Expression and function of microRNA-188-5p in activated rheumatoid arthritis synovial fibroblasts

Activated synovial fibroblasts in rheumatoid arthritis (RASF) play a critical role in the pathology of rheumatoid arthritis (RA). Recent studies suggested that deregulation of microRNAs (miRs) affects the development and progression of RA. Therefore, we aimed to identify de-regulated miRs in RASF and to identify target genes that may contribute to the aggressive phenotype of RASF. Quantitative real-time PCR revealed a marked downregulation of miR-188-5p in synovial tissue samples of RA patients as well as in RASF. Exposure to the cytokine interleukine-1β lead to a further downregulation of miR-188-5p expression levels compared to control cells. Re-expression of miR-188-5p in RASF by transient transfection significantly inhibited cell migration. However, miR-188-5p re-expression had no effects on glycosaminoglycan degradation or expression of repellent factors, which have been previously shown to affect the invasive behavior of RASF. In search for target genes of miR-188-5p in RASF we performed gene expression profiling in RASF and found a strong regulatory effect of miR-188-5p on the hyaluronan binding protein KIAA1199 as well as collagens COL1A1 and COL12A1, which was confirmed by qRT-PCR. In silico analysis revealed that KIAA1199 carries a 3’UTR binding site for miR-188-5p. COL1A1 and COL12A1 showed no binding site in the mRNA region, suggesting an indirect regulation of these two genes by miR-188-5p. In summary, our study showed that miR-188-5p is down-regulated in RA in vitro and in vivo, most likely triggered by an inflammatory environment. MiR-188-5p expression is correlated to the activation state of RASF and inhibits migration of these cells. Furthermore, miR-188-5p is directly and indirectly regulating the expression of genes, which may play a role in extracellular matrix formation and destruction in RA. Herewith, this study identified potential novel therapeutic targets to inhibit the development and progression of RA.     

The CCC2000 Birth Cohort Study of Register-Based Family History of Mental Disorders and Psychotic Experiences in Offspring

Psychotic experiences (PE) in individuals of the general population are hypothesized to mark the early expression of the pathology underlying psychosis. This notion of PE as an intermediate phenotype is based on the premise that PE share genetic liability with psychosis. We examined whether PE in childhood was predicted by a family history of mental disorder with psychosis rather than a family history of nonpsychotic mental disorder and whether this association differed by severity of PE. The study examined data on 1632 children from a general population birth cohort assessed at age 11–12 years by use of a semistructured interview covering 22 psychotic symptoms. The Danish national registers were linked to describe the complete family history of hospital-based psychiatric diagnoses. Uni- and multivariable logistic regressions were used to test whether a family history of any mental disorder with psychosis, or of nonpsychotic mental disorder, vs no diagnoses was associated with increased risk of PE in offspring (hierarchical exposure variable). The occurrence of PE in offspring was significantly associated with a history of psychosis among the first-degree relatives (adjusted relative risk [RR] = 3.29, 95% CI: 1.82–5.93). The risk increased for combined hallucinations and delusions (adjusted RR = 5.90, 95% CI: 2.64–13.16). A history of nonpsychotic mental disorders in first-degree relatives did not contribute to the risk of PE in offspring nor did any mental disorder among second-degree relatives. Our findings support the notion of PE as a vulnerability marker of transdiagnostic psychosis. The effect of psychosis in first-degree relatives may operate through shared genetic and environmental factors.Key words: psychosis, schizophrenia, epidemiology, family liability, general population, psychiatric family history     

Amyotrophic lateral sclerosis affects cortical and subcortical activity underlying motor inhibition and action monitoring

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by muscular atrophy, spasticity, and bulbar signs caused by loss of upper and lower motor neurons. Evidence suggests that ALS additionally affects other brain areas including premotor cortex and supplementary motor area. Here, we studied movement execution and inhibition in ALS patients using a stop‐signal paradigm and functional magnetic resonance imaging. Seventeen ALS patients and 17 age‐matched healthy controls performed a stop‐signal task that required responding with a button press to a right‐ or left‐pointing black arrow (go‐stimuli). In stop‐trials, a red arrow (stop‐stimulus) was presented shortly after the black arrow indicating to withhold the prepared movement. Patients had by trend higher reaction times in go‐trials but did not differ significantly in their inhibition performance. Patients showed stronger inhibition‐related activity in inferior, superior, and middle frontal gyri as well as in putamen and pallidum. Error‐related activity, conversely, was found to be stronger in healthy controls, particularly in the insula bilaterally. Patients also showed increased activity in the motor cortex during button presses. The results provide evidence for altered prefrontal and subcortical networks underlying motor execution, motor inhibition, and error monitoring in ALS. Hum Brain Mapp 36:2878–2889, 2015. © 2015 Wiley Periodicals, Inc.     

Single-Nucleus and In Situ RNA–Sequencing Reveal Cell Topographies in the Human Pancreas

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Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors

Foxp3⁺ regulatory T cells (Tregs) are often highly enriched within the tumor-infiltrating T cell pool. Using a well-characterised model of carcinogen-induced fibrosarcomas we show that the enriched tumor-infiltrating Treg population comprises largely of CXCR3⁺ T-bet⁺ ‘T_H1-like’ Tregs which are thymus-derived Helios⁺ cells. Whilst IL-2 maintains homeostatic ratios of Tregs in lymphoid organs, we found that the perturbation in Treg frequencies in tumors is IL-2 independent. Moreover, we show that the T_H1 phenotype of tumor-infiltrating Tregs is dispensable for their ability to influence tumor progression. We did however find that unlike Tconvs, the majority of intra-tumoral Tregs express the activation markers CD69, CD25, ICOS, CD103 and CTLA4 and are significantly more proliferative than Tconvs. Moreover, we have found that CD69⁺ Tregs are more suppressive than their CD69⁻ counterparts. Collectively, these data indicate superior activation of Tregs in the tumor microenvironment, promoting their suppressive ability and selective proliferation at this site.     

Recruitment and coaching of healthy elderly subjects for invasive cardiovascular research with right-sided catheterisation

BACKGROUND AND AIMS: Heart failure is primarily a disorder of the elderly. To investigate a non-invasive method to diagnose heart failure in the elderly, right-sided catheterisation was needed in healthy elderly subjects. We studied the feasibility of recruitment of healthy elderly subjects for this invasive investigation and aimed to identify the factors important for recruitment and for successful participation. METHODS: Healthy subjects, aged >/=65 years, were invited by advertisement in a local newspaper to participate in an invasive study, preceded by extensive medical examination. An experienced research nurse provided coaching and care on an individual basis. Motivation to participate, satisfaction and the expected and perceived burden were assessed with a questionnaire before and after catheterisation. RESULTS: From 180 subjects responding, 53 were invited for screening of whom 38 were included. Cardiovascular examination was the most important reason for participation. The questionnaire showed considerable satisfaction about the information and care given and about participating in the study in general. CONCLUSIONS: Recruitment of healthy elderly subjects for an invasive cardiovascular study is feasible. Individual coaching contributed to the satisfaction experienced. The appointment of an experienced research nurse appears important for successful recruitment and participation of healthy elderly subjects in an invasive cardiovascular study.     

Perceptions of informed consent in the care of elderly people in five European countries

The focus of this article is on elderly patients' and nursing staff perceptions of informed consent in the care of elderly patients/residents in five European countries. The results suggest that patients and nurses differ in their views on how informed consent is implemented. Among elderly patients the highest frequency for securing informed consent was reported in Finland; the lowest was in Germany. In contrast, among nurses, the highest frequency was reported in the UK (Scotland) and the lowest in Finland. In a comparison of patients' and nurses' perceptions, nurses had more positive views than patients in all countries except Finland. Patients with less need for nursing interventions in Greece and Spain gave their consent less often. The German and Greek patients were older, and the results also point to an association between this and their lower frequency of giving consent. In Spain, patients who were married or who had a family member or friend to look after their personal affairs were more likely to be included in the group whose consent was sought less often. This is the fourth of a set of five articles published together in this issue of Nursing Ethics in which the results of this comparative research project are presented.