Graphical abstract Schematic representation of the adaptive and protective inducible expression of cx43 in chronic and acute-on-chronic liver injuries. Upon hepatic insult, endogenous expression of ...Cx26 and Cx32 is reduced to alleviate the spread out of noxious injurious agents among the hepatocytes, whereas Cx43 expression is induced between hepatocytes and endothelial cells, to drain out the hepatic metabolites and endotoxin into the draining veins. It is assumed that in this way the inducible Cx43 expression during the hepatic injury exerts a protective effect and therefore, inhibition of Cx43 by a mimetic peptide accentuates the hepatic injury following bile duct ligation in mice.
Epilepsy-associated dysbiosis in gut microbiota has been previously described, but the mechanistic roles of the gut microbiome in epileptogenesis among children with cerebral palsy (CP) have yet to ...be illustrated.
Using shotgun metagenomic sequencing coupled with untargeted metabolomics analysis, this observational study compared the gut microbiome and metabolome of eight children with non-epileptic cerebral palsy (NECP) to those of 13 children with cerebral palsy with epilepsy (CPE). Among children with CPE, 8 had drug-sensitive epilepsy (DSE) and five had drug-resistant epilepsy (DRE). Characteristics at enrollment, medication history, and 7-day dietary intake were compared between groups.
At the species level, CPE subjects had significantly lower abundances of
and
but higher abundances of
and
. By contrast, DRE subjects had a significantly higher colonization of
. Regarding microbial functional pathways, CPE subjects had decreased abundances of pathways for serine degradation, quinolinic acid degradation, glutamate degradation I, glycerol degradation, sulfate reduction, and nitrate reduction but increased abundances of pathways related to ethanol production. As for metabolites, CPE subjects had higher concentrations of kynurenic acid, 2-oxindole, dopamine, 2-hydroxyphenyalanine, 3,4-dihydroxyphenylglycol, L-tartaric acid, and D-saccharic acid; DRE subjects had increased concentrations of indole and homovanilic acid.
In this study, we found evidence of gut dysbiosis amongst children with cerebral palsy and epilepsy in terms of gut microbiota species, functional pathways, and metabolites. The combined metagenomic and metabolomic analyses have shed insights on the potential roles of
and
in neuroprotection. The combined analyses have also provided evidence for the involvement of GMBA in the epilepsy-related dysbiosis of kynurenine, serotonin, and dopamine pathways and their complex interplay with neuroimmune and neuroendocrinological pathways.
Many treatments for autoimmune diseases, caused by the loss of immune self-tolerance, are broadly immunosuppressive. Dendritic cells (DCs) can be induced to develop anti-inflammatory/tolerogenic ...properties to suppress aberrant self-directed immunity by promoting immune tolerance in an antigen-specific manner. Dexamethasone can generate tolerogenic DCs and upregulates MERTK expression. As MERTK can inhibit inflammation, we investigated whether dexamethasone’s tolerogenic effects are mediated via MERTK, potentially providing a novel therapeutic approach. Monocyte-derived DCs were treated with dexamethasone, and with and without MERTK ligands or MERTK inhibitors. Flow cytometry was used to assess effects of MERTK modulation on co-stimulatory molecule expression, efferocytosis, cytokine secretion and T cell proliferation. The influence on expression of Rab17, which coordinates the diversion of efferocytosed material away from cell surface presentation, was assessed. Dexamethasone-treated DCs had upregulated MERTK expression, decreased expression of co-stimulatory molecules, maturation and proliferation of co-cultured T cells and increased uptake of myelin debris. MERTK ligands did not potentiate these properties, whilst specific MERTK inhibition only reversed dexamethasone’s effect on myelin uptake. Cells undergoing efferocytosis had higher Rab17 expression. Dexamethasone-enhanced efferocytosis in DCs is MERTK-dependent and could exert its tolerogenic effects by increasing Rab17 expression to prevent the presentation of efferocytosed material on the cell surface to activate adaptive immune responses.
ObjectivesCharacterise telehealth use in MS clinics during the COVID–19 pandemic.Assess patient and clinician attitudes towards telehealth.Compare telehealth–based and physical EDSS obtained during ...period of telehealth implementation.MethodsClinic records from Mar-Dec 2020 were reviewed. Patients and clinicians completed questionnaires about experiences using Telehealth. The iMed database was searched for EDSS recorded via face-to-face and telehealth appointments during and compared to face-to-face EDSS preceding and following the study period. T-test and Chi-square test were used for between-group comparisons.Results2023 appointments (27% face-to-face, 35% video, 37% telephone) were conducted. New referrals were predominantly face-to-face (66%).89% of patients were satisfied with telehealth. 58% felt they were as good as face-to-face visits, whilst only 11% of clinicians agreed. Many patients favoured a hybrid model. Safety during the COVID-19 pandemic was important to both groups.EDSS increase from the preceding visit was recorded in a significantly higher proportion of face-to-face than telehealth appointments (p=0.027), with the increase driven by patients with baseline EDSS≤4.0. Amongst patients with EDSS increases, similar numbers of suspected relapses were seen via both modalities. Absolute increase in EDSS was also significantly greater amongst patients seen face-to-face (p<0.0001). There was no significant difference in EDSS change at subsequent follow-up in patients with consecutive face-to-face versus intervening telehealth appointments.ConclusionPatient satisfaction with telehealth was high, whilst clinicians preferred face-to-face consultations. EDSS increase was more frequently recorded via face-to-face than telehealth appointments, which may underestimate lower EDSS. Future clinics could combine both modalities.
ObjectiveTo examine factors determining risk of self-reported infections and antimicrobial use in patients receiving Ocrelizumab for MS.MethodsRetrospective, observational cohort study conducted in ...Ocrelizumab-treated patients at the Royal Melbourne Hospital. The association of clinical and laboratory factors with self-reported infection rate and antimicrobial use were estimated using univariate and multivariable logistic regression models.Results185 patients were included in the study, and 176 infections were reported in 89 patients (46.1%), and in 47 patients (25.3%) antimicrobial use was identified. In univariate analyses, a higher serum IgA was associated with reduced odds of infection (OR 0.44, 95% CI 0.25 - 0.76). In multivariable analyses, older age (OR 0.94, 95% CI 0.88 - 0.99), higher serum IgA (OR 0.37, 95% CI 0.17 - 0.80) and higher serum IgG (OR 0.81, 95% CI 0.67 - 0.99) were associated with reduced odds of infection. Older age (OR 0.85, 95% CI 0.75 - 0.96) and higher serum IgA (OR 0.23, 95% CI 0.07 - 0.79) were associated with reduced odds of antimicrobial use, whilst longer MS disease duration (OR 1.22, 95% CI 1.06 - 1.41) and higher EDSS (OR 1.99, 95% CI 1.02 - 3.86) were associated with increased odds of antimicrobial use.ConclusionsHigher serum IgA, IgG and older age were associated with reduced odds of infection. Our findings highlight non-uniformity of infection risk in Ocrelizumab-treated MS patients, and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy.
Patients with congestive myelopathy due to spinal dural arteriovenous fistula (SDAVF) typically present with progressive sensory and motor disturbance in association with sphincter dysfunction. ...Spinal MRI usually shows longitudinally extensive T2 signal change. Here, we report four patients with progressive myelopathy due to SDAVF who also presented with findings on cerebrospinal fluid (CSF) examination suggestive of an inflammatory aetiology. Such CSF findings in SDAVF are important to recognise, to avoid the erroneous diagnosis of an inflammatory myelitis and inappropriate treatment with immunosuppression. SDAVF can be difficult to detect and may require repeated investigation, with formal angiography as the gold standard.
Despite the success of disease-modifying treatments in relapsing multiple sclerosis, for many individuals living with multiple sclerosis, progressive disability continues to accrue. How to interrupt ...the complex pathological processes underlying progression remains a daunting and ongoing challenge. Since 2014, several immunomodulatory approaches that have modest but clinically meaningful effects have been approved for the management of progressive multiple sclerosis, primarily for people who have active inflammatory disease. The approval of these drugs required large phase 3 trials that were sufficiently powered to detect meaningful effects on disability. New classes of drug, such as Bruton tyrosine-kinase inhibitors, are coming to the end of their trial stages, several candidate neuroprotective compounds have been successful in phase 2 trials, and innovative approaches to remyelination are now also being explored in clinical trials. Work continues to define intermediate outcomes that can provide results in phase 2 trials more quickly than disability measures, and more efficient trial designs, such as multi-arm multi-stage and futility approaches, are increasingly being used. Collaborations between patient organisations, pharmaceutical companies, and academic researchers will be crucial to ensure that future trials maintain this momentum and generate results that are relevant for people living with progressive multiple sclerosis.
Myasthenia gravis (MG) is a disorder affecting neuromuscular transmission with heterogeneous manifestations and treatments. This study describes clinical features and management of MG patients at a ...metropolitan hospital in Australia. Overall findings were consistent with previously published data. However, frequency of intravenous immuno‐globulin use was higher, reasons for which are explored. Management is best conducted through specialist clinics with necessary expertise and standardised treatment protocols.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system resulting from loss of immune tolerance. Many disease-modifying therapies for MS have broad ...immunosuppressive effects on peripheral immune cells, but this can increase risks of infection and attenuate vaccine-elicited immunity. A more targeted approach is to re-establish immune tolerance in an autoantigen-specific manner. This review discusses methods to achieve this, focusing on tolerogenic dendritic cells. Clinical trials in other autoimmune diseases also provide learnings with regards to clinical translation of this approach, including identification of autoantigen(s), selection of appropriate patients and administration route and frequency.
•Many current treatments for multiple sclerosis have broad immunosuppressive effects.•Tolerogenic dendritic cells aim to restore immune tolerance lost in autoimmunity.•Dendritic cells with anti-inflammatory properties can be generated in vitro.•Dendritic cells are primed with specific autoantigens to target autoreactive cells.•Tolerogenic dendritic cells in MS were found to be safe in early clinical trials.
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