Towards Personalized Medicine in Myasthenia Gravis: Role of Circulating microRNAs miR-30e-5p, miR-150-5p and miR-21-5p.

Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by fatigable skeletal muscle weakness with a fluctuating unpredictable course. One main concern in MG is the lack of objective biomarkers to guide individualized treatment decisions. Specific circulating serum microRNAs (miRNAs) miR-30e-5p, miR-150-5p and miR-21-5p levels have been shown to correlate with clinical course in specific MG patient subgroups. The aim of our study was to better characterize these miRNAs, regardless of the MG subgroup, at an early stage from diagnosis and determine their sensitivity and specificity for MG diagnosis, as well as their predictive power for disease relapse. Serum levels of these miRNAs in 27 newly diagnosed MG patients were compared with 245 healthy individuals and 20 patients with non-MG neuroimmune diseases. Levels of miR-30e-5p and miR-150-5p significantly differed between MG patients and healthy controls; however, no difference was seen compared with patients affected by other neuroimmune diseases. High levels of miR-30e-5p predicted MG relapse (p = 0.049) with a hazard ratio of 2.81. In summary, miR-150-5p is highly sensitive but has low specificity for MG, while miR-30e-5p has the greatest potential as a predictive biomarker for the disease course in MG, regardless of subgroup.

Case Report: Concomitant Massive Cerebral Venous Thrombosis and Internal Iliac Vein Thrombosis Related to Paucisymptomatic COVID-19 Infection.

Thrombotic complications are common in COVID-19 patients, but cerebral venous system involvement, timing after infection, optimal treatment, and long-term outcome are uncertain. We report a case of massive cerebral venous thrombosis and concomitant internal iliac vein thrombosis occurring in the late phase of paucisymptomatic COVID-19 infection. Mild respiratory symptoms, without fever, started 3 weeks before headache and acute neurological deficits. The patient had silent hypoxemia and typical COVID-19 associated interstitial pneumonia. Brain CT scan showed a left parietal hypodense lesion with associated sulcal subarachnoid hemorrhage. CT cerebral venography showed a massive cerebral venous thrombosis involving the right transverse sinus, the right jugular bulb, the superior sagittal sinus, the straight sinus, the vein of Galen, and both internal cerebral veins. Abdominal CT scan showed no malignancy but revealed an asymptomatic right internal iliac vein thrombosis. Both cerebral venous thrombosis and pelvic vein thrombosis were effectively treated with unfractionated heparin started on the day of admission, then shifted to low molecular weight heparin, with a favorable clinical course. Nasopharyngel swab, repeated twice, tested negative for SARS-CoV-2. Serological tests confirmed SARS-CoV-2 infection. Our case supports active surveillance and prevention of thrombotic complications associated with COVID-19, which may affect both peripheral and cerebral venous system. Early initiation of unfractionated heparin may lead to good neurologic outcome.

Reasons for hospitalization in Parkinson's disease: a case-control study.

BACKGROUND: To characterize reasons for hospital admission, mortality and surgical procedures in patients with Parkinson's disease (PD) compared to controls. METHODS: The clinical features of all consecutive patients from 2000 to 2007 were reviewed. We identified patients with PD (ICD 9 code 332.0) from a database of our General Hospital (Vimercate) with a catchment's population of 180,000. Data on admitting wards as well as reasons for admission, surgical procedures performed and clinical outcome were collected. Clinical data were compared to an age and sex matched control population admitted in the same period of time. RESULTS: The total number of admissions was 367. Mean age was 76.7 years. The mean duration of stay was 9.2 days for controls and 9.7 for PD patients. A comorbid disorder was the cause of admission in 80% of cases and 79% of cases came from the Emergency Room. Infectious diseases, mainly respiratory infections, were more frequent in PD of both sexes, while trauma was significantly higher only in PD men. Percentage of patients treated surgically was similar in both cases and controls. Intrahospital mortality was 6% both in PD and controls. Infectious diseases were more frequent in PD patients while cardiovascular death was more frequent in controls. CONCLUSIONS: Comorbidity in PD is higher than reported in other reports. In our study PD patients had the same length of hospitalization and intrahospital mortality as controls. The presence of a control population allows to discriminate between general complications of the elderly and specific vulnerabilities of PD patients.

The GluR2 subunit inhibits proliferation by inactivating Src-MAPK signalling and induces apoptosis by means of caspase 3/6-dependent activation in glioma cells.

Glioblastoma multiforme (GBM) is the most invasive and undifferentiated type of brain tumour, and so surgical interventions are ineffective. We found that GluR2 is absent in fast-growing GBM-derived tumour stem cells and high-grade glioma specimens, but is expressed in slow-growing stem cells and low-grade glioma specimens. More remarkably, GluR2 overexpression in U-87MG cells inhibits proliferation by inactivating extracellular signal-regulated kinase (ERK)1/2-Src phosphorylation and induces apoptosis. Mechanistically, we observed that the scaffold protein GRIP is essential for the effect of GluR2 on ERK-Src inactivation. These findings indicate that the absence of the GluR2 subunit favours malignancy.

Extracellular interactions between GluR2 and N-cadherin in spine regulation.

Via its extracellular N-terminal domain (NTD), the AMPA receptor subunit GluR2 promotes the formation and growth of dendritic spines in cultured hippocampal neurons. Here we show that the first N-terminal 92 amino acids of the extracellular domain are necessary and sufficient for GluR2's spine-promoting activity. Moreover, overexpression of this extracellular domain increases the frequency of miniature excitatory postsynaptic currents (mEPSCs). Biochemically, the NTD of GluR2 can interact directly with the cell adhesion molecule N-cadherin, in cis or in trans. N-cadherin-coated beads recruit GluR2 on the surface of hippocampal neurons, and N-cadherin immobilization decreases GluR2 lateral diffusion on the neuronal surface. RNAi knockdown of N-cadherin prevents the enhancing effect of GluR2 on spine morphogenesis and mEPSC frequency. Our data indicate that in hippocampal neurons N-cadherin and GluR2 form a synaptic complex that stimulates presynaptic development and function as well as promoting dendritic spine formation.

NSF interaction is important for direct insertion of GluR2 at synaptic sites.

Here, we use a cell surface thrombin cleavage assay to investigate directly the role of NSF in the surface delivery and synaptic accumulation of alpha-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA) receptors. In cultured hippocampal neurons, the GluR2 subunit (which specifically interacts with NSF) inserts rapidly into the plasma membrane from intracellular compartments and accumulates in synaptic sites. In contrast, surface accumulation of GluR3 (a subunit that does not interact with NSF) or a GluR2 mutant defective in NSF binding (DeltaA849-Q853) occurs initially at extrasynaptic sites and is kinetically slower than wild-type GluR2. Introducing a binding site for NSF into GluR3 (GluR3NSF) generates a subunit that behaves like GluR2 in terms of kinetics and site of surface insertion. These data suggest that the NSF interaction is necessary for rapid incorporation of AMPA receptor subunits into synapses and is sufficient to confer this property on GluR3.