There is a growing optimism about the potential of new disease-modifying therapies (DMTs) in the management of relapsing-remitting multiple sclerosis (RRMS) patients. However, this initial enthusiasm ...has been tempered by evidence indicating that multiple sclerosis (MS) patients undergoing DMT may be at higher risk of developing infections through incompletely understood mechanisms. As neutrophils provide the first line of defense against pathogens, here we have compared the effects of some of the commonly used MS DMTs (i.e., moderate-efficacy injective, first-line: interferonβ-1b (IFNβ-1b), glatiramer acetate (GA); and high-efficacy, second-line: fingolimod (FTY) and natalizumab (NAT)) on the in vitro viability and functions of neutrophils isolated from healthy subjects. All the DMTs tested impaired the ability of neutrophils to kill Klebsiella pneumoniae, whereas none of them affected the rate of neutrophil apoptosis or CD11b and CD62L cell surface expression. Intriguingly, only FTY exposure negatively affected K. pneumoniae-induced production of reactive oxygen species (ROS) in polymorphonuclear leukocytes (PMNs). Furthermore, neutrophils exposed to K. pneumoniae secreted enhanced amounts of CXCL8, IL-1β and TNF-α, which were differentially regulated following DMT pretreatment. Altogether, these findings suggest that DMTs may increase the susceptibility of MS patients to microbial infections, in part, through inhibition of neutrophil functions. In light of these data, we recommend that the design of personalized therapies for RRMS patients should take into account not just the mechanism of action of the chosen DMT but also the potential risk of infection associated with the administration of such therapeutic compounds to this highly vulnerable population.
Exposure to Pulsed Electromagnetic Field (PEMF) has been shown to affect proliferation and differentiation of human mesenchymal stem cells derived from bone marrow stroma (BM-hMSC). These cells offer ...considerable promise in the field of regenerative medicine, but their clinical application is hampered by major limitations such as poor availability and the time required to differentiate up to a stage suitable for implantation. For this reason, several research efforts are focusing on identifying strategies to speed up the differentiation process. In this work we investigated the in vitro effect of PEMF on Ca(2+)-related mechanisms promoting the osteogenic differentiation of BM-hMSC. Cells were daily exposed to PEMF while subjected to osteogenic differentiation and various Ca(2+)-related mechanisms were monitored using multiple approaches for identifying functional and structural modifications related to this process. The results indicate that PEMF exposure promotes chemically induced osteogenesis by mechanisms that mainly interfere with some of the calcium-related osteogenic pathways, such as permeation and regulation of cytosolic concentration, leaving others, such as extracellular deposition, unaffected. The PEMF effect is primarily associated to early enhancement of intracellular calcium concentration, which is proposed here as a reliable hallmark of the osteogenic developmental stage.
Abstract
Exposure to Pulsed Electromagnetic Field (PEMF) has been shown to affect proliferation and differentiation of human mesenchymal stem cells derived from bone marrow stroma (BM-hMSC). These ...cells offer considerable promise in the field of regenerative medicine, but their clinical application is hampered by major limitations such as poor availability and the time required to differentiate up to a stage suitable for implantation. For this reason, several research efforts are focusing on identifying strategies to speed up the differentiation process. In this work we investigated the
in vitro
effect of PEMF on Ca
2+
-related mechanisms promoting the osteogenic differentiation of BM-hMSC. Cells were daily exposed to PEMF while subjected to osteogenic differentiation and various Ca
2+
-related mechanisms were monitored using multiple approaches for identifying functional and structural modifications related to this process. The results indicate that PEMF exposure promotes chemically induced osteogenesis by mechanisms that mainly interfere with some of the calcium-related osteogenic pathways, such as permeation and regulation of cytosolic concentration, leaving others, such as extracellular deposition, unaffected. The PEMF effect is primarily associated to early enhancement of intracellular calcium concentration, which is proposed here as a reliable hallmark of the osteogenic developmental stage.
Abstract Biofilm production is the crucial pathogenic mechanism of the implant-associated infection and a primary target for new anti-infective strategies. Silver nanoparticles (AgNPs) are attracting ...interest for their multifaceted potential biomedical applications. As endowed with highest surface/mass ratio and potent antibacterial activity, they can profitably be applied as monolayers at biomaterial surfaces. Desirably, in order to minimize the risks of toxic effects from freely circulating detached nanoparticles, AgNPs should firmly be anchored to the modified biomaterial surfaces. Here we focus on a newly designed glass surface modified with AgNPs and on its antibiofilm properties. Link of a self-assembled monolayer of AgNPs to glass was obtained through preliminary amino-silanization of the glass followed by immersion in an AgNPs colloidal suspension. Static contact angle measure, AFM, TEM, UV-Vis spectroscopy, ICP atomic emission spectroscopy were used for characterization. Antibiofilm activity against the biofilm-producer Staphylococcus epidermidis RP62A was assayed by both CFU method and CLSM. Performances of AgNPs-glasses were: i) excellent stability in aqueous medium; ii) prolonged release and high local concentration of Ag+ without any detaching of AgNPs; iii) strong antibiofilm activity against S. epidermidis RP62A. This AgNPs surface-modification can be applied to a large variety of biomaterials by simply depositing glass-like SiO2 films on their surfaces.
Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the ...progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving “chronic” worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion‐independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1–20
Recently, concern has been raised about the influence of the previous disease-modifying treatments (DMTs) on the clinical efficacy of ocrelizumab (OCR).
We aimed to evaluate whether the previous DMT ...affects the lymphocyte subset kinetics in people with Multiple Sclerosis (MS) switching to OCR.
This is a multicenter, retrospective, real-world study on consecutive MS patients who started or switched to OCR. We grouped them by prior DMT in: (i) naïve-to-treatment (NTT), (ii) switching from fingolimod (SF) and (iii) switching from natalizumab (SN). Differences in absolute lymphocyte count and lymphocyte subset count changes, considering the period from baseline to 6 months, over all the three groups were assessed with an inverse-probability-weighted regression adjustment model.
Mean T CD4+ cell count reduction from baseline to the six-month follow-up was more pronounced in the SN group compared to the NTT (p = 0,026). Further, patients in the SF group experienced a less pronounced CD4 T cell number decrease than both NTT and SN groups (p = 0,04 and p < 0,001, respectively). Patients in the SF group experienced an increase in CD8 T cell absolute number, whereas those in the NTT and SN groups experienced a significant decrease (p = 0,015 and p < 0,001, respectively). Patients experiencing early inflammatory activity showed a lower CD8+ cell count at baseline than stable patients (p = 0,02).
Previous DMTs influence the lymphocyte kinetics in people with MS switching to OCR. Reassessment of these findings over a larger population may help optimize the switch.
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•Ocrelizumab affects the T cell compartment.•The previous DMT affects T cell kinetics under ocrelizumab treatment.•Low CD8+ T cell count at baseline is associated with inflammatory activity under ocrelizumab treatment.
Introduction
The COVID-19 pandemic caused major changes in the lifestyle and in the access to health services worldwide. Progressive multiple sclerosis (pMS) patients are a vulnerable population at ...high risk of disability worsening.
Objective and Methods
The objective of this study was to assess the health outcomes of COVID-19 lockdown in a cohort of 225 pMS patients.
Results
Worsening of neurological disability (19.7%) and fatigue (32.4%), depression (30.4%), and weight increase (28.3%) were observed in pMS patients during lockdown, along with discontinuation of regular physical exercise (47.1%) and of physical therapy (59.3%).
Conclusion
These results highlight the adverse impact, on pMS patients, of the public health measures implemented for the containment of the pandemic.
Background: The reason why some multiple sclerosis (MS) patients show disease activity after alemtuzumab (ALM) is still unclear, but ocrelizumab (OCR) could represent an interesting sequential ...therapeutic approach. Objectives: To investigate safety and efficacy of OCR in MS patients with disease activity after two ALM courses. Methods: Observational retrospective multi-centers Italian cohort study. Results: Seventy-two subjects were included. Mean follow-up (FU) was 2.4 (±1) years. Forty-five patients (62.5%) experienced at least one adverse event (AE), with infections accounting for 96.7% of cases. A reduction in total lymphocytes was observed between OCR start and 6 months FU, driven by BCD19+ lymphocytes depletion ( p < 0.001). Immunoglobulin M (IgM) levels decreased between OCR start and 6 months FU ( p < 0.001). At 2-year FU, relapse, magnetic resonance imaging (MRI) activity and disability worsening-free survival were 92.1%, 90.8%, and 89.2%. The evidence of inflammatory activity between the two ALM courses was associated with higher risk of relapse, MRI activity, and NEDA-3 status loss in relapsing-remitting multiple sclerosis (RRMS; p = 0.02, p = 0.05, p = 0.01, respectively). Conclusions: OCR after two ALM courses seemed to be safe and effective. Early IgM hypogammaglobulinemia occurred in a high proportion of patients. The evidence of inflammatory activity between ALM courses seemed to increase the risk of MS re-activation on OCR treatment.
Extracellular matrix (ECM) components initiate crucial biochemical and biomechanical cues that are required for bone marrow homeostasis. In our research, we prove that a peri-cellular matrix composed ...primarily of type III and type IV collagens, and fibronectin surrounds human megakaryocytes in the bone marrow. The data we collected support the hypothesis that bone marrow megakaryocytes possess a complete mechanism to synthesize the ECM components, and that thrombopoietin is a pivotal regulator of this new function inducing transforming growth factor-β1 (TGF-β1) release and consequent activation of the downstream pathways, both in vitro and in vivo. This activation results in a dose dependent increase of ECM component synthesis by megakaryocytes, which is reverted upon incubation with JAK and TGF-β1 receptor specific inhibitors. These data are pivotal for understanding the central role of megakaryocytes in creating their own regulatory niche within the bone marrow environment.
Grey Matter Pathology in Multiple Sclerosis Vercellino, Marco; Plano, Federica; Votta, Barbara ...
Journal of neuropathology and experimental neurology,
2005-December, Letnik:
64, Številka:
12
Journal Article
Recenzirano
Odprti dostop
ABSTRACTThe aim of our study is to evaluate the extent and distribution of grey matter demyelinating lesions in multiple sclerosis (MS), addressing also neuronal loss and synaptic loss. Whole coronal ...sections of 6 MS brains and 6 control brains were selected. Immunohistochemistry was performed for myelin basic protein, neurofilaments, synaptophysin, ubiquitin, and activated caspase-3. Neuronal density and optical density of synaptophysin staining were estimated in cortical lesions and compared with those observed in corresponding areas of normal (i.e. nondemyelinated) cortex in the same section. Demyelinating lesions were observed in the cerebral cortex, in the thalamus, basal ganglia, and in the hippocampus. The percentage of demyelinated cortex was remarkable in 2 cases of secondary progressive MS (48% and 25.5%, respectively). Neuronal density was significantly reduced in cortical lesions (18-23% reduction), if compared with adjacent normal cortex, in the 2 cases showing the higher extent of cortical demyelination; in the same cases, very rare apoptotic neurons expressing caspase-3 were observed in cortical lesions and not in adjacent normal cortex. No significant decrease in optical density of synaptophysin staining was observed in cortical lesions. Grey matter demyelination and neuronal loss could contribute to disability and cognitive dysfunctions in MS.
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