Dyskinesias after neural transplantation in Parkinson's disease: what do we know and what is next?

Since the 1980 s, when cell transplantation into the brain as a cure for Parkinson's disease hit the headlines, several patients with Parkinson's disease have received transplantation of cells from aborted fetuses with the aim of replacing the dopamine cells destroyed by the disease. The results in human studies were unpredictable and raised controversy. Some patients showed remarkable improvement, but many of the patients who underwent transplantation experienced serious disabling adverse reactions, putting an end to human trials since the late 1990 s. These side effects consisted of patients' developing troublesome involuntary, uncontrolled movements in the absence of dopaminergic medication, so-called off-phase, graft-induced dyskinesias. Notwithstanding the several mechanisms having been proposed, the pathogenesis of this type of dyskinesias remained unclear and there was no effective treatment. It has been suggested that graft-induced dyskinesias could be related to fiber outgrowth from the graft causing increased dopamine release, that could be related to the failure of grafts to restore a precise distribution of dopaminergic synaptic contacts on host neurons or may also be induced by inflammatory and immune responses around the graft. A recent study, however, hypothesized that an important factor for the development of graft-induced dyskinesias could include the composition of the cell suspension and specifically that a high proportion of serotonergic neurons cografted in these transplants engage in nonphysiological properties such as false transmitter release. The findings from this study showed serotonergic hyperinnervation in the grafted striatum of two patients with Parkinson's disease who exhibited major motor recovery after transplantation with fetal mesencephalic tissue but later developed graft-induced dyskinesias. Moreover, the dyskinesias were significantly attenuated by administration of a serotonin agonist, which activates the inhibitory serotonin autoreceptors and attenuates transmitter release from serotonergic neurons, indicating that graft-induced dyskinesias were caused by the dense serotonergic innervation engaging in false transmitter release. Here the implications of the recent findings for the development of new human trials testing the safety and efficacy of cell transplantation in patients with Parkinson's disease are discussed

Chaos, containment and change: responding to persistent offending by young people

This article reviews policy developments in Scotland concerning 'persistent young offenders' and then describes the design of a study intended to assist a local planning group in developing its response. The key findings of a review of casefiles of young people involved in persistent offending are reported. It emerges that youth crime and young people involved in offending are more complex and heterogeneous than is sometimes assumed. This, along with a review of some literature about desistance from offending, reaffirms the need for properly individualised interventions. Studies of 'desisters' suggest the centrality of effective and engaging working relationships in this process. However, these studies also re-assert the significance of the social contexts of workers’ efforts to bring 'change' out of 'chaos'. We conclude therefore that the 'new correctionalism' must be tempered with appreciation of the social exclusion of young people who offend

Who are these youths? Language in the service of policy

In the 1990s policy relating to children and young people who offend developed as a result of the interplay of political imperatives and populist demands. The ‘responsibilisation’ of young offenders and the ‘no excuses’ culture of youth justice have been ‘marketed’ through a discourse which evidences linguistic changes. This article focuses on one particular area of policy change, that relating to the prosecutorial decision, to show how particular images of children were both reflected and constructed through a changing selection of words to describe the non-adult suspect and offender. In such minutiae of discourse can be found not only the signifiers of public attitudinal and policy change but also the means by which undesirable policy developments can be challenged

Young people, crime and school exclusion: a case of some surprises

During the 1990s the number of young people being permanently excluded from schools in England and Wales increased dramatically from 2,910 (1990/91) to a peak of 12,700 (1996/97). Coinciding with this rise was a resurgence of the debate centring on lawless and delinquent youth. With the publication of Young People and Crime (Graham and Bowling 1995) and Misspent Youth (Audit Commission 1996) the 'common sense assumption' that exclusion from school inexorably promoted crime received wide support, with the school excludee portrayed as another latter day 'folk devil'. This article explores the link between school exclusion and juvenile crime, and offers some key findings from a research study undertaken with 56 young people who had experience of being excluded from school. Self-report interview questions reveal that whilst 40 of the young people had offended, 90% (36) reported that the onset of their offending commenced prior to their first exclusion. Moreover, 50 (89.2% of the total number of young people in the sample), stated that they were no more likely to offend subsequent to being excluded and 31 (55.4%) stated that they were less likely to offend during their exclusion period. Often, this was because on being excluded, they were 'grounded' by their parents

The Reframing of Methodology: Revisiting a PhD Study

The paper draws on a PhD study to explore some methodological dilemmas associated with the execution of qualitative research when framed within positivist study design. The PhD was linked to an externally funded research project which evaluated the implementation of a custody-based intervention in the secure estate. While the PhD was conceived as a qualitative study, informed by interpretivist methodology and associated epistemology, the wider funded study was informed by positivist tradition and used a quantitative method. This led to dilemmas of both practical and methodological nature. The author revisits her study's methodological position to review issues raised by the research design and suggests an alternative proposal informed methodologically by critical realism which may better serve the study's interests. In doing so, the paper suggests how revisiting previous research may assist us in gaining methodological understanding and allow us to reframe our future endeavours to more useful end

Pregnancy in multiple system atrophy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Multiple system atrophy is a late, adult-onset α-synucleinopathy with no data on the effect of pregnancy on the disease course. Early stage multiple system atrophy can be difficult to distinguish from Parkinson's disease.</p> <p>Case presentation</p> <p>We describe the case of an Irish woman with parkinsonism starting at age 31, initially diagnosed as having dopa-responsive, idiopathic Parkinson's disease, who successfully delivered a full-term child at age 35. Her pregnancy was complicated by severe orthostatic hypotension and motor fluctuations. Two years post-partum, she underwent bilateral subthalamic nuclei deep brain stimulation for intractable motor fluctuations and disabling dyskinesia. After this treatment course she experienced deterioration of motor symptoms and death eight years after disease onset. Post-mortem neuropathological examination revealed striatonigral degeneration and α-synuclein-positive glial cytoplasmic inclusions in brain stem nuclei, basal ganglia and white matter tracts, consistent with a neuropathological diagnosis of multiple system atrophy.</p> <p>Conclusions</p> <p>Multiple system atrophy can affect women of child-bearing age and pregnancy may be associated with marked disease progression.</p

Quantifying the profile and progression of impairments, activity, participation, and quality of life in people with Parkinson disease : protocol for a prospective cohort study

Background Despite the finding that Parkinson disease (PD) occurs in more than one in every 1000 people older than 60 years, there have been few attempts to quantify how deficits in impairments, activity, participation, and quality of life progress in this debilitating condition. It is unclear which tools are most appropriate for measuring change over time in PD. Methods and design This protocol describes a prospective analysis of changes in impairments, activity, participation, and quality of life over a 12 month period together with an economic analysis of costs associated with PD. One-hundred participants will be included, provided they have idiopathic PD rated I-IV on the modified Hoehn &amp; Yahr (1967) scale and fulfil the inclusion criteria. The study aims to determine which clinical and economic measures best quantify the natural history and progression of PD in a sample of people receiving services from the Victorian Comprehensive Parkinson\u27s Program, Australia. When the data become available, the results will be expressed as baseline scores and changes over 3 months and 12 months for impairment, activity, participation, and quality of life together with a cost analysis. Discussion This study has the potential to identify baseline characteristics of PD for different Hoehn &amp; Yahr stages, to determine the influence of disease duration on performance, and to calculate the costs associated with idiopathic PD. Valid clinical and economic measures for quantifying the natural history and progression of PD will also be identified

Clinical application of stem cell therapy in Parkinson's disease

Cell replacement therapies in Parkinson's disease (PD) aim to provide long-lasting relief of patients' symptoms. Previous clinical trials using transplantation of human fetal ventral mesencephalic (hfVM) tissue in the striata of PD patients have provided proof-of-principle that such grafts can restore striatal dopaminergic (DA-ergic) function. The transplants survive, reinnervate the striatum, and generate adequate symptomatic relief in some patients for more than a decade following operation. However, the initial clinical trials lacked homogeneity of outcomes and were hindered by the development of troublesome graft-induced dyskinesias in a subgroup of patients. Although recent knowledge has provided insights for overcoming these obstacles, it is unlikely that transplantation of hfVM tissue will become routine treatment for PD owing to problems with tissue availability and standardization of the grafts. The main focus now is on producing DA-ergic neuroblasts for transplantation from stem cells (SCs). There is a range of emerging sources of SCs for generating a DA-ergic fate in vitro. However, the translation of these efforts in vivo currently lacks efficacy and sustainability. A successful, clinically competitive SC therapy in PD needs to produce long-lasting symptomatic relief without side effects while counteracting PD progression

Implanted reuptake-deficient or wild-type dopaminergic neurons improve ON l-dopa dyskinesias without OFF-dyskinesias in a rat model of Parkinson's disease

OFF-l-dopa dyskinesias have been a surprising side-effect of intrastriatal foetal ventral mesencephalic transplantation in patients with Parkinson's disease. It has been proposed that excessive and unregulated dopaminergic stimulation of host post-synaptic striatal neurons by the grafts could be responsible for these dyskinesias. To address this issue we transplanted foetal dopaminergic neurons from mice lacking the dopamine transporter (DATKO) or from wild-type mice, into a rat model of Parkinson's disease and l-dopa-induced dyskinesias. Both wild-type and DATKO grafts reinnervated the host striatum to a similar extent, but DATKO grafts produced a greater and more diffuse increase in extra-cellular striatal dopamine levels. Interestingly, grafts containing wild-type dopaminergic neurons improved parkinsonian signs to a similar extent as DATKO grafts, but provided a more complete reduction of l-dopa induced dyskinesias. Neither DATKO nor wild-type grafts induced OFF-l-dopa dyskinesias. Behavioural and receptor autoradiography analyses demonstrated that DATKO grafts induced a greater normalization of striatal dopaminergic receptor supersensitivity than wild-type grafts. Both graft types induced a similar downregulation and normalization of PEnk and fosb/Δfosb in striatal neurons. In summary, DATKO grafts causing high and diffuse extra-cellular dompamine levels do not per se alter graft-induced recovery or produce OFF-l-dopa dyskinesias. Wild-type dopaminergic neurons appear to be the most effective neuronal type to restore function and reduce l-dopa-induced dyskinesias