117 research outputs found
Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue
Abstract.: The dystrophin glycoprotein complex (DGC) is a multimeric protein assembly associated with either the X-linked cytoskeletal protein dystrophin or its autosomal homologue utrophin. In striated muscle cells, the DGC links the extracellular matrix to the actin cytoskeleton and mediates three major functions: structural stability of the plasma membrane, ion homeostasis, and transmembrane signaling. Mutations affecting the DGC underlie major forms of congenital muscle dystrophies. The DGC is prominent also in the central and peripheral nervous system and in tissues with a secretory function or which form barriers between functional compartments, such as the blood-brain barrier, choroid plexus, or kidney. A considerable molecular heterogeneity arises from cell-specific expression of its constituent proteins, notably short C-terminal isoforms of dystrophin. Experimentally, the generation of mice carrying targeted gene deletions affecting the DGC has clarified the interdependence of DGC proteins for assembly of the complex and revealed its importance for brain development and regulation of the 'milieu intérieur. Here, we focus on recent studies of the DGC in brain, blood-brain barrier and choroid plexus, retina, and kidney and discuss the role of dystrophin isoforms and utrophin for assembly of the complex in these tissue
Mineral exploration potential of ERTS-1 data
The author has identified the following significant results. ERTS-1 imagery of an area approximately 15,000 square miles in Arizona was interpreted for regional structure and tectonic units. Eight fault systems were identified by trend, of which two, northeast and northwest, are considered to be related to porphyry copper mineralization. Nine tectonic units can be identified on the imagery as distinct geological identities. The boundaries between these units can be correlated with theoretical shear directions related to the San Andreas stress system. Fourier analysis of the N 50 W fault trend indicates a fundamental spacing between Fourier energy maxima that can be related to distances between copper deposits
Full Connectivity: Corners, edges and faces
We develop a cluster expansion for the probability of full connectivity of
high density random networks in confined geometries. In contrast to percolation
phenomena at lower densities, boundary effects, which have previously been
largely neglected, are not only relevant but dominant. We derive general
analytical formulas that show a persistence of universality in a different form
to percolation theory, and provide numerical confirmation. We also demonstrate
the simplicity of our approach in three simple but instructive examples and
discuss the practical benefits of its application to different models.Comment: 28 pages, 8 figure
Effects of brain tissue oxygen (PbtO2) guided management on patient outcomes following severe traumatic brain injury: A systematic review and meta-analysis.
Monitoring and optimisation of brain tissue oxygen tension (PbtO2) has been associated with improved neurological outcome and survival in observational studies of severe traumatic brain injury (TBI). We carried out a systematic review of randomized controlled trials to determine if PbtO2-guided management is associated with differential neurological outcomes, survival, and adverse events. Searches were carried out to 10 February 2022 in Medline (OvidSP), 11 February in EMBASE (OvidSP) and 8 February in Cochrane library. Randomized controlled trials comparing PbtO2 and ICP-guided management to ICP-guided management alone were included. The primary outcome was survival with favourable neurological outcome at 6-months post injury. Data were extracted by two independent authors and GRADE certainty of evidence assessed. There was no difference in the proportion of patients with favourable neurological outcomes with PbtO2-guided management (relative risk [RR] 1.42, 95% CI 0.97 to 2.08; p = 0.07; I2 = 0%, very low certainty evidence) but PbtO2-guided management was associated with reduced mortality (RR 0.54, 95% CI 0.31 to 0.93; p = 0.03; I2 = 42%; very low certainty evidence) and ICP (mean difference (MD) - 4.62, 95% CI - 8.27 to - 0.98; p = 0.01; I2 = 63%; very low certainty evidence). There was no significant difference in the risk of adverse respiratory or cardiovascular events. PbtO2-guided management in addition to ICP-based care was not significantly associated with increased favourable neurological outcomes, but was associated with increased survival and reduced ICP, with no difference in respiratory or cardiovascular adverse events. However, based on GRADE criteria, the certainty of evidence provided by this meta-analysis was consistently very low. MESH: Brain Ischemia; Intensive Care; Glasgow Outcome Scale; Randomized Controlled Trial; Craniocerebral Trauma
Multinational development and validation of an early prediction model for delirium in ICU patients
Rationale
Delirium incidence in intensive care unit (ICU) patients is high and associated with poor outcome. Identification of high-risk patients may facilitate its prevention.
Purpose
To develop and validate a model based on data available at ICU admission to predict delirium development during a patient’s complete ICU stay and to determine the predictive value of this model in relation to the time of delirium development.
Methods
Prospective cohort study in 13 ICUs from seven countries. Multiple logistic regression analysis was used to develop the early prediction (E-PRE-DELIRIC) model on data of the first two-thirds and validated on data of the last one-third of the patients from every participating ICU.
Results
In total, 2914 patients were included. Delirium incidence was 23.6 %. The E-PRE-DELIRIC model consists of nine predictors assessed at ICU admission: age, history of cognitive impairment, history of alcohol abuse, blood urea nitrogen, admission category, urgent admission, mean arterial blood pressure, use of corticosteroids, and respiratory failure. The area under the receiver operating characteristic curve (AUROC) was 0.76 [95 % confidence interval (CI) 0.73–0.77] in the development dataset and 0.75 (95 % CI 0.71–0.79) in the validation dataset. The model was well calibrated. AUROC increased from 0.70 (95 % CI 0.67–0.74), for delirium that developed 6 days.
Conclusion
Patients’ delirium risk for the complete ICU length of stay can be predicted at admission using the E-PRE-DELIRIC model, allowing early preventive interventions aimed to reduce incidence and severity of ICU delirium
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Recalibration of the delirium prediction model for ICU patients (PRE-DELIRIC): a multinational observational study
Purpose
Recalibration and determining discriminative power, internationally, of the existing delirium prediction model (PRE-DELIRIC) for intensive care patients.
Methods
A prospective multicenter cohort study was performed in eight intensive care units (ICUs) in six countries. The ten predictors (age, APACHE-II, urgent and admission category, infection, coma, sedation, morphine use, urea level, metabolic acidosis) were collected within 24 h after ICU admission. The confusion assessment method for the intensive care unit (CAM-ICU) was used to identify ICU delirium. CAM-ICU screening compliance and inter-rater reliability measurements were used to secure the quality of the data.
Results
A total of 2,852 adult ICU patients were screened of which 1,824 (64 %) were eligible for the study. Main reasons for exclusion were length of stay <1 day (19.1 %) and sustained coma (4.1 %). CAM-ICU compliance was mean (SD) 82 ± 16 % and inter-rater reliability 0.87 ± 0.17. The median delirium incidence was 22.5 % (IQR 12.8–36.6 %). Although the incidence of all ten predictors differed significantly between centers, the area under the receiver operating characteristic (AUROC) curve of the eight participating centers remained good: 0.77 (95 % CI 0.74–0.79). The linear predictor and intercept of the prediction rule were adjusted and resulted in improved re-calibration of the PRE-DELIRIC model.
Conclusions
In this multinational study, we recalibrated the PRE-DELIRIC model. Despite differences in the incidence of predictors between the centers in the different countries, the performance of the PRE-DELIRIC-model remained good. Following validation of the PRE-DELIRIC model, it may facilitate implementation of strategies to prevent delirium and aid improvements in delirium management of ICU patients
Dystroglycan versatility in cell adhesion: a tale of multiple motifs
Dystroglycan is a ubiquitously expressed heterodimeric adhesion receptor. The extracellular a-subunit makes connections
with a number of laminin G domain ligands including laminins, agrin and perlecan in the extracellular
matrix and the transmembrane b-subunit makes connections to the actin filament network via cytoskeletal linkers
including dystrophin, utrophin, ezrin and plectin, depending on context. Originally discovered as part of the dystrophin
glycoprotein complex of skeletal muscle, dystroglycan is an important adhesion molecule and signalling scaffold
in a multitude of cell types and tissues and is involved in several diseases. Dystroglycan has emerged as a
multifunctional adhesion platform with many interacting partners associating with its short unstructured cytoplasmic
domain. Two particular hotspots are the cytoplasmic juxtamembrane region and at the very carboxy terminus
of dystroglycan. Regions which between them have several overlapping functions: in the juxtamembrane region; a
nuclear localisation signal, ezrin/radixin/moesin protein, rapsyn and ERK MAP Kinase binding function, and at the C
terminus a regulatory tyrosine governing WW, SH2 and SH3 domain interactions. We will discuss the binding partners
for these motifs and how their interactions and regulation can modulate the involvement of dystroglycan in a
range of different adhesion structures and functions depending on context. Thus dystroglycan presents as a multifunctional
scaffold involved in adhesion and adhesion-mediated signalling with its functions under exquisite spatiotemporal
regulation
Three-Dimensional Regulation of Radial Glial Functions by Lis1-Nde1 and Dystrophin Glycoprotein Complexes
Lis1-Nde1 integrates cerebral cortical neurogenesis with neuronal migration by stabilizing the basal-lateral surface of radial glial cells
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