Effects of an Early Intensive Blood Pressure-lowering Strategy Using Remifentanil and Dexmedetomidine in Patients with Spontaneous Intracerebral Hemorrhage: A Multicenter, Prospective, Superiority, Randomized Controlled Trial.

BACKGROUND: Although it has been established that elevated blood pressure and its variability worsen outcomes in spontaneous intracerebral hemorrhage, antihypertensives use during the acute phase still lacks robust evidence. A blood pressure-lowering regimen using remifentanil and dexmedetomidine might be a reasonable therapeutic option given their analgesic and antisympathetic effects. The objective of this superiority trial was to validate the efficacy and safety of this blood pressure-lowering strategy that uses remifentanil and dexmedetomidine in patients with acute intracerebral hemorrhage. METHODS: In this multicenter, prospective, single-blinded, superiority randomized controlled trial, patients with intracerebral hemorrhage and systolic blood pressure (SBP) 150 mmHg or greater were randomly allocated to the intervention group (a preset protocol with a standard guideline management using remifentanil and dexmedetomidine) or the control group (standard guideline-based management) to receive blood pressure-lowering treatment. The primary outcome was the SBP control rate (less than 140 mmHg) at 1 h posttreatment initiation. Secondary outcomes included blood pressure variability, neurologic function, and clinical outcomes. RESULTS: A total of 338 patients were allocated to the intervention (n = 167) or control group (n = 171). The SBP control rate at 1 h posttreatment initiation in the intervention group was higher than that in controls (101 of 161, 62.7% vs. 66 of 166, 39.8%; difference, 23.2%; 95% CI, 12.4 to 34.1%; P < 0.001). Analysis of secondary outcomes indicated that patients in the intervention group could effectively reduce agitation while achieving lighter sedation, but no improvement in clinical outcomes was observed. Regarding safety, the incidence of bradycardia and respiratory depression was higher in the intervention group. CONCLUSIONS: Among intracerebral hemorrhage patients with a SBP 150 mmHg or greater, a preset protocol using a remifentanil and dexmedetomidine-based standard guideline management significantly increased the SBP control rate at 1 h posttreatment compared with the standard guideline-based management.

Synergism between the phosphatidylinositol 3-kinase p110ß isoform inhibitor AZD6482 and the mixed lineage kinase 3 inhibitor URMC-099 on the blockade of glioblastoma cell motility and focal adhesion formation.

BACKGROUND: Glioblastoma multiforme, the most aggressive and malignant primary brain tumor, is characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma. Our previous studies delineated a crosstalk between PI3K/Akt and JNK signaling pathways, and a moderate anti-glioblastoma synergism caused by the combined inhibition of PI3K p110ß (PI3Kß) isoform and JNK. However, this combination strategy is not potent enough. MLK3, an upstream regulator of ERK and JNK, may replace JNK to exert stronger synergism with PI3Kß. METHODS: To develop a new combination strategy with stronger synergism, the expression pattern and roles of MLK3 in glioblastoma patient's specimens and cell lines were firstly investigated. Then glioblastoma cells and xenografts in nude mice were treated with the PI3Kß inhibitor AZD6482 and the MLK3 inhibitor URMC-099 alone or in combination to evaluate their combination effects on tumor cell growth and motility. The combination effects on cytoskeletal structures such as lamellipodia and focal adhesions were also evaluated. RESULTS: MLK3 protein was overexpressed in both newly diagnosed and relapsing glioblastoma patients' specimens. Silencing of MLK3 using siRNA duplexes significantly suppressed migration and invasion, but promoted attachment of glioblastoma cells. Combined inhibition of PI3Kß and MLK3 exhibited synergistic inhibitory effects on glioblastoma cell proliferation, migration and invasion, as well as the formation of lamellipodia and focal adhesions. Furthermore, combination of AZD6482 and URMC-099 effectively decreased glioblastoma xenograft growth in nude mice. Glioblastoma cells treated with this drug combination showed reduced phosphorylation of Akt and ERK, and decreased protein expression of ROCK2 and Zyxin. CONCLUSION: Taken together, combination of AZD6482 and URMC-099 showed strong synergistic anti-tumor effects on glioblastoma in vitro and in vivo. Our findings suggest that combined inhibition of PI3Kß and MLK3 may serve as an attractive therapeutic approach for glioblastoma multiforme.

A mathematical model for predicting intracranial pressure based on noninvasively acquired PC-MRI parameters in communicating hydrocephalus.

To develop and validate a mathematical model for predicting intracranial pressure (ICP) noninvasively using phase-contrast cine MRI (PC-MRI). We performed a retrospective analysis of PC-MRI from patients with communicating hydrocephalus (n = 138). The patients were recruited from Shenzhen Second People's Hospital between November 2017 and April 2020, and randomly allocated into training (n = 97) and independent validation (n = 41) groups. All participants underwent lumbar puncture and PC-MRI in order to evaluate ICP and cerebrospinal fluid (CSF) parameters (i.e., aqueduct diameter and flow velocity), respectively. A novel ICP-predicting model was then developed based on the nonlinear relationships between the CSF parameters, using the Levenberg-Marquardt and general global optimisation methods. There was no significant difference in baseline demographic characteristics between the training and independent validation groups. The accuracy of the model for predicting ICP was 0.899 in the training cohort (n = 97) and 0.861 in the independent validation cohort (n = 41). We obtained an ICP-predicting model that showed excellent performance in the noninvasive diagnosis of clinically significant communicating hydrocephalus.

Mechanisms Underlying H2O2-Evoked Carbonyl Modification of Cytoskeletal Protein and Axon Injury in PC-12 Cells.

BACKGROUND/AIMS: To investigate the mechanism that enables oxidative stress and cytoskeleton protein carbonylation to contribute to axonal dysfunction in traumatic brain injury (TBI). METHODS: We created an in vitro model of neuronal oxidative damage by exposing a neuron-like cell line (PC-12) to different concentrations (100 µM, 200 µM, and 300 µM) of H2O2 for 24 h or 48 h. Carbonyl modification of cytoskeletal proteins (ß-actin and ß-tubulin) and its impact on ß-actin/ß-tubulin filament dynamics were determined by enzyme-linked immunosorbent assay, immunostaining, and western blotting. Depolymerization of ß-actin/ß-tubulin filaments was evaluated using the monomer/polymer ratio of each protein via western blotting. Phosphorylation of the neurofilament heavy chain (P-NFH) was used as an axonal injury marker and detected by immunostaining. RESULTS: Our results showed that H2O2 treatment led to increased oxidative stress in PC-12 cells, as indicated by the increased generation of malondialdehyde and 8-hydroxydeoxyguanosine and decreased intracellular glutathione levels. H2O2 treatment also increased carbonyl modification of total proteins and cytoskeleton proteins ß-actin/ß-tubulin, which occurred concurrently with the suppression of proteasome activity. Moreover, H2O2 treatment increased the generation of the axonal injury marker P-NFH, and depolymerization of the ß-actin/ß-tubulin filaments was indicated by increased monomer/polymer ratios of each protein. Lastly, overexpression of the proteasome ß5 subunit in PC-12 cells significantly reduced the H2O2-induced accumulation of carbonylated ß-actin/ ß-tubulin, P-NFH, and ß-actin/ß-tubulin depolymerization. CONCLUSIONS: We concluded that carbonylation of cytoskeleton proteins could lead to depolymerization of their filaments and axonal injury, and proteasome suppression contributes to the accumulation of carbonylated proteins under oxidative conditions.

Treatment of hemimasticatory spasm secondary to parry-romberg syndrome via partial resection of the trigeminal nerve motor branch under intraoperative neurophysiological monitoring: A case report and literature review.

Parry-Romberg syndrome (PRS) combined with hemimasticatory spasm (HMS) is a rare craniofacial disorder characterized by unilateral facial tissue atrophy with paroxysmal involuntary contractions of the jaw-closing muscles. Although a majority believe that this is a result of demyelination changes from the effect of the facial involvement of PRS on the trigeminal nerve motor branches, the mechanism of PRS is presently unclear. Moreover, the therapeutic effects of existing drugs that target PRS have not been satisfactory. For intolerable spasms of the masticatory muscles, botulinum toxin injection may temporarily relieve the symptoms of spasms. We report a case of HMS secondary to PRS that was treated via a partial resection of the trigeminal nerve motor branch under intraoperative neurophysiological monitoring.

Intranasal 15d-PGJ2 inhibits the growth of rat lactotroph pituitary neuroendocrine tumors by inducing PPARγ-dependent apoptotic and autophagic cell death.

PPARγ agonists have been reported to induce cell death in pituitary neuroendocrine tumor (PitNET) cell cultures. However, the therapeutic effects of PPARγ agonists in vivo remain unclear. In the present study, we found that intranasal 15d-PGJ2, an endogenous PPARγ agonist, resulted in growth suppression of Fischer 344 rat lactotroph PitNETs induced by subcutaneous implantation with a mini-osmotic pump containing estradiol. Intranasal 15d-PGJ2 reduced the volume and weight of the pituitary gland and the level of serum prolactin (PRL) in rat lactotroph PitNETs. 15d-PGJ2 treatment attenuated pathological changes and significantly decreased the ratio of PRL/pituitary-specific transcription factor 1 (Pit-1) and estrogen receptor α (ERα)/Pit-1 double-positive cells. Moreover, 15d-PGJ2 treatment induced apoptosis in the pituitary gland characterized by an increased ratio of TUNEL-positive cells, cleavage of caspase-3, and elevated activity of caspase-3. 15d-PGJ2 treatment decreased the levels of cytokines, including TNF-α, IL-1ß, and IL-6. Furthermore, 15d-PGJ2 treatment markedly increased the protein expression of PPARγ and blocked autophagic flux, as evidenced by the accumulation of LC3-II and SQSTM1/p62 and the decrease in LAMP-1 expression. Importantly, all these effects mediated by 15d-PGJ2 were abolished by cotreatment with the PPARγ antagonist GW9662. In conclusion, intranasal 15d-PGJ2 suppressed the growth of rat lactotroph PitNETs by inducing PPARγ-dependent apoptotic and autophagic cell death. Therefore, 15d-PGJ2 may be a potential new drug for lactotroph PitNETs.

The epidemiology of traumatic brain injuries in the fastest-paced city in China: a retrospective study.

Introduction: Traumatic brain injury (TBI) seriously affects the quality of human health and the prognosis of the patient, but the epidemiological characteristics of TBI can vary among populations. Numerous changes have occurred in the epidemiological characteristics of individuals with TBI in the fast-paced city of Shenzhen, China. However, little is known about these characteristics. This study aimed to investigate the changes in TBI epidemiology, help clinicians improve medical treatment. Methods: In this retrospective cross-sectional analysis, we collected the data of 4,229 patients with TBI admitted to 20 hospitals in Shenzhen in 2017. We collected data on age, gender, cause and severity of the injury, eventual diagnosis, time from injury to admission in a neurosurgery department, and patient outcomes. Two neurosurgeons simultaneously collected the data. We compared these results with a similar study conducted in Shenzhen during the period from 1994 to 2003 to clarify and explain the changes in the epidemiological characteristics of TBI. Results: The majority of respondents were men [2,830 (66.9%)]. The mean age was 32.5 ± 21.4 years. The youngest patient was less than 1 year old, and the oldest patient was 101 years old. A total of 3,947 (93.3%) patients had a favorable outcome, 219 (5.2%) had an unfavorable outcome, and 63 (1.5%) died. The predominant external cause was falls (1,779 [42.1%]); this was the most common cause of TBI in children and older adults. Riders of electric bicycles (423 [29.0%]) were the most vulnerable to traffic accident-related injuries. Time greater than 50 h from injury to admission to a neurosurgical department had a significant effect on prognosis (p < 0.001). Conclusion: The epidemiological characteristics of TBI have changed significantly over the past 20 years. Falls, rather than traffic accidents, were the most common cause of TBI. Further research is needed to devise solutions to decrease the incidence of falls and improve the outcomes of TBI.

Blood-brain barrier permeability is positively correlated with cerebral microvascular perfusion in the early fluid percussion-injured brain of the rat.

The blood-brain barrier (BBB) opening following traumatic brain injury (TBI) provides a chance for therapeutic agents to cross the barrier, yet the reduction of the cerebral microvascular perfusion after TBI may limit the intervention. Meanwhile, optimizing the cerebral capillary perfusion by the strategies such as fluid administration may cause brain edema due to the BBB opening post trauma. To guide the TBI therapy, we characterized the relationship between the changes in the cerebral capillary perfusion and BBB permeability after TBI. First, we observed the changes of the cerebral capillary perfusion by the intracardiac perfusion of Evans Blue and the BBB disruption with magnetic resonance imaging (MRI) in the rat subjected to lateral fluid percussion (FP) brain injury. The correlation between two variables was next evaluated with the correlation analysis. Since related to BBB breakdown, matrix metalloproteinase-9 (MMP-9) activity was finally detected by gelatin zymography. We found that the ratios of the perfused microvessel numbers in the lesioned cortices were significantly reduced at 0 and 1 h post trauma compared with that in the normal cortex, which then dramatically recovered at 4 and 24 h after injury, and that the BBB permeability was greatly augmented in the ipsilateral parts at 4, 12, and 24 h, and in the contralateral area at 24 h after injury compared with that in the uninjured brain. The correlation analysis showed that the BBB permeability increase was related to the restoration of the cerebral capillary perfusion over a 24-h period post trauma. Moreover, the gelatin zymography analysis indicated that the MMP-9 activity in the injured brain increased at 4 h and significantly elevated at 12 and 24 h as compared to that at 0 or 1 h after TBI. Our findings demonstrate that the 4 h post trauma is a critical turning point during the development of TBI, and, importantly, the correlation analysis may guide us how to treat TBI.

Delivery of large molecules via poly(butyl cyanoacrylate) nanoparticles into the injured rat brain.

Poly(n-butyl-2-cyanoacrylate) (PBCA) nanoparticles have been successfully applied to deliver small-molecule drugs to the central nervous system (CNS). However, it is unclear whether PBCA nanoparticles can be used as the delivery system for large molecules to potentially treat traumatic brain injury (TBI). In this study, we tested the capacity of PBCA nanoparticles in passing through the blood-brain barrier (BBB) and transporting large molecules into normal and injured brains in the rat. We first synthesized PBCA nanoparticles by dispersion polymerization and then loaded the particles with either horseradish peroxidase (HRP, 44 kDa) or enhanced green fluorescent protein (EGFP, 29 kDa), which were further coated with polysorbate 80. Next, the polysorbate 80-coated HRP or EGFP-loaded PBCA nanoparticles were intravenously injected into the normal and brain-injured rats. We found that, at 45 min after injection, PBCA nanoparticle-delivered HRP or EGFP was hardly detected in the normal brains of the rats, but a small amount of EGFP carried by PBCA nanoparticles was noted in the normal brains 48 h after administration, which was further confirmed by immunolocalization with anti-EGFP antibodies. In contrast, at 4 h after TBI with a circulation time of 45 min, although the penetration of HRP or EGFP alone was hampered by the BBB, the PBCA nanoparticle-delivered HRP or EGFP was widely distributed near injured sites. Together, our findings provide histological evidence that PBCA nanoparticles can be used as an efficient delivery system for large molecules to overcome the barrier in the brain with TBI.

Knockdown of rno_circRNA_009194 Improves Outcomes in Traumatic Brain Injury Rats through Inhibiting Voltage-Gated Sodium Channel Nav1.3.

Excessive activation of voltage-gated sodium channel Nav1.3 has been recently reported in secondary traumatic brain injury (TBI). However, the molecular mechanisms underlying regulating voltage-gated sodium channel (Nav1.3) have not been well understood. The present study used a TBI rat model induced by a fluid percussion device and performed a circular RNA (circRNA) microarray (n = 3) to profile the altered circRNAs in the hippocampus after TBI. After polymerase chain reaction (PCR) validation, certain circRNAs were selected to investigate the function and mechanism in regulating Nav1.3 in the TBI rat model by intracerebroventricular injection with lentivirus. The neurological outcome was evaluated by Morris water maze test, modified Neurological Severity Score (mNSS), brain water content measurement, and hematoxylin and eosin staining. The related molecular mechanisms were explored with PCR, Western blotting, luciferase reporter, chromatin immunoprecipitation assay, and electrophoretic mobility shift assay (EMSA). A total of 347 circRNAs were observed to be differentially expressed (fold change [FC] ≥ 1.2 and p < 0.05) after TBI, including 234 up-regulated and 113 down-regulated circRNAs. Among 10 validated circRNAs, we selected circRNA_009194 with the maximized up-regulated fold change (n = 5, FC = 4.45, p < 0.001) for the in vivo functional experiments. Down-regulation of circRNA_009194 resulted in a 27.5% reduced mNSS in rat brain (n = 6, p < 0.01) after TBI and regulated the expression levels of miR-145-3p, Sp1, and Nav1.3, which was reversed by sh-miR-145-3p or Sp1/Nav1.3 overexpression (n = 5, p < 0.05). Mechanistically, circRNA_009194 might act as a sponge for miR-145-3p to regulate Sp1-mediated Nav1.3. This study demonstrated that circRNA_009194 knockdown could improve neurological outcomes in TBI in vivo by inhibiting Nav1.3, directly or indirectly.

Immunoexpression of MMP-8 and MMP-9 in chronic subdural hematoma.

To determine the possible role of matrix metallopeptidase (MMP)-8 and MMP-9 in the development of chronic subdural hematoma (CSDH), we investigated their expression in CSDH. In our previous study, we analyzed hematoma fluid and peripheral blood of 83 patients with CSDH, including 17 postoperative patients. Based on these results, we included 50 people in the normal group and analyzed 20 markers in the peripheral blood of each person. In order to identify representative markers, it was assessed by using overall differential gene expression. The concentration of MMP-8 was significantly higher in the normal group than that in the preoperative and postoperative groups. The concentration of MMP-9 was significantly lower in the normal group than in both preoperative and postoperative groups. Immunohistochemistry confirmed the expression of MMP-8 and MMP-9 in CSDH membranes. In conclusion, our results provide evidence of the expression of MMP-8 and MMP-9 in CSDH. In addition, the expression of MMP-8 and MMP-9 suggests angiogenesis in CSDH formation.

Serum Levels of MMP-8 and MMP-9 as Markers in Chronic Subdural Hematoma.

Chronic subdural hematoma (CSDH) is a common neurological disease that involves the collection of blood products in the subdural space. The progression of CSDH is an angiogenic and inflammatory process, but the multifactorial mechanisms underlying CSDH are still not fully understood. We aimed to identify one or more factors that may play an important role in the development of CSDH. We enrolled 83 patients with CSDH, including 17 postoperative patients, and analyzed 20 markers in the hematoma fluid and peripheral blood of each patient. Overall differential gene expression was examined to identify the representative markers. The concentration of MMP-8 was significantly lower in the postoperative group than in the preoperative group. The concentration of MMP-9 was significantly higher in the postoperative group than in the preoperative group. These findings indicate that MMP-8 and MMP-9 may play important roles in the pathophysiology of CSDH. Understanding the pathways associated with CSDH may provide insights for improving disease outcomes.

Decreased Level of Exosomal miR-5121 Released from Microglia Suppresses Neurite Outgrowth and Synapse Recovery of Neurons Following Traumatic Brain Injury.

Activated microglia can suppress neurite outgrowth and synapse recovery in the acute stage following traumatic brain injury (TBI). However, the underlying mechanism has not been clearly elucidated. Exosomes derived from microglia have been reported to play a critical role in microglia-neuron interaction in healthy and pathological brains. Here, we aimed to investigate the role of microglia-derived exosomes in regulating neurite outgrowth and synapse recovery following TBI. In our study, exosomes derived from microglia were co-cultured with stretch-injured neurons in vitro and intravenously injected into mice that underwent fluid percussion injury (FPI) by tail vein injection in vivo. The results showed that microglia-derived exosomes could be absorbed by neurons in vitro and in vivo. Moreover, exosomes derived from stretch-injured microglia decreased the protein levels of GAP43, PSD-95, GluR1, and Synaptophysin and dendritic complexity in stretch-injured neurons in vitro, and reduced GAP43+ NEUN cell percentage and apical dendritic spine density in the pericontusion region in vivo. Motor coordination was also impaired in mice treated with stretch-injured microglia-derived exosomes after FPI. A microRNA microarray showed that the level of miR-5121 was decreased most greatly in exosomes derived from stretch-injured microglia. Overexpression of miR-5121 in stretch-injured microglia-derived exosomes partly reversed the suppression of neurite outgrowth and synapse recovery of neurons both in vitro and in vivo. Moreover, motor coordination in miR-5121 overexpressed exosomes treated mice was significantly improved after FPI. Following mechanistic study demonstrated that miR-5121 might promote neurite outgrowth and synapse recovery by directly targeting RGMa. In conclusion, our finding revealed a novel exosome-mediated mechanism of microglia-neuron interaction that suppressed neurite outgrowth and synapse recovery of neurons following TBI.

Prospective Randomized Evaluation of Decompressive Ipsilateral Craniectomy for Traumatic Acute Epidural Hematoma (PREDICT-AEDH): study protocol for a randomized controlled trial.

BACKGROUND: The expeditious surgical evacuation of acute epidural hematoma (AEDH) is an attainable gold standard and is often expected to have a good clinical outcome for patients with surgical indications. However, controversy exists on the optimal surgical options for AEDH, especially for patients with brain herniation. Neurosurgeons are confronted with the decision to evacuate the hematoma with decompressive craniectomy (DC) or craniotomy. METHODS/DESIGN: Patients of both sexes, age between 18 and 65 years, who presented to the emergency room with a clinical and radiological diagnosis of AEDH with herniation, were assessed against the inclusion and exclusion criteria to be enrolled in the study. Clinical and radiological information, including diagnosis of AEDH, treatment procedures, and follow-up data at 1, 3, and 6 months after injury, was collected from 120 eligible patients in 51 centers. The patients were randomized into groups of DC versus craniotomy in a 1:1 ratio. The primary outcome was the Glasgow Outcome Score-Extended (GOSE) at 6 months post-injury. Secondary outcomes included incidence of postoperative cerebral infarction, incidence of additional craniocerebral surgery, and other evaluation indicators within 6 months post-injury. DISCUSSION: This study is expected to support neurosurgeons in their decision to evacuate the epidural hematoma with or without a DC, especially in patients with brain herniation, and provide additional evidence to improve the knowledge in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04261673 . Registered on 04 February 2020.

Long-standing overt ventriculomegaly in adulthood with primary presentation of psychiatric disturbance: A case report.

RATIONALE: Hydrocephalus is a common disease in neurosurgery. The typical symptoms of hydrocephalus include urinary incontinence, gait instability, and cognitive decline. Irritability rarely occurs in patients with hydrocephalus. Irritability rarely occurs in patients with hydrocephalus, especially in long-standing overt ventriculomegaly of adulthood (LOVA). PATIENT CONCERNS: A 30-year-old female was admitted to our hospital because of mental retardation and unstable gait for more than 15 years. She had undergone ventriculoperitoneal shunt 15 years prior due to ventriculomegaly and related symptoms. However, the shunt catheter was removed shortly after surgery because of blockage, with no further postoperative treatment. DIAGNOSIS: The patient was diagnosed with long-standing overt ventriculomegaly according to her head circumference and clinical symptoms, including adult hydrocephalus development, overt triventriculomegaly and absence of a secondary cause for aqueductal stenosis in adulthood. INTERVENTIONS: After considerable discussion, she underwent ventriculoperitoneal shunt placement and showed dramatic and sustained improvement. OUTCOMES: The patient has been followed at 3-month intervals for over 2 years since discharge, and both the patient and family have reported a significant change in their daily life. She was able to live independently and control her emotions. Slight epilepsy was noted approximately 5 months after surgery but recovered 2 months later. LESSONS: It is difficult to decide whether to treat LOVA when the in patients whose symptoms are not significant. We believe that early diagnosis and positive treatment can help improve outcomes and would recommend ventriculoperitoneal (VP) shunting in patients with LOVA.

Safety and efficacy of long-term mild hypothermia for severe traumatic brain injury with refractory intracranial hypertension (LTH-1): A multicenter randomized controlled trial.

BACKGROUND: Therapeutic hypothermia may need prolonged duration for the patients with severe traumatic brain injury (sTBI). METHODS: The Long-Term Hypothermia trial was a prospective, multicenter, randomized, controlled clinical trial to examine the safety and efficacy in adults with sTBI. Eligible patients were 18-65, Glasgow Coma Scale score at 4 to 8, and initial intracranial pressure (ICP) ≥ 25 mm Hg, randomly assigned to the long-term mild hypothermia group (34-35 °C for 5 days) or normothermia group at 37 °C. The primary outcome was the Glasgow outcome scale (GOS) at 6 months. Secondary outcomes included ICP control, complications and laboratory findings, the length of ICU and hospital stay, and GOS at 6 months in patients with initial ICP ≥ 30 mm Hg. This trial is registered with ClinicalTrials.gov, NCT01886222. FINDINGS: 302 patients were enrolled from June 25, 2013, to December 31, 2018, with 6 months follow-up in 14 hospitals, 156 in hypothermia group and 146 in normothermia group. There was no difference in favorable outcome (OR 1·55, 95%CI 0·91-2·64; P = 0·105) and in mortality (P = 0·111) between groups. In patients with an initial ICP ≥ 30 mm Hg, hypothermic treatment significantly increased favorable outcome over normothermia group (60·82%, 42·71%, respectively; OR 1·861, 95%CI 1·031-3·361; P = 0·039). Long-term mild hypothermia did not increase the incidences of complications. INTERPRETATION: Long-term mild hypothermia did not improve the neurological outcomes. However, it may be a potential option in sTBI patients with initial ICP ≥ 30 mm Hg. FUNDING: : Shanghai municipal government and Shanghai Jiao Tong University/School of Medicine.

Idiopathic Normal Pressure Hydrocephalus and Elderly Acquired Hydrocephalus: Evaluation With Cerebrospinal Fluid Flow and Ventricular Volume Parameters.

PURPOSE: To investigate differences in cerebrospinal fluid (CSF) flow through the aqueduct and to determine whether there is a relationship between CSF flow and ventricular volume parameters in idiopathic normal pressure hydrocephalus (iNPH) patients, elderly acquired hydrocephalus patients and age-matched healthy volunteers by phase-contrast MR (PC-MR). METHODS: A total of 40 iNPH patients and 41 elderly acquired hydrocephalus patients and 26 age-matched healthy volunteers in the normal control (NC) group were included between November 2017 and October 2019 in this retrospective study. The following CSF flow parameters were measured with PC-MR: peak velocity, average velocity (AV), aqueductal stroke volume (ASV), net ASV, and net flow. The following ventricular volume parameters were measured: ventricular volume (VV), brain volume, total intracranial volume, and relative VV. Differences between the iNPH and acquired hydrocephalus groups were compared Mann-Whitney U test and correlations between CSF flow and ventricular volume parameters were assessed using the Spearman correlation coefficient. RESULTS: Aqueductal stroke volume was significantly higher in the iNPH and acquired hydrocephalus groups than in the NC group, but did not differ significantly between the iNPH group and acquired hydrocephalus group. The AV, net ASV, and net flow in the iNPH and acquired hydrocephalus groups were significantly higher than those in the NC group (P < 0.0001), and those in the acquired hydrocephalus group were significantly higher than those in the iNPH group (P = 0.01, P = 0.007, P = 0.002, respectively). The direction of the AV and net ASV significantly differed among the three groups. There were no associations between the volume parameters and CSF flow according to PC-MR among the three groups. CONCLUSION: Compared with iNPH, elderly acquired hydrocephalus demonstrated higher CSF hyperdynamic flow. Although increased CSF flow may contribute to further changes in ventricular morphology, there is no linear relationship between them. These findings might help increase our understanding of flow dynamics in iNPH and elderly acquired hydrocephalus.

Depletion of Microglia Attenuates Dendritic Spine Loss and Neuronal Apoptosis in the Acute Stage of Moderate Traumatic Brain Injury in Mice.

Microglia are the primary immune cells in the central nervous system and undergo significant morphological and transcriptional changes after traumatic brain injury (TBI). However, their exact contribution to the pathogenesis of TBI is still debated and remains to be elucidated. In the present study, thy-1 GFP mice received a colony-stimulating factor 1 receptor inhibitor (PLX3397) for 21 consecutive days, then were subjected to moderate fluid percussion injury (FPI). Brain samples were collected at 1 day and 3 days after FPI for flow cytometry analysis, immunofluorescence, dendrite spine quantification, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and Western blot. We found that PLX3397 treatment significantly attenuated the percentages of resident microglia and infiltrated immune cells. Depletion of microglia promoted neurite outgrowth, preserved dendritic spines and reduced total brain cell and neuronal apoptosis after FPI, which was accompanied by decreased the protein levels of endoplasmic reticulum stress marker proteins, C/EBP-homologous protein and inositol-requiring kinase 1α. Taken together, these findings suggest that microglial depletion may exert beneficial effects in the acute stage of FPI.

Relationship between intracranial pressure and phase-contrast cine MRI-derived measures of cerebrospinal fluid parameters in communicating hydrocephalus.

BACKGROUND: To explore the correlation between intracranial pressure (ICP) and cerebrospinal fluid (CSF) parameters assessed by phase-contrast cine MRI (PC-MRI). METHODS: Fifteen normal people and 80 subjects with communicating hydrocephalus who underwent PC-MRI examinations from a single center were included in this cross-sectional study. In addition to recording patient's age, heart rate, blood pressure and body mass index (BMI), ICP and CSF hemodynamic parameters, such as flow velocity and aqueduct diameter, were measured for correlation analysis. RESULTS: The mean ICP and CSF aqueduct diameter in hydrocephalus patients were 151.05 mmH2O and 2.877 mm, respectively, and the maximum (6.938 cm/s) and mean (0.845 cm/s) CSF flow velocities were significantly higher in these patients compared with the controls (P<0.05). After adjusting for age, heart rate, blood pressure, and BMI, there was no significant relationship between peak velocity and ICP (P>0.05). Furthermore, a nonlinear relationship was observed between the ICP and the average velocity of CSF, and the ICP and aqueduct diameter. The ICP increased with the average velocity above 1.628 cm/s (P≤0.01), and the aqueduct diameter increased more than 3.6 mm (P<0.001). CONCLUSIONS: This study found significant correlations between ICP and average velocity and aqueduct diameter. These findings can be useful in assisting clinicians in predicting ICP more effectively, thus improving patient management.