Ruimte voor goed bestuur: tussen prestatie, proces en principe - 2

Political Scienc

Structural and functional characterisation of human RNA helicase DHX8 provides insights into the mechanism of RNA-stimulated ADP release.

DHX8 is a crucial DEAH-box RNA helicase involved in splicing and required for the release of mature mRNA from the spliceosome. Here, we report the biochemical characterisation of full-length human DHX8 and the catalytically active helicase core DHX8Δ547, alongside crystal structures of DHX8Δ547 bound to ADP and a structure of DHX8Δ547 bound to poly(A)6 single-strand RNA. Our results reveal that DHX8 has an in vitro binding preference for adenine-rich RNA and that RNA binding triggers the release of ADP through significant conformational flexibility in the conserved DEAH-, P-loop and hook-turn motifs. We demonstrate the importance of R620 and both the hook-turn and hook-loop regions for DHX8 helicase activity and propose that the hook-turn acts as a gatekeeper to regulate the directional movement of the 3' end of RNA through the RNA-binding channel. This study provides an in-depth understanding of the activity of DHX8 and contributes insights into the RNA-unwinding mechanisms of the DEAH-box helicase family

Structure of the Cytoplasmic Loop between Putative Helices II and III of the Mannitol Permease of Escherichia coli: A Tryptophan and 5-Fluorotryptophan Spectroscopy Study

In this work, four single tryptophan (Trp) mutants of the dimeric mannitol transporter of Escherichia coli, EIImtl, are characterized using Trp and 5-fluoroTrp (5-FTrp) fluorescence spectroscopy. The four positions, 97, 114, 126, and 133, are located in a region shown by recent studies to be involved in the mannitol translocation process. To spectroscopically distinguish between the Trp positions in each subunit of dimeric EIImtl, 5-FTrp was biosynthetically incorporated because of its much simpler photophysics compared to those of Trp. The steady-state and time-resolved fluorescence methodologies used point out that all four positions are in structured environments, both in the absence and in the presence of a saturating concentration of mannitol. The fluorescence decay of all 5-FTrp-containing mutants was highly homogeneous, suggesting similar microenvironments for both probes per dimer. However, Stern-Volmer quenching experiments using potassium iodide indicate different solvent accessibilities for the two probes at positions 97 and 133. A 5 Å two-dimensional (2D) projection map of the membrane-embedded IICmtl dimer showing 2-fold symmetry is available. The results of this work are in better agreement with a 7 Å projection map from a single 2D crystal on which no symmetry was imposed.

Basal forebrain cholinergic system volume is associated with general cognitive ability in the elderly

OBJECTIVE: At the present, it is unclear whether association of basal forebrain cholinergic system (BFCS) volume with cognitive performance exists in healthy as well as in cognitively impaired elderly subjects. Whereas one small study reported an association of BFCS volume with general cognitive ability 'g' in healthy ageing, effects on specific cognitive domains have only been found in subjects with cognitive decline. Here we aim to clarify whether an association of BFCS volume and 'g' is present in a larger sample of elderly subjects without obvious symptoms of dementia and whether similar associations can also be observed in specific cognitive domains. METHODS: 282 pre-surgical patients from the BioCog study (aged 72.7±4.9 years with a range of 65-87 years, 110 women) with a median MMSE score of 29 points (range 24-30) were investigated. BFCS and brain volume as well as brain parenchymal fraction were assessed in T1-weighted MR images using SPM12 and a probabilistic map of the BFCS. Neuropsychological assessment comprised the CANTAB cognitive battery and paper-and-pencil based tests. For data analysis, generalised linear models and quantile regression were applied. RESULTS: Significant associations of BFCS volume with 'g' and several cognitive domains were found, with the strongest association found for 'g'. BFCS volume explained less variance in cognitive performance than brain volume. The association was not confounded by brain parenchymal fraction. Furthermore, the association of BFCS volume and 'g' was similar in high- and low-performers. CONCLUSION: Our results extend previous study findings on BFCS volume associations with cognition in elderly subjects. Despite the observed associations of BFCS volume and cognitive performance, this association seems to reflect a more general association of brain volume and cognition. Accordingly, a specific association of BFCS volume and cognition in non-demented elderly subjects is questionable

Stability of neuropsychological test performance in older adults serving as normative controls for a study on postoperative cognitive dysfunction

OBJECTIVE: Studies of postoperative cognitive dysfunction (POCD) rely on repeat neuropsychological testing. The stability of the applied instruments, which are affected by natural variability in performance and measurement imprecision, is often unclear. We determined the stability of a neuropsychological test battery using a sample of older adults from the general population. Forty-five participants aged 65 to 89 years performed six computerized and non-computerized neuropsychological tests at baseline and again at 7 day and 3 months follow-up sessions. Mean scores on each test were compared across time points using repeated measures analyses of variance (ANOVA) with pairwise comparison. Two-way mixed effects, absolute agreement analyses of variance intra-class correlation coefficients (ICC) determined test-retest reliability. RESULTS: All tests had moderate to excellent test-retest reliability during 7-day (ICC range 0.63 to 0.94; all p < 0.01) and 3-month intervals (ICC range 0.60 to 0.92; all p < 0.01) though confidence intervals of ICC estimates were large throughout. Practice effects apparent at 7 days eased off by 3 months. No substantial differences between computerized and non-computerized tests were observed. We conclude that the present six-test neuropsychological test battery is appropriate for use in POCD research though small sample size of our study needs to be recognized as a limitation. Trial registration ClinicalTrials.gov Identifier NCT02265263 (15th October 2014)

Contribution of IQ in young adulthood to the associations of education and occupation with cognitive ability in older age

BACKGROUND: Studies suggest that a higher education and occupation are each associated with a higher late-life cognitive ability, but their inter-relationships in their association with cognitive ability and the contribution of peak IQ in young adulthood ('pre-morbid IQ') often remain unclear. METHODS: Cross-sectional analysis of 623 participants aged ≥65 years of the BioCog study. Education was coded according to the International Standard Classification of Education (ISCED; range 1 to 6). Occupation was coded as 'semi/unskilled', 'skilled manual', 'skilled non-manual', 'managerial', 'professional'. A summary score of global ability (‘g’) was constructed from six cognitive tests. Pre-morbid IQ was estimated from vocabulary. The Geriatric Depression Scale assessed symptoms of depression. Age- and sex-adjusted analyses of covariance were performed. RESULTS: Education (partial eta2 0.076; p < 0.001) and occupation (partial eta2 = 0.037; p < 0.001) were each significantly associated with g. For education, the association was attenuated but remained statistically significant when pre-morbid IQ was controlled for (partial eta2 0.036; p < 0.001) and was unchanged with additional adjustment for depression (partial eta2 0.037; p < 0.001). For occupation, the association with g was no longer significant when pre-morbid IQ (partial eta2 = 0.015; p = 0.06) and depression (partial eta2 = 0.011; p = 0.18) were entered as covariates in separate steps. When education and occupation were entered concurrently into the fully adjusted model, only education was independently associated with g (partial eta2 0.030; p < 0.001; occupation, p = 0.93). CONCLUSION: While a higher education and a higher occupation were each associated with a higher late-life cognitive ability, only for education some unique contribution to cognitive ability remained over and above its relationship with pre-morbid IQ, depression, and occupation. Further research is needed to address whether a longer time spent in education may promote late-life cognitive ability

fMRI network correlates of predisposing risk factors for delirium: a cross-sectional study

Delirium, the clinical expression of acute encephalopathy, is a common neuropsychiatric syndrome that is related to poor outcomes, such as long-term cognitive impairment. Disturbances of functional brain networks are hypothesized to predispose for delirium. The aim of this study in non-delirious elderly individuals was to investigate whether predisposing risk factors for delirium are associated with fMRI network characteristics that have been observed during delirium. As predisposing risk factors, we studied age, alcohol misuse, cognitive impairment, depression, functional impairment, history of transient ischemic attack or stroke, and physical status. In this multicenter study, we included 554 subjects and analyzed resting-state fMRI data from 222 elderly subjects (63% male, age range: 65-85 year) after rigorous motion correction. Functional network characteristics were analyzed and based on the minimum spanning tree (MST). Global functional connectivity strength, network efficiency (MST diameter) and network integration (MST leaf fraction) were analyzed, as these measures were altered during delirium in previous studies. Linear regression analyses were used to investigate the relation between predisposing delirium risk factors and delirium-related fMRI characteristics, adjusted for confounding and multiple testing. Predisposing risk factors for delirium were not associated with delirium-related fMRI network characteristics. Older age within our elderly cohort was related to global functional connectivity strength (beta = 0.182, p < 0.05), but in the opposite direction than hypothesized. Delirium-related functional network impairments can therefore not be considered as the common mechanism for predisposition for delirium.Neuro Imaging Researc

Radiographic rib fracture nonunion and association with fracture classification in adults with multiple rib fractures without flail segment:A multicenter prospective cohort study

Background: Rib fracture nonunion is a probable cause of chronic pain following chest trauma, although its prevalence remains unknown. The aims of this study were to determine rib fracture nonunion prevalence following nonoperative management and to determine if presence of nonunion was associated with the number of rib fractures, or the rib fracture classification of anatomical location, type, and displacement. Methods: This multicenter prospective cohort study included trauma patients with three or more fractured ribs but without a flail segment, who participated in the nonoperative management group of the FixCon trial between January 2019 and June 2022. The number and classification of rib fractures were assessed on trauma chest CT. Chest CTs conducted six months post-trauma were evaluated for the presence of nonunion. Radiological characteristics of nonunions were compared with normally healed rib fractures using the Mann-Whitney U, χ2 test, and Fisher's exact test as appropriate. A generalized linear model adjusted for multiple observations per patient when assessing the associations between nonunion and fracture characteristics. Results: A total of 68 patients were included with 561 post-traumatic fractures in 429 ribs. Chest CT after six months revealed nonunions in 67 (12 %) rib fractures in 29 (43 %) patients with a median of 2 (P25-P75 1–3) nonunions per patient. Nonunion was most commonly observed in ribs seven to 10 (20–23 %, p &lt; 0.001, adjusted p = 0.006). Nonunion occurred in 14 (5 %) undisplaced, 22 (19 %) offset, and 20 (23 %) displaced rib fractures (p &lt; 0.001). No statistically significant association between rib fracture type and nonunion was found. Conclusions: Forty-three percent of patients with multiple rib fractures had radiographic nonunion six months after trauma. Fractures in ribs seven to 10 and dislocated fractures had an increased risk of rib fracture nonunion.</p

Radiographic rib fracture nonunion and association with fracture classification in adults with multiple rib fractures without flail segment:A multicenter prospective cohort study

Background: Rib fracture nonunion is a probable cause of chronic pain following chest trauma, although its prevalence remains unknown. The aims of this study were to determine rib fracture nonunion prevalence following nonoperative management and to determine if presence of nonunion was associated with the number of rib fractures, or the rib fracture classification of anatomical location, type, and displacement. Methods: This multicenter prospective cohort study included trauma patients with three or more fractured ribs but without a flail segment, who participated in the nonoperative management group of the FixCon trial between January 2019 and June 2022. The number and classification of rib fractures were assessed on trauma chest CT. Chest CTs conducted six months post-trauma were evaluated for the presence of nonunion. Radiological characteristics of nonunions were compared with normally healed rib fractures using the Mann-Whitney U, χ2 test, and Fisher's exact test as appropriate. A generalized linear model adjusted for multiple observations per patient when assessing the associations between nonunion and fracture characteristics. Results: A total of 68 patients were included with 561 post-traumatic fractures in 429 ribs. Chest CT after six months revealed nonunions in 67 (12 %) rib fractures in 29 (43 %) patients with a median of 2 (P25-P75 1–3) nonunions per patient. Nonunion was most commonly observed in ribs seven to 10 (20–23 %, p &lt; 0.001, adjusted p = 0.006). Nonunion occurred in 14 (5 %) undisplaced, 22 (19 %) offset, and 20 (23 %) displaced rib fractures (p &lt; 0.001). No statistically significant association between rib fracture type and nonunion was found. Conclusions: Forty-three percent of patients with multiple rib fractures had radiographic nonunion six months after trauma. Fractures in ribs seven to 10 and dislocated fractures had an increased risk of rib fracture nonunion.</p