Cognitive Function in Children With Type 1 Diabetes: A meta-analysis

OBJECTIVE—To quantify the magnitude and pattern of cognitive difficulties in pediatric type 1 diabetes as well as the effects associated with earlier disease onset and severe hypoglycemia

Biometal Dyshomeostasis in Olfactory Mucosa of Alzheimer's Disease Patients

Olfactory function, orchestrated by the cells of the olfactory mucosa at the rooftop of the nasal cavity, is disturbed early in the pathogenesis of Alzheimer's disease (AD). Biometals including zinc and calcium are known to be important for sense of smell and to be altered in the brains of AD patients. Little is known about elemental homeostasis in the AD patient olfactory mucosa. Here we aimed to assess whether the disease-related alterations to biometal homeostasis observed in the brain are also reflected in the olfactory mucosa. We applied RNA sequencing to discover gene expression changes related to metals in olfactory mucosal cells of cognitively healthy controls, individuals with mild cognitive impairment and AD patients, and performed analysis of the elemental content to determine metal levels. Results demonstrate that the levels of zinc, calcium and sodium are increased in the AD olfactory mucosa concomitantly with alterations to 17 genes related to metal-ion binding or metal-related function of the protein product. A significant elevation in alpha-2-macroglobulin, a known metal-binding biomarker correlated with brain disease burden, was observed on the gene and protein levels in the olfactory mucosa cells of AD patients. These data demonstrate that the olfactory mucosa cells derived from AD patients recapitulate certain impairments of biometal homeostasis observed in the brains of patients.Peer reviewe

Single-Cell RNA-Seq Analysis of Olfactory Mucosal Cells of Alzheimer's Disease Patients

Olfaction is orchestrated by olfactory mucosal cells located in the upper nasal cavity. Olfactory dysfunction manifests early in several neurodegenerative disorders including Alzheimer's disease, however, disease-related alterations to the olfactory mucosal cells remain poorly described. The aim of this study was to evaluate the olfactory mucosa differences between cognitively healthy individuals and Alzheimer's disease patients. We report increased amyloid-beta secretion in Alzheimer's disease olfactory mucosal cells and detail cell-type-specific gene expression patterns, unveiling 240 differentially expressed disease-associated genes compared to the cognitively healthy controls, and five distinct cell populations. Overall, alterations of RNA and protein metabolism, inflammatory processes, and signal transduction were observed in multiple cell populations, suggesting their role in Alzheimer's disease-related olfactory mucosa pathophysiology. Furthermore, the single-cell RNA-sequencing proposed alterations in gene expression of mitochondrially located genes in AD OM cells, which were verified by functional assays, demonstrating altered mitochondrial respiration and a reduction of ATP production. Our results reveal disease-related changes of olfactory mucosal cells in Alzheimer's disease and demonstrate the utility of single-cell RNA sequencing data for investigating molecular and cellular mechanisms associated with the disease.Peer reviewe

Glycoprotein YKL-40: A potential biomarker of disease activity in rheumatoid arthritis during intensive treatment with csDMARDs and infliximab. Evidence from the randomised controlled NEO-RACo trial

ObjectiveYKL-40, a chitinase-like glycoprotein associated with inflammation and tissue remodeling, is produced by joint tissues and recognized as a candidate auto-antigen in rheumatoid arthritis (RA). In the present study, we investigated YKL-40 as a potential biomarker of disease activity in patients with early RA at baseline and during intensive treatment aiming for early remission.MethodsNinety-nine patients with early DMARD-naive RA participated in the NEO-RACo study. For the first four weeks, the patients were treated with the combination of sulphasalazine, methotrexate, hydroxychloroquine and low dose prednisolone (FIN-RACo DMARD combination), and subsequently randomized to receive placebo or infliximab added on the treatment for further 22 weeks. Disease activity was evaluated using the 28-joint disease activity score and plasma YKL-40 concentrations were measured by immunoassay.ResultsAt the baseline, plasma YKL-40 concentration was 57 +/- 37 ( mean +/- SD) ng/ml. YKL-40 was significantly associated with the disease activity score, interleukin-6 and erythrocyte sedimentation rate both at the baseline and during the 26 weeks' treatment. The csDMARD combination decreased YKL-40 levels already during the first four weeks of treatment, and there was no further reduction when the tumour necrosis factor-alpha antagonist infliximab was added on the combination treatment.ConclusionsHigh YKL-40 levels were found to be associated with disease activity in early DMARD-naive RA and during intensive treat-to-target therapy. The present results suggest YKL-40 as a useful biomarker of disease activity in RA to be used to steer treatment towards remission

Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force

Background Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. Objective To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. Methods A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. Results The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). Conclusions The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA