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

Abstract (provisional)

Since the 1980s, 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 1990s. 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.

The promise and pitfalls of the internet for cognitive behavioral therapyInternet directed cognitive behavioural therapy

Abstract (provisional)

Internet-administered cognitive behavior therapy is a promising new way to deliver psychological treatment. There are an increasing number of controlled trials in various fields such as anxiety disorders, mood disorders and health conditions such as headache and insomnia. Among the advantages for the field of cognitive behavior therapy is the dissemination of the treatment, being able to access treatment from a distance, and possibilities to tailor the interventions. To date, studies in which large effects have been obtained have included patient support from a clinician. Recent trials suggest that this support may come from non-clinicians and that therapist effects are minimal. Since studies also suggest that internet-delivered cognitive behavior therapy can be equally effective as face-to-face cognitive behavior therapy, this is a finding that may have implications for CBT practitioners. However, there are other aspects to consider for implementation, as while clinicians may hold positive attitudes towards internet-delivered CBT a recent study suggested that patients are more skeptical and may prefer face-to-face treatment. In the present work, I argue that internet-delivered CBT may help to increase adherence to treatment protocols, that training can be facilitated by means of internet support, and that research on internet interventions can lead to new insights regarding what happens in regular CBT. Moreover, I conclude that internet-delivered CBT works best when support is provided, leaving an important role for clinicians who can incorporate internet treatment in their services. However, I also warn against disseminating internet-delivered CBT to patients for whom it is not suitable, and that clinical skills may suffer if clinicians are trained and practice mainly using the internet.

The relationship between smoking and lung function

Abstract (provisional)

Background

The rate of forced expiratory volume in 1 second (FEV1) decline ("beta") is a marker of chronic obstructive pulmonary disease risk. The reduction in beta after quitting smoking is an upper limit for the reduction achievable from switching to novel nicotine delivery products. We review available evidence to estimate this reduction and quantify the relationship of smoking to beta.

Methods

Studies were identified, in healthy individuals or patients with respiratory disease, that provided data on beta over at least 2 years of follow-up, separately for those who gave up smoking and other smoking groups. Publications to June 2010 were considered. Independent beta estimates were derived for four main smoking groups: never smokers, ex-smokers (before baseline), quitters (during follow-up) and continuing smokers. Unweighted and inverse variance-weighted regression analyses compared betas in the smoking groups, and in continuing smokers by amount smoked, and estimated whether beta or beta differences between smoking groups varied by age, sex and other factors.

Results

Forty-seven studies had relevant data, 28 for both sexes and 19 for males. Sixteen studies started before 1970. Mean follow-up was 11 years. On the basis of weighted analysis of 303 betas for the four smoking groups, never smokers had a beta 10.8 mL/yr (95% confidence interval (CI), 8.9 to 12.8) less than continuing smokers. Betas for ex-smokers were 12.4 mL/yr (95% CI, 10.1 to 14.7) less than for continuing smokers, and for quitters, 8.5 mL/yr (95% CI, 5.6 to 11.4) less. These betas were similar to that for never smokers. In continuing smokers, beta increased 0.33 mL/yr per cigarette/day. Beta differences between continuing smokers and those who gave up were greater in patients with respiratory disease or with reduced baseline lung function, but were not clearly related to age or sex.

Conclusion

The available data have numerous limitations, but clearly show that continuing smokers have a beta that is dose-related and over 10 mL/yr greater than in never smokers, ex-smokers or quitters. The greater decline in those with respiratory disease or reduced lung function is consistent with some smokers having a more rapid rate of FEV1 decline. These results help in designing studies comparing continuing smokers of conventional cigarettes and switchers to novel products.