Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci

Spreading depolarizations (SDs) indicate injury progression and predict worse clinical outcome in acute brain injury. We demonstrate in rodents that acute brain swelling upon cerebral ischemia impairs astroglial glutamate clearance and increases the tissue area invaded by SD. The cytotoxic extracellular glutamate accumulation (>15 mu M) predisposes an extensive bulk of tissue (4-5 mm(2)) for a yet undescribed simultaneous depolarization (SiD). We confirm in rat brain slices exposed to osmotic stress that SiD is the pathological expansion of prior punctual SD foci (0.5-1 mm(2)), is associated with astrocyte swelling, and triggers oncotic neuron death. The blockade of astrocytic aquaporin-4 channels and Na+/K+/Cl- co-transporters, or volume-regulated anion channels mitigated slice edema, extracellular glutamate accumulation (<10 mu M) and SiD occurrence. Reversal of slice swelling by hyperosmotic mannitol counteracted glutamate accumulation and prevented SiD. In contrast, inhibition of glial metabolism or inhibition of astrocyte glutamate transporters reproduced the SiD phenotype. Finally, we show in the rodent water intoxication model of cytotoxic edema that astrocyte swelling and altered astrocyte calcium waves are central in the evolution of SiD. We discuss our results in the light of evidence for SiD in the human cortex. Our results emphasize the need of preventive osmotherapy in acute brain injury

Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci

Spreading depolarizations (SDs) indicate injury progression and predict worse clinical outcome in acute brain injury. We demonstrate in rodents that acute brain swelling upon cerebral ischemia impairs astroglial glutamate clearance and increases the tissue area invaded by SD. The cytotoxic extracellular glutamate accumulation (>15 mu M) predisposes an extensive bulk of tissue (4-5 mm(2)) for a yet undescribed simultaneous depolarization (SiD). We confirm in rat brain slices exposed to osmotic stress that SiD is the pathological expansion of prior punctual SD foci (0.5-1 mm(2)), is associated with astrocyte swelling, and triggers oncotic neuron death. The blockade of astrocytic aquaporin-4 channels and Na+/K+/Cl- co-transporters, or volume-regulated anion channels mitigated slice edema, extracellular glutamate accumulation (<10 mu M) and SiD occurrence. Reversal of slice swelling by hyperosmotic mannitol counteracted glutamate accumulation and prevented SiD. In contrast, inhibition of glial metabolism or inhibition of astrocyte glutamate transporters reproduced the SiD phenotype. Finally, we show in the rodent water intoxication model of cytotoxic edema that astrocyte swelling and altered astrocyte calcium waves are central in the evolution of SiD. We discuss our results in the light of evidence for SiD in the human cortex. Our results emphasize the need of preventive osmotherapy in acute brain injury

MicroRNAs as Biomarkers and Therapeutic Targets in Heart Failure

Heart failure still represents a real challenge both in everyday practice and research, due to the complex issues related to its pathogenesis and management. Humoral biomarkers have emerged in the last decades as useful tools in the diagnosis, risk stratification and guiding the treatment of heart failure. These molecules are related to different pathological and adaptive processes, like myocardial injury, neurohormonal activation and cardiac remodeling, their most widespread representatives being the natriuretic peptides (e.g. NT-proBNP). The role of altered gene expression and transcription as the basis of myocardial structural and functional changes in heart failure is largely recognized. MicroRNAs (miRNAs) are non-coding RNAs which have a major role in post-transcriptional gene expression by interfering with messenger RNA molecules. Our short review summarizes the molecular biology of miRNAs and their possible role as biomarkers in the diagnosis and prognosis of heart failure. Furthermore, the therapeutical perspectives conferred by these molecules are also presented

Pathophysiological background and clinical practice of lung ultrasound in COVID-19 patients

The pathological consequences of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) are multiple, with interstitial pneumonia and consecutive respiratory failure being the most dangerous clinical manifestations. Timely diagnosis and follow-up of pulmonary involvement need a comprehensive imaging strategy, which includes standard chest X-ray, chest computed tomography and lung ultrasound (LUS). In the last 10 years, LUS has become a useful, bedside and easily reproducible tool for lung examination. In the first part of this review, we present the pathophysiological background, technical principles and practical aspects of LUS in patients with SARS-CoV-2 infection. In the second part, the main echographic findings, their interpretation, and the clinical applications of LUS are overviewed. The review ends with the presentation of our work methodology, illustrated with images recorded from COVID-19 patients in our department