Automated Detection of Cortical Lesions in Multiple Sclerosis Patients with 7T MRI

The automated detection of cortical lesions (CLs) in patients with multiple sclerosis (MS) is a challenging task that, despite its clinical relevance, has received very little attention. Accurate detection of the small and scarce lesions requires specialized sequences and high or ultra- high field MRI. For supervised training based on multimodal structural MRI at 7T, two experts generated ground truth segmentation masks of 60 patients with 2014 CLs. We implemented a simplified 3D U-Net with three resolution levels (3D U-Net-). By increasing the complexity of the task (adding brain tissue segmentation), while randomly dropping input channels during training, we improved the performance compared to the baseline. Considering a minimum lesion size of 0.75 μL, we achieved a lesion-wise cortical lesion detection rate of 67% and a false positive rate of 42%. However, 393 (24%) of the lesions reported as false positives were post-hoc confirmed as potential or definite lesions by an expert. This indicates the potential of the proposed method to support experts in the tedious process of CL manual segmentation

Impact of a peer-review network on the quality of inpatient low secure mental health services: cluster randomised control trial.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Peer-review networks aim to help services to improve the quality of care they provide, however, there is very little evidence about their impact. We conducted a cluster randomized controlled trial of a peer-review quality network for low-secure mental health services to examine the impact of network membership on the process and outcomes of care over a 12 month period. METHODS: Thirty-eight low secure units were randomly allocated to either the active intervention (participation in the network n = 18) or the control arm (delayed participation in the network n = 20). A total of 75 wards were assessed at baseline and 8 wards dropped out the study before the data collection at 12 month follow up. The primary outcome measure was the quality of the physical environment and facilities of the services. The secondary outcomes included: safety of the ward, patient mental wellbeing and satisfaction with care, staff burnout, training and supervision. We hypothesised that, relative to control wards, the quality of the physical environment and facilities would be higher on wards in the active arm of the trial 12 months after randomization. RESULTS: The difference in the primary outcome between the groups was not statistically significant (4.1; 95% CI [- 0.2, 8.3] p = 0.06). The median number of untoward incidents rose in control services and remained the same at the member of the network (Difference between members and non-members = 0.55; 95% IC [0.29, 1.07] p = 0.08). At follow up, a higher proportion of staff in the active arm of the trial indicated that they felt safe on the ward relative to those in the control services (p = 0.04), despite reporting more physical assaults (p = 0.04). Staff working in services in the active arm of the trial reported higher levels of burnout relative to those in the control group. No difference was seen in patient outcomes. CONCLUSIONS: We did not find evidence that participation in a peer-review network led to marked changes in the quality of the physical environment of low secure mental health services at 12 months. Future research should explore the impact of accreditation schemes and examine longer term outcomes of participation in such networks. TRIAL REGISTRATION: ISRCTN79614916 . Retrospectively registered 28 March 2014.Royal College of Psychiatrists’ College Centre for Quality Improvemen

Inhibiting mevalonate pathway enzymes increases stromal cell resilience to a cholesterol-dependent cytolysin

Animal health depends on the ability of immune cells to kill invading pathogens, and on the resilience of tissues to tolerate the presence of pathogens. Trueperella pyogenes causes tissue pathology in many mammals by secreting a cholesterol-dependent cytolysin, pyolysin (PLO), which targets stromal cells. Cellular cholesterol is derived from squalene, which is synthesized via the mevalonate pathway enzymes, including HMGCR, FDPS and FDFT1. The present study tested the hypothesis that inhibiting enzymes in the mevalonate pathway to reduce cellular cholesterol increases the resilience of stromal cells to PLO. We first verified that depleting cellular cholesterol with methyl-β-cyclodextrin increased the resilience of stromal cells to PLO. We then used siRNA to deplete mevalonate pathway enzyme gene expression, and used pharmaceutical inhibitors, atorvastatin, alendronate or zaragozic acid to inhibit the activity of HMGCR, FDPS and FDFT1, respectively. These approaches successfully reduced cellular cholesterol abundance, but mevalonate pathway enzymes did not affect cellular resilience equally. Inhibiting FDFT1 was most effective, with zaragozic acid reducing the impact of PLO on cell viability. The present study provides evidence that inhibiting FDFT1 increases stromal cell resilience to a cholesterol-dependent cytolysin

Cholesterol Depletion Alters Cardiomyocyte Subcellular Signaling and Increases Contractility

<div><p>Membrane cholesterol levels play an important factor in regulating cell function. Sarcolemmal cholesterol is concentrated in lipid rafts and caveolae, which are flask-shaped invaginations of the plasma membrane. The scaffolding protein caveolin permits the enrichment of cholesterol in caveolae, and caveolin interactions with numerous proteins regulate their function. The purpose of this study was to determine whether acute reductions in cardiomyocyte cholesterol levels alter subcellular protein kinase activation, intracellular Ca²⁺ and contractility. <b>Methods</b>: Ventricular myocytes, isolated from adult Sprague Dawley rats, were treated with the cholesterol reducing agent methyl-β-cyclodextrin (MβCD, 5 mM, 1 hr, room temperature). Total cellular cholesterol levels, caveolin-3 localization, subcellular, ERK and p38 mitogen activated protein kinase (MAPK) signaling, contractility, and [Ca²⁺]i were assessed. <b>Results</b>: Treatment with MβCD reduced cholesterol levels by ~45 and shifted caveolin-3 from cytoskeleton and triton-insoluble fractions to the triton-soluble fraction, and increased ERK isoform phosphorylation in cytoskeletal, cytosolic, triton-soluble and triton-insoluble membrane fractions without altering their subcellular distributions. In contrast the primary effect of MβCD was on p38 subcellular distribution of p38α with little effect on p38 phosphorylation. Cholesterol depletion increased cardiomyocyte twitch amplitude and the rates of shortening and relaxation in conjunction with increased diastolic and systolic [Ca²⁺]i. <b>Conclusions</b>: These results indicate that acute reductions in membrane cholesterol levels differentially modulate basal cardiomyocyte subcellular MAPK signaling, as well as increasing [Ca²⁺]_i and contractility.</p></div

The chameleon of neuroinflammation:magnetic resonance imaging characteristics of natalizumab-associated progressive multifocal leukoencephalopathy

<p>Natalizumab is a monoclonal antibody against 4-integrin approved for the treatment of multiple sclerosis (MS) due to a positive effect on clinical and magnetic resonance imaging (MRI) outcome measures. However, one relatively rare but serious side effect of this drug is a higher risk of developing progressive multifocal leukoencephalopathy (PML). Since the FDA approval, more than 300 natalizumab-associated PML cases have been documented among more than 100,000 treated MS patients. MRI is a crucial tool in the surveillance of patients treated with natalizumab in order to detect possible signs of PML in the asymptomatic stage. Although classical imaging characteristics of PML are well established, MRI findings in natalizumab-associated PML, particularly in early disease stages, show rather new and heterogeneous imaging findings including different patterns of inflammation with contrast enhancement. This review provides a comprehensive overview of the heterogeneous imaging findings in natalizumab-associated PML in the context of the underlying pathophysiology, histopathology, and the diagnostic procedure. We describe the MRI patterns of PML lesion evolution and complications including immune reconstitution inflammatory syndrome (IRIS). Finally, we present guidelines to differentiate MRI findings in PML from inflammatory demyelinating lesions, to facilitate the early diagnosis of PML in patients treated with natalizumab.</p>