes a deep tributary, connects the brachial (venae com itantes) system at the brachial artery bifurcation. To create an antecu- bital autogenous site, there are two general approaches; the surgeon either m obilizes the cephalic vein directly into the brachial artery (C) or “anastom oses” the deep connector between the m edian antecubital vein and the brachial veins directly to the adjacent artery.

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Process evaluation of complex interventions: Medical Research Council guidance 20 mg cialis soft overnight delivery. Chronic disease management: what will it take to improve care for chronic illness? Barriers to service use for postpartum depression symptoms among low-income ethnic minority mothers in the United States 20 mg cialis soft sale. Does the chronic care model serve also as a template for improving prevention? Hoffmann TC order 20mg cialis soft, Glasziou PP, Boutron I, Milne R, Perera R, Moher D, et al. Morse JM, Stern PN, Corbin J, Bowers B, Clarke AE, Charmaz K. Developing Grounded Theory: The Second Generation (Developing Qualitative Inquiry). May C, Murray E, Finch T, Mair F, Treweek SA, Ballini L, et al. Questions asked and answered in pilot and feasibility randomized controlled trials. Bugge C, Williams B, Hagen S, Logan J, Glazener C, Pringle S, et al. A process for Decision-making after Pilot and feasibility Trials (ADePT): development following a feasibility study of a complex intervention for pelvic organ prolapse. 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 83 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. Fellow-Smith E, Moss-Morris R, Tylee A, Fossey M, Cohen A, Nixon T. Investing in Emotional and Psychological Wellbeing for Patients with Long-term Conditions. The Family Nurse Partnership Programme: Information Leaflet. The Cardinal Needs Schedule – a modified version of the MRC Needs for Care Assessment Schedule. CAN: Camberwell Assessment of Need: A Comprehensive Needs Assessment Tool for People with Severe Mental Illness. The development and evaluation of a holistic needs assessment and care planning learning package targeted at cancer nurses in the UK. Building the House of Care for people with long-term conditions: the foundation of the House of Care framework. How Healthcare Professionals in Scotland Develop their Communication Skills, Attitudes and Behaviours. An Independent Report for NHS Education for Scotland. Making it Easy, A Health Literacy Plan for Scotland. How to Score the SF-12 Physical and Mental Health Summary Scales. Boston, MA: The Health Institute, New England Medical Center; 1998. SF12: Stata Module to Validate SF12 Input and Calculate SF12 Version 2 t Scores. It encourages linking with other sectors to more appropriately address these problems for patients and to access alternative types of resources. The PCAM also encourages new ways of working that enhance opportunities for health promotion, even in those with few current health or social problems, to maintain healthy behaviour. This will, hopefully, lead to improved quality of life for patients and better patient/ professional interactions and relationships. Nurses need to be supported in such tasks and, therefore, the PCAM intervention consists of three essential elements: 1. Training in the importance of addressing biopsychosocial needs and the evidence supporting this, as well as training in how to implement the PCAM within the context of LTC management in primary care. The PCAM tool to support systematic assessment of needs based on the domains of: l health and well-being (covering physical health needs, impact of physical health on mental health, lifestyle behaviours, mental well-being) l social environment (covering home safety and stability, daily activities, social networks; financial resources) l health literacy and communication (covering understanding of symptoms, self-care and healthy behaviour, how engaged patient is in discussions). A locally derived resource pack that includes options for signposting or referral to other agencies in response to identified needs. The PCAM training was based upon learning from the Keep Well MECAM study and was informed by How Healthcare Professionals in Scotland Develop Their Communication Skills, Attitudes and Behaviours. 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 85 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. In order to do this: l nurses were asked to provide anonymous case studies l evidence was presented for each of the LTCs under consideration l nurses were asked to share and reflect on the evidence and their case study patients. Each case was discussed in terms of suitability and application of the PCAM tool l nurses were provided with some examples as to how the PCAM items may be introduced and discussed, and then invited to role play l each nurse was encouraged to practice the PCAM with around 10 patients. For the sake of the study, these did not always have to be LTC patients. In order to build experience and confidence, it was suggested that they begin with just a few domains. They should reflect on each experience and discuss with colleagues as required l a researcher was attached to the practice and provided support in one additional face-to-face session, online and by telephone. In addition, the nursing team were provided with: l hard copies of the presentation slides l a copy of Making it Easy, a Health Literacy Plan for Scotland64 l a copy of Good Mental Health For All. However, after the first session it became apparent that nurses: l would be unlikely to be able to dedicate a full unbroken half-day l may benefit from focusing the evidence further on their own experience l may benefit from time to reflect on the evidence and the PCAM introduction, and some distance in time before trying to integrate it into their practice. In order to respond to this, the training was adapted over the course of the study: l advance creation and sending of three case studies each l 2. An additional two sections comprised information relating to: 1. Within each section, information comprised national resources [e. 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 87 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. APPENDIX 1 Information about each resource comprised: l name of resource (e. Each section was printed on plain white paper and placed together in clip file with a front index for ease of use. To make the pack usable for nurses, the lists of resources were not exhaustive, but were targeted. In addition, the low-technology approach was somewhat influenced by the feasibility nature of the research, but was appreciated by nurses. Copies of example resource packs are available on request from: pcam@stir. However, the support of a PM was helpful in some circumstances for enabling scheduling of time for training. Item 5: who provided each aspect of the intervention? Training was delivered by the research team, led by Carina Hibberd (who developed the training resources for the Keep Well study as well as the adapted training for this study in collaboration with RP). Carina Hibberd has a PhD in biological sciences, in exploring and understanding the links between physical and emotional responses. Each session was delivered by Carina Hibberd and another researcher (EC or PA, both of whom had received 5 hours of training, in a train-the-trainer model, from Carina Hibberd). Training covered use of the PCAM tool and nurses received copies of the PCAM at this stage. Patricia Aitchison developed the bespoke resource packs for each practice; however, these were then reviewed by local PMs and PNs who were encouraged to add and amend these resources as local knowledge emerged. Patricia Aitchison has been engaged in primary care research for over a decade.

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Second generic cialis soft 20 mg, parents called for research that identified how therapists could best be kept informed about new evidence cheap 20mg cialis soft mastercard, equipment and treatment options buy cialis soft 20 mg overnight delivery. Foundational or underpinning research Professionals identified three main streams of work that can be defined as foundational to, or underpinning, evaluation studies. These were: l understanding of neurodisability l understanding of therapy interventions l defining participation. Understanding of neurodisability Understanding of the conditions and condition trajectories On numerous occasions, a desire for evidence on the long-term outcomes of children with neurodisability, including into adulthood, was voiced. The view was that very little is understood about this group, particularly those with complex needs and acquired brain injury (where understanding of the trajectory of, and potential for, recovery is poorly understood). Such evidence, it was argued, was needed so that therapy interventions could be designed or developed with longer-term outcomes in mind. In addition to body function and structure issues, some interviewees highlighted the importance of research to develop understanding of symptoms such as pain and fatigue (this latter issue was noted particularly for children with acquired brain injury): My first question would be, what is the prevalence of pain? Then, after looking at the prevalence of pain, then looking at strategies to reduce pain, and how pain impacts on participation and quality of life. 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. VIEWS ON RESEARCH PRIORITIES A few interviewees specifically stressed the need for research on the social inclusion of disabled children in mainstream settings. The argument was made that higher-level outcomes (such as inclusion or participation) may not happen simply because wider issues have not been recognised or addressed:... Q2 Understanding the development of children with neurodisability Addressing the lack of understanding of cognitive and motor development in children with neurodisability was also raised as key contextual, or background, evidence gap. For example, a number of interviewees highlighted the lack of understanding about language and communication development in non-verbal children with learning difficulties. This meant that the design of communication systems (e. O2 In addition, some interviewees reported a lack of agreement about whether or not working on some skills can result in improvements, or about what the maximum expected improvement might be. Systems and technologies to support the use of eye-gaze, and therefore to improve eye-gaze skills, for supporting communication was frequently mentioned in relation to this. Understanding therapy interventions Defining new and emerging approaches A few interviewees pondered the implications of goals- and participation-focused approaches, and potential future shifts in their work or focus of activity. Therapy interventions [sometimes] claim to target every outcome at every level of the ICF. But, sometimes you need to spend a bit of time working out what the heck is the intended outcome? And that, to medical leaders, can seem really weird. Or how far should it be [based on] a strong theoretical position? P3 In addition, the need to identify and understand the active ingredients of an intervention – be it with respect to an overall approach, a care pathway, or specific techniques – was frequently raised by study participants as a key research area, and foundational to other research. As already reported, interviewees believed that the active ingredients were multifaceted: In day-to-day practice we see the positive impacts on children, but we need the evidence to demonstrate and quantify this positive impact. M2 We need to understand more about contributing factors. Is it [the technique or approach], or is it motivation, or is it the family environment? Q1 Related to this was the need for systems by which interventions can be specified, or defined, in order to allow the replication of studies. Thus, finding ways to systematically describe the complex and multifaceted nature of therapy interventions was identified by many as a research priority: We have to have a way of describing the intervention in a succinct and manageable way. N2 Some interviewees dwelt on the challenges this presented. So I think that the state of our effectiveness research in therapies is at quite an early stage really. There are some very fundamental issues we need to address before we are able to meaningfully evaluate stuff. L1 TIDieR (Template for Intervention Description and Replication) guidance29 on reporting interventions, and other guidance being specifically written for electronic device interventions,39 was identified as a useful resource and offering a way forward. Interviewees appeared to think that this would vary between interventions and depending on factors such as intervention objectives and child and impairment characteristics. Finally, the measurement of active ingredients was regarded as key element of future research on active ingredients. 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. I2 Two key reasons appeared to underlie the prioritising of research in this area. Second, this meant that therapists had little idea of the impacts of therapy on the everyday lives of children and families. With respect to this, particular reference was made to situations in which parents may be quite intensively involved and/or multiple professionals are working with a family concurrently. One reason for prioritising this was its potential contribution to understanding interventions in terms of mechanisms of action and active ingredients. Another rationale was that it would help to inform ways to approach implementing evidence-based, or evidence-informed, change. Defining participation As reported earlier (see Chapter 7), the notion of participation, although widely accepted, was felt by many participants to be a nebulous, or poorly defined, construct. One issue some participants highlighted was the need to further specify the different aspects of participation: I think to treat participation as a single outcome is a bit crazy. O1 On a slightly different note, some interviewees believed that, for some groups of children (e. These participants prioritised research in that area. There was strong consensus that, in carrying out work on this topic, there needed to be extensive and close work and consultation with parents and children. C1 Some interviewees, when discussing the importance of economic evaluation being nested within outcome evaluations, noted that a holistic approach would need to be taken, and one that could take a long-term view on outcomes (in terms of both child and parent) as well as on what an effective intervention prevents. In addition, some interviewees stressed that any economic evaluation needed to capture or incorporate notions of quality of life, including for those children with the most profound impairments:. Z1 Implementation science was identified by some as a core element of future evaluation research. This included developing an evidence base on effective ways to embed evidence-based, or evidence-informed, practice within therapy teams: How do we train therapists in whatever the active ingredients are that make interventions work, and then how do we implement that within a clinical team in the community? Q1 The problem is getting the research information to the jobbing physiotherapist and their managers. What is needed is to develop some pretty quick ways of telling the troops on the ground this way is better than that. 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 81 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. VIEWS ON RESEARCH PRIORITIES A further issue concerned developing an evidence base on ways to maintain the implementation of proven interventions by others involved in delivering therapies to children with neurodisability, including parents and school staff. We turn now to report the three domains of evaluation research identified by professionals taking part in our study. As noted earlier, these were: l evaluation of overall approaches to therapy interventions l evaluation of service organisation and delivery l evaluation of techniques, procedures and equipment. Evaluation of overall approaches to therapy interventions In Chapter 4 we described the shifts in thinking regarding therapy objectives and ways of working currently taking place across physiotherapy, occupational therapy and speech and language therapy. A number of research priorities were identified relating to the evaluation of these emerging approaches. A number of diverse questions about the overall approach to therapy interventions were identified.

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However discount cialis soft 20 mg amex, several incompatibil- ities have developed between the characteristics of the dopa- The presentation of TD is typical of a dyskinesia cialis soft 20mg fast delivery, with oro- minergic model and the presentation of the disorder (10) cheap cialis soft 20 mg mastercard. The -aminobutyric acid (GABA)–ergic transmission within the movements worsen with stress and concomitant physical basal ganglia has also been targeted as the putative patho- activity and diminish or disappear during sleep. Here, although biochemical char- defining, in that all dyskinesias with their first onset within 6 acteristics between the model and the disease have appeared months of ongoing antipsychotic treatment are diagnosed compatible, therapeutic implications have not been fully as TD (50). Consequently, it is expected that the diagnosis met, possibly because of inadequate pharmacologic tools will be confounded by other categories of dyskinesia, includ- (10). TD is Research has suggested that both these transmitter altera- distinguished from parkinsonism, the other major category tions, dopaminergic and GABAergic, may reflect an action of antipsychotic-induced movements, by being hyperki- of antipsychotic drugs on neuronal activity within the basal netic, with delayed onset and delayed resolution after medi- ganglia thalamocortical motor circuit. Clinically, antipsy- cation discontinuation, and by its contrasting pharma- chotic drug action overall tends to normalize mental status cology. On a cellular basis, gradual alterations produced by these Although TD has a characteristic pharmacology, none of drugs over time, within selected subcortical brain regions the drugs that suppress movements in probe studies are and at selected synapses of this circuit, likely result in TD. Treatment The mechanism of all these clinical actions is thought to approaches for TD are discussed later. Tamminga: Maryland Psychiatric Research Center, University pine, with which reduced risk is probable. Therefore, even of Maryland School of Medicine, Baltimore, Maryland. Woerner: Department of Psychiatry Research, Hillside Hos- though TD may be diminishing as a significant clinical risk pital, Long Island Jewish Health System, Glen Oaks, New York. CUMULATIVE INCIDENCE OF TARDIVE DYSKINESIA Tardive Dyskinesia Persistent Tardive Neuroleptic Cumulative Incidence, Dyskinesia, (85% CI) Tardive Dyskinesia Exposure (y) (95% CI) Cumulative Incidence Hazard Ratea 1. The number represents the average yearly hazard rate over the 5-year block of time. Data from a prospective study of 971 young adult psychiat- Preliminary data suggest that prognosis for TD remission ric patients followed for up to 20years indicated a increasing is better for patients who are treated for shorter times within cumulative incidence rate of TD over the 20-year interval the follow-up period after TD diagnosis and for those (Table 126. The cumulative incidence of persistent TD treated with lower doses of antipsychotic during follow-up was lower but increased proportionally (40). These facts about TD encourage future study in ani- consistent with a declining rate of TD over time, illustrated mals and humans on TD mechanisms and treatment and by the declining hazard rate (Table 126. A similar pattern facilitate the research by providing a firm baseline and a develops in the hazard rates over 20years for persistent TD. A decline in hazard rate over time was also reported by Morganstern and Glazer (46), although their data show a sharper decline after the first 5 years. FUNCTIONAL HUMAN NEUROANATOMY OF Rates of TD are significantly affected by the age and ANTIPSYCHOTIC DRUG ACTION other characteristics of the several samples studied. An in- creased vulnerability to TD associated with increasing age The human central nervous system (CNS) has been the is the most consistently reported finding in TD research. These antipsychotic data are 53% after, 1, 2, and 3 years of antipsychotic drug treatment relevant to TD mechanisms insofar as the localization of (74). In the younger adult sample (40), the can suggest the regions that likely contain the neurochemi- hazard rate for TD was lowest for patients in their twenties cal disorder underlying TD. The firm association between and thirties at study entry, increased for those in their for- striatal dopamine-receptor blockade and antipsychotic drug ties, and sharply increased for those aged 50to 60years. It has been suggested TD risk in the prospective study (Table 126. Alternatively, as argued here, antidopaminergic peaks in dosage of antipsychotic drug (more than 1,000 mg drugs could deliver their antipsychotic action by altering in chlorpromazine equivalents), and intermittent antipsy- activity in neuronal populations within the long-loop feed- chotic treatment. Treatment with lithium is associated with back neurons in the basal ganglia thalamocortical pathways, a lower risk of TD development. The mechanisms responsible for TD may well occur (Table 126. Of these persistent Early investigators observed an elevation of neuronal ac- cases, 68% remitted within the next 2 years. For the half tivity in the human caudate and putamen with antipsy- whose initial episode was transient, there was a high risk chotic drug treatment using functional in vivo imaging (33, (32%) of developing a persistent episode within 1 year of 69). To refine the localization of the signal, our laboratory Chapter 126: Tardive Dyskinesia 1833 FIGURE 126. The regions of color indicate quantitativelythe areas of regional cerebral blood flow (rCBF) activation (ON-30 day OFF) or inhibition (30 dayOFF-ON) with subchronic haloperidol treat- ment (0. In the top two figures, at 04 and 00 mm from the anterior commisure/poste- rior commissure line (ACPC) plane, the basal ganglia show significant rCBF activation with haloperidol. In the bottom two figures, at 04 and 04 mm from the ACPC plane, both the anterior cingulate cortex and the middle frontal cortex show sig- nificant diminished rCBF with halo- peridol. In an animal prepara- using [18F]fluorodeoxyglucose carried out at the end of each tion, Abercrombie and DeBoer demonstrated the principle treatment period (35). Regional cerebral metabolic rates of that a pharmacologic perturbation delivered to a restricted glucose, calculated using the usual analytic techniques, were region in the basal ganglia (e. Haloperidol neurochemical and functional effects (1). The model of significantly activated neuronal activity in the basal ganglia antipsychotic drug action we propose suggests that a pri- (caudate and putamen) and thalamus, whereas the frontal mary effect of dopamine-receptor blockade occurs in the cortex (especially the middle and inferior regions) and the caudate and putamen with antipsychotic drug treatment, anterior cingulate cortex demonstrated a reduction in re- and the transmission of this primary action through the gional cerebral metabolic rates of glucose with haloperidol basal ganglia thalamocortical pathway to limbic and neocor- (Fig. Activational differences between the on-drug tex mediates antipsychotic and motor aspect of the drug and off-drug conditions were surprisingly restricted to these actions in humans. The full mechanism of antidopami- areas, despite the systemic manner of drug delivery and nergic actions therefore could include altered GABAergic steady-state kinetic conditions at testing. The striatal transmission in the globus pallidus (GP), which alters activ- changes had been previously reported (6,68). Subsequent ity in the basal ganglia output nuclei; these changes then evaluation of haloperidol action using regional cerebral modify GABAergic transmission from substantia nigra pars blood flow analysis pharmacodynamically verified these re- reticulata (SNR) to the thalamus, inhibit thalamic nuclei, gional actions. These observations suggest the hypothesis that the whose activity is perturbed by haloperidol, are the same same basal ganglia thalamocortical circuits that mediate 1834 Neuropsychopharmacology: The Fifth Generation of Progress basal ganglia modulatory influence on prefrontal cortex may models of the condition have been developed in nonhuman also mediate the therapeutic effect of antidopaminergic anti- primates and in small animals using long-term administra- psychotic compounds in schizophrenia. We have reasoned tion of antipsychotics and applied to the study of TD mech- that a drug-induced regional change, occurring over time anisms. The structural and functional brain characteristics within this basal ganglia–thalamocortical pathway, associ- of nonhuman primates are reasonably similar to those of ated with a regional increase in the thalamocortical signal human primates; hence, primate preparations may make could be associated with TD. Yet, it is the reality of nonhuman primate models that many treatment years are required for ROLE OF THE BASAL GANGLIA dyskinesia development (2 to 6 years), and monkey care is THALAMOCORTICAL PATHWAY IN involved and expensive. Alternatively, putative rat models MEDIATING AND TRANSMITTING THE have also been proposed; rat oral dyskinesias develop faster ANTIDOPAMINERGIC ACTION IN with chronic treatment (6 to 12 months), yet they retain STRIATUM TO CORTEX many phenomenologic and pharmacologic characteristics of human TD (61,70). These models often provide a more Basal ganglia and thalamic structures modulate functions realistic experimental platform, even if not more valid, than of the frontal cortex through parallel segregated circuits, a the nonhuman primate for developing hypotheses about process that has been most fully studied for motor function. For the Animal models of all human diseases have been sought CNS motor system, specific areas of primary motor cortex, for pursuing pathophysiologic hypotheses and for identify- primary sensory cortex, and supplementary motor cortex ing new therapeutics. Investigators have suggested the char- project topographically to the putamen. These projections acteristics of good animal models for an expressed human are thought to remain segregated but parallel throughout illness as similarities in (a) origin, (b) phenomenology, (c) the full course of the circuit, but they are subject to basal biochemical characteristics, and (d) pharmacology (45,73). Investi- Similarities of these features provide greater validation of gators have proposed a family of these frontal circuits whose the model. Across all the TD models, both primate and pathways originate in specific frontal cortex areas, course rodent, origin and phenomenology approximate character- through the basal ganglia and thalamus, and return to the istics of human TD. Biochemical determinants are un- same areas of cortex, to modulate regional frontal cortical known for the TD models as well as for the disease itself. For the motor system, these subcortical struc- However, extensive similarities exist in pharmacologic re- tures appear to contribute to the planning and execution sponse between the human illness (TD) and the model of body movements; for other frontal systems, these same preparations. Because rodent models are more practical to subcortical structures may contribute to maintenance and pursue, their pharmacology has been more broadly de- switching of behaviors and aspects of cognition (2,26). It would be obvious to The thalamus exerts an excitatory effect on frontal cortex suggest that the use of both rat and monkey models would pyramidal cell activity, partially delivered within each fron- be ideal, as the efficiency and specificity of the questions tal region by the paired parallel segregated circuit. These inhibitory output nuclei Nonhuman Primate Models stimuli are, in turn, regulated by two parallel but opposing pathways from the caudate and putamen, one excitatory Antipsychotic treatment in the nonhuman primate has been and the other inhibitory. The primary cortical signal to basal studied to define the mechanism of acute drug-induced par- ganglia is mediated by an excitatory glutamatergic pathway. It would be rational to suspect some role of these parallel Gunne et al.

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