Extreme Telomere Length Dimorphism in the Tasmanian Devil and Related Marsupials Suggests Parental Control of Telomere Length

Telomeres, specialised structures that protect chromosome ends, play a critical role in preserving chromosome integrity. Telomere dynamics in the Tasmanian devil (Sarcophilus harrisii) are of particular interest in light of the emergence of devil facial tumour disease (DFTD), a transmissible malignancy that causes rapid mortality and threatens the species with extinction. We used fluorescent in situ hybridisation to investigate telomere length in DFTD cells, in healthy Tasmanian devils and in four closely related marsupial species. Here we report that animals in the Order Dasyuromorphia have chromosomes characterised by striking telomere length dimorphism between homologues. Findings in sex chromosomes suggest that telomere length dimorphism may be regulated by events in the parental germlines. Long telomeres on the Y chromosome imply that telomere lengthening occurs during spermatogenesis, whereas telomere diminution occurs during oogenesis. Although found in several somatic cell tissue types, telomere length dimorphism was not found in DFTD cancer cells, which are characterised by uniformly short telomeres. This is, to our knowledge, the first report of naturally occurring telomere length dimorphism in any species and suggests a novel strategy of telomere length control. Comparative studies in five distantly related marsupials and a monotreme indicate that telomere dimorphism evolved at least 50 million years ago. © 2012 Bender et al

Deepening democracy within Ireland's social partnership

Ireland's social partnership process, now under attack from a number of quarters, has repeatedly been charged with being 'undemocratic' in that it undermines the sovereign position of elected political representatives, with key policy formulation and decision-making taking place in fora outside the institutions of representative democracy. These critiques echo those against new forms of networked governance more globally. A key question therefore is how (and if) democracy may be deepened within social partnership or its potential successor(s). This article addresses this question by employing a post-liberal democratic framework to examine social partnership in practice, and by drawing lessons from another partnership process, Malawi's PRSP. Drawing from Malawi's experience, it is argued that democracy can be deepened within social partnership when governance deliberations and negotiations are conducted under conditions of vibrant public debate and genuine perspective-based representation, and when the communicative and discursive norms are widened to allow for such representation

International Guillain-Barré Syndrome Outcome Study (IGOS): protocol of a prospective observational cohort study on clinical and biological predictors of disease course and outcome in Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy with a highly variable clinical presentation, course, and outcome. The factors that determine the clinical variation of GBS are poorly understood which complicates the care and treatment of individual patients. The protocol of the ongoing International GBS Outcome Study (IGOS), a prospective, observational, multi-centre cohort study that aims to identify the clinical and biological determinants and predictors of disease onset, subtype, course and outcome of GBS is presented here. Patients fulfilling the diagnostic criteria for GBS, regardless of age, disease severity, variant forms, or treatment, can participate if included within two weeks after onset of weakness. Information about demography, preceding infections, clinical features, diagnostic findings, treatment, course and outcome is collected. In addition, cerebrospinal fluid and serial blood samples for serum and DNA is collected at standard time points. The original aim was to include at least 1000 patients with a follow-up of 1-3 years. Data are collected via a web-based data entry system and stored anonymously. IGOS started in May 2012 and by January 2017 included more than 1400 participants from 143 active centres in 19 countries across 5 continents. The IGOS data/biobank is available for research projects conducted by expertise groups focusing on specific topics including epidemiology, diagnostic criteria, clinimetrics, electrophysiology, antecedent events, antibodies, genetics, prognostic modelling, treatment effects and long-term outcome of GBS. The IGOS will help to standardize the international collection of data and biosamples for future research of GBS. ClinicalTrials.gov Identifier: NCT01582763

Exact Solution of an Evolutionary Model without Ageing

We introduce an age-structured asexual population model containing all the relevant features of evolutionary ageing theories. Beneficial as well as deleterious mutations, heredity and arbitrary fecundity are present and managed by natural selection. An exact solution without ageing is found. We show that fertility is associated with generalized forms of the Fibonacci sequence, while mutations and natural selection are merged into an integral equation which is solved by Fourier series. Average survival probabilities and Malthusian growth exponents are calculated indicating that the system may exhibit mutational meltdown. The relevance of the model in the context of fissile reproduction groups as many protozoa and coelenterates is discussed.Comment: LaTeX file, 15 pages, 2 ps figures, to appear in Phys. Rev.

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

Clinical implications of the Royal College of Physicians three questions in routine asthma care: A real-life validation study

BACKGROUND: Annual recording of the Royal College of Physicians three questions (RCP3Q) morbidity score is rewarded within the UK 'pay-for-performance' Quality and Outcomes Framework. AIMS: To investigate the performance of the RCP3Qs for assessing control in real-life practice compared with the validated Asthma Control Questionnaire (ACQ) administered by self-completed questionnaire. METHODS: We compared the RCP3Q score extracted from a patient's computerised medical record with the ACQ self-completed after the consultation. The anonymous data were paired by practice, age, sex, and dates of completion. We calculated the sensitivity and specificity of the RCP3Q scale compared with the threshold for good/poor asthma control (ACQ greater than 1). RESULTS: Of 291 ACQ questionnaires returned from 12 participating practices, 129 could be paired with complete RCP3Q data. Twenty-five of 27 patients who scored zero on the RCP3Q were well controlled (ACQ less than 1). An RCP3Q score greater than 1 predicted inadequate control (ACQ greater than 1) with a sensitivity of 0.96 and specificity of 0.34. Comparable values for RCP3Q greater than 2 were sensitivity 0.50 and specificity 0.94. The intraclass correlation coefficient of 0.13 indicated substantial variability between practices. Exacerbations and use of reliever inhalers were moderately correlated with ACQ (Spearman's rho 0.3 and 0.35) and may reflect different aspects of control. CONCLUSIONS: In routine practice, an RCP3Q score of zero indicates good asthma control and a score of 2 or 3 indicates poor control. An RCP3Q score of 1 has good sensitivity but poor specificity for suboptimal control and should provoke further enquiry and consideration of other aspects of control such as exacerbations and use of reliever inhalers

MicroRNA-296 is enriched in cancer cells and downregulates p21WAF1 mRNA expression via interaction with its 3′ untranslated region

MicroRNAs (miRNAs) are a class of noncoding small RNAs that act as negative regulators of gene expression. To identify miRNAs that may regulate human cell immortalization and carcinogenesis, we performed comparative miRNA array profiling of human normal and SV40-T antigen immortalized cells. We found that miR-296 was upregulated in immortalized cells that also had activation of telomerase. By an independent experiment on genomic analysis of cancer cells we found that chromosome region (20q13.32), where miR-296 is located, was amplified in 28/36 cell lines, and most of these showed enriched miR-296 expression. Overexpression of miR-296 in human cancer cells, with and without telomerase activity, had no effect on their telomerase function. Instead, it suppressed p53 function that is frequently downregulated during human cell immortalization and carcinogenesis. By monitoring the activity of a luciferase reporter connected to p53 and p21WAF1 (p21) untranslated regions (UTRs), we demonstrate that miR-296 interacts with the p21-3′UTR, and the Hu binding site of p21-3′UTR was identified as a potential miR-296 target site. We demonstrate for the first time that miR-296 is frequently upregulated during immortalization of human cells and contributes to carcinogenesis by downregulation of p53-p21WAF1 pathway

What predicts change in pulmonary function and quality of life in asthma or COPD ?

Information about predictors of decline in pulmonary function (forced expiratory volume in 1 second [FE

A qualitative study of the impact of severe asthma and its treatment showing that treatment burden is neglected in existing asthma assessment scales

Background People with severe asthma experience significant respiratory symptoms and suffer adverse effects of oral corticosteroids (OCS), including disturbed mood and physical symptoms. OCS impacts on health-related quality of life (HRQoL) have not been quantified. Asthma HRQoL scales are valid as outcome measures for patients requiring OCS only if they assess the deficits imposed by OCS. Aims The aim of this study was to compare the burden of disease and treatment in patients with severe asthma with items in eight asthma-specific HRQoL scales. Methods Twenty-three patients with severe asthma recruited from a severe asthma clinic were interviewed about the impact of their respiratory symptoms and the burden of their treatment. The domains from a thematic analysis of these interviews were compared with the items of eight asthma-specific HRQoL scales. Results In addition to the burden caused by symptoms, ten domains of OCS impact on HRQoL were identified: depression, irritability, sleep, hunger, weight, skin, gastric, pain, disease anxiety, and medication anxiety. Some patients experienced substantial HRQoL deficits attributed to OCS. Although all HRQoL scales include some OCS-relevant items, all eight scales fail to adequately assess the several types of burden experienced by some patients while on OCS. Conclusion The burden of OCS in severe asthma is neglected in policy and practice because it is not assessed in outcome studies. Existing asthma HRQoL scales provide an overly positive estimation of HRQoL in patients with frequent exposure to OCS and underestimate the benefit of interventions that reduce OCS exposure. Changes to existing measurement procedures are needed