Bacteria associated with early life stages of the great scallop, Pecten maximus: impact on larval survival

International audienceA bacteriological study was carried out at a scallop (Pecten maximus) hatchery near Bergen, western Norway following a severe increase in mortality rates during the larval stages of the scallops. No larvae survived to settling, except for those in groups treated prophylactically with chloramphenicol. In order to identify pathogenic strains of bacteria, we performed a challenge test on 10- to 16-day-old larvae using isolated bacterial strains from the hatchery. Infection with six of these strains produced mortalities that were not statistically different from that resulting from infection with the known pathogen Vibrio pectenicida. However, about 5% of the strains tested in the challenge experiment produced higher motility rates than found in the unchallenged control group, indicating a possible probiotic effect. On the basis of 16S rDNA analysis on these strains, the phylogenetic tree indicated two groups of apparent pathogens: (1) one strain, LT13, grouped together with Alteromonas/Pseudoalteromonas; (2) a cluster of strains grouped together with Vibrio splendidus (LT06, LT21, LT73, PMV18 and PMV19). Strain LT13 was isolated from cultures of the microalga Chaetoceros calcitrans used for feed, while the other strains were isolated from larval cultures. Transmission electron microscopy showed intracellular bacteria that resembled bacteria in the groups Chlamydiaceae and Rickettsiaceae

Neurofilament light chain as a biomarker in multiple sclerosis

Due to the unpredictable course and heterogenous treatment response in multiple sclerosis (MS), there is a clear need for biomarkers that reflect disease activity in the clinical follow-up of these patients. Neurofilaments are neuron-specific components of the cytoskeleton that can be assayed in different body compartments. They have been explored as potential biomarkers for many years. Neurofilament light chain (NF-L) appears the most promising biomarker in MS patients, and there is now little doubt that NF-L should have a role in the follow-up of MS patients. Newer assays and techniques for NF-L detection available in serum samples confirms the usefulness of NF-L as a biomarker. Nevertheless, there is still a need for prospective studies, and studies to determine clinical useful cut-off values. This review evaluates the strengths and weaknesses of NF-L as a biomarker in patients with MS.publishedVersio

Safety of breast feeding during rituximab treatment in multiple sclerosis

Background There are limited data on the safety of breast feeding during rituximab therapy. Our objective is to determine exposure from breast feeding and biological effects of rituximab in breastfed infants. Methods In our case series of six mother–infant pairs, the nursing mothers with relapsing-remitting multiple sclerosis received rituximab during breast feeding. As part of clinical follow-up, six serial breast milk samples, and blood samples from both mothers and infants, were collected and analysed. Results The median average rituximab concentration (Cavg) in breast milk was 0.04 µg/mL and the estimated relative infant dose (RID) was 0.07%. The highest measured concentration of rituximab in the breast milk samples was 0.25 µg/mL, giving an estimated RID of 0.26%. All infant serum rituximab concentrations were below 0.01 µg/mL. The CD19 +B cell count values were within the 10th– 90th percentiles of reported normal ranges in healthy infants. Conclusions We found minimal transfer of rituximab into breast milk and could not reliably detect levels of rituximab in infant serum. B cell counts in infants were unaffected.publishedVersio

Neurofilament Light Chain as a Biomarker in Multiple Sclerosis

Due to the unpredictable course and heterogenous treatment response in multiple sclerosis (MS), there is a clear need for biomarkers that reflect disease activity in the clinical follow-up of these patients. Neurofilaments are neuron-specific components of the cytoskeleton that can be assayed in different body compartments. They have been explored as potential biomarkers for many years. Neurofilament light chain (NF-L) appears the most promising biomarker in MS patients, and there is now little doubt that NF-L should have a role in the follow-up of MS patients. Newer assays and techniques for NF-L detection available in serum samples confirms the usefulness of NF-L as a biomarker. Nevertheless, there is still a need for prospective studies, and studies to determine clinical useful cut-off values. This review evaluates the strengths and weaknesses of NF-L as a biomarker in patients with MS

Brief international cognitive assessment for MS (BICAMS) and global brain volumes in early stages of MS – A longitudinal correlation study

Background Cognitive impairment is common in patients with multiple sclerosis, even in the early stages of the disease. The Brief International Cognitive Assessment for multiple sclerosis (BICAMS) is a short screening tool developed to assess cognitive function in everyday clinical practice. Objective To investigate associations between volumetric brain measures derived from a magnetic resonance imaging (MRI) examination and performance on BICAMS subtests in early stages of multiple sclerosis (MS). Methods BICAMS was used to assess cognitive function in 49 MS patients at baseline and after one and two years. The patients were separated into two groups (with or without cognitive impairment) based on their performances on BICAMSs subtests. MRI data were analysed by a software tool (MSMetrix), yielding normalized measures of global brain volumes and lesion volumes. Associations between cognitive tests and brain MRI measures were analysed by running correlation analyses, and differences between subgroups and changes over time with independent and paired samples tests, respectively. Results The strongest baseline correlations were found between the BICAMS subtests and normalized whole brain volume (NBV) and grey matter volume (NGV); processing speed r = 0.54/r = 0.48, verbal memory r = 0.49/ r = 0.42, visual memory r = 0.48 /r = 0.39. Only the verbal memory test had significant correlations with T2 and T1 lesion volumes (LV) at both time points; T2LV r = 0.39, T1LV r = 0.38. There were significant loss of grey matter and white matter volume overall (NGV p<0.001, NWV p = 0.003), as well as an increase in T1LV (p = 0.013). The longitudinally defined confirmed cognitively impaired (CCI) and preserved (CCP) patients showed significant group differences on all MRI volume measures at both time points, except for NWV. Only the CCI subgroup showed significant white matter atrophy (p = 0.006) and increase in T2LV (p = 0.029). Conclusions The present study found strong correlations between whole brain and grey matter volumes and performance on the BICAMS subtests as well as significant changes in global volumes from baseline to follow-up with clear differences between patients defined as cognitively impaired and preserved at both baseline and follow-up.publishedVersio

Safety and efficacy of rituximab as first- and second line treatment in multiple sclerosis – A cohort study

Background Rituximab is increasingly used as off-label therapy in multiple sclerosis (MS). More data are needed on safety and efficacy of rituximab, particularly in cohorts of de novo patients and patients in early therapy escalation. Objective To investigate the safety and efficacy of off-label treatment with rituximab in an MS-cohort of predominantly de novo patients or as therapy escalation. Methods We retrieved safety and efficacy data from the Norwegian MS-registry and biobank for all MS-patients treated with rituximab at Haukeland University Hospital, Bergen, Norway, during a four year period. Results In the 365 MS-patients (320 relapsing-remitting MS (RRMS), 23 secondary progressive MS (SPMS), and 22 primary progressive MS (PPMS)), the overall annualized relapse rate (ARR) was 0.03 and annualized drug discontinuation rate (ADDR) was 0.05. NEDA-3 was achived in 79% of patients with available data (n=351). Sixty-one patients experienced infusion-related adverse events of which two were serious (CTCAE grade 3–4). Eighteen patients experienced serious non-infusion related adverse events, of which 16 were infections. Infections (n = 34; 9.3%, CTCAE grade 2-5), hypogammaglobulinemia (n = 19, 5.2%) and neutropenia (n = 16; 4.4%) were the most common non-infusion-related adverse events. Conclusion Rituximab was a safe and highly efficient disease modifying therapy in this cohort of MS-patients; however, infections and neutropenia need to be monitored.publishedVersio

Impact of previous disease-modifying treatment on safety and efficacy in patients with MS treated with AHSCT

Background Autologous haematopoietic stem cell transplantation (AHSCT) is a highly effective treatment for multiple sclerosis (MS). The impact of previous long-lasting disease-modifying treatments (DMT) for safety and efficacy of AHSCT is unknown. Objective To explore whether previous DMTs with long-lasting effects on the immune system (anti-CD20 therapy, alemtuzumab and cladribine) affect treatment-related complications, long-term outcome and risk of new MS disease activity in patients treated with AHSCT. Methods Retrospective observational study of 104 relapsing remitting patients with MS treated by AHSCT in Sweden and Norway from 2011 to 2021, grouped according to the last DMT used ≤6 months prior to AHSCT. The primary outcomes were early AHSCT-related complications (mortality, neutropenic fever and hospitalisation length), long-term complications (secondary autoimmunity) and proportion of patients with No Evidence of Disease Activity (NEDA-3 status): no new relapses, no MRI activity and no disease progression during the follow-up. Results The mean follow-up time was 39.5 months (range 1–95). Neutropenic fever was a common AHSCT-related complication affecting 69 (66%) patients. There was no treatment-related mortality. During the follow-up period, 20 patients (19%) were diagnosed with autoimmunity. Occurrence of neutropenic fever, hospitalisation length or secondary autoimmunity did not vary dependent on the last DMT used prior to AHSCT. A total of 84 patients (81%) achieved NEDA-3 status, including all patients (100%) using rituximab, alemtuzumab or cladribine before AHSCT. Conclusion This study provides level 4 evidence that AHSCT in patients previously treated with alemtuzumab, cladribine or rituximab is safe and efficacious.publishedVersio

In-depth cerebrospinal fluid quantitative proteome and deglycoproteome analysis: presenting a comprehensive picture of pathways and processes affected by multiple sclerosis

In the current study, we conducted a quantitative in-depth proteome and deglycoproteome analysis of cerebrospinal fluid (CSF) from relapsing-remitting multiple sclerosis (RRMS) and neurological controls using mass spectrometry and pathway analysis. More than 2000 proteins and 1700 deglycopeptides were quantified, with 484 proteins and 180 deglycopeptides significantly changed between pools of RRMS and pools of controls. Approximately 300 of the significantly changed proteins were assigned to various biological processes including inflammation, extracellular matrix organization, cell adhesion, immune response, and neuron development. Ninety-six significantly changed deglycopeptides mapped to proteins that were not found changed in the global protein study. In addition, four mapped to the proteins oligo-myelin glycoprotein and noelin, which were found oppositely changed in the global study. Both are ligands to the nogo receptor, and the glycosylation of these proteins appears to be affected by RRMS. Our study gives the most extensive overview of the RRMS affected processes observed from the CSF proteome to date, and the list of differential proteins will have great value for selection of biomarker candidates for further verification.acceptedVersio

Month of birth and risk of multiple sclerosis: confounding and adjustments

A month of birth effect on multiple sclerosis (MS) risk has been reported from different countries. Recent critics have suggested that this finding is caused by confounding and that adequately adjusting for year and place of birth would markedly reduce this effect. All inhabitants in Norway are registered in the Norwegian Population Registry (Statistics Norway), making this an ideal area for performing adjusted analyses. Using the entire Norwegian population born between 1930 and 1979 (n = 2,899,260), we calculated the excess between observed and expected number of births for each month for 6649 Norwegian MS patients, 5711 mothers, 5247 fathers, and 8956 unaffected siblings. The analyses were adjusted for year of birth and place of birth according to the 19 counties in Norway. An unadjusted analysis revealed 13% fewer MS births than expected in February (P = 0.0015; Bonferroni corrected P = 0.018), 10% more in April (P = 0.0083; Bonferroni corrected P = 0.0996) and 15% more in December (P = 0.00058; Bonferroni corrected P = 0.007). Adjustments for both year and place of birth significantly altered our results for February and December, but even after these adjustments there were still 10% more MS births than expected in April (P = 0.00796; Bonferroni corrected P = 0.096). MS patients had a higher incidence of April births than their siblings (Fisher-exact test; P = 0.011), mothers (Fisher-exact test; P = 0.004), and fathers (Fisher-exact test; P = 0.011) without MS. Adjustments for confounding significantly affected our results. However, even after adjustments, there appears to be a persistent higher than expected frequency of April births in the MS population. © 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association

Humoral response to Epstein-Barr virus in patients with multiple sclerosis treated with B cell depletion therapy

Background B cell depletion therapy is highly effective in relapsing-remitting multiple sclerosis (RRMS). However, the precise underlying mechanisms of action for its biological effects in MS have still not been clarified. Epstein-Barr virus (EBV) is a known risk factor for MS and seems to be a prerequisite for disease development. EBV resides latently in the memory B cells, and may not only increase the risk of developing MS, but also contribute to disease activity and disability progression. Therefore, the effects of B cell depletion in MS could be associated with the depletion of EBV-infected cells and the altered immune response to the virus. In this study, we investigate the impact of B cell depletion on the humoral immune response specific to EBV in patients with MS. Methods Newly diagnosed, treatment-naïve patients with RRMS were followed up to 18 months after initiation of B-cell depletion therapy in the Overlord-MS study, a phase III trial (NCT04578639). We analyzed serum sampled before treatment and after 3, 6, 12 and 18 months for immunoglobulin γ (IgG) against Epstein-Barr nuclear antigen 1 (EBNA1) and Epstein-Barr viral capsid antigen (VCA). We analyzed antibodies to cytomegalovirus (CMV) and total IgG in serum, as controls for viral and overall humoral immunity. The risk allele, HLA-DRB1*15:01, and the protective allele, HLA-A*02:01, were determined in all participants. In addition, polymerase chain reaction (PCR) for circulating EBV-DNA was performed in the first 156 samples drawn. The associations between time on B cell-depletion therapy and serum anti-EBV antibody levels were estimated using linear mixed-effects models. Results A total of 290 serum samples from 99 patients were available for analysis. After 6, 12 and 18 months, the EBNA1 IgG levels decreased by 12.7 % (95 % CI -18.8 to -6.60, p < 0.001), 12.1 % (95 % CI -19.8 to -3.7, p = 0.006) and 14.6 % (95 % CI to -25.3 to -2.4, p = 0.02) respectively, compared to baseline level. Carriers of the HLA-DRB1*15:01 allele had higher EBNA1 IgG levels at baseline (p = 0.02). The VCA IgG levels significantly increased by 13.7 % (95 % CI 9.4 to 18.1, p < 0.001) after 3 months, compared to baseline, and persisted at this level throughout the follow-up. CMV IgG levels decreased, but to a lesser extent than the decrease of EBNA1 IgG, and total IgG levels decreased during therapy. Circulating EBV-DNA was found in only three of 156 samples from 64 patients. Conclusions EBNA1 IgG levels decreased, while VCA IgG levels increased, during B cell depletion therapy. This supports the hypothesis that the mechanism of action for B cell depletion therapy might be mediated by effects on EBV infection, which, in turn, mitigate immune cross-reactivity and disease perpetuation.publishedVersio