mGluR5 protect astrocytes from ischemic damage in postnatal CNS white matter

AbstractAstrocytes perform essential neuron-supporting functions in the central nervous system (CNS) and their disruption has devastating effects on neuronal integrity in multiple neuropathologies. Although astrocytes are considered resistant to most pathological insults, ischemia can result in astrocyte injury and astrocytes in postnatal white matter are particularly vulnerable. Metabotropic glutamate receptors (mGluR) are neuroprotective in ischemia and are widely expressed by astrocytes throughout CNS grey matter, but their potential cytoprotective role in astrocytes had not been determined. Here, we identify functional expression of group I mGluR in white matter astrocytes and demonstrate their activation protects astrocytes from ischemic damage in the postnatal mouse optic nerve. Optic nerve astrocytes are shown to express mGluR5 using immunolabelling of sections and explant cultures from transgenic reporter mice in which GFAP drives expression of EGFP. In addition, using Fluo-4 calcium imaging in isolated intact optic nerves, we show that the group I/II mGluR agonist ACPD and the specific group I mGluR agonist DHPG evoke glial Ca2+ signals that were significantly inhibited by the group I mGluR antagonist AIDA. A key finding is that activation of group I mGluR protects astrocytes against oxygen-glucose deprivation (OGD) in situ, in isolated intact optic nerves from GFAP-EGFP mice. This study identifies a role for group I mGluR in protecting astrocytes against ischemia in postnatal white matter and suggests this may be a strategy for limiting damage in neuropathologies involving excitotoxity

Metabotropic Glutamate Receptors Protect Oligodendrocytes from Acute Ischemia in the Mouse Optic Nerve.

Studies by Bruce Ransom and colleagues have made a major contribution to show that white matter is susceptible to ischemia/hypoxia. White matter contains axons and the glia that support them, notably myelinating oligodendrocytes, which are highly vulnerable to ischemic-hypoxic damage. Previous studies have shown that metabotropic GluRs (mGluRs) are cytoprotective for oligodendrocyte precursor cells and immature oligodendrocytes, but their potential role in adult white matter was unresolved. Here, we report that group 1 mGluR1/5 and group 2 mGluR3 subunits are expressed in optic nerves from mice aged postnatal day (P)8-12 and P30-35. We demonstrate that activation of group 1 mGluR protects oligodendrocytes against oxygen-glucose deprivation (OGD) in developing and young adult optic nerves. In contrast, group 2 mGluR are shown to be protective for oligodendrocytes against OGD in postnatal but not young adult optic nerves. The cytoprotective effect of group 1 mGluR requires activation of PKC, whilst group 2 mGluR are dependent on negatively regulating adenylyl cyclase and cAMP. Our results identify a role for mGluR in limiting injury of oligodendrocytes in developing and young adult white matter, which may be useful for protecting oligodendrocytes in neuropathologies involving excitoxicity and ischemia/hypoxia

Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer's disease

There is increasing evidence that myelin disruption is related to cognitive decline in Alzheimer's disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by adult oligodendrocyte progenitor cells (OPCs), also known as NG2-glia. To address whether alterations in myelination are related to age-dependent changes in OPCs, we analyzed NG2 and myelin basic protein (MBP) immunolabelling in the hippocampus of 3×Tg-AD mice at 6 and 24 months of age, compared with non-Tg age-matched controls. There was an age-related decrease in MBP immunostaining and OPC density, together with a decline in the number of OPC sister cells, a measure of OPC replication. Notably, the loss of myelin and OPC sister cells occurred earlier at 6 months in 3xTg-AD, suggesting accelerated aging, although there was not a concomitant decline in OPC numbers at this age, suggesting the observed changes in myelin were not a consequence of replicative exhaustion, but possibly of OPC disruption or senescence. In line with this, a key finding is that compared to age-match controls, OPC displayed marked morphological atrophy at 6 months in 3xTg-AD followed by morphological hypertrophy at 24 months, as deduced from significant changes in total cell surface area, total cell volume, somata volume and branching of main processes. Moreover, we show that hypertrophic OPCs surround and infiltrate amyloid-β (Aβ) plaques, a key pathological hallmark of AD. The results indicate that OPCs undergo complex age-related remodeling in the hippocampus of the 3xTg-AD mouse model. We conclude that OPC disruption is an early pathological sign in AD and is a potential factor in accelerated myelin loss and cognitive decline.</p

Treatment of metastatic neuroendocrine carcinomas based on WHO classification

A single institution prospective trial was conducted to evaluate the efficacy of biotherapy or chemotherapy in metastatic neuroendocrine carcinomas (NECs). The choice of therapy was based on the revised histological classification criteria of the WHO in an effort to define a standardized protocol for therapy of these cancers. Patients with well-differentiated NECs (WD-NECs; n=11) received therapy with octreotide long-acting release and interferon-alpha-2b for a maximum of 1 year; cases with poorly-differentiated NECs (PD-NECs; n=8) were given combination cisplatin, L-leucovorin and 5-fluorouracil chemotherapy for a maximum of 9 cycles. Five patients (4 with WD-NECs) had carcinoid syndrome. Among the patients with WD-NECs (median follow-up 20 months, range 4-40), 4 had partial responses and 7 had stable disease. In patients with PD-NECs (median follow-up 10.5 months, range 3-30), 3 had partial response, 2 stable disease, and the disease progressed in 3 cases. The 2-year survival rate in WD-NECs and PD-NECs was 88% and 66%, respectively. Grade 3-4 side-effects were limited to 9% thrombocytopenia and 12.5% neutropenia. Both these treatment regimens had a good therapeutic index and compared favourably with those previously reported for metastatic WD-NECs and PD-NECs

Including mRECIST in the Metroticket 2.0 criteria improves prediction of hepatocellular carcinoma-related death after liver transplant

S AIMS: The weight of response to neo-adjuvant therapies, to select candidates with hepatocellular carcinoma (HCC) for liver transplantation (LT) at acceptable risk of recurrence, remains partially unsolved for most of post-LT prediction models. Aim of this study was to embed radiological response in the Metroticket 2.0 model for post-LT prediction of "HCC-related death" to provide more usefulness in the modern clinical scenario

CT-derived Chest Muscle Metrics for Outcome Prediction in Patients with COVID-19

Background Lower muscle mass is a known predictor of unfavorable outcome, but its prognostic impact on COVID-19 patients is unknown. Purpose To investigate the contribution of CT-derived muscle status in predicting clinical outcomes in COVID-19 patients. Materials and Methods Clinical/laboratory data and outcomes (intensive care unit [ICU] admission and death) were retrospectively retrieved for patients with reverse transcriptase polymerase chain reaction-confirmed COVID-19, who underwent chest CT on admission in four hospitals in Northern Italy from February 21 to April 30, 2020. Extent and type of pulmonary involvement, mediastinal lymphadenopathy, and pleural effusion were assessed. Cross-sectional areas and attenuation of paravertebral muscles were measured on axial CT images at T5 and T12 vertebral level. Multivariable linear and binary logistic regression, including calculation odds ratios (OR) with 95% confidence intervals (CIs), were used to build four models to predict ICU admission and death, tested and compared using receiver operating characteristic curve (ROC) analysis. Results A total 552 patients (364 men; median age 65 years, interquartile range 54-75) were included. In a CT-based model, lower-than-median T5 paravertebral muscle area showed the highest ORs for ICU admission (OR 4.8, 95% CI 2.7-8.5; P<.001) and death (OR 2.3, 95% CI 1.0-2.9; P=.027). When clinical variables were included in the model, lower-than-median T5 paravertebral muscle area still showed the highest ORs both for ICU admission (OR 4.3; 95% CI 2.5-7.7; P<.001) and death (OR 2.3, 95% CI 1.3-3.7; P=.001). At ROC analysis, the CT-based model and the model including clinical variables showed the same area under the curve (AUC) for ICU admission prediction (AUC 0.83, P=.380) and were not different in predicting death (AUC 0.86 versus AUC 0.87, respectively, P=.282). Conclusion In hospitalized patients with COVID-19, lower muscle mass on CT was independently associated with ICU admission and hospital mortality

Machine Learning to Predict In-Hospital Mortality in COVID-19 Patients Using Computed Tomography-Derived Pulmonary and Vascular Features

Pulmonary parenchymal and vascular damage are frequently reported in COVID-19 patients and can be assessed with unenhanced chest computed tomography (CT), widely used as a triaging exam. Integrating clinical data, chest CT features, and CT-derived vascular metrics, we aimed to build a predictive model of in-hospital mortality using univariate analysis (Mann–Whitney U test) and machine learning models (support vectors machines (SVM) and multilayer perceptrons (MLP)). Patients with RT-PCR-confirmed SARS-CoV-2 infection and unenhanced chest CT performed on emergency department admission were included after retrieving their outcome (discharge or death), with an 85/15% training/test dataset split. Out of 897 patients, the 229 (26%) patients who died during hospitalization had higher median pulmonary artery diameter (29.0 mm) than patients who survived (27.0 mm, p &lt; 0.001) and higher median ascending aortic diameter (36.6 mm versus 34.0 mm, p &lt; 0.001). SVM and MLP best models considered the same ten input features, yielding a 0.747 (precision 0.522, recall 0.800) and 0.844 (precision 0.680, recall 0.567) area under the curve, respectively. In this model integrating clinical and radiological data, pulmonary artery diameter was the third most important predictor after age and parenchymal involvement extent, contributing to reliable in-hospital mortality prediction, highlighting the value of vascular metrics in improving patient stratification