Functional MRI and voxel-based morphometry are important in neuroscience. They are technically challenging with no globally optimal analysis method, and the multiple approaches have been shown to ...produce different results. It is useful to be able to meta-analyse results from such studies that tested a similar hypothesis potentially using different analysis methods. The aim is to identify replicable results and infer hypothesis specific effects. Coordinate based meta-analysis (CBMA) offers this, but the multiple algorithms can produce different results, making interpretation conditional on the algorithm.
Here a new model based CBMA algorithm, Analysis of Brain Coordinates (ABC), is presented. ABC aims to be simple to understand by avoiding empirical elements where possible and by using a simple to interpret statistical threshold, which relates to the primary aim of detecting replicable effects.
ABC is compared to both the most used and the most recently developed CBMA algorithms, by reproducing a published meta-analysis of localised grey matter changes in schizophrenia. There are some differences in results and the type of data that can be analysed, which are related to the algorithm specifics.
Compared to other algorithms ABC eliminates empirical elements where possible and uses a simple to interpret statistical threshold.
There may be no optimal way to meta-analyse neuroimaging studies using CBMA. However, by eliminating some empirical elements and relating the statistical threshold directly to the aim of finding replicable effects, ABC makes the impact of the algorithm on any conclusion easier to understand.
•CBMA algorithm with fewer empirical components.•Easy to interpret statistical threshold.•Computationally efficient.•Free to use software.
Multiple sclerosis is an inflammatory neurodegenerative disease of the central nervous system (CNS) and the most frequent cause of non-traumatic disability in adults in the Western world. Currently, ...several drugs have been approved for the treatment of multiple sclerosis. While the newer drugs are more effective, they have less favourable safety profiles. Thus, there is a need to identify new targets for effective and safe therapies, particularly in patients with progressive disease for whom no treatments are available. One such target is granulocyte-macrophage colony-stimulating factor (GM-CSF) or its receptor. In this article we review data on the potential role of GM-CSF and GM-CSF inhibition in MS. We discuss the expression and function of GM-CSF and its receptor in the CNS, as well as data from animal studies and clinical trials in MS.
The therapeutic options for disease modification in relapsing-remitting multiple sclerosis (RRMS) have expanded remarkably in the last 15 years. Although intravenous immunoglobulins (IVIg) have shown ...some therapeutic effects in multiple sclerosis, reducing global supplies, restriction of treatment to essential indications and availability of effective alternative treatments for MS currently exclude IVIg from being an accepted therapy for MS, other than for some exceptional considerations. We report the case of a female patient with RRMS who was diagnosed with Ehlers-Danlos syndrome (EDS) and Muir-Torre syndrome (MTS) soon after the diagnosis of active RRMS was made. The coexisting conditions precluded the use of available disease-modifying treatments. She benefited from monthly and then bi-monthly IVIg, with a single mild relapse over 10 years. Discontinuation of IVIg due to reduced availability with a brief aborted course of subcutaneous PEGylated interferon-beta was followed by significant relapses. Five months after the first ocrelizumab infusion, she developed caecal cancer requiring colectomy. Reinstitution of IVIg is contemplated.
Background: Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating and degenerative disease of the central nervous system (CNS). To date, there is no definitive imaging biomarker for ...diagnosing MS. The current diagnostic criteria are mainly based on clinical relapses supported by the presence of white matter lesions (WMLs) on MRI. However, misdiagnosis of MS is still a significant clinical problem. The paramagnetic, iron rims (IRs) around white matter lesions have been proposed to be an imaging biomarker in MS. This study aimed to carry out a systematic mapping review to explore the detection of iron rim lesions (IRLs), on clinical MR scans, and describe the characteristics of IRLs presence in MS versus other MS-mimic disorders. Methods: Publications from 2001 on IRs lesions were reviewed in three databases: PubMed, Web of Science and Embase. From the initial result set 718 publications, a final total of 38 papers were selected. Results: The study revealed an increasing interest in iron/paramagnetic rims lesions studies. IRs were more frequently found in periventricular regions and appear to be absent in MS-mimics. Conclusions IR is proposed as a promising imaging biomarker for MS.
Oral sesame oil-based formulation facilitates the delivery of poorly water-soluble drug cannabidiol (CBD) to the lymphatic system and blood circulation. However, this natural oil-based formulation ...also leads to considerable variability in absorption of CBD. In this work, the performance of lipid-based formulations with the addition of medium-chain triglyceride (MCT) or surfactants to the sesame oil vehicle has been tested in vitro and in vivo using CBD as a model drug. The in vitro lipolysis has shown that addition of the MCT leads to a higher distribution of CBD into the micellar phase. Further addition of surfactants to MCT-containing formulations did not improve distribution of the drug into the micellar phase. In vivo, formulations containing MCT led to lower or similar concentrations of CBD in serum, lymph and MLNs, but with reduced variability. MCT improves the emulsification and micellar solubilization of CBD, but surfactants did not facilitate further the rate and extent of lipolysis. Even though addition of MCT reduces the variability, the in vivo performance for the extent of both lymphatic transport and systemic bioavailability remains superior with a pure natural oil vehicle.
Abstract Background Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS. Therapies that affect the endocannabinoid (EC) system may have immunomodulatory, symptomatic and ...neuroprotective effects. Aim The aim of this study was to determine how levels of EC and related compounds are altered in MS. Methods Plasma and whole blood were collected from 24 MS patients (10 relapsing–remitting (RR); 8 secondary-progressive (SP); 6 primary-progressive (PP); 19 females; 25–66 years) and 17 controls (10 females; 22–62 years). Plasma EC and related compounds were quantified by liquid chromatography–tandem mass spectrometry. Fatty acid amide hydrolase (FAAH), cannabinoid receptors CB1 and CB2 mRNA were measured by quantitative reverse transcriptase-polymerase chain reaction. Results Anandamide (AEA) and palmitoylethanolamide (PEA) were higher in RRMS compared to controls ( p = 0.001 and p = 0.027). AEA, PEA and oleoylethanolamide were also increased in SPMS plasma ( p = 0.001, p = 0.004, and p = 0.005). PPMS patients had higher AEA plasma levels compared to controls ( p = 0.009). FAAH mRNA was decreased in SPMS ( p = 0.04) but not in RRMS or PPMS blood. CB1 ( p = 0.012) and CB2 mRNA ( p = 0.003) were increased in the PPMS. Conclusion The EC system is altered in MS. It may be dynamically modulated depending on the subtype of the disease, but further studies with larger subgroups are needed to confirm this.
Previous exposure to Epstein–Barr virus (EBV) is strongly associated with the development of multiple sclerosis (MS). By contrast, past cytomegalovirus (CMV) infection may have no association, or be ...negatively associated with MS. This study aimed to investigate the associations of herpesvirus infections with MS in an Italian population. Serum samples (n = 200) from Italian people with multiple sclerosis (PwMS) classified as the relapsing-and-remitting clinical phenotype and (n = 137) healthy controls (HCs) were obtained from the CRESM Biobank, Orbassano, Italy. Both PwMS and HCs samples were selected according to age group (20–39 years, and 40 or more years) and sex. EBV virus capsid antigen (VCA) IgG, EBV nucleic acid-1 antigen (EBNA-1) IgG, CMV IgG, herpes simplex virus (HSV) IgG, and varicella zoster virus (VZV) IgG testing was undertaken using commercial ELISAs. EBV VCA IgG and EBNA-1 IgG seroprevalences were 100% in PwMS and 93.4% and 92.4%, respectively, in HCs. EBV VCA IgG and EBNA-1 IgG levels were higher (p < 0.001) in PwMS compared with HCs. For PwMS, the EBNA-1 IgG levels decreased with age, particularly in females. The CMV IgG seroprevalence was 58.7% in PwMS and 62.9% in HCs. CMV IgG seroprevalence increased with age. The HSV IgG seroprevalence was 71.2% in PwMS and 70.8% in HCs. HSV IgG levels were lower (p = 0.0005) in PwMS compared with HCs. VZV IgG seroprevalence was 97.5% in PwMS and 98.5% in HCs. In the population studied, several herpesvirus infections markers may have been influenced by the age and sex of the groups studied. The lack of a negative association of MS with CMV infection, and the observation of lower levels of HSV IgG in PwMS compared with HCs are findings worthy of further investigation.
Introduction
Natalizumab (NTZ), a monoclonal antibody against the integrin α4β1 (VLA-4) found on activated T cells and B cells, blocks the interaction of this integrin with adhesion molecules of ...central nervous system (CNS) endothelial cells and lymphocyte migration through the blood–brain barrier, effectively preventing new lesion formation and relapses in multiple sclerosis (MS). Whether NTZ treatment has additional effects on the peripheral immune system cells, and how its actions compare with other MS disease-modifying treatments, have not been extensively investigated. In particular, its effect on the proportions of circulating regulatory T cells (Treg) is unclear.
Methods
In this study, we investigated the effect of NTZ treatment in 12 patients with relapsing MS, at 6 and 12 months after the start of treatment. We evaluated the proportions of regulatory T cells (Treg), defined by flow cytometry as CD4+ CD25++ FoxP3+ cells and CD4+ CD25++ CD127– cells at these intervals. As an exploratory study, we also investigated the NTZ effects on the proportions of bulk T and B lymphocyte populations, and of those expressing novel the markers CD195 (CCR5), CD196 (CCR6), or CD161 (KLRB1), which are involved in MS pathogenesis but have been studied less in the context of MS treatment. The effects of NTZ were compared to those obtained with 11 patients under interferon-beta-1a (IFN-β1a) treatment, and against 9 healthy volunteers.
Results
We observed a transient increment in the proportion of Treg cells at 6 months, which was not sustained at 12 months. We observed a reduction in the proportion of T cells expressing CD195 (CCR5) and CD161 (KLRB1) subsets of T cells.
Conclusion
We conclude that NTZ does not have an effect on the proportion of Treg cells over 1 year, but it may affect the expression of molecules important for some aspects MS pathogenesis, in a manner that is not shared with IFN-β1a.
Coordinate based meta-analysis (CBMA) is widely used to find regions of consistent activation across fMRI studies that have been selected for their functional relevance to a given hypothesis. Only ...reported coordinates (foci), and a model of their spatial uncertainty, are used in the analysis. Results are clusters of foci where multiple studies have reported in the same spatial region, indicating functional relevance. There are several published methods that perform the analysis in a voxel-wise manner, resulting in around 10(5) statistical tests, and considerable emphasis placed on controlling the risk of type 1 statistical error. Here we address this issue by dramatically reducing the number of tests, and by introducing a new false discovery rate control: the false cluster discovery rate (FCDR). FCDR is particularly interpretable and relevant to the results of CBMA, controlling the type 1 error by limiting the proportion of clusters that are expected under the null hypothesis. We also introduce a data diagnostic scheme to help ensure quality of the analysis, and demonstrate its use in the example studies. We show that we control the false clusters better than the widely used ALE method by performing numerical experiments, and that our clustering scheme results in more complete reporting of structures relevant to the functional task.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Time-lapse microscopy of human lung cancer (H460) cells showed that the endogenous cannabinoid anandamide (AEA), the phyto-cannabinoid Δ-9-tetrahydrocannabinol (THC) and a synthetic cannabinoid HU ...210 all caused morphological changes characteristic of apoptosis. Janus green assays of H460 cell viability showed that AEA and THC caused significant increases in OD 595
nm at lower concentrations (10–50
μM) and significant decreases at 100
μM, whilst HU 210 caused significant decreases at all concentrations. In rat heart mitochondria, all three ligands caused significant decreases in oxygen consumption and mitochondrial membrane potential. THC and HU 210 caused significant increases in mitochondrial hydrogen peroxide production, whereas AEA was without significant effect. All three ligands induced biphasic changes in either mitochondrial complex I activity and/or mitochondrial complex II–III activity. These data demonstrate that AEA, THC, and HU 210 are all able to cause changes in integrated mitochondrial function, directly, in the absence of cannabinoid receptors.
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