Centre-level variation in outcomes and treatment for otitis media with effusion and hearing loss and the association of hearing loss with developmental outcomes at ages 5 and 7 years in children with non-syndromic unilateral cleft lip and palate:the Cleft Care UK study. Part 2

Objectives: To explore centre-level variation in otitis media with effusion (OME), hearing loss and treatments in children in Cleft Care UK (CCUK) and to examine the association between OME, hearing loss and developmental outcomes at 5 and 7 years. Setting and Sample Population: Two hundred and sixty-eight 5-year-old British children with non-syndromic unilateral cleft lip and palate (UCLP) recruited to CCUK. Materials and Methods: Children had air and bone conduction audiometry at age 5. Information on grommet and hearing aid treatment was obtained from parental questionnaire and medical notes. Hearing loss at age 5 was defined as >20 dB in the better ear and history of OME and hearing loss was determined from past treatment. Children with sensorineural hearing loss were excluded. Associations were examined with speech, behaviour and self-confidence at age 5 and educational attainment at age 7. Centre variation was examined using hierarchical models and associations between hearing variables and developmental outcomes were examined using logistic regression. Results: There was centre-level variation in early grommet placement (variance partition coefficient (VPC) 18%, P=.001) and fitting of hearing aids (VPC 8%, P=.03). A history of OME and hearing loss was associated with poor intelligibility of speech (adjusted odds ratio=2.87, 95% CI 1.42-5.77) and aspects of educational attainment. Conclusions: Hearing loss is an important determinant of poor speech and treatment variation across centres suggest management of OME and hearing loss could be improved

From genetics to epigenetics: new perpectives in Tourette Syndrome research

Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder marked by the appearance of multiple involuntary motor and vocal tics. TS presents high comorbidity rates with other disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). TS is highly heritable and has a complex polygenic background. However, environmental factors also play a role in the manifestation of symptoms. Different epigenetic mechanisms may represent the link between these two causalities. Epigenetic regulation has been shown to have an impact in the development of many neuropsychiatric disorders, however very little is known about its effects on Tourette Syndrome.This review provides a summary of the recent findings in the genetic background of TS, followed by an overview on different epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs in the regulation of gene expression. Epigenetic studies in other neurological and psychiatric disorders are discussed along with the TS-related epigenetic findings available in the literature to date. Moreover, we are proposing that some general epigenetic mechanisms seen in other neuropsychiatric disorders may also play a role in the pathogenesis of TS

Basic Science of Liver Cancer Stem Cells and Hepatocarcinogenesis

The basic science of liver cancer stem cells (LCSCs) and hepatocarcinogenesis is best understood by familiarity with the increasingly complex epidemiology of hepatocellular carcinoma (HCC), with the still unknown cell origin(s) of HCC, with the anatomy and function of the liver lobule and with the historical and some novel methods for the study and identification of adult tissue stem cells and LCSCs

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field