CNS inflammatory demyelinating events after COVID-19 vaccines: A case series and systematic review

BackgroundVaccinations provided the most effective tool to fight the SARS-CoV-2 pandemic. It is now well established that COVID-19 vaccines are safe for the general population; however, some cases of rare adverse events following immunization have been described, including CNS Inflammatory Demyelinating Events (CIDEs). Although observational studies are showing that these events are rare and vaccines' benefits highly outweigh the risks, collecting and characterizing post-COVID-19 vaccine CIDEs might be relevant to single out potential risk factors and suggest possible underlying mechanisms. MethodsHere we describe six CIDEs, including two acute transverse myelitis (ATM), three multiple sclerosis (MS), and one neuromyelitis optica spectrum disorder (NMOSD), occurring between 8 and 35 days from a COVID-19 vaccine. Moreover, we performed a systematic literature search of post-COVID-19 vaccines CIDEs, including ATM, ADEM, MS, and NMOSD/MOGAD, published worldwide between December 2020 and December 2021, during 1 year of the vaccination campaign. Clinical/MRI and CSF/serum characteristics were extracted from reviewed studies and pooled-analyzed. ResultsForty-nine studies were included in the systematic review, reporting a total amount of 85 CIDEs. Considering our additional six cases, 91 CIDEs were summarized, including 24 ATM, 11 ADEM, 47 MS, and nine NMOSD/MOGAD. Overall, CIDEs occurred after both mRNA (n = 46), adenoviral-vectored (n = 37), and inactivated vaccines (n = 8). Adenoviral-vectored vaccines accounted for the majority of ADEM (55%) and NMOSD/MOGAD (56%), while mRNA vaccines were more frequent in MS new diagnoses (87%) and relapses (56%). Age was heterogeneous (19-88) and the female sex was prevalent. Time from vaccine to symptoms onset was notably variable: ADEM and NMOSD/MOGAD had a longer median time of onset (12.5 and 10 days) compared to ATM and MS (6 and 7 days) and further timing differences were observed between events following different vaccine types, with ATM and MS after mRNA-vaccines occurring earlier than those following adenoviral-vectored ones. ConclusionBoth the prevalence of vaccine types for certain CIDEs and the heterogeneity in time of onset suggest that different mechanisms-with distinct dynamic/kinetic-might underly these events. While epidemiological studies have assessed the safety of COVID-19 vaccines, descriptions and pooled analyses of sporadic cases may still be valuable to gain insights into CIDE's pathophysiology

Echocardiographic advances in hypertrophic cardiomyopathy: Three-dimensional and strain imaging echocardiography

In the recent past, new ultrasound technologies, such as three-dimensional echocardiography and strain imaging echocardiography, raised up in clinical practice leading to a better assessment of cardiac morphology and performance. These tools may assess regional cardiac mechanics, detecting clinical and subclinical myocardial dysfunction in different settings such as ischemic heart disease, cardiomyopathies, and heart valve diseases. Interesting results derive from patients affected from hypertrophic cardiomyopathy (HCM). Particularly, the mentioned techniques are progressively redefining the role of echocardiography in diagnostic evaluation of HCM variants such as apical HCM, detection of the underlying conditions of increased wall thickness, assessment of subclinical myocardial impairment, and potentially refine risk stratification and prognosis. In this review, we describe the clinical uses of these methodologies and the perspective application in HCM patients

Eating Hubs in Multiple Sclerosis: Exploring the Relationship Between Mediterranean Diet and Disability Status in Italy

Background: Multiple Sclerosis (MS) is a complex disease in which multiple factors contribute to disability accrual. Mediterranean Diet (MeDi) has shown beneficial effects across neurodegenerative diseases. We hypothesize that specific food habits, rather than global adherence to MeDi, might impact on MS. We aimed to (i) evaluate differences in adherence to MeDi between people living with MS (PwMS) and healthy controls (HC); (ii) characterize eating patterns in PwMS and HC, identifying the most influential MeDi items for each group by the use of network analysis; (iii) explore the relationship between patients’ eating habits and disability. Materials and Methods: In this cross-sectional study, we consecutively recruited 424 PwMS and 165 matched HC. Data were obtained through the administration of self- reported questionnaires. Expanded Disability Status Scale (EDSS) and Fatigue Severity Scale (FSS) were evaluated in the MS population. We performed between-groups comparisons via unpaired two-sample t-test and X2 test as appropriate. We calculated food networks in both MS cases and HC using and tested the association between hub nodes and disability. Finally, we conducted a post-hoc analysis, investigating the relationship between food items, lifestyle factors (smoking, exercise) and clinical outcomes. Results: Most participants adhered sufficiently to MeDi. Exploring each group separately, fruit, vegetables, cereal, and fish were identified as hubs in PwMS, while meat and alcohol were identified as hubs in HC. Hubs were all inter-correlated, indicating that eating habits of PwMS include a large intake of all the foods identified as hubs. EDSS was predicted by the intake of vegetables (beta = −0.36, p < 0.03) and fish (beta = −0.34, p < 0.02). The model including smoking pack/year, International Physical Activity Questionnaire (IPAQ) score and intake of “negative foods” predicted 6% of the variance in EDSS (p < 0.001), while the model including smoking pack/year and IPAQ score predicted 4% of the variance in FSS (p < 0.001). Felicetti et al. Eating Hubs in Multiple Sclerosis Conclusions: We identified a sufficient adherence to MeDi in our population. PwMS showed overall a healthier dietary pattern than HC. Vegetables and fish intake were associated with disability outcomes. Future longitudinal studies applying integrated approaches are needed to understand lifestyle added value to the use of standard pharmacological therapies

Potential rotective role of pregnancy and breastfeeding in delaying onset symptoms related to multiple sclerosis

The impact of pregnancy and breastfeeding on the development and outcomes of Multiple sclerosis (MS) has been debated for decades. Since several factors can influence the evolution of the disease, the protective role of multiparity and breastfeeding remains uncertain, as well the role of hormone replacement therapy in the perimenopausal period. We report two cases of relatively late-onset MS in two parous women, who developed their first neurological symptoms after six and nine pregnancies, respectively. Both women breastfed each of their children for 3 to 12 months. One of them underwent surgical menopause and received hormone replacement therapy for 7 years before MS onset. We performed a systematic literature review to highlight the characteristics shared by women who develop the disease in similar conditions, after unique hormonal imbalances, and to collect promising evidence on this controversial issue. Several studies suggest that the beneficial effects of pregnancy and breastfeeding on MS onset and disability accumulation may only be realized when several pregnancies occur. However, these data on pregnancy and breastfeeding and their long-term benefits on MS outcomes suffer from the possibility of reverse causality, as women with milder impairment might choose to become pregnant more readily than those with a higher level of disability. Thus, the hypothesis that multiparity might have a protective role on MS outcomes needs to be tested in larger prospective cohort studies of neo-diagnosed women, evaluating both clinical and radiological features at presentation

Influence of age and menopausal status on phatologic and biologic features of breast cancer

The distribution of the main prognostic factors in different age groups was evaluated in 1226 patients operated on for primary breast cancer, in order to identify those in\uafuenced by age and/or menopausal status. Patients were divided into the following groups: 1) 40 years of age and under; 2) premenopausal over 40 years of age; 3) postmenopausal under 75 years of age and 4) 75 years of age and over. Our findings showed that the youngest patients had the worst prognostic pattern, which improves as age increases and is the best in patients over 75 years of age. Some of the parameters investigated (tumour size, histologic and nuclear grade, tumour infiltrating lymphocytes, p53 and Ki 67) were found to be in\uafuenced by age, some (necrosis and oestrogen receptors) were induced by menopausal status and/or age, some (vascular invasion, ploidy, S-phase and progesterone receptors) showed significant differences in different age groups but there was no consistent relation with patient age or menopausal status, and others (node status, ErbB2/Neu and Cathepsin D) were not induced by age or menopause

MSCs influence C2C12 myoblast proliferation through paracrine mechanisms.

<p>C2C12 cells were grown in single culture (C2C12) or exposed to MSC-derived CM (C2C12/MSC-CM) and their proliferative activity assessed by time lapse videomicroscopy (A-C), EdU (green) incorporation (D, E), Notch-1 and Hes-1 expression by RT-PCR (F), Western blotting (G) and confocal immunofluorescence (H). Quantitative analyses of the results shown are reported in the histograms. Data represent the results of at least three independent experiments with similar results. * <i>p<0.05</i> versus T0; ° <i>p<0.05</i> versus the earlier time points; § <i>p<0.05</i> vs 9 h; # <i>p<0.05</i> versus single culture. D,E: * <i>p<0.05</i>.</p

MSCs influence C2C12 myoblast proliferation through the release of VEGF.

<p>A) Cytokine and growth factor secretion profiles by MSCs grown in C2C12 differentiation medium (MSC-CM). B) Western Blotting analysis of VEGFR2 expression in C2C12 cells in single culture (C2C12) or exposed to MSC-CM (C2C12/MSC-CM), in the presence or absence of VEGFR2 inhibitor, KRN633. C) Superimposed DIC and fluorescence image showing cellular localization of VEGFR2 in C2C12 cells; the staining (green) is mainly localized at the cell surface. D) VEGFR2 phosphorylation in C2C12 cells in the noted experimental conditions, assayed by Western Blotting analysis performed on the immunoprecipitated VEGFR2 protein. Note that VEGFR2 expression and phosphorylation levels increase in the cells exposed to MSC-CM as compared with control. E) Superimposed DIC and fluorescence image showing nuclear EdU (green) staining and corresponding quantitative analysis. (F,G) Notch-1 expression by (F) Western blotting and (G) confocal immunofluorescence in C2C12 cells in the indicated experimental conditions. The quantitative analyses are reported in the histograms. Note that EdU staining and Notch-1 expression are significantly affected by treatment with the VEGFR2 inhibitor, KRN633. Data represent the results of at least three independent experiments with similar results. * <i>p<0.05.</i></p

Assessment of myoblast cell proliferation by cyclin A expression.

<p>C2C12 cells in single and co-culture with <i>Dil</i>(red)- or <i>GFP</i>(green)-labeled MSCs for 24 h were incubated with specific antibodies against cyclin A (green, A,B; red, D-G) and observed by confocal microscopy. Notably, the cells with the higher immunofluorescence intensity are those located in close contact with MSCs. C) Quantitative analysis of the number of cells positive for cyclin A. Data represent the results of at least three independent experiments with similar results. *<i>p<0.05.</i></p

Effects of soluble VEGF on C2C12 myoblast proliferation and differentiation.

<p>C2C12 cells in single culture were treated with different concentrations of soluble VEGF and assayed for Notch-1 and Hes-1 expression by RT-PCR (A), myogenin expression (green) by confocal immunofluorescence (B), and for myotube formation by phase contrast microscopy (C). The quantitative analyses are reported in the histograms. Data represent the results of at least three independent experiments with similar results.* <i>p<0.05.</i></p

Notch-1 signaling is activated in C2C12 myoblasts upon co-culture with MSCs.

<p>Confocal immunofluorescence analysis of Notch-1 (A-C) and Hes-1 (D-F) expression in C2C12 cells in single and co-culture with <i>Dil</i>(red)- or <i>GFP</i>(green)-labeled MSCs for 24 h. After the co-culture, C2C12 cells reveal a stronger reactivity for the activated Notch-intracellular domain (Notch-ICD) and for Hes-1, which is visible inside the nucleus. As shown in the inserts, Notch-1 is preferentially located at the cell membrane (arrows) in the single cultured C2C12 cells, whereas it is found within the cytoplasm (white arrowheads) and nucleus (grey arrowheads) in the co-cultured cells. E) C2C12 myoblast were treated with 5 µM DAPT to inhibit Notch-1 activation and assayed for Hes-1 expression. The corresponding quantitative analysis is reported in the histograms (G,H). Data represent the results of at least three independent experiments with similar results. *p<0.05.</p