Issues surrounding orphan disease and orphan drug policies in Europe

An orphan disease is a disease with a very low prevalence. Although there are 5000–7000 orphan diseases, only 50 orphan drugs (i.e. drugs developed to treat orphan diseases) were marketed in the EU by the end of 2008. In 2000, the EU implemented policies specifically designed to stimulate the development of orphan drugs. While decisions on orphan designation and the marketing authorization of orphan drugs are made at the EU level, decisions on drug reimbursement are made at the member state level. The specific features of orphan diseases and orphan drugs make them a high-priority issue for policy makers. The aim of this article is to identify and discuss several issues surrounding orphan disease and drug policies in Europe. The present system of orphan designation allows for drugs for non-orphan diseases to be designated as orphan drugs. The economic factors underlying orphan designation can be questioned in some cases, as a low prevalence of a certain indication does not equal a low return on investment for the drug across its indications. High-quality evidence about the clinical added value of orphan drugs is rarely available at the time of marketing authorization, due to the low number of patients. A balance must be struck between ethical and economic concerns. To this effect, there is a need to initiate a societal dialogue on this issue, to clarify what society wants and accepts in terms of ethical and economic consequences. The growing budgetary impact of orphan drugs puts pressure on drug expenditure. Indications can be extended for an orphan drug and the total prevalence across indications is not considered. Finally, cooperation needs to be fostered in the EU, particularly through a standardized approach to the creation and use of registries. These issues require further attention from researchers, policy makers, health professionals, patients, pharmaceutical companies and other stakeholders with a view to optimizing orphan disease and drug policies in Europe.     

Community-level social capital and recurrence of acute coronary syndrome

Social capital has been shown to be associated with reduced mortality due to cardiovascular disease. Our aim was to determine the association of time-varying community-level social capital (CSC) with recurrence of acute coronary syndrome using a retrospective cohort study design. A total of 34,752 men and women were identified, aged 30-85 years, who were hospitalized for acute coronary syndrome between January 1, 1998 and December 31, 2002 in Kaiser Permanente Northern California, USA, an integrated health care delivery system. The primary outcome was recurrent non-fatal or fatal acute coronary syndrome; median follow-up was 19 months. We estimated random-effects, three-level Cox proportional hazard models adjusting for sex, age, race/ethnicity, comorbidities, medication use, and revascularization procedures at level 1, median household income for the census block-group at level 2, and income inequality, racial/ethnic concentration, penetration of health maintenance organizations, and CSC at level 3. Our measure of CSC was the previously validated Petris Social Capital Index (PSCI). We found that a one-standard deviation increase in the PSCI, after adjusting for the above covariates, was significantly associated with decreased recurrence of acute coronary syndrome only for those living in areas where block-group level median household income was below the grand median compared to those living in areas where block-group level median household income was at the grand median or above. These results suggest that community-level social capital may be negatively associated with recurrence of acute coronary syndrome among lower-income individuals.     

Behavioural responses to perceived risk of tick-borne encephalitis: vaccination and avoidance in the Baltics and Slovenia

Tick-borne encephalitis (TBE) incidence increased markedly in the Baltics and Slovenia in the early 1990s, but then declined again in some places. Our analyses of temporal and spatial data on TBE incidence and vaccination revealed that over 1970-2005 up-take of vaccination varied in both time and space according to incidence, i.e. was apparently responsive to perceived risk. Since 1999, however, decreases in incidence in many counties within each country have far exceeded vaccination rates or immunity through natural exposure, and in Latvia and Lithuania these changes are correlated with previous incidence. Survey data on human activities in Latvia revealed that people in socio-economic groups whose behaviour put them at highest risk of exposure to ticks in forests, including people with lower education and lowest incomes, are least likely to be vaccinated. We conclude that risk avoidance through changing human behaviour has driven incidence-dependent decreases in TBE infection, but targeted vaccination campaigns could provide more secure protection.     

Therapeutic approach in patients with age-related macular degeneration and cataract

Management of the patient with coexisting cataract and AMD presents unique challenges to the cataract surgeon, the retina specialist, and the patient. A common clinical scenario is the patient in whom both the cataract and macular pathology appear to be contributing to decreased visual acuity. As with any surgery, the expectations from cataract removal must be evaluated thoroughly and understood clearly by both the patient and the cataract surgeon. Most patients with AMD who undergo cataract surgery feel that the surgery is worthwhile, and they report improvement of visual function and quality of life. In patients with mild AMD, improvement in central visual acuity and attainment of driving vision are realistic and achievable goals. In an eye with central disciform scarring or geographic atrophy there may be potential for improvement in color discrimination, contrast, or clarity of peripheral vision. In cases of dense cataract obscuring macular detail, cataract removal may be necessary to allow for adequate biomicroscopy and angiography, especially in an eye that may be at high risk for the development of choroidal neovascularization. It is often challenging to estimate the relative impact on visual impairment made by the lens opacities and the macular changes and the benefits and risks of cataract surgery in eyes with AMD should be carefully evaluated. Is cataract surgery justified in these patients? Does cataract surgery aggravate AMD in some patients?     

Chronic combined stress induces selective and long-lasting inflammatory response evoked by changes in corticosterone accumulation and signaling in rat hippocampus

Metabolic Brain Disease - Hippocampus is believed to be selectively vulnerable to stress. We hypothesized that this phenomenon may be mediated by relatively high vulnerability to neuroinflammation...     

Fear-relevant change detection in spider-fearful and non-fearful participants

Features of threatening stimuli are proposed to be processed fast and automatically, as they call for immediate attention. Phobic patients typically exhibit these attentional biases for stimuli that are relevant for their particular type of fear. In the present study, it was examined whether a change detection paradigm can be used to study attentional bias for fear-related stimuli. Twenty-five spider-fearful and 25 non-fearful participants were confronted with a series of pictures, in which sometimes a spider gradually appeared, sometimes a fear-irrelevant stimulus appeared, and sometimes no change occurred. Participants had to indicate whenever they noticed a change in the picture. Results showed a pattern of fear-relevant change detection. That is, spider changes were more frequently detected than fear-irrelevant changes, and spider-fearful participants detected more spider changes than non-fearful controls. Further, it was found that high-trait anxious participants did not detect more changes than low-trait anxious participants.     

Cerebellar Granule Cell Death Induced by Aluminum

Using flow cytometry of acutely isolated cerebellar granule cell neurons, we have determined the effects of Al (III) on viability, membrane potential, intracellular calcium concentration and generation of reactive oxygen species (ROS). Al (III) killed granule cells in a time- and concentration-dependent fashion when monitored by use of the DNA-binding dye, propidium iodide. The threshold concentration was about 50 micromolar, and cell death at 100 micromolar was apparent after 30 min exposure and increased over time. Cell death was accompanied by cell swelling and a decrease in membrane potential, and was not dependent on external calcium concentration. While exposure to Al (III) was accompanied by an increase in ROS and an elevation of intracellular calcium concentration, calcium chelators and ROS scavengers did not reduce cell death. The action of Al (III) was not accompanied by activation of caspase-3 or an increase in annexin-V binding, both indicators of apoptosis. In the presence of intracellular O,O'-bis(2-aminophenyl)ethyleneglycol-N,N,N',N'-tetraacetic acid (BAPTA) and absence of extracellular calcium there was still a fluo-3 signal, which likely reflects an accumulation of intracellular Al (III). These observations suggest that the cell death is subsequent to intracellular accumulation of Al (III) and subsequent perturbation of cellular metabolism.