Elevated O-GlcNAc levels activate epigenetically repressed genes and delay mouse ES cell differentiation without affecting naive to primed cell transition

The differentiation of mouse embryonic stem (ES) cells is controlled by the interaction of multiple signaling pathways, typically mediated by post-translational protein modifications. The addition of O-linked N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of nuclear and cytoplasmic proteins is one such modification (O-GlcNAcylation), whose function in ES cells is only now beginning to be elucidated. Here we demonstrate that the specific inhibition of O-GlcNAc hydrolase (Oga) causes increased levels of protein O-GlcNAcylation and impairs differentiation of mouse ES cells both in serum-free monolayer and in embryoid bodies (EBs). Use of reporter cell lines demonstrates that Oga inhibition leads to a reduction in the number of Sox1-expressing neural progenitors generated following induction of neural differentiation, as well as maintained expression of the ES cell marker Oct4 (Pou5f1). In EBs expression of mesodermal and endodermal markers is also delayed. However, the transition of naïve cells to primed pluripotency indicated by Rex1 (Zfp42), Nanog, Esrrb and Dppa3 downregulation and Fgf5 upregulation remains unchanged. Finally, we demonstrate that increased O-GlcNAcylation results in upregulation of genes normally epigenetically silenced in ES cells, supporting the emerging role for this protein modification in the regulation of histone modifications and DNA methylation. Stem Cells 2014

Economic Issues in Funding and Supplying Public Sector Information

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly being used for diagnosis of Alzheimer's disease (AD). OBJECTIVE: We investigated the influence of CSF intralaboratory and interlaboratory variability on diagnostic CSF-based AD classification of subjects and identified causes of this variation. METHODS: We measured CSF amyloid-beta (Abeta) 1-42, total tau (t-tau), and phosphorylated tau (p-tau) by INNOTEST enzyme-linked-immunosorbent assays (ELISA) in a memory clinic population (n = 126). Samples were measured twice in a single or two laboratories that served as reference labs for CSF analyses in the Netherlands. Predefined cut-offs were used to classify CSF biomarkers as normal or abnormal/AD pattern. RESULTS: CSF intralaboratory variability was higher for Abeta1-42 than for t-tau and p-tau. Reanalysis led to a change in biomarker classification (normal vs. abnormal) of 26% of the subjects based on Abeta1-42, 10% based on t-tau, and 29% based on p-tau. The changes in absolute biomarker concentrations were paralleled by a similar change in levels of internal control samples between different assay lots. CSF interlaboratory variability was higher for p-tau than for Abeta1-42 and t-tau, and reanalysis led to a change in biomarker classification of 12% of the subjects based on Abeta1-42, 1% based on t-tau, and 22% based on p-tau. CONCLUSIONS: Intralaboratory and interlaboratory CSF variability frequently led to change in diagnostic CSF-based AD classification for Abeta1-42 and p-tau. Lot-to-lot variation was a major cause of intralaboratory variability. This will have implications for the use of these biomarkers in clinical practice

Hebben verzorgende familieleden invloed op probleemgedrag bij dementie?

Er is weinig bekend over strategiee¨n die familieleden kunnen hanteren in de zorg voor een dementerende oudere. Het identificeren van verschillende strategiee¨n is van belang om inzicht te krijgen in de omgang met en manifestatie van psychologische en gedragsmatige veranderingen bij dementie. In de MAAstricht Study of BEhaviour in Dementia werden 99 patie¨nten met dementie en hun zorgverlenende familieleden gedurende 1 jaar gevolgd en om het half jaar terug gezien. Gedragsstoornissen bij de patie¨nt werden gemeten met de NeuroPsychiatric Inventory (NPI). Interviews werden gebruikt omzorgstrategiee¨n te identificeren. Met een herhaalde meting analyse werd de invloed vastgesteld van zorgstrategiee¨n op gedrag van de patie¨nt. Er werden drie verschillende zorgstrategiee¨n geı¨dentificeerd, gebaseerd op het al dan niet geaccepteerd hebben van de ziekte. Een strategie die werd gekenmerkt door onbegrip en een gebrek aan acceptatie werd getypeerd als “niet-adaptief”; strategiee¨n gekenmerkt door acceptatie werden onderverdeeld in een “zorgende” en een “ondersteunende” strategie. Kenmerken van de verzorgers zoals geslacht, opleiding en persoonlijkheid waren belangrijke determinanten van zorgstrategiee¨n. Bovendien werd in de niet-adaptieve groep meer hyperactiviteit gerapporteerd bij de patie¨nt en voelden de verzorgers zich het minst competent. In de ondersteunende groep voelden de verzorgers zich het meest competent en werd de minste hyperactiviteit bij de patie¨nt gerapporteerd. Concluderend geven de resultaten aan dat zorgstrategiee¨n verband houden met gedragsproblemen hij de patie¨nt en gevoelens van competentie bij de verzorger. Interventies gericht op het aanleren van adequate zorgstrategiee¨n bij verzorgers zouden mogelijk het probleemgedrag bij de patie¨nt en de belasting van de verzorger kunnen verminderen

Diagnosing Alzheimer's disease: A systematic review of economic evaluations

Background: The objective of this study is to systematically review the literature on economic evaluations of interventions for the early diagnosis of Alzheimer's disease (AD) and related disorders and to describe their general and methodological characteristics. We focused on the diagnostic aspects of the decision models to assess the applicability of existing decision models for the evaluation of the recently revised diagnostic research criteria for AD. Methods: PubMed and the National Institute for Health Research Economic Evaluation database were searched for English-language publications related to economic evaluations on diagnostic technologies. Trial-based economic evaluations were assessed using the Consensus on Health Economic Criteria list. Modeling studies were assessed using the framework for quality assessment of decision-analytic models. Results: The search retrieved 2109 items, from which eight decision-analytic modeling studies and one trial-based economic evaluation met all eligibility criteria. Conclusions: Diversity among the study objective and characteristics was considerable and, despite considerable methodological quality, several flaws were indicated. Recommendations were focused on diagnostic aspects and the applicability of existing models for the evaluation of recently revised diagnostic research criteria for AD. (C) 2014 The Alzheimer's Association. All rights reserved

Optimizing the use of expert panel reference diagnoses in diagnostic studies of multidimensional syndromes

__Abstract__ Background: In the absence of a gold standard, a panel of experts can be invited to assign a reference diagnosis for use in research. Available literature offers limited guidance on assembling and working with an expert panel for this purpose. We aimed to develop a protocol for an expert panel consensus diagnosis and evaluated its applicability in a pilot project. Methods: An adjusted Delphi method was used, which started with the assessment of clinical vignettes by 3 experts individually, followed by a consensus discussion meeting to solve diagnostic discrepancies. A panel facilitator ensured that all experts were able to express their views, and encouraged the use of argumentation to arrive at a specific diagnosis, until consensus was reached by all experts. Eleven vignettes of patients suspected of having a primary neurodegenerative disease were presented to the experts. Clinical information was provided stepwise and included medical history, neurological, physical and cognitive function, brain MRI scan, and follow-up assessments over 2 years. After the consensus discussion meeting, the procedure was evaluated by the experts. Results: The average degree of consensus for the reference diagnosis increased from 52% after individual assessment of the vignettes to 94% after the consensus discussion meeting. Average confidence in the diagnosis after individual assessment was 85%. This did not increase after the consensus discussion meeting. The process evaluation led to several recommendations for improvement of the protocol. Conclusion: A protocol for attaining a reference diagnosis based on expert panel consensus was shown feasible in research practice

Reduced functional measure of cardiovascular reserve predicts admission to critical care unit following kidney transplantation

Background: There is currently no effective preoperative assessment for patients undergoing kidney transplantation that is able to identify those at high perioperative risk requiring admission to critical care unit (CCU). We sought to determine if functional measures of cardiovascular reserve, in particular the anaerobic threshold (VO2AT) could identify these patients. Methods: Adult patients were assessed within 4 weeks prior to kidney transplantation in a University hospital with a 37-bed CCU, between April 2010 and June 2012. Cardiopulmonary exercise testing (CPET), echocardiography and arterial applanation tonometry were performed. Results: There were 70 participants (age 41.7614.5 years, 60% male, 91.4% living donor kidney recipients, 23.4% were desensitized). 14 patients (20%) required escalation of care from the ward to CCU following transplantation. Reduced anaerobic threshold (VO2AT) was the most significant predictor, independently (OR = 0.43; 95% CI 0.27–0.68; p,0.001) and in the multivariate logistic regression analysis (adjusted OR = 0.26; 95% CI 0.12–0.59; p = 0.001). The area under the receiveroperating- characteristic curve was 0.93, based on a risk prediction model that incorporated VO2AT, body mass index and desensitization status. Neither echocardiographic nor measures of aortic compliance were significantly associated with CCU admission. Conclusions: To our knowledge, this is the first prospective observational study to demonstrate the usefulness of CPET as a preoperative risk stratification tool for patients undergoing kidney transplantation. The study suggests that VO2AT has the potential to predict perioperative morbidity in kidney transplant recipients

Trajectories and Determinants of Quality of Life in Dementia with Lewy Bodies and Alzheimer's Disease

Background: Quality of Life (QoL) is an important outcome measure in dementia, particularly in the context of interventions. Research investigating longitudinal QoL in dementia with Lewy bodies (DLB) is currently lacking. Objective: To investigate determinants and trajectories of QoL in DLB compared to Alzheimer’s disease (AD) and controls. Methods: QoL was assessed annually in 138 individuals, using the EQ5D-utility-score (0–100) and the health-related Visual Analogue Scale (VAS, 0–100). Twenty-nine DLB patients (age 69 ± 6), 68 AD patients (age 70 ± 6), and 41 controls (age 70 ± 5) were selected from the Dutch Parelsnoer Institute-Neurodegenerative diseases and Amsterdam Dementia Cohort. We examined clinical work-up over time as determinants of QoL, including cognitive tests, neuropsychiatric inventory, Geriatric Depression Scale (GDS), and disability assessment of dementia (DAD). Results: Mixed models showed lower baseline VAS-scores in DLB compared to AD and controls (AD: ±SE = -7.6 ± 2.8, controls: ±SE = -7.9 ± 3.0, p < 0.05). An interaction between diagnosis and time since diagnosis indicated steeper decline on VAS-scores for AD patients compared to DLB patients (±SE = 2.9 ± 1.5, p < 0.1). EQ5D-utility-scores over time did not differ between groups. Higher GDS and lower DAD-scores were independently associated with lower QoL in dementia patients (GDS: VAS ±SE = -1.8 ± 0.3, EQ5D-utility ±SE = -3.7 ± 0.4; DAD: VAS = 0.1 ± 0.0, EQ5D-utility ±SE = 0.1 ± 0.1, p < 0.05). No associations between cognitive tests and QoL remained in the multivariate model. Conclusion: QoL is lower in DLB, while in AD QoL shows steepe