A perspective on "cure" for Rett syndrome

The reversal of the Rett syndrome disease process in the Mecp2 mouse model of Guy et al. (2007) has motivated families and researchers to work on this condition. The reversibility in adult mice suggests that there is potentially much to be gained from rational treatments applied to patients of any age. However, it may be difficult to strike the right balance between enthusiasm on the one hand and realism on the other. One effect of this has been a fragmentation of the “Rett syndrome community” with some groups giving priority to work aimed at a cure while fewer resources are devoted to medical or therapy-based interventions to enhance the quality of life of affected patients or provide support for their families. Several possible therapeutic approaches are under development that, it is claimed and hoped, may lead to a “cure” for patients with Rett syndrome. While all have a rationale, there are potential obstacles to each being both safe and effective. Furthermore, any strategy that succeeded in restoring normal levels of MECP2 gene expression throughout the brain carries potential pitfalls, so that it will be of crucial importance to introduce any clinical trials of such therapies with great care. Expectations of families for a radical, rational treatment should not be inflated beyond a cautious optimism. This is particularly because affected patients with us now may not be able to reap the full benefits of a “cure”. Thus, interventions aimed at enhancing the quality of life of affected patients should not be forgone and their importance should not be minimised

General and age-specific fertility rates in non-affective psychosis : population-based analysis of Scottish women

The study was funded by Chief Scientist Office, Scottish Government Health and Social Care Directorate (Grant CZH/4/951), NHS Research Scotland (NHS Research Scotland Career Research Fellowship).Peer reviewedPublisher PD

Three nested randomized controlled trials of peer only or multiple stakeholder group feedback within Delphi surveys during core outcome and information set development

Top 10 items rated essential in round 1. (DOCX 17 kb

RT 03: Challenges for sustainable production around the world

MutifunctionalityQualityContinuityResiliencePublishe

Catchment-wide interactive effects of anthropogenic structures and river levels on fish spawning migrations

Worldwide, rivers are extensively fragmented by anthropogenic structures, reducing longitudinal connectivity, inhibiting migration and leading to severe declines in many fish populations, especially for diadromous species. However, few studies have determined the effects of annual differences in hydrology on catchment penetration past barriers to spawning habitats. We investigated the upstream spawning migration of 120 (n = 61 & 59) acoustic tagged river lamprey (Lampetra fluviatilis) across two contrasting (dry and wet) years in the River Yorkshire Ouse, England. Overall, significantly more lamprey reached spawning habitat (76% vs 39%) and penetrated significantly further upstream (median [km] from release, 53.9 vs 16.8) in the wet year than the dry year. Passage at weirs was almost exclusively during elevated river levels, which directly and collectively influenced catchment-wide distribution, especially in the dry year. Indeed, higher proportions entered two upper tributaries in the wet year (9.8% vs 27.1% and 9.8% vs 30.5%), due to increased passage efficiencies at the two main river weirs (60.5–87.5% and 54.5–83.8%), and reached assumed spawning locations 66.5% and 10.9% quicker. By contrast, there was no difference in numbers of lamprey entering, or time taken to arrive at assumed spawning location, in the two lower river tributaries between years. Our study supports the landscape-scale paradigm for ecosystem restoration because of the observed catchment-level effects of hydrology and barrier distribution on fish migration. Connectivity restoration for migratory fish should be implemented at a catchment scale, with planning incorporating spatial information regarding accessibility to key habitats to reap the largest gains

General and age-specific fertility rates in non-affective psychosis : population-based analysis of Scottish women

Women diagnosed with non-affective psychosis have a lower general fertility rate (GFR) and age-specific fertility rate (ASFR) than women in the general population. Contemporary data on GFR in this group remain limited, despite substantive changes in prescribing and management. We calculated contemporary estimates of the GFR and ASFR for women diagnosed with non-affective psychosis compared with the general population of women without this diagnosis. A population-based design combined routinely collected historical maternity and psychiatric data from two representative areas of Scotland. Women were included from the NHS Grampian or Greater Glasgow and Clyde areas and were aged 15-44 between 2005 and 2013 inclusive. The 'exposed' group had a diagnosis of non-affective psychosis (ICD-10 F20-F29) and was compared to the general population of 'unexposed' women in the same geographical areas. Annual GFR between 2005 and 2013 for women with non-affective psychosis varied from 9.6 to 21.3 live births/1000 women per year in the exposed cohort and 52.7 to 57.8 live births/1000 women per year in the unexposed cohort, a rate ratio (RR) of 0.28 [

Transcriptional and phenotypic comparisons of Ppara knockout and siRNA knockdown mice

RNA interference (RNAi) has great potential as a tool for studying gene function in mammals. However, the specificity and magnitude of the in vivo response to RNAi remains to be fully characterized. A molecular and phenotypic comparison of a genetic knockout mouse and the corresponding knockdown version would help clarify the utility of the RNAi approach. Here, we used hydrodynamic delivery of small interfering RNA (siRNA) to knockdown peroxisome proliferator activated receptor alpha (Ppara), a gene that is central to the regulation of fatty acid metabolism. We found that Ppara knockdown in the liver results in a transcript profile and metabolic phenotype that is comparable to those of Ppara(−/−) mice. Combining the profiles from mice treated with the PPARα agonist fenofibrate, we confirmed the specificity of the RNAi response and identified candidate genes proximal to PPARα regulation. Ppara knockdown animals developed hypoglycemia and hypertriglyceridemia, phenotypes observed in Ppara(−/−) mice. In contrast to Ppara(−/−) mice, fasting was not required to uncover these phenotypes. Together, these data validate the utility of the RNAi approach and suggest that siRNA can be used as a complement to classical knockout technology in gene function studies