Interestingly generic finax 1 mg online, stimulation slightly posterior prove all of the cardinal features of parkinsonism and reduce and medial to the VIM—close to the centromedian and the severity of levodopa motor complications (220–222) order 1mg finax amex. Unfortu- but a prospective controlled trial has yet to be performed nately generic 1 mg finax with visa, DBS-VIM does not meaningfully improve the more to objectively compare these two targets. This shortcoming has led to consideration of other targets for DBS, such as the GPi and the STN (see General Adverse Effects of DBS below). DBS-VIM remains a very valuable procedure for PD patients for whom tremor is the main handicap. Adverse effects of DBS can be related to the surgical proce- dure, the device, and the stimulation itself. Surgical compli- cations involve hemorrhage and infarction and occur in less Deep Brain Stimulation of the Subthalamic than 3% of cases. The electrode itself does not seem to be Nucleus (DBS-STN) toxic to local tissues, as in the only postmortem pathologic A large body of experimental evidence has pointed toward study available, gliosis around the electrode tip was less than targeting the STN as a treatment for PD: (a) neurons in 1 mm in diameter (223). Problems associated with the im- the STN are hyperactive in PD (203,211); (b) lesions of planted material (infection, dislodgment, mechanical dys- the STN provide benefit to MPTP-treated primates (204, function) occur in 1% to 3% of cases and may lead to the 205); (c) improvement in contralateral parkinsonism fol- need to replace the electrode. Stimulation-related side ef- lowing a spontaneous hemorrhage into the STN of a PD fects include paresthesiae, motor twitch, dysarthria, and eye patient (212); and (d) improvement in MPTP-treated mon- movement disorders. They are usually transient and control- keys following stimulation of the STN (213). Finally, the battery has lim- findings, DBS-STN was introduced as a treatment for PD ited longevity, ranging from 6 months to 5 years or more, patients (214–216). The battery in the chest wall can be easily (233–238). Results were somewhat inconsistent among the replaced under local anesthesia in most cases. In one study using a predeter- the risk of permanent side effects is less than with ablative mined transplant protocol, six PD patients who could not procedures, particularly when bilateral with procedures be improved with medical management experienced signifi- (224). The variability in Management of DBS clinical response in the different centers may have related Optimization of stimulator settings is necessary to achieve to the use of different transplant variables (e. This is not an easy method of tissue storage, target site for transplant, volume task because of the large number of stimulation variables. In trials documenting clinical ben- width, and frequency. Determination of the optimal stimu- efit, striatal fluorodopa uptake on PET demonstrated a sig- lation settings may be complicated and time consuming nificant and progressive increase in striatal fluorodopa (hours) and may require multiple visits. Benefits on PET correlated with im- rapid and simple method for determining stimulator adjust- provement in motor scores (238,241). Postmortem studies ment will enhance the utilization of these techniques. These studies demonstrated ro- this cannot otherwise be attained with medical therapy. Fur- bust survival of implanted neurons and reinnervation of the ther, this can be accomplished without the need to make a striatum in an organotypic fashion (242). In this study, destructive brain lesion with its accompanying side effects. Nevertheless, studies performed to Following these open studies, two prospective random- date indicate that this procedure has much to offer patients ized double-blind placebo-controlled trials have been initi- with advanced PD. STN appears to provide the best clinical effects and is pres- Two donors per side were implanted into the caudate and ently considered to be the stimulation target of choice. It putamen bilaterally, without immunosuppression (244). However, significant improvement in UPDRS superior in the future. The second study is a 2-year study that compares bilateral transplantation into the postcommissural putamen Transplantation Procedures with one versus four donors per side (174). Immunosup- Yet another approach to the treatment of patients with ad- pression with cyclosporine was employed in this study. The vanced PD is transplantation of dopaminergic neurons study is still ongoing and will terminate in 2001. Transplantation is a rational strategy plant procedures. In general, the procedure has been well for treating PD because (a) PD is due to specific degenera- tolerated, especially when performed in major university tion of dopaminergic nigrostriatal neurons and its symp- centers. There is one report of a death due to obstructive toms are dramatically relieved by dopaminergic treatment; hydrocephalus caused by graft migration into the 4th ventri- and (b) the striatum, which is denervated in PD, is a well- cle. Postmortem study revealed that the migrated tissue was defined target for transplantation (225). In animal models, composed of nonneural tissue containing bone, cartilage, fetal nigral neurons have been shown to survive, reinnervate hair, and epithelium (243). This study illustrates the impor- the striatum, produce dopamine, and improve motor dys- tance of developing experience in transplant biology and function in rodent and primate models of PD (226–229). There has also been a report in abstract tion of adrenal medullary cells into the caudate nucleus, but form of new-onset disabling dyskinesia that persists even despite the initial encouraging reports (230), the inconsis- when levodopa is withdrawn for prolonged periods of time tent outcomes and the associated adverse events led to this (245). The frequency, clinical significance, and basis for procedure being abandoned (231,232). Human fetal nigral this problem remain unknown, but clearly warrant further grafts provide more potent results in animal models (225), investigation. Glutamate antagonists have already been agents, and trophic factors, or modifications in the type of shown to have antidyskinetic effects in some PD patients donors, the amount of cells transplanted, and the site of (133–135), but they are complicated by mental side effects transplantation may all enhance transplant benefits. However, other agents such as alternate sources of dopaminergic tissues will have to be riluzole that inhibit sodium channels and impair glutamate found to avoid the societal and logistical problems associ- release have also been reported to improve dyskinesia and ated with the use of fetal human tissue. The adenosine A2A receptor is fetal porcine nigral cells has been shown to provide some localized to striatal cholinergic interneurons, and antago- clinical benefit and postmortem cell survival (246), and a nists to the adenosine A2A receptor have been shown to prospective double-blind clinical trial is ongoing. Other ex- increase motor activity in rodent and primate models of perimental approaches to repopulating the basal ganglia PD, without provoking a dyskinetic response, even when with dopaminergic cells include the use of stem cells and administered to levodopa-primed animals (251,252). The concept of restoring dopaminergic in- cal trials of this agent are currently under way. Nicotine nervation to the basal ganglia is appealing, and to some receptors are present on terminals of nigrostriatal neurons, extent it is now clear that this can be accomplished. For and their stimulation has been shown to increase dopamine the present, however, transplant therapies must still be con- release in the rat nucleus accumbens (253). This may ac- sidered experimental and not a practical option for PD pa- count for why cigarette smoking is addictive, and why there tients outside of research trials. In MPTP-treated primates, nicotine has no effect on the basal motor disability or on levodopa-induced dyskine- sia, but muscarinic agonists and antagonists did influence FUTURE RESEARCH DIRECTIONS levodopa-induced dyskinesia (255,256). Symptomatic Therapies: Nondopaminergic Agents Restorative Therapies Despite the advances in the therapeutics of PD, patients continue to experience parkinsonian disability and disabling The threshold for developing levodopa-induced dyskinesias motor complications. New treatment strategies aimed at appears to depend on the degree of denervation of the SNc providing more continuous dopaminergic stimulation to (42,257). This has led to the hypothesis that increasing the prevent motor complications and surgical approaches to number of dopaminergic terminals might better regulate ameliorate them represent major advances.

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However finax 1mg visa, (publications or numbers of researchers per they have evolved largely from setting research capita) by a factor of 50 buy finax 1 mg amex. However generic finax 1 mg overnight delivery, the current priorities for selected health topics (Box 4. How then can nations research, across all aspects of health, have not develop the capacity to exploit the full potential usually been well documented, and there is little of health research? Setting priorities for research on selected health topics The majority of priority-setting exercises in health research have focused on specific topics. They have typically been carried out from the perspective of different thematic groups within the research community rather than being initiated by national governments. A selection of examples is listed in the table below. Priority-setting for research on specifc topics Health topic Focus Preterm births and stillbirths Community level (18) Birth asphyxia Reducing mortality (19) Childhood pneumonia Reducing mortality (20) Childhood diarrhoea Reducing mortality (21) Child health South Africa (22) Mental health Low- and middle-income countries (23) Mental health and psychosocial support Humanitarian settings (24) Tuberculosis From R&D to operational research (25–28) Malaria Eradication: drugs (29) Malaria Eradication: health systems and operational research (30) Leishmaniasis Middle East and North Africa (31) Leishmaniasis Vaccines (32) Chagas disease, human African trypanosomiasis and Diagnostics, drugs, vaccines, vector control and health leishmaniasis systems (33) Neglected infectious diseases Latin America and the Caribbean (34) Helminth infections Epidemiology and interventions against all major human helminths (35) Zoonoses and infections of marginalized human Epidemiology and interventions; research within and populations beyond the health sector (36) Noncommunicable diseases Low- and middle-income countries (37) Human resources for health Low- and middle-income countries (38) Health systems fnancing “Developing” countries (39) Research and development for a national health service Interface between primary and secondary care in the United Kingdom (40) Equity and health Social determinants of health (41) R&D, research and development. A framework for by the ESSENCE on Health Research initiative. But here it means the abili- vide enabling mechanisms to address needs and ties of individuals, institutions and networks, priorities within national strategies on research nationally and internationally, to undertake and for health. Te principles are as follows (5): disseminate research fndings of the highest qual- ■ Participation and alignment – a common ity (7). Te general principles have been framed efort of funders and local partners is 99 Research for universal health coverage Box 4. Setting priorities for research in Brazil Since 2000, the Brazilian government has made health research a national priority (44). Public resources have been used for fundamental and translational research (see definitions in Box 2. The fair allocation of research funds has been guided by six objec- tives, namely: (i) to improve population health, (ii) to overcome inequity and discrimination, (iii) to respect life and dignity, (iv) to ensure high ethical standards in research, (v) to respect methodological and philosophical plurality, and (vi) to ensure social inclusion, environmental protection and sustainability. Most funds were allocated to the “industrial health complex” (biotechnology, equipment and materials, health and technology service providers), to clinical research and to communicable diseases. Health technology assessment includes specifc research studies, systematic reviews and economic evaluations. Some 4000 research grants were awarded during this period, and around US$ 545 million were invested in health research across the country by 2010. The south-east region (including Rio de Janeiro and Sao Paulo) carried out 40% of all projects and received 60% of funds. The research has helped to improve treatments, prevention and diagnoses, to develop new products and services, and to strengthen the patient-oriented health-care system (44). AIDS, acquired immunodefciency syndrome; HIV, human immunodefciency virus; MDGs, Millennium Development Goals. The role of health ministries in developing research capacity: the examples of Guinea Bissau and Paraguay The Guinea Bissau health research system has evolved under the strong influence of international donors and technical partners who have provided funds and scientific expertise (51). Research has been carried out chiefly by the Bandim Health Project, the National Laboratory for Public Health, the Department of Epidemiology and the Instituto Nacional de Estudos e Pesquisa (INEP) which is oriented to the social sciences. Research priorities have been set largely by expatriate researchers and have focused on understanding and reducing child mortality. Recognizing the need to set national research priorities, align funding, build local research capacity and link research to decision-making, the Ministry of Health established the National Institute of Public Health (INASA) in 2010. External technical support is led by the West African Health Organisation (WAHO), which works in partnership with the Council on Health Research for Development (COHRED) and the International Development Research Centre (IDRC). The commitment of the Ministry of Health to invest in research has been central to success. The main challenges facing Guinea Bissau are the limited number of skilled researchers and dependence on foreign assistance. Paraguay has a stronger research base than Guinea Bissau, with more staff and institutions engaged in health research. In 2007, therefore, the Ministry of Health formed a new directorate for research and in 2009 set up an inter-institutional committee to create a framework for health research. The committee included the Minister of Education and representatives of UNICEF and the Pan American Health Organization. Drawing on the experience of other countries, and especially Mexico, the commit- tee drafted a government policy on research for health and set up the first National Council of Research for Health. As part of the drive to improve health research, all research institutions in the country are under evaluation. An online database of researchers has been created, and only registered researchers are eligible for funding from the Council of Science and Technology. The database provides information about the training of researchers, their experience, and current research topics. The intention is to manage dedicated funding through a health research trust and to allocate these funds transparently on merit. As in Guinea Bissau, the support of the Minister of Health backed by the President of Paraguay has been a key factor in the development of a national health research system. Examples of eforts to build research capacity, ranging from individual to global movements Supranational health research bodies National health research systems Organizational development Institutional development National health research councils Individual training WHO / TDR US NIH Wellcome Trust TDR, Special Programme for Research and Training in Tropical Diseases; US NIH, United States National Institutes for Health. Adapted, by permission of the publisher, from Lansang & Dennis (52). Te decision to build and strengthen research any setting depends on the strategic vision for capacity, and to allocate the necessary funds, is the research and what is needed from research. Tus the Task Force on Malaria Research include a skilled and self-confdent workforce Capability Strengthening in Africa is part of the with strong leadership, adequate funding with Multilateral Initiative on Malaria, which is coor- transparent and accountable methods for allo- dinated by the Special Programme for Research cating funds, and well equipped research institu- and Training in Tropical Diseases (TDR). Views also difer on the emphasis to be placed One framework for capacity-building, on, for example, building elite institutions, cre- which has the ingredients of many others, is ating international networks, boosting transla- represented in Fig. A framework to guide capacity-building, highlighting approaches and targets, the likelihood of sustainability, and the research focus Entity targeted Approach to capacity strengthening Graduate or Learning Institutional partnerships Centres of postgraduate training by doing between countries excellence Individuala +++ + ++ + Institution +++ ++ +++ +++ Network ++ ++ +++ ++ National level + ++ ++ +++ Supranational level ++ +++ ++ Financial investmentb ++ + +++ +++ Research focus Research skills Programme, policy, systems development Likelihood of + +++ sustainabilityc a Plus (+) signs indicate the entity is targeted + sometimes, ++ often, +++ frequently. Reproduced, by permission of the publisher, from Lansang & Dennis (52). For instance, of activities mattered more during the expan- graduate and postgraduate training are more sion stage. Funding for core activities and local likely to be efective when the host institutions management were vital during the consolidation are also strong (Table 4. From the outset, any programme to Te following sections look more closely at strengthen research capacity must defne, moni- three elements of capacity that are universally tor and evaluate success – an area in which important: building the research workforce, knowledge is still sparse (52, 53, 58–60). A simple tracking fnancial fows, and developing institu- geographical mapping of research activity can be tions and networks. One evalu- Creating and retaining a ation examined which indicators of research skilled research workforce capacity were most useful in four diferent set- tings: evidence-based health care in Ghana, The world health report 2006 − working together HIV voluntary counselling and testing services for health highlighted the critical role, and the in Kenya, poverty as a determinant of access to chronic shortage, of health workers, especially TB services in Malawi, and the promotion of in low-income countries (62). Here the vital community health in the Democratic Republic contribution made by health researchers as of the Congo (6). Te most expedient indicators part of the health workforce is underscored changed as programmes matured. Geographical distribution of research capacity in Africa Research output (Number of articles per city) 31–99 100–249 250–499 500–999 >1000 R&D, research and development. Note: Mapping of top 40 African cities by research output shows hotspots and coldspots of R&D activity and highlights inequi- ties in R&D productivity across the continent.

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