Characterization of endothelial cells of lymphatic vessels

Endothelial cells form the inner lining of blood and lymphatic vessels. In mice only tumours of the blood vessel endothelium (haemangiomas) have been thus far reported. In the first part of this thesis is described a highly reproducible method for the induction of benign tumours of the lymphatic endothelial cells (lymphangioma) in mice, by intraperitoneal injection of incomplete Freund's adjuvant. Different criteria have been used in order to establish the nature of the induced lesion. Morphological and histophatological studies of the tumour developed in the peritoneal cavity revealed the presence of cells at various levels of vascular development. Expression of the endothelial markers PECAM/CD31, ICAM-l/CD54, ICAM 2/CDI02 as well as the vascular endothelial growth factor (VEGF) receptor Flk-I, the endothelial cell specific receptors Tie-I, Tie-2, and the lymphatic endothelial specific Flt-4 was identified. When the lesion was induced in ~- galactosidase knock-in Flt-4+/- mice, the tumour endothelia could be stained blue in a number of tumour cells. Tumour-derived cells were propagated in vitro where they spontaneously differentiated, forming vessel-like structures. This evidence leads to the conclusion that this is the first experimental protocol for the induction of a lymphatic endothelium hyperplasia in mice peritoneum. The second part of this thesis describes the use of this model system to investigate the profile of chemokine expression in murine lymphangiomas and in lymphangioma-derived lymphatic endothelial primary cultures. Chemokines are a superfamily of small, secreted chemoattractant molecules that plays a key role in the immune cell trafficking. Although production of chemokines by vascular endothelial cells has been extensively documented, there is much less information regarding the lymphatic endothelium. The reported results are the first detailed analysis of chemokine production by lymphatic endothelial cells. Chemokines belonging to all three subfamilies (CXC, CC and C), were found to be expressed in lymphangioma. Among these molecules is remarkable the identification of CIO, a molecule previously identified only in the bone marrow. The molecular as well as functional assays performed provide an indication of the signals that mediate the recruitment of leukocytes into lymphatic vessels

Tubulin-related cerebellar dysplasia: definition of a distinct pattern of cerebellar malformation

none25siTo determine the neuroimaging pattern of cerebellar dysplasia (CD) and other posterior fossa morphological anomalies associated with mutations in tubulin genes and to perform clinical and genetic correlations.Erratum to: Tubulin-related cerebellar dysplasia: definition of a distinct pattern of cerebellar malformation. [Eur Radiol. 2017]Romaniello, Romina; Arrigoni, Filippo; Panzeri, Elena; Poretti, Andrea; Micalizzi, Alessia; Citterio, Andrea; Bedeschi, Maria Francesca; Berardinelli, Angela; Cusmai, Raffaella; D'Arrigo, Stefano; Ferraris, Alessandro; Hackenberg, Annette; Kuechler, Alma; Mancardi, Margherita; Nuovo, Sara; Oehl-Jaschkowitz, Barbara; Rossi, Andrea; Signorini, Sabrina; Tüttelmann, Frank; Wahl, Dagmar; Hehr, Ute; Boltshauser, Eugen; Bassi, Maria Teresa; Valente, Enza Maria; Borgatti, RenatoRomaniello, Romina; Arrigoni, Filippo; Panzeri, Elena; Poretti, Andrea; Micalizzi, Alessia; Citterio, Andrea; Bedeschi, Maria Francesca; Berardinelli, ANGELA LUCIA; Cusmai, Raffaella; D'Arrigo, Stefano; Ferraris, Alessandro; Hackenberg, Annette; Kuechler, Alma; Mancardi, Margherita; Nuovo, Sara; Oehl Jaschkowitz, Barbara; Rossi, Andrea; Signorini, SABRINA GIOVANNA; Tüttelmann, Frank; Wahl, Dagmar; Hehr, Ute; Boltshauser, Eugen; Bassi, Maria Teresa; Valente, ENZA MARIA; Borgatti, Renat

Early immunotherapy and longer corticosteroid treatment are associated with lower risk of relapsing disease course in pediatric MOGAD

Background and objectives: We sought to identify early factors associated with relapse and outcome in paediatric-onset myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD). Methods: In a multicenter retrospective cohort of pediatric MOGAD (≤18 years), onset features and treatment were compared in patients with monophasic vs relapsing disease (including cases with follow-up ≥12 months after onset or relapse at any time) and in patients with final Expanded Disability Status Scale (EDSS) 0 vs ≥1 at last follow-up (including cases with follow-up >3 months after last event or EDSS0 at any time). Multivariable logistic regression models were used to evaluate factors associated with relapsing disease course and EDSS ≥ 1 at final follow-up. Results: Seventy-five children were included (median onset age 7 years; median 30 months of follow-up). Presentation with acute disseminated encephalomyelitis was more frequent in children aged 8 years or younger (66.7%, 28/42) than in older patients (30.3%, 10/33) (p = 0.002), whereas presentation with optic neuritis was more common in children older than 8 years (57.6%, 19/33) than in younger patients (21.4%, 9/42) (p = 0.001). 40.0% (26/65) of patients relapsed. Time to first relapse was longer in children aged 8 years or younger than in older patients (median 18 vs 4 months) (p = 0.013). Factors at first event independently associated with lower risk of relapsing disease course were immunotherapy <7 days from onset (6.7-fold reduced odds of relapsing course, OR 0.15, 95% CI 0.03-0.61, p = 0.009), corticosteroid treatment for ≥5 weeks (6.7-fold reduced odds of relapse, OR 0.15, 95% CI 0.03-0.80, p = 0.026), and abnormal optic nerves on onset MRI (12.5-fold reduced odds of relapse, OR 0.08, 95% CI 0.01-0.50, p = 0.007). 21.1% (15/71) had EDSS ≥ 1 at final follow-up. Patients with a relapsing course had a higher proportion of final EDSS ≥ 1 (37.5%, 9/24) than children with monophasic disease (12.8%, 5/39) (p = 0.022, univariate analysis). Each 1-point increment in worst EDSS at onset was independently associated with 6.7-fold increased odds of final EDSS ≥ 1 (OR 6.65, 95% CI 1.33-33.26, p = 0.021). Discussion: At first attack of pediatric MOGAD, early immunotherapy, longer duration of corticosteroid treatment, and abnormal optic nerves on MRI seem associated with lower risk of relapse, whereas higher disease severity is associated with greater risk of final disability (EDSS ≥ 1)