We present the neuropathological description of an autoptic case of fatal rebound of disease activity after fingolimod discontinuation in a multiple sclerosis patient. MRI prior to the fatal outcome ...showed several large tumefactive demyelinating lesions. These lesions were characterized by prominent astrocytic gliosis, with a remarkable preponderance of large hypertrophic reactive astrocytes showing intense expression of sphingosine-1-phosphate receptor 1. Prominent astrocytic gliosis was also diffusely observed in the normal-appearing white matter. Dysregulated sphingosine-1-phosphate signaling on astrocytes following fingolimod withdrawal might represent a possible contributing mechanism to disease rebound and might account for the unusual radiological and neuropathological features observed in the present case.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder consisting of progressive loss of motor neurons. TDP‐43 has been identified as a component of ubiquitin‐immunoreactive inclusions ...of motor neurons in ALS. We focused on the diffuse cytoplasmic TDP‐43 immunoreactivity in ALS neurons, and quantitatively assessed it in comparison with skein/round TDP‐43 and ubiquitin immunostaining in motor neurons of 30 sporadic ALS cases. The percentage of spinal motor neurons with cytoplasmic TDP‐43 immunoreactivity was higher than that of ubiquitin‐immunoreactive ones. The percentage of TDP‐43‐positive motor neurons was independent of neuron counts in anterior horns, while the percentage of ubiquitinated neurons was inversely correlated. Aiming to define the cytosolic localization of TDP‐43, the immunoblot analysis of spinal cord and frontal cortex showed that full‐length TDP‐43, the 45 kDa form and ubiquitinated TDP‐43 are found in the soluble inclusion‐free fraction. The present data suggest that delocalization, accumulation and ubiquitination of TDP‐43 in the cytoplasm of motor neurons are early dysfunctions in the cascade of the events leading to motor neuron degeneration in ALS, preceding the formation of insoluble inclusion bodies. Being cytoplasmic accumulation an ongoing event during the course of the illness, a therapeutic approach to this incurable disease can be envisaged.
Several studies have shown that low-level laser irradiation (LLLI) has beneficial effects on bone regeneration. The objective of this study was to examine the in vitro effects of LLLI on ...proliferation and differentiation of a human osteoblast-like cell line (Saos-2 cell line). Cultured cells were exposed to different doses of LLLI with a semiconductor diode laser (659 nm; 10 mW power output). The effects of laser on proliferation were assessed daily up to seven days of culture in cells irradiated once or for three consecutive days with laser doses of 1 or 3 J/cm2. The obtained results showed that laser stimulation enhances the proliferation potential of Saos-2 cells without changing their telomerase pattern or morphological characteristics. The effects on cell differentiation were assessed after three consecutive laser irradiation treatments in the presence or absence of osteo-inductive factors on day 14. Enhanced secretion of proteins specific for differentiation toward bone as well as calcium deposition and alkaline phosphatase activity were observed in irradiated cells cultured in a medium not supplemented with osteogenic factors. Taken together these findings indicate that laser treatment enhances the in vitro proliferation of Saos-2 cells, and also influences their osteogenic maturation, which suggest it is a helpful application for bone tissue regeneration.
On 2–3 October 2020, a heavy precipitation event severely affected northern Italy and in particular the western Alps, with rainfall amount exceeding 600 mm over 24 h. This event was associated with ...an upper-level trough over the western Mediterranean basin, a large-scale configuration typical of heavy precipitation phenomena on the southern side of the Alps, since it induces a northward transport of large amounts of moisture impinging on the orography. The present study shows that a relevant amount of moisture moved towards the Mediterranean basin in the form of an atmospheric river (AR), a long and narrow filament-shaped structure crossing the whole Atlantic Ocean, characterized in the present case by a maximum Integrated Vapour Transport exceeding 1000 kg m−1 s−1. Therefore, in addition to the local contribution from the Mediterranean Sea, a relevant amount of moisture moved from the Tropics towards the Mediterranean, feeding the precipitation systems.
The presence of an AR represented a distinguishing aspect of the event, superimposed on the well-known dynamic-thermodynamic mechanisms of heavy precipitation over the Alps. High-resolution numerical simulations and diagnostic tools have been exploited to investigate in detail how the transport of water vapour associated with the AR has influenced the dynamics and favoured the severity of the heavy precipitation processes.
The results disclose the role of the AR and add further details to the theoretical framework of heavy precipitation mechanisms in the Alpine area, improving our understanding of the complex interaction between large-scale flows and mesoscale dynamics during extreme precipitation episodes. Due to the relatively fast evolution of the synoptic disturbance, the typical mesoscale mechanisms would have led only to an ordinary intense rainfall event. The contribution of the AR turned the event into a devastating flood.
Evidence underlines the importance of microRNAs (miRNAs) in the pathogenesis of multiple sclerosis (MS). Based on the fact that miRNAs are present in human biological fluids, we previously showed ...that miR-223, miR-23a and miR-15b levels were downregulated in the sera of MS patients versus controls. Here, the expression levels of these candidate miRNAs were determined in peripheral blood mononuclear cells (PBMCs) and the serum of MS patients, in addition to three genotyped single nucleotide polymorphisms (SNPs). Mapping in the genomic regions of miR-223, miR-23a and miR-15b genes, 399 cases and 420 controls were tested. Expression levels of miR-223 and miR-23a were altered in PBMCs from MS patients versus controls. Conversely, there were no differences in the expression levels of miR-15b. A significantly decreased genotypic frequency of miR-223 rs1044165 T/T genotype was observed in MS patients. Moreover, the allelic frequency of miR-23a rs3745453 C allele was significantly increased in patients versus controls. In contrast, there were no differences in the distribution of miR-15b SNP. In conclusion, our results suggest that miR-223 and miR-23a could play a role in the pathogenesis of MS. Moreover, miR-223 rs1044165 polymorphism likely acts as a protective factor, while miR-23a rs3745453 variant seems to act as a risk factor for MS.
Introduction:
Limited data are available on the course of Coronavirus disease 2019 (COVID-19) in people with Multiple Sclerosis (MS). More real-world data are needed to help the MS community to ...manage MS treatment properly. In particular, it is important to understand the impact of immunosuppressive therapies used to treat MS on the outcome of COVID-19.
Methods:
We retrospectively collected data on all confirmed cases of COVID-19 in MS patients treated with ocrelizumab, followed in two MS Centers based in University Hospitals in Northern Italy from February 2020 to June 2021.
Results:
We identified 15 MS patients treated with ocrelizumab with confirmed COVID-19 (mean age, 50.47 ± 9.1 years; median EDSS, 3.0; range 1.0–7.0). Of these, 14 were confirmed by nasal swab and 1 was confirmed by a serological test. COVID-19 severity was mild to moderate in the majority of patients (
n
= 11, 73.3%; mean age, 49.73; median EDSS 3.0). Four patients (26.7%; mean age, 52.5 years; median EDSS, 6) had severe disease and were hospitalized; one of them died (age 50, EDSS 6.0, no other comorbidities). None of them had underlying respiratory comorbidities.
Conclusion:
This case series highlights the large variability of the course of COVID-19 in ocrelizumab-treated MS patients. The challenges encountered by the healthcare system in the early phase of the COVID-19 pandemic might have contributed to the case fatality ratio observed in this series. Higher MS-related disability was associated with a more severe COVID-19 course.
Kappa free light chains (κ-FLC) in the cerebrospinal fluid (CSF) are an emerging biomarker in multiple sclerosis (MS).
To investigate whether κ-FLC index has similar diagnostic value in patients with ...primary progressive multiple sclerosis (PPMS) compared to oligoclonal bands (OCB).
Patients with PPMS were recruited through 11 MS centres across 7 countries. κ-FLC were measured by immunonephelometry/-turbidimetry. OCB were determined by isoelectric focusing and immunofixation.
A total of 174 patients (mean age of 52±11 years, 51% males) were included. κ-FLC index using a cut-off of 6.1 was positive in 161 (93%) and OCB in 153 (88%) patients.
κ-FLC index shows similar diagnostic sensitivity than OCB in PPMS.
Background:
Progranulin (GRN) is a multifunctional protein involved in inflammation and repair, and also a neurotrophic factor critical for neuronal survival. Progranulin is strongly expressed in ...multiple sclerosis (MS) brains by macrophages and microglia.
Methods:
In this study we evaluated GRN genetic variability in 400 MS patients, in correlation with clinical variables such as disease severity and relapse recovery. We also evaluated serum progranulin levels in the different groups of GRN variants carriers.
Results:
We found that incomplete recovery after a relapse is correlated with an increased frequency of the rs9897526 A allele (odds ratio (OR) 4.367, p = 0.005). A more severe disease course (Multiple Sclerosis Severity Score > 5) is correlated with an increased frequency of the rs9897526 A allele (OR 1.886, p = 0.002) and of the rs5848 T allele (OR 1.580, p = 0.019). Carriers of the variants associated with a more severe disease course (rs9897526 A, rs5848 T) have significantly lower levels of circulating progranulin (80.5 ± 9.1 ng/mL vs. 165.7 ng/mL, p = 0.01).
Conclusion:
GRN genetic polymorphisms likely influence disease course and relapse recovery in MS.
Background: Progranulin (PGRN) is a fundamental neurotrophic factor, and is also involved in inflammation and wound repair. PGRN may have pro- or anti-inflammatory properties, depending upon ...proteolysis of the anti-inflammatory parent PGRN protein and the generation of pro-inflammatory granulin peptides.
Objectives: Our objectives were as follows: (1) to evaluate the presence and distribution of PGRN in multiple sclerosis (MS) brain tissue, correlating it with demyelination and inflammation; (2) to evaluate cerebrospinal fluid (CSF) PGRN concentrations in patients with MS and controls, in relationship to the clinical features of the disease.
Methods: Our study involved the following: (1) neuropathological study of PGRN on post-mortem tissue of 19 MS and six control brains; (2) evaluation of PGRN CSF concentration in 40 MS patients, 15 non-inflammatory controls and five inflammatory controls (viral encephalitis).
Results: In active demyelinating lesions, PGRN was expressed on macrophages/microglia. In the normal-appearing white matter (NAWM), expression of PGRN was observed on activated microglia. PGRN was expressed by neurons and microglia in cortical lesions and in normal-appearing cortex. No expression of PGRN was observed in controls, except on neurons. PGRN CSF concentrations were significantly higher in patients with relapsing–remitting MS during relapses and in progressive MS patients, compared with relapsing–remitting MS patients during remissions and with non-inflammatory controls.
Conclusions: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS.
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