| 1. |
- Bengzon, J, et al.
(författare)
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Regulation of neurotrophin and trkA, trkB and trkC tyrosine kinase receptor messenger RNA expression in kindling
- 1993
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Ingår i: Neuroscience. - 0306-4522. ; 53:2, s. 433-446
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Tidskriftsartikel (refereegranskat)abstract
- Levels of messenger RNA for nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and the tyrosine kinase receptors trkA, trkB and trkC have been studied using in situ hybridization in the rat brain 2 h and four weeks after kindling-induced seizures. Epileptiform activity evoked by hippocampal stimulation and exceeding 70 s lead to a concomitant and transient increase of brain- derived neurotrophic factor, nerve growth factor, trkB and trkC messenger RNA expression in dentate granule cells after both focal and generalized seizures. Brain-derived neurotrophic factor messenger RNA levels were also increased bilaterally in the CA1-CA3 regions, amygdala and the piriform, entorhinal, perirhinal, retrosplenial and temporal cortices after generalized seizures. The magnitude of the increases was similar throughout the development of kindling and in the fully kindled brain. No changes of trkA messenger RNA were observed. In amygdalar kindling, elevated brain-derived neurotrophic factor messenger RNA levels developed more rapidly in the amygdala-piriform cortex than after stimulation in the hippocampus but changes in the hippocampal formation were only seen in few animals. Intraventricular 6-hydroxydopamine or a bilateral fimbria-fornix lesion did not alter basal expression or seizure-evoked changes in messenger RNA levels for neurotrophins or trk receptors but increased the number of animals exhibiting elevated levels after the first stimulation, probably due to a prolongation of seizure activity. Both in sham-operated and fimbria-fornix-lesioned rats seizure activity caused a marked reduction of neurotrophin-3 messenger RNA levels in dentate granule cells. The results indicate that activation of the brain-derived neurotrophic factor gene, at least in dentate granule cells, is an "all-or-none" type of response and dependent on the duration but not the severity of seizures or the stage of kindling epileptogenesis. Changes in brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 and trkB and trkC were observed concomitantly in the dentate gyrus, which suggests that seizure activity sets in motion a cascade of genomic events possibly mediated via a common mechanism. Since altered messenger RNA levels outside hippocampus were detected only for brain-derived neurotrophic factor, neurotrophin and trk gene expression in these regions seems to be regulated differently.
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| 2. |
- Brundin, P, et al.
(författare)
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Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson's disease
- 1986
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Ingår i: Experimental Brain Research. - 0014-4819. ; 65:1, s. 40-235
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Tidskriftsartikel (refereegranskat)abstract
- The ventral mesencephalon, containing the developing dopaminergic neurons of the substantia nigra-ventral tegmental region, was obtained from aborted human fetuses of 9-19 weeks of gestation. The tissue was grafted into the striatum of rats previously subjected to a 6-hydroxydopamine lesion of the mesostriatal dopamine pathway. The graft recipients were immunosuppressed by daily injections of Cyclosporin A. Amphetamine-induced motor asymmetry was reduced, and finally totally reversed, only in rats receiving grafts from the 9-week old fetal donor. The fluorescence microscopic analysis revealed large numbers of surviving dopamine neurons, and extensive fiber outgrowth into the host striatum, in these rats. By contrast, rats receiving grafts from 11-19 week old donors had at most only few surviving dopamine neurons. These results indicate that human fetal mesencephalic tissue may be an efficient source of dopamine neurons for functional intracerebral grafting in patients with Parkinson's disease.
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| 3. |
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| 4. |
- Brundin, Patrik, et al.
(författare)
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Human fetal dopamine neurons grafted in a rat model of Parkinson's disease : immunological aspects, spontaneous and drug-induced behaviour, and dopamine release
- 1988
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Ingår i: Experimental Brain Research. - 0014-4819. ; 70:1, s. 192-208
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Tidskriftsartikel (refereegranskat)abstract
- We have used a rat model of Parkinson's disease (PD) to address issues of importance for a future clinical application of dopamine (DA) neuron grafting in patients with PD. Human mesencephalic DA neurons, obtained from 6.5-8 week old fetuses, were found to survive intracerebral cell suspension xenografting to the striatum of rats immunosuppressed with Cyclosporin A. The grafts produced an extensive new DA-containing terminal network in the previously denervated caudate-putamen, and they normalized amphetamine-induced, apomorphine-induced and spontaneous motor asymmetry in rats with unilateral lesions of the mesostriatal DA pathway. Grafts from an 11.5-week old donor exhibited a lower survival rate and smaller functional effects. As assessed with the intracerebral dialysis technique the grafted DA neurons were found to restore spontaneous DA release in the reinnervated host striatum to normal levels. The neurons responded with large increases in extracellular striatal DA levels after the intrastriatal administration of the DA-releasing agent d-amphetamine and the DA-reuptake blocker nomifensine, although not to the same extent as seen in striata with an intact mesostriatal DA system. DA fiber outgrowth from the grafts was dependent on the localization of the graft tissue. Thus, grafts located within the striatum gave rise to an extensive axonal network throughout the whole host striatum, whereas grafted DA neurons localized in the neocortex had their outgrowing fibers confined within the grafts themselves. In contrast to the good graft survival and behavioural effects obtained in immunosuppressed rats, there was no survival, or behavioural effects, of human DA neurons implanted in rats that did not receive immunosuppression. In addition, we found that all the graft recipients were immunized, having formed antibodies against antigens present on human T-cells. This supports the notion that the human neurons grafted to the non-immunosuppressed rats underwent immunological rejection. Based on an estimation of the survival rate and extent of fiber outgrowth from the grafted human fetal DA neurons, we suggest that DA neurons that can be obtained from one fetus may be sufficient to restore significant DA neurotransmission unilaterally, in one putamen, in an immunosuppressed PD patient.
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| 5. |
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| 6. |
- Kalén, P, et al.
(författare)
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Intracerebral microdialysis as a tool to monitor transmitter release from grafted cholinergic and monoaminergic neurons
- 1990
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Ingår i: Journal of Neuroscience Methods. - 0165-0270. ; 34:1-3, s. 15-107
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Tidskriftsartikel (refereegranskat)abstract
- In the present study the microdialysis technique has been used as a tool for the study of functional regulation of intracerebrally grafted cholinergic and monoaminergic neurons as well as for the analysis of graft-host interactions. Fetal noradrenergic, serotonergic, dopaminergic, and cholinergic neurons were transplanted into the hippocampus or striatum previously denervated of their intrinsic monoaminergic or cholinergic afferents. After a few months survival, when the grafts had reinnervated the surrounding target, dialysis probes were implanted into the graft-reinnervated region. Although the graft-derived fiber and terminal density varied substantially from one animal to another the transmitters in the extracellular space were maintained at near-normal levels, not only under baseline conditions, but also during K(+)-induced depolarization, transmitter-selective uptake blockade, and tetrodotoxin. This suggests that the grafted neurons possess efficient autoregulatory properties despite their ectopic location. The results also show that monoamine release in the graft-reinnervated host target is impulse-dependent, and that the neurons are spontaneously functionally active at the synaptic level. Electrical stimulation of the lateral habenula (which has previously been identified as a powerful activator of the intrinsic hippocampal cholinergic and noradrenergic afferents) produced a similar increase in the release of these transmitters in the intact and grafted hippocampi. A complex environmental stimulus, such as handling, induced a consistent increase in acetylcholine but not noradrenaline release in the hippocampus. These findings suggest that grafted cholinergic and noradrenergic neurons can be functionally activated by host brain inputs.
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| 7. |
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| 8. |
- Lindvall, O, et al.
(författare)
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Cell therapy and transplantation in Parkinson's disease
- 2001
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Ingår i: Clinical Chemistry and Laboratory Medicine. - : De Gruyter. - 1434-6621 .- 1437-4331. ; 39:4, s. 356-361
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Tidskriftsartikel (refereegranskat)abstract
- Transplanted human fetal dopamine neurons can reinnervate the striatum in patients with Parkinson's disease (PD). Recent findings using positron emission tomography indicate that the grafts are functionally integrated and restore dopamine release in the patient's striatum. The grafts can exhibit long-term survival without immunological rejection and despite an ongoing disease process and continuous antiparkinsonian drug treatment. In the most successful cases, patients have been able to withdraw L-dopa treatment after transplantation and resume an independent life. About two-thirds of grafted patients have shown clinically useful, partial recovery of motor function. The major obstacle for the further development of this cell replacement strategy is that large amounts of human fetal mesencephalic tissue are needed for therapeutic effects. Stem cells hold promise as a virtually unlimited source of self-renewing progenitors for transplantation. The possibility to generate dopamine neurons from such cells is now being explored using different approaches. However, so far the generated neurons have survived poorly after transplantation in animals.
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| 9. |
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| 10. |
- Austrell, Per Erik, et al.
(författare)
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Development of an extremely fatigue-resistant Shock Absorber
- 2014
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Ingår i: Kgk: Kautschuk Gummi Kunststoffe. - 0948-3276. ; 67:11-12, s. 24-31
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Tidskriftsartikel (refereegranskat)abstract
- An extremely fatigue resistant shock absorber was developed from basic mechanics principles using nonlinear elastic material models and finite element analysis. Prototypes were manufactured and tested to confirm the calculations and to find out the fatigue properties. The rubber body fills a cavity at gradually increasing compression. This idea has some clear advantages: A large part of the rubber body is protected against accidental external influences and it is backed up during the deformation by the cavity walls. Also, the stress in the rubber body becomes evenly distributed as only compressive stress is developed in it. The prototypes were tested in nearly 6 million cycles with no visible defects.
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| 11. |
- Ballagi, A E, et al.
(författare)
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Platelet-derived growth factor receptor expression after neural grafting in a rat model of Parkinson's disease
- 1994
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Ingår i: Cell Transplantation. - 0963-6897 .- 1555-3892. ; 3:6, s. 453-460
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) has trophic effect on dopaminergic neurons in vitro. We have previously shown dynamic changes in the expression of PDGF in embryonic mesencephalic grafts and surrounding host striatal tissue following intracerebral transplantation in a rat model of Parkinson's disease. In this study the expression of the PDGF receptors was examined in the same model using immunohistochemistry. Most ventral mesencephalic (VM) cells from E13-E15 rat embryos possessed both PDGF alpha- and beta-receptors before implantation. Double immunofluorescence staining revealed that about 10% of the cells also expressed tyrosine hydroxylase (TH). The PDGF alpha-receptor was detectable in the graft up to 1 wk after transplantation but had disappeared at 3 wk. In the host tissue, scattered glial cells were positive for the alpha-receptor but the expression was unchanged following transplantation. The beta-receptor expression almost completely disappeared from the grafted tissue by 4 h following transplantation, and only a few cells of the host striatum showed immunoreactivity. However, after 3 wk beta-receptor positive cells were again detectable in the graft. These cells appeared to be endothelial cells as identified by an antibody against von Willebrand's factor. Our data suggest that PDGF might act locally on embryonic dopaminergic cells in an autocrine or juxtacrine manner before and shortly after transplantation, and on surrounding glial cells in a paracrine manner after transplantation. Furthermore, PDGF-BB might influence neovascularization in the graft.
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| 12. |
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| 13. |
- Blomqvist, P., et al.
(författare)
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Delayed postischemic hypoperfusion : Evidence against involvement of the noradrenergic locus ceruleus system
- 1984
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 4:3, s. 425-429
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Tidskriftsartikel (refereegranskat)abstract
- This study explores the possibility that the delayed hypoperfusion observed after an ischemic insult might be due to vasoconstriction induced by the release of noradrenaline from nerves originating in the locus ceruleus. Bilateral 6-hydroxydopamine lesions of the ascending bundles from the locus ceruleus were carried out in the caudal mesencephalon of rats. Local CBF was measured with an autoradiographic technique 60 min following the start of recirculation after incomplete forebrain ischemia. No significant differences in CBF between nonoperated, sham-operated, and noradrenaline-depleted animals were observed in any structure of the forebrain. It is concluded that the noradrenergic locus ceruleus system does not contribute to the development of delayed postischemic hypoperfusion.
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| 14. |
- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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| 15. |
- Brundin, Patrik, et al.
(författare)
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Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease
- 2000
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Ingår i: Brain. - 1460-2156. ; 123, s. 1380-1390
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Tidskriftsartikel (refereegranskat)abstract
- Five parkinsonian patients were transplanted bilaterally into the putamen and caudate nucleus with human embryonic mesencephalic tissue from between seven and nine donors. To increase graft survival, the lipid peroxidation inhibitor tirilazad mesylate was administered to the tissue before implantation and intravenously to the patients for 3 days thereafter. During the second postoperative year, the mean daily L-dopa dose was reduced by 54% and the UPDRS (Unified Parkinson's Disease Rating Scale) motor score in 'off' phase was reduced by a mean of 40%. At 10-23 months after grafting, PET showed a mean 61% increase of 6-L-[(18)F]fluorodopa uptake in the putamen, and 24% increase in the caudate nucleus, compared with preoperative values. No obvious differences in the pattern of motor recovery were observed between these and other previously studied cases with putamen grafts alone. The amount of mesencephalic tissue implanted in each putamen and caudate nucleus was 42 and 50% lower, respectively, compared with previously transplanted patients from our centre. Despite this reduction in grafted tissue, the magnitudes of symptomatic relief and graft survival were very similar. These findings suggest that tirilazad mesylate may improve survival of grafted dopamine neurons in patients, which is in agreement with observations in experimental animals.
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| 16. |
- Del Giudice, Rita, et al.
(författare)
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The Apparent Organ-Specificity of Amyloidogenic ApoA-I Variants Is Linked to Tissue-Specific Extracellular Matrix Components
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein A-I (ApoA-I) amyloidosis is a rare protein misfolding disease where fibrils of the N-terminal domain of the protein accumulate in several organs, leading to their failure. Although ApoA-I amyloidosis is systemic, the different amyloidogenic variants show a preferential tissue accumulation that appears to correlate with the location of the mutation in the protein sequence and with the local extracellular microenvironment. However, the factors leading to cell/tissues damage, as well as the mechanisms behind the observed organ specificity are mostly unknown. Therefore, we investigated the impact of ApoA-I variants on cell physiology and the mechanisms driving the observed tissue specificity. We focused on four ApoA-I amyloidogenic variants and analyzed their cytotoxicity as well as their ability to alter redox homeostasis in cell lines from different tissues (liver, kidney, heart, skin). Moreover, variant-specific interactions with extracellular matrix (ECM) components were measured by synchrotron radiation circular dichroism and enzyme-linked immunosorbent assay. Data indicated that ApoA-I variants exerted a cytotoxic effect in a time and cell-type-specific manner that seems to be due to protein accumulation in lysosomes. Interestingly, the ApoA-I variants exhibited specific preferential binding to the ECM components, reflecting their tissue accumulation pattern in vivo. While the binding did not to appear to affect protein conformations in solution, extended incubation of the amyloidogenic variants in the presence of different ECM components resulted in different aggregation propensity and aggregation patterns.
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| 17. |
- Dias, David O., et al.
(författare)
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Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report that in all mouse models that develop fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes. Perivascular cells with a type A pericyte marker profile also exist in the human brain and spinal cord. We uncover type A pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.
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| 18. |
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| 19. |
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| 20. |
- Geser, F, et al.
(författare)
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The European Multiple System Atrophy-Study Group (EMSA-SG)
- 2005
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Ingår i: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 112:12, s. 1677-1686
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson's Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and - to a lesser degree - of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.
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| 21. |
- Gutnichenko, O., et al.
(författare)
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Improvement of tool utilization when hard turning with cBN tools at varying process parameters
- 2021
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Ingår i: Wear. - : Elsevier BV. - 0043-1648. ; 477
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Tidskriftsartikel (refereegranskat)abstract
- Hard turning of helical gear hubs produced from low-carbon alloyed steel with a bulk hardness of HRC 35, and case hardened up to HRC 60–63 with PCBN tools was considered in this study. The workpieces after heat treatment are characterized by a non-uniform thickness of the hardened surface layer which results in a high variation of measured HRC hardness. The deviation of surface microhardness is even greater (HV 314–742) due to the presence of an oxidized layer that should be removed before measurements. When also considering workpiece run-out and deviations in depth-of-cut due to the distribution of the workpiece diameter, all those factors result in a non-uniform development of tool wear that leads to a large deviation in tool life. To uphold quality and avoid scrap, industry uses a fixed conservative tool life (number of parts machined), which leads to many inserts being underutilized, which in turn, means extra expenses considering the price of PCBN tools. The present study addresses the development of different strategies for monitoring of tool wear and prediction of tool life aimed to increase productivity. Laboratory machining tests are performed to optimize the type and number of sensors necessary for data acquisition, to estimate the significance of the data used for the development of prediction model, as well as the efficiency of machine learning algorithms for the selected data and strategies to increase the algorithm's accuracy.
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| 22. |
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| 23. |
- Hagell, Peter, et al.
(författare)
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Health-related quality of life following bilateral intrastriatal transplantation in Parkinson's disease
- 2000
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Ingår i: Movement Disorders. - 0885-3185. ; 15:2, s. 224-229
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Tidskriftsartikel (refereegranskat)abstract
- Intrastriatal transplantation of embryonic dopaminergic tissue is a new, experimental approach for the treatment of Parkinson's disease (PD). Clinical trials have shown longterm graft survival and therapeutically valuable improvements with decreased L-dopa dose and time spent in the "off"-phase, and reduced rigidity and hypokinesia. We have measured health-related quality of life (HRQoL) using the Nottingham Health Profile (NHP) in five patients subjected to bilateral transplantation in the caudate and putamen to explore the influence of intrastriatal grafts on HRQoL and the value of such measures in trials of restorative therapies. The results demonstrate improved HRQoL following transplantation, with individual patients showing striking improvements within different dimensions of the NHP as well as the NHP distress index (NHPD). The most pronounced improvements after grafting were observed for physical mobility along with emotional reactions and energy. These results indicate that intrastriatal transplantation of embryonic dopaminergic tissue can give rise to improvements within most areas of HRQoL, and that HRQoL measurements provide important information additional to that obtained by traditional, symptom-oriented assessment protocols. However, the optimal approach to HRQoL measurement in PD remains to be determined.
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| 24. |
- Herzog, Jan, et al.
(författare)
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Deep brain stimulation in Parkinson's disease following fetal nigral transplantation
- 2008
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 23:9, s. 1293-1296
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Tidskriftsartikel (refereegranskat)abstract
- OFF-period dyskinesias have been reported as a consequence of fetal nigral transplantation for Parkinson's disease. This type of dyskinesias may appear in patients even in the prolonged absence of antiparkinson medication and be aggravated by levodopa. Therefore, pharmacological therapeutic approaches in these patients are limited. Here we report two patients with bilateral fetal nigral grafts in the caudate and putamen subjected to deep brain stimulation (DBS) of the globus pallidus internus (GPi) or subthalamic nucleus (STN). Clinical assessment was performed according to UPDRS and the clinical dyskinesia rating scale. In both patients, we found significant improvement in OFF-period symptoms as well as levodopa-induced dyskinesias. However, only GPi-DBS led to a significant reduction of OFF-period dyskinesias whereas STN-DBS did not influence dyskinesias unrelated to external dopaminergic application. These findings, based on two case reports, highlight the pivotal role of the GPi in mediating dyskinesia-related neural activity within the basal ganglia loop. (C) 2008 Movement Disorder Society.
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| 25. |
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| 26. |
- Kjellman, Christian, et al.
(författare)
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Expression of TGF-beta isoforms, TGF-beta receptors, and SMAD molecules at different stages of human glioma
- 2000
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Ingår i: International Journal of Cancer. - 0020-7136. ; 89:3, s. 251-258
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Tidskriftsartikel (refereegranskat)abstract
- Human gliomas express TGF-beta but, so far the expression of downstream mediators has been investigated in only a few cell lines. We have examined tissue specimens of 23 gliomas: 3 astrocytomas grade II (AST), 8 anaplastic astrocytomas grade III (AAST), and 12 glioblastoma multiforme grade IV (GBM). We analyzed the mRNA expression of TGF-beta1, TGF-beta2, TGF-beta3, the TGF-beta receptors type I (TbetaR-I) and type II (TbetaR-II), Smad2, Smad3, and Smad4. mRNA expression of IL-10 and CD95 (FAS/APO-1) were also studied. We detected increased mRNA levels of the 3 TGF-beta isoforms, correlating with the degree of malignancy. TGF-beta3 mRNA was increased, particularly in AST and AAST, while TGF-beta1 and TGF-beta2 mRNAs were strongly expressed in GBM. TGF-beta normally up-regulates the TGF-beta receptors, and TbetaR-I and TbetaR-II showed stronger expression in all gliomas when compared to normal tissues. However, the mRNA expression of Smad2, Smad3, and Smad4 was decreased in GBM. IL-10 mRNA expression was detected in glioma tissues but not in glioma cell lines. No marked increase in the expression of soluble CD95 splicing variants was found in the gliomas compared with normal tissue. However, total CD95 mRNA was elevated among GBM tissues.
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| 27. |
- Kokaia, Z, et al.
(författare)
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BDNF makes cultured dentate granule cells more resistant to hypoglycaemic damage
- 1994
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Ingår i: NeuroReport. - : Ovid Technologies (Wolters Kluwer Health). - 0959-4965 .- 1473-558X. ; 5:10, s. 4-1241
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to explore whether brain-derived neurotrophic factor (BDNF) can improve neuronal survival in cell cultures of rat dentate gyrus subjected to a hypoglycaemic insult. Glucose deprivation for 15 h caused severe neuronal loss (about 70%). BDNF added either 24 h before or 4 h after onset of hypoglycaemia completely protected granule cells against this insult-induced damage. Nerve growth factor (NGF) had similar effects. These findings support the hypothesis that the rapid upregulation of BDNF mRNA in dentate granule cells after brief periods of hypoglycaemic coma and other insults is a local protective mechanism.
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| 28. |
- Kokaia, Zaal, et al.
(författare)
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Regional brain-derived neurotrophic factor mRNA and protein levels following transient forebrain ischemia in the rat
- 1996
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Ingår i: Brain Research. Molecular Brain Research. - 0169-328X. ; 38:1, s. 139-144
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Tidskriftsartikel (refereegranskat)abstract
- Levels of BDNF mRNA and protein were measured in the rat brain using in situ hybridization and a two-site enzyme immunoassay. Under basal conditions, the highest BDNF concentration was found in the dentate gyrus (88 ng/g), while the levels in CA3 (50 ng/g), CA1 (18 ng/g) and parietal cortex (8 ng/g) were markedly lower. Following 10 min of forebrain ischemia, BDNF protein increased transiently in the dentate gyrus (to 124% of control at 6 h after the insult) and CA3 region (to 131% of control, at 1 week after the insult). In CA1 and parietal cortex, BDNF protein decreased to 73-75% of control at 24 h. In contrast, BDNF mRNA expression in dentate granule cells and CA3 pyramidal layer was transiently elevated to 287 and 293% of control, respectively, at 2 h, whereas no change was detected in CA1 or neocortex. The regional BDNF protein levels shown here correlate at least partly with regional differences in cellular resistance to ischemic damage, which is consistent with the hypothesis of a neuroprotective role of BDNF.
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| 29. |
- Kokaia, Z., et al.
(författare)
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Transplantation of reprogrammed neurons for improved recovery after stroke
- 2017
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Ingår i: Functional Neural Transplantation IV Translation to Clinical Application, Part B. - : Elsevier. - 0079-6123. - 9780128138793 ; 231, s. 245-263
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Bokkapitel (refereegranskat)abstract
- Somatic cells such as fibroblasts, reprogrammed to induced pluripotent stem cells, can be used to generate neural stem/progenitor cells or neuroblasts for transplantation. In this review, we summarize recent studies demonstrating that when grafted intracerebrally in animal models of stroke, reprogrammed neurons improve function, probably by several different mechanisms, e.g., trophic actions, modulation of inflammation, promotion of angiogenesis, cellular and synaptic plasticity, and neuroprotection. In our own work, we have shown that human skin-derived reprogrammed neurons, fated to cortical progeny, integrate in stroke-injured neuronal network and form functional afferent synapses with host neurons, responding to peripheral sensory stimulation. However, whether neuronal replacement plays a role for the improvement of sensory, motor, and cognitive deficits after transplantation of reprogrammed neurons is still unclear. We conclude that further preclinical studies are needed to understand the therapeutic potential of grafted reprogrammed neurons and to define a road map for their clinical translation in stroke.
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| 30. |
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| 31. |
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| 32. |
- Lindahl, Niklas, 1981, et al.
(författare)
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Determination of the Bending Rigidity of Graphene via Electrostatic Actuation of Buckled Membranes
- 2012
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Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6984 .- 1530-6992. ; 12:7, s. 3526-3531
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Tidskriftsartikel (refereegranskat)abstract
- Classical continuum mechanics is used extensively to predict the properties of nanoscale materials such as graphene. The bending rigidity, kappa, is an important parameter that is used, for example, to predict the performance of graphene nanoelectromechanical devices and also ripple formation. Despite its importance, there is a large spread in the theoretical predictions of kappa for few-layer graphene. We have used the snap-through behavior of convex buckled graphene membranes under the application of electrostatic pressure to determine experimentally values of kappa for double-layer graphene membranes. We demonstrate how to prepare convex-buckled suspended graphene ribbons and fully clamped suspended membranes and show how the determination of the curvature of the membranes and the critical snap-through voltage, using AFM, allows us to extract kappa. The bending rigidity of bilayer graphene membranes under ambient conditions was determined to be 35.5(-15.0)(+20.0) eV. Monolayers are shown to have significantly lower kappa than bilayers.
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| 33. |
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| 34. |
- Lindvall, Niclas, 1985, et al.
(författare)
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Towards transfer-free fabrication of graphene NEMS grown by chemical vapour deposition
- 2012
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Ingår i: Micro and Nano Letters. - : Institution of Engineering and Technology (IET). - 1750-0443. ; 7:8, s. 749-752
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Tidskriftsartikel (refereegranskat)abstract
- Graphene, an atomic monolayer of sp(2)-hybridised carbon atoms, is a promising material for future NEMS based on its remarkable electronic and mechanical properties. Through the rapid progress of chemical vapour deposition of large-scale, high-quality graphene, these applications seem to be close to reality. However, issues related to the graphene transfer process limit the reproducibility of such devices. In this Letter, the authors present two different approaches for fabricating suspended graphene devices without any transfer step, using both catalytically and non-catalytically grown graphene. The authors achieve high reproducibility in manufacturing flat and uniform suspended graphene beams. While good mechanical properties are observed, the electrical performance is still poor, requiring improvements.
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| 35. |
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| 36. |
- Lindvall, O., et al.
(författare)
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Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma
- 1992
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 89:2, s. 648-652
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Tidskriftsartikel (refereegranskat)abstract
- In situ hybridization was used to study expression of mRNAs for members of the nerve growth factor (NGF) family in the rat brain after 2 and 10 min of forebrain ischemia and 1 and 30 min of insulin-induced hypoglycemic coma. Two hours after the ischemic insults, the level of brain-derived neurotrophic factor (BDNF) mRNA was markedly increased in the granule cells of the dentate gyrus, and at 24 h it was still significantly elevated. NGF mRNA showed a pronounced increase 4 h after 2 min of ischemia but had returned to a control level at 24 h. Both 2 and 10 min of ischemia caused a clear reduction of the level of mRNA for neurotrophin 3 (NT-3) in the dentate granule cells and in regions CA2 and medial CA1 of the hippocampus 2 and 4 h after the insults. The increase of BDNF mRNA could be partially blocked by the α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist NBQX but was not influenced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. Both NBQX and MK-801 attenuated the decrease of NT-3 mRNA after ischemia. One and 30 min of hypoglycemic coma also induced marked increases in BDNF and NGF mRNA in dentate granule cells with maximal levels at 2 h. If the changes of mRNA expression lead to alterations in the relative availability of neurotrophic factors, this could influence functional outcome and neuronal necrosis following ischemic and hypoglycemic insults.
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| 37. |
- Lindvall, O, et al.
(författare)
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Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson's disease
- 1994
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134. ; 35:2, s. 80-172
-
Tidskriftsartikel (refereegranskat)abstract
- Two patients with idiopathic Parkinson's disease (Patients 3 and 4 in our series) were followed up to 3 years after grafting of human embryonic dopamine-rich mesencephalic tissue unilaterally into the putamen. During the first postoperative year both patients showed significant amelioration of parkinsonian symptoms and increased 6-L-[18F]-fluorodopa uptake in the grafted putamen, as assessed with positron emission tomography. Three years after grafting the patients still exhibited increased fluorodopa uptake in the grafted putamen and significant clinical improvements, evidenced by a reduction of the severity of symptoms and of the time spent in the "off" phase, and by a prolongation of the effect of a single dose of L-dopa. Between 1 and 3 years after surgery, Patient 3 showed only minor changes of parkinsonian symptoms on the side contralateral to the graft, whereas there was a worsening on the ipsilateral side. Fluorodopa uptake decreased in the nongrafted putamen but was unchanged in the grafted putamen. Patient 4 continued to improve after the first postoperative year and L-dopa was withdrawn after 32 months. The reduction of parkinsonian symptoms on the side contralateral to the graft became more pronounced between 1 and 3 years after surgery. Fluorodopa uptake further increased in the grafted putamen, whereas no change was detected on the non-grafted side. These results indicate that grafts of embryonic dopamine neurons can survive, grow, and exert functional effects up to at least 3 years after surgery in the parkinsonian brain, despite an ongoing disease process leading to degeneration of the intrinsic dopamine system.
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| 38. |
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| 39. |
- Lindvall, O, et al.
(författare)
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Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease
- 1990
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 247:4942, s. 7-574
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Tidskriftsartikel (refereegranskat)abstract
- Neural transplantation can restore striatal dopaminergic neurotransmission in animal models of Parkinson's disease. It has now been shown that mesencephalic dopamine neurons, obtained from human fetuses of 8 to 9 weeks gestational age, can survive in the human brain and produce marked and sustained symptomatic relief in a patient severely affected with idiopathic Parkinson's disease. The grafts, which were implanted unilaterally into the putamen by stereotactic surgery, restored dopamine synthesis and storage in the grafted area, as assessed by positron emission tomography with 6-L-[18F]fluorodopa. This neurochemical change was accompanied by a therapeutically significant reduction in the patient's severe rigidity and bradykinesia and a marked diminuation of the fluctuations in the patient's condition during optimum medication (the "on-off" phenomenon). The clinical improvement was most marked on the side contralateral to the transplant.
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| 40. |
- Lindvall, O, et al.
(författare)
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Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up
- 1989
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Ingår i: Archives of Neurology. - : American Medical Association (AMA). - 0003-9942. ; 46:6, s. 31-615
-
Tidskriftsartikel (refereegranskat)abstract
- By using stereotaxic surgical techniques, ventral mesencephalic tissues from aborted human fetuses of 8 to 10 weeks' gestational age were implanted unilaterally into the striata in two patients with advanced Parkinson's disease. The patients were treated with a cyclosporine, azathioprine, and steroid regimen to minimize the risk for graft rejection. They were examined for 6 months preoperatively and 6 months postoperatively and continued to receive the same doses of antiparkinsonian medication. There were no significant postoperative complications. No major therapeutic effect from the operation was observed. However, in the clinical tests, both patients showed small but significant increases of movement speed for repeated pronation-supination, fist clenching, and foot lifting. The rate of walking also increased in the one patient tested. For both patients, there was an initial worsening postoperatively, followed by improvement vs preoperative performance at 1 to 3 months. Both patients also showed significant improvement in the magnitude of response to a single dose of levodopa (L-dopa), but there was no increase in the duration of drug action. The motor readiness potential increased in both patients postoperatively, primarily over the operated hemisphere. Neurophysiological measurements also showed a more rapid performance of simple and complex arm and hand movements on the side contralateral to transplantation in one patient at 5 months postoperatively. Positron emission tomography demonstrated no increased uptake of 6-L-(18F)-fluorodopa in the transplanted striatum at 5 and 6 months. Taken together, these results suggest that the fetal nigral implants may have provided a modest improvement in motor function, consistent with the presence of small surviving grafts. Although our results support further scientific experimentation with transplantation in Parkinson's disease, widespread clinical trials with this procedure are probably not warranted at this time.
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| 41. |
- Lindvall, O, et al.
(författare)
-
In reply : Fetal brain grafts and Parkinson's disease
- 1990
-
Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 250:4986, s. 1435-1435
-
Tidskriftsartikel (refereegranskat)
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| 42. |
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| 43. |
- Lindvall, O, et al.
(författare)
-
Transplantation of fetal dopamine neurons in Parkinson's disease : one-year clinical and neurophysiological observations in two patients with putaminal implants
- 1992
-
Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 31:2, s. 65-155
-
Tidskriftsartikel (refereegranskat)abstract
- Ventral mesencephalic tissue from aborted human fetuses (age, 6-7 weeks' postconception) was implanted unilaterally into the putamen using stereotaxic surgery in 2 immunosuppressed patients (Patients 3 and 4 in our series) with advanced idiopathic Parkinson's disease. Tissue from 4 fetuses was grafted to each patient. Compared with our previous 2 patients, the following changes in the grafting procedure were introduced: the implantation instrument was thinner, more tissue was placed in the operated structure, and the time between abortion and grafting was shorter. There were no postoperative complications. Both patients showed a gradual and significant amelioration of parkinsonian symptoms (most marked in Patient 3) starting at 6 and 12 weeks after grafting, respectively, reaching maximum stability at approximately 4 to 5 months; patients remained relatively stable thereafter during the 1-year follow-up period. Clinical improvement was observed as a reduction of the time spent in the "off" phase and the number of daily "off" periods; a lessening of bradykinesia and rigidity during the "off" phase, mainly but not solely on the side contralateral to the graft; and a prolongation and change in the pattern of the effect of a single dose of L-dopa. Neurophysiological measurements revealed a more rapid performance of simple and complex arm and hand movements bilaterally, but primarily contralateral to the graft. The results indicate that patients with Parkinson's disease can show significant and sustained improvement of motor function after intrastriatal implantation of fetal dopamine-rich mesencephalic tissue. The accompanying paper by Sawle and colleagues describes the results of repeated positron emission tomography scans in these patients.
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| 44. |
- Lindvall, O., et al.
(författare)
-
Transplantation strategies in the treatment of Parkinson's disease : experimental basis and clinical trials
- 1989
-
Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 80, s. 197-210
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract– Neural grafting has over the last decade emerged as a possible tool for the substitution of damaged neurons in the central nervous system and for the promotion of symptomatic recovery after brain damage. Transplantation studies in the 6‐hydroxydopamine lesion rat model of Parkinson's disease were initiated in the late seventies. The first studies were based on the neuronal replacement paradigm, using developing dopamine brain cells obtained from the substantia nigra region of embryonic cadavers. When implanted into the striatum such grafts were found to reinnervate part of the previously denervated striatum and restore dopamine turnover and release to near‐normal levels. In both rats and monkeys the nigral grafts have been shown to normalize some, but not all, Parkinson‐like symptoms in the dopamine deficient recipients. Grafting of adrenal medullary tissue was introduced in the early eighties as an alternative to the use of embryonic cadaver tissue. The adrenal medullary grafts have, however, so far shown poor long‐term survival in both rats and monkeys, and consistent with this no sustained dopamine release have been observed in the brain of long‐term grafted animals. Likewise, no long‐lasting effects of adrenal medullary grafts on spontaneous motor or sensori‐motor behavior have so far been documented in either the rat or the monkey model. The results so far reported from trials using adrenal medullary grafts in patients with Parkinson's disease appear to conform to the available animal experimental data at least in two important respects: significant long‐term graft survival has not been possible to document, and any clear‐cut functional effects consistent with sustained graft‐induced dopamine release have not been demonstrated. Initial results from ongoing trials using grafts of fetal nigral tissue are presented and discussed.
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| 45. |
- Magnusson, JP, et al.
(författare)
-
A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse
- 2014
-
Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 346:6206, s. 237-241
-
Tidskriftsartikel (refereegranskat)abstract
- Neurogenesis is restricted in the adult mammalian brain; most neurons are neither exchanged during normal life nor replaced in pathological situations. We report that stroke elicits a latent neurogenic program in striatal astrocytes in mice. Notch1 signaling is reduced in astrocytes after stroke, and attenuated Notch1 signaling is necessary for neurogenesis by striatal astrocytes. Blocking Notch signaling triggers astrocytes in the striatum and the medial cortex to enter a neurogenic program, even in the absence of stroke, resulting in 850 ± 210 (mean ± SEM) new neurons in a mouse striatum. Thus, under Notch signaling regulation, astrocytes in the adult mouse brain parenchyma carry a latent neurogenic program that may potentially be useful for neuronal replacement strategies.
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| 46. |
- Nilsson, Oktawia, et al.
(författare)
-
Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux
- 2021
-
Ingår i: Journal of Lipid Research. - 0022-2275. ; 62
-
Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein A-I (ApoA-I) of high density lipoproteins (HDLs) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in ApoA-I of HDLs are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL cholesterol. To explain this paradox, we show that the HDL particle profiles of patients carrying either L75P or L174S ApoA-I amyloidogenic variants show a higher relative abundance of the 8.4-nm versus 9.6-nm particles and that serum from patients, as well as reconstituted 8.4- and 9.6-nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogendeuterium exchange revealed that the variants in 8.4-nm rHDL have altered secondary structure composition and display a more flexible binding to lipids than their native counterpart. The reduced HDL cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles, and better cholesterol efflux due to altered, region-specific protein structure dynamics.
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| 47. |
- Nilsson, Oktawia, et al.
(författare)
-
Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux
- 2021
-
Ingår i: Journal of Lipid Research. - : Elsevier. - 0022-2275 .- 1539-7262. ; 62
-
Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein A-I (ApoA-I) of high density lipoproteins (HDLs) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in ApoA-I of HDLs are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/HDL cholesterol. To explain this paradox, we show that the HDL particle profiles of patients carrying either L75P or L174S ApoA-I amyloidogenic variants show a higher relative abundance of the 8.4-nm versus 9.6-nm particles and that serum from patients, as well as reconstituted 8.4- and 9.6-nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4-nm rHDL have altered secondary structure composition and display a more flexible binding to lipids than their native counterpart. The reduced HDL cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles, and better cholesterol efflux due to altered, region-specific protein structure dynamics.
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| 48. |
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| 49. |
- Othberg, A, et al.
(författare)
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Specific effects of platelet derived growth factor (PDGF) on fetal rat and human dopaminergic neurons in vitro
- 1995
-
Ingår i: Experimental Brain Research. - 0014-4819. ; 105:1, s. 22-111
-
Tidskriftsartikel (refereegranskat)abstract
- The neurotrophic effects of the BB isoform of platelet-derived growth factor (PDGF) on rat and human fetal mesencephalic dopaminergic neurons have been characterized in vitro. A dose-response analysis demonstrated maximal responses at 30 ng/ml of PDGF-BB. This concentration resulted in a marked increase in the survival and neurite outgrowth from rat and human tyrosine hydroxylase-(TH) positive, presumed dopaminergic neurons after 7 days in vitro. The effects of PDGF-BB on survival of TH-positive neurons were comparable to those of brain-derived neurotrophic factor (BDNF), whereas neurite outgrowth was more pronounced after addition of BDNF. The combination of BDNF and PDGF-BB yielded no additive effects. Double immunohistochemical staining of rat cultures demonstrated PDGF beta-receptors on about 90% of the TH-positive neurons. PDGF-BB treatment of rat mesencephalic cultures induced an upregulation of c-fos and TH mRNA with maximal levels after 0.5-2 h as assessed by quantitative PCR analysis. An increased number of Fos protein-positive cells was detected immunohistochemically after 4 h of PDGF-BB treatment. The present results provide further evidence for specific and direct effects of PDGF-BB on gene expression, survival and neurite outgrowth of mesencephalic dopaminergic neurons of rat and human origin.
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| 50. |
- Piccini, P, et al.
(författare)
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Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient
- 1999
-
Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1546-1726 .- 1097-6256. ; 2:12, s. 1137-1140
-
Tidskriftsartikel (refereegranskat)abstract
- Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinson's disease using [11C]-raclopride positron emission tomography to measure dopamine D2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.
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