Corrigendum: Ultrastructural characteristics of neuronal death and white matter injury in mouse brain tissues after intracerebral hemorrhage: coexistence of ferroptosis, autophagy, and necrosis.

[This corrects the article DOI: 10.3389/fneur.2018.00581.].

Prevalence and clinical outcomes of hospitalized patients with upper extremity deep vein thrombosis.

OBJECTIVE: Upper extremity (UE) deep vein thrombosis (DVT) is a common and increasing complication in hospitalized patients. The objective of the present study was to determine the prevalence, treatment strategies, complications, and outcomes of UE-DVT. METHODS: We performed a retrospective single-institution study of patients with a diagnosis of UE-DVT from January 2016 through February 2018 (26 months). Patients aged ≥18 years who had been admitted to the hospital and who had had positive UE duplex ultrasound findings for acute UE-DVT were included in the present study. The outcomes were in-hospital mortality, major bleeding, pulmonary embolism (PE), and recurrent UE-DVT. RESULTS: Among 63,045 patients admitted to the hospital, 1000 (1.6%) had been diagnosed with UE-DVT. Of 3695 UE venous duplex ultrasound examinations performed during the study period, almost one third (27.0%) were positive for acute UE-DVT. The mean age was 55.0 ± 17.2 years, and most patients were men (58.3%), white (49.2%), and overweight (mean body mass index, 29.4 ± 10.3 kg/m2). The most affected vein was the right internal jugular vein (54.8%). Most of the patients (96.9%) has been receiving venous thromboembolism prophylaxis or anticoagulation therapy at the diagnosis. Most patients (77.8%) had had an intravenous device (IVD) in place at the diagnosis. Most of the patients (84.4%) were treated with anticoagulation therapy in the hospital but only one half (54.5%) were discharged with anticoagulation therapy. In-hospital mortality was 12.1% unrelated to UE-DVT, major bleeding occurred in 47.6% of the patients during hospitalization (fatal bleeding, 1%), PE was diagnosed in 4.8% of the patients, and 0.7% were fatal. Recurrent UE-DVT occurred in 6.1% of the patients. On multivariable analysis, the risk of death was increased by older age, cancer, intensive care unit admission, concomitant lower extremity DVT, and bleeding before the UE-DVT diagnosis. The presence of an IVD increased the risk of PE and the risk of recurrent UE-DVT. The risk of major bleeding was increased by the presence of an IVD, female sex, and concomitant lower extremity DVT. CONCLUSIONS: UE-DVT is a common complication in hospitalized patients (1.6%). Consequent acute PE and recurrent DVT remain important complications, as does bleeding. It is unclear whether standard thromboprophylaxis effectively protects against UE-DVT. More studies dedicated to UE-DVT are required to provide appropriate guidance on prophylaxis and treatment.

Microglia-derived interleukin-10 accelerates post-intracerebral hemorrhage hematoma clearance by regulating CD36.

Hematoma size after intracerebral hemorrhage (ICH) significantly affects patient outcome. However, our knowledge of endogenous mechanisms that underlie hematoma clearance and the potential role of the anti-inflammatory cytokine interleukin-10 (IL-10) is limited. Using organotypic hippocampal slice cultures and a collagenase-induced ICH mouse model, we investigated the role of microglial IL-10 in phagocytosis ex vivo and hematoma clearance in vivo. In slice culture, exposure to hemoglobin induced IL-10 expression in microglia and enhanced phagocytosis that depended on IL-10-regulated expression of CD36. Following ICH, IL-10-deficient mice had more severe neuroinflammation, brain edema, iron deposition, and neurologic deficits associated with delayed hematoma clearance. Intranasal administration of recombinant IL-10 accelerated hematoma clearance and improved neurologic function. Additionally, IL-10-deficient mice had weakened in vivo phagocytic ability owing to decreased expression of microglial CD36. Moreover, loss of IL-10 significantly increased monocyte-derived macrophage infiltration and enhanced brain inflammation in vivo. These results indicate that IL-10 regulates microglial phagocytosis and monocyte-derived macrophage infiltration after ICH and that CD36 is a key phagocytosis effector regulated by IL-10. Leveraging the innate immune response to ICH by augmenting IL-10 signaling may provide a useful strategy for accelerating hematoma clearance and improving neurologic outcome in clinical translation studies.

Safety of exercise therapy after acute pulmonary embolism.

OBJECTIVE: The role of exercise therapy after acute pulmonary embolism (PE) is unknown. Exercise therapy is safely used after myocardial infarction and chronic obstructive pulmonary disease. The aim of this study was to investigate the safety of exercise therapy after acute PE. METHODS: We implemented a 3-month exercise program after acute PE. Outcomes were death, bleeding, readmissions, recurrent events, changes in peak VO2 and quality of life (QoL). RESULTS: A total of 23 patients were enrolled and received anticoagulation; no adverse events were reported during the exercise period. One death, 1 DVT and 5 readmissions were reported due to non-exercise related reasons. Functional capacity improved as evidenced by an increased peak VO2 at 3 months (+3.9 ± 5.6 mL/kg/min; p = 0.05). Improvement in QoL was observed at 6-months on the functional (+17.0 ± 22.6, p = 0.03) and physical health factor scales (+0.9 ± 4.6, p = 0.03). CONCLUSION: Exercise therapy is feasible and safe in appropriately anticoagulated patients after PE.

Ultrastructural Characteristics of Neuronal Death and White Matter Injury in Mouse Brain Tissues After Intracerebral Hemorrhage: Coexistence of Ferroptosis, Autophagy, and Necrosis.

Although intracerebral hemorrhage (ICH) is a devastating disease worldwide, the pathologic changes in ultrastructure during the acute and chronic phases of ICH are poorly described. In this study, transmission electron microscopy was used to examine the ultrastructure of ICH-induced pathology. ICH was induced in mice by an intrastriatal injection of collagenase. Pathologic changes were observed in the acute (3 days), subacute (6 days), and chronic (28 days) phases. Compared with sham animals, we observed various types of cell death in the injured striatum during the acute phase of ICH, including necrosis, ferroptosis, and autophagy. Different degrees of axon degeneration in the striatum were seen in the acute phase, and axonal demyelination was observed in the ipsilateral striatum and corpus callosum at late time points. In addition, phagocytes, resident microglia, and infiltrating monocyte-macrophages were present around red blood cells and degenerating neurons and were observed to engulf red blood cells and other debris. Many synapses appeared abnormal or were lost. This systematic analysis of the pathologic changes in ultrastructure after ICH in mice provides information that will be valuable for future ICH pathology studies.

Inhibition of neuronal ferroptosis protects hemorrhagic brain.

Intracerebral hemorrhage (ICH) causes high mortality and morbidity, but our knowledge of post-ICH neuronal death and related mechanisms is limited. In this study, we first demonstrated that ferroptosis, a newly identified form of cell death, occurs in the collagenase-induced ICH model in mice. We found that administration of ferrostatin-1, a specific inhibitor of ferroptosis, prevented neuronal death and reduced iron deposition induced by hemoglobin in organotypic hippocampal slice cultures (OHSCs). Mice treated with ferrostatin-1 after ICH exhibited marked brain protection and improved neurologic function. Additionally, we found that ferrostatin-1 reduced lipid reactive oxygen species production and attenuated the increased expression level of PTGS2 and its gene product cyclooxygenase-2 ex vivo and in vivo. Moreover, ferrostatin-1 in combination with other inhibitors that target different forms of cell death prevented hemoglobin-induced cell death in OHSCs and human induced pluripotent stem cell-derived neurons better than any inhibitor alone. These results indicate that ferroptosis contributes to neuronal death after ICH, that administration of ferrostatin-1 protects hemorrhagic brain, and that cyclooxygenase-2 could be a biomarker of ferroptosis. The insights gained from this study will advance our knowledge of the post-ICH cell death cascade and be essential for future preclinical studies.