Pharmacologic Toll-like receptor 4 inhibition skews toward a favorable A1/A2 astrocytic ratio improving neurocognitive outcomes following traumatic brain injury.

BACKGROUND: Astrocytes are critical neuroimmune cells that modulate the neuroinflammatory response following traumatic brain injury (TBI) because of their ability to acquire neurotoxic (A1) or neuroprotective (A2) phenotypes. Using C34, a novel pharmacologic Toll-like receptor (TLR) 4 inhibitor, we explored their respective polarization states after TBI. METHODS: A murine controlled cortical impact model was used, and the results were analyzed on postinjury days (PIDs) 1, 7, and 28. The experimental groups are as follows: (1) sham, (2) sham + C34, (3) TBI, and (4) TBI + C34. Quantitative real-time polymerase chain reaction was used to quantify gene expression associated with proinflammatory (A1) and anti-inflammatory (A2) phenotypes. Morris water maze was used to assess neurocognitive outcomes. Fixed frozen cortical samples were sectioned, stained for myelin basic protein and 4',6-diamidino-2-phenylindole, and then imaged. Student t test and one-way analysis of variance were used for statistical analysis with significance achieved when p < 0.05. RESULTS: On quantitative real-time polymerase chain reaction, C34-treated groups showed a significant decrease in the expression of A1 markers such as Gbp2 and a significant increase in the expression of A2 markers such as Emp1 when compared with untreated groups on PID 1. On PIDs 7 and 28, the expression of most A1 and A2 markers was also significantly decreased in the C34-treated groups. On immunohistochemistry, C34-treated groups demonstrated increased myelin basic protein staining into the lesion by PID 28. C34-treated groups showed more platform entries on Morris water maze when compared with untreated groups on PID 7 and PID 28. CONCLUSION: Following TBI, early TLR4 blockade modulates astrocytic function and shifts its polarization toward the anti-inflammatory A2-like phenotype. This is accompanied by an increase in myelin regeneration, providing better neuroprotection and improved neurocognitive outcomes. Targeting A1/A2 balance with TLR4 inhibition provides a potential therapeutic target to improve neurobehavioral outcomes in the setting of TBI.

Infiltrating anti-inflammatory monocytes modulate microglial activation through toll-like receptor 4/interferon-dependent pathways following traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is the leading cause of morbidity and mortality in the pediatric population. Microglia and infiltrating monocyte-derived macrophages are crucial immune cells that modulate the neuroinflammatory response following TBI. Using C34, a novel pharmacologic toll-like receptor 4 inhibitor, we investigated the intricate interactions between these cells in a murine TBI model. METHODS: A murine controlled cortical impact model was used, and the results were analyzed on postinjury days 1, 7, 28, and 35. The experimental groups are as follows: (1) sham C57BL/6 wild-type (WT), (2) TBI WT, (3) sham WT + C34, and (4) TBI WT + C34. Quantitative real-time polymerase chain reaction was used to quantify gene expression associated with microglial activation, apoptotic pathways, and type 1 interferon pathway. Flow cytometry was used to isolate microglia and infiltrating monocytes. Brain lesion volumes were assessed using magnetic resonance imaging. Last, neurocognitive outcomes were evaluated using the Morris Water Maze test. Student's t test and one-way analysis of variance were used for statistical analysis with significance achieved when p < 0.05. RESULTS: Toll-like receptor 4 inhibition leads to improved neurological sequela post-TBI, possibly because of an increase in infiltrating anti-inflammatory monocytes and a decrease in IFN regulatory factor 7 during acute inflammation, followed by a reduction in apoptosis and M2 microglial expression during chronic inflammation. CONCLUSION: Toll-like receptor 4 inhibition with C34 skews infiltrating monocytes toward an anti-inflammatory phenotype, leading to enhanced neurocognitive outcomes. Moreover, although M2 microglia have been consistently shown as inducers of neuroprotection, our results clearly demonstrate their detrimental role during the chronic phases of healing post-TBI.

Early risk factors of operative management for hospitalization children with spontaneous pneumothorax.

BACKGROUND: The optimal timing of operative management in children with primary spontaneous pneumothorax (PSP) remains controversial. This study sought to determine early risk factors for failure of chest tube nonoperative management during the initial hospitalization in adolescents with PSP. METHODS: A retrospective review was conducted for children (aged ≤18 years) admitted to a single tertiary care referral center for their first presentation of a PSP managed with at least 48 h of chest tube decompression (CTD) alone. Patient outcomes and early risk factors for operative management were analyzed by multivariate regression. RESULTS: Of the 39 patients who met inclusion criteria, 15 (38.5%) patients failed nonoperative treatment while 24 (61.5%) patients were managed with CTD therapy alone. Progression to thoracoscopic surgery was associated with longer CTD of 8 vs 3 days and hospital length of stay of 9 vs 4 days when compared to nonoperative management (p < 0.001, both). Air leak and increase in pneumothorax size at 24 h after CTD were independently associated with progression to surgery (p = 0.007, p = 0.002). Combined, these risk factors were associated with a significant increase in recurrence (OR 6.00, 95% CI 1.11-41.11, p = 0.048). There were no significant differences between PSP management strategies regarding cumulative radiation exposure or 2 year recurrence. CONCLUSIONS: Air leak or increasing pneumothorax size within 24 h of CTD are highly correlated with failed nonoperative management during the initial hospitalization in pediatric patients with PSP. This data may be useful in the development of pediatric-specific treatment algorithms to optimally manage these patients. LEVEL OF EVIDENCE: Treatment study, Level III.

Contemporary Role of Computed Tomography in Managing Pediatric Primary Spontaneous Pneumothorax.

INTRODUCTION: The value of chest computed tomography (CT) in pediatric primary spontaneous pneumothorax (PSP) remains controversial. This study sought to evaluate the utility of CT scans in a contemporary cohort of children with PSP. MATERIALS AND METHODS: An institutional review board approval was obtained for a retrospective review of all children (aged ≤18 y) who underwent video-assisted thoracoscopic surgery (VATS) for PSP between 2009 and 2019 at a university-affiliated pediatric hospital. Preoperative CT scans were evaluated for diagnostic accuracy of the CT of bleb disease. RESULTS: Thirty nine patients underwent VATS procedures for PSP, 34 (87%) of the patients were noted to have blebs. Twenty eight (72%) patients received preoperative CT scans with a 5.5:1 male to female ratio. On CT, 17 (61%) were diagnosed with blebs and all had blebs intraoperatively. CT did not identify disease in 11 patients, but seven had blebs intraoperatively. The positive and negative predictive values of preoperative CT for detecting ipsilateral bleb disease were 100% and 36%, respectively, with a sensitivity of 71%. Eleven patients had a contralateral disease on CT (39%). Five received elective contralateral VATS and three developed spontaneous PSP, with intraoperative blebs in all eight patients. Three never developed contralateral PSP. Six (21%) patients with no contralateral disease on CT developed spontaneous PSP with intraoperative blebs. CONCLUSIONS: The decision to operate for PSP should be made based on clinical findings rather than on the presence or absence of blebs identified by CT.

High-Dose Levetiracetam for Neonatal Seizures: A Retrospective Review.

BACKGROUND: Neonatal seizures are frequently encountered in the neonatal intensive care unit and may be associated with serious long-term neurological sequelae. Response to treatment continues to be modest, and treatment guidelines remain unclear. The use of levetiracetam has been on the rise in the past several years due to its favorable safety profile in the face of limited data on its efficacy and optimal dosing regimens. Unlike the older age groups, the benefit of escalating to high-dose levetiracetam of 80-100 mg/kg/day in neonates not responding to the standard used dosing regimen (40-60 mg/kg/day) is not studied. We sought to investigate the safety and efficacy of levetiracetam escalation to high dose regimens for neonatal seizures. METHODS: A retrospective chart review over a 7-year period was conducted at the American University of Beirut to identify neonates with electrographically proven seizures treated with levetiracetam. Data was collected on electroclinical seizure characteristics, underlying etiology, seizure control, other anti-seizure medications, and adverse effects. RESULTS: Electronic chart review revealed a total of 15 neonates with electrographically confirmed seizures treated with levetiracetam, with escalation to high doses in seven. As a first line drug, levetiracetam monotherapy terminated seizures in six out 10 neonates, two of whom had complete seizure cessation only after escalation to high doses of 80 or 100 mg/kg/day. When used in combination with other anti-seizure medications, four out of five neonates achieved complete seizure cessation upon escalation to high doses of levetiracetam. No adverse effects were noted. CONCLUSIONS: In neonates not responding to the standard used levetiracetam doses, incremental increases to 80-100 mg/kg/day may be considered. Prospective studies are needed to confirm the promising role of such high dosing regimens, and to better elucidate the role of levetiracetam in neonatal seizures.