Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction

Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1β), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased levels of angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs but it decreased the level of IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations

Design and Rationale of a Prospective International Follow-Up Study on Intensive Care Survivors of COVID-19 : The Long-Term Impact in Intensive Care Survivors of Coronavirus Disease-19–AFTERCOR

Background: In a disease that has only existed for 18 months, it is difficult to be fully informed of the long-term sequelae of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Evidence is growing that most organ systems can be affected by the virus, causing severe disabilities in survivors. The extent of the aftermath will declare itself over the next 5–10 years, but it is likely to be substantial with profound socio-economic impact on society. Methods: This is an international multi-center, prospective long-term follow-up study of patients who developed severe coronavirus disease-2019 (COVID-19) and were admitted to Intensive Care Units (ICUs). The study will be conducted at international tertiary hospitals. Patients will be monitored from time of ICU discharge up to 24 months. Information will be collected on demographics, co-existing illnesses before ICU admission, severity of illness during ICU admission and post-ICU quality of life as well as organ dysfunction and recovery. Statistical analysis will consist of patient trajectories over time for the key variables of quality of life and organ function. Using latent class analysis, we will determine if there are distinct patterns of patients in terms of recovery. Multivariable regression analyses will be used to examine associations between baseline characteristics and severity variables upon admission and discharge in the ICU, and how these impact outcomes at all follow-up time points up to 2 years. Ethics and Dissemination: The core study team and local principal investigators will ensure that the study adheres to all relevant national and local regulations, and that the necessary approvals are in place before a site may enroll patients. Clinical Trial Registration: anzctr.org.au: ACTRN12620000799954.</p

Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial

Abstract Background Hypothermia is neuroprotective in some ischemia–reperfusion injuries. Ischemia–reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia–reperfusion injury and improve global neurologic outcome. Methods This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. Results Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. Conclusions This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups