Cerebrospinal Fluid from Patients After Craniotomy with the Appearance of Interleukin-6 Storm Can Activate Microglia to Damage the Hypothalamic Neurons in Mice.

We monitored CSF (cerebrospinal fluid) for Th1/Th2 inflammatory cytokines in a patient with unexplained postoperative disturbance of consciousness after craniotomy and found that the level of IL-6 (interleukin-6) concentrations was extremely high, meeting the traditional criteria for an inflammatory cytokine storm. Subsequently, the cerebrospinal fluid specimens of several patients were tested, and it was found that IL-6 levels were increased in different degrees after craniotomy. Previous studies have focused more on mild and long-term IL-6 elevation, but less on the effects of this short-term IL-6 inflammatory cytokine storm. Cerebrospinal fluid rich in IL-6 may play a significant role in patients after craniotomy. The objective is to explore the degree of IL-6 elevation and the incidence of IL-6 inflammatory cytokine storm in patients after craniotomy, as well as the effect of IL-6 elevation on the brain. In this study, the levels and clinical manifestations of inflammatory factors in cerebrospinal fluid after craniotomy were statistically classified, and the underlying mechanisms were discussed preliminarily. CSF specimens of patients after craniotomy were collected, IL-6 level was measured at 1, 5, and 10 days after operation, and cognitive function was analyzed at 1, 10, and 180 days after surgery. Craniotomy mouse model, cerebrospinal fluid of patients with the appearance of IL-6 storm after craniotomy, and IL-6 at the same concentration stimulation model were established. Behavioral tests, fluorescence in situ hybridization (FISH), pathological means, western blot, and ELISA (enzyme-linked immune-sorbent assay) were performed for verification. CSF from patients after craniotomy caused disturbance of consciousness in mice, affected neuronal damage in the hypothalamus, activation of microglia in the hypothalamus, and decreased expression of barrier proteins in the hypothalamus and brain. The large amount of interleukin-6 in CSF after craniotomy was found to be mainly derived from astrocytes. The IL-6 level in CSF after craniotomy correlated inversely with patients' performance in MoCA test. High levels of IL-6 in the cerebrospinal fluid derived from astrocytes after craniotomy may lead to disruption of the brain-cerebrospinal fluid barrier, most notably around the hypothalamus, which might result in inflammatory activation of microglia to damage the hypothalamic neurons and impaired cognitive function/more gradual cognitive repairment in patients after craniotomy with the appearance of IL-6 storm.

Chinese guideline on the application of anti-seizure medications in the perioperative period of supratentorial craniocerebral surgery.

Seizures are a common symptom of craniocerebral diseases, and epilepsy is one of the comorbidities of craniocerebral diseases. However, how to rationally use anti-seizure medications (ASMs) in the perioperative period of craniocerebral surgery to control or avoid seizures and reduce their associated harm is a problem. The China Association Against Epilepsy (CAAE) united with the Trauma Group of the Chinese Neurosurgery Society, Glioma Professional Committee of the Chinese Anti-Cancer Association, Neuro-Oncology Branch of the Chinese Neuroscience Society, and Neurotraumatic Group of Chinese Trauma Society, and selected experts for consultancy regarding outcomes from evidence-based medicine in domestic and foreign literature. These experts referred to the existing research evidence, drug characteristics, Chinese FDA-approved indications, and expert experience, and finished the current guideline on the application of ASMs during the perioperative period of craniocerebral surgery, aiming to guide relevant clinical practice. This guideline consists of six sections: application scope of guideline, concepts of craniocerebral surgery-related seizures and epilepsy, postoperative application of ASMs in patients without seizures before surgery, application of ASMs in patients with seizures associated with lesions before surgery, emergency treatment of postoperative seizures, and 16 recommendations.

Identification of Novel Cerebrospinal Fluid Biomarkers for Cognitive Decline in Aneurysmal Subarachnoid Hemorrhage: A Proteomic Approach.

Background: Cognitive impairment commonly occurs in aneurysmal subarachnoid hemorrhage (aSAH) survivors. Cerebrospinal fluid (CSF) biomarkers have been proven useful in several central neurological disorders. No such diagnostic biomarkers are available for predicting cognitive impairment after aSAH to date. Here, we aimed to identify novel CSF biomarkers for cognitive deficits after aSAH using an in-depth proteomic approach. Methods: We applied mass spectrometry with data independent acquisition (DIA) quantification to identify biomarker candidates in CSF samples from a well-characterized cohort comprising patients with impaired cognition (n = 9) and patients with intact cognition (n = 9). The potential biological processes and signaling pathways associated with differential proteins were analyzed using R software. The candidates were further validated in a larger independent cohort (n = 40) using ELISA. The diagnostic utility of these proteins was investigated by using receiver operating characteristic curve analysis. Results: In total, we identified 628 proteins. The discovery cohort revealed that 115 proteins were differentially expressed in cognitive impairment patients compared to patients with intact cognition (P < 0.05). Independent cohort replication confirmed NCAM2, NPTXR, NRXN2, RELN, and CNTN2 as sensitive and specific candidate biomarkers for disorders of cognition. Lower CSF levels of all biomarker candidates, except RELN, were associated with more pronounced cognitive decline. Conclusion: We identified and validated five CSF biomarkers for cognitive impairment in aSAH patients. These particular proteins have important predictive and discriminative potential for cognitive impairment in aSAH and could be potential targets for early disease intervention.

Activation of Age-Related Nuclear Factor-κB Signaling Pathway Leads to Chronic Inflammation and Pituitary Fibrosis.

OBJECTIVE: The purpose of the present study was to investigate the mechanism of pituitary fibrosis in elderly people. METHODS: First, 20 pituitary glands obtained from 11 elderly people and 9 young people were studied using Masson's trichrome staining for fibrosis detection. Second, pituitary glands from 12 male rats, including 6 aged rats (OM group) and 6 young rats (YM group), were also studied. Western blotting was performed to detect collagen 1 and phosphorylation of the nuclear factor (NF)-κB subunit p65 in the OM and YM groups. The levels of 8 proinflammatory cytokines (interleukin [IL]-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, interferon-γ, and tumor necrosis factor-α) in the rat pituitary glands were detected using liquid suspension chip technology. Enzyme-linked immunosorbent assays were performed to detect the growth hormone (GH) levels in the venous blood samples from the rats. Next, 12 aged rats were randomly divided into 2 groups: the QNZ (Q)+OM and normal physiological saline (N)+OM groups. The Q+OM and N+OM groups had undergone intervention by intraperitoneally injection of QNZ and physiological saline (1 mg/kg) for 28 days, respectively. Finally, biochemical and histological examinations were performed, including Masson's trichrome staining for fibrosis, Western blotting for phosphorylation of p65, Millipore multiplex bead arrays (Millipore, Billerica, Massachusetts, USA) for proinflammatory cytokine levels, and enzyme-linked immunosorbent assays for GH secretion. RESULTS: Fibrosis was detected in the elderly patient group. Collagen 1, phosphorylation of the NF-κB signaling pathway, and the proinflammatory cytokine levels showed a significant increase in the OM group. Compared with the N+OM group, pituitary fibrosis was alleviated in the Q+OM group, with an increase in GH secretion and decreased proinflammatory cytokine levels and NF-κB. CONCLUSIONS: Pituitary fibrosis was found in the elderly group, and the pathological change was antagonized by decreasing the proinflammatory cytokine levels using QNZ and further increasing GH secretion.

Reinvestigating Tumor-Ventricle Relationship of Craniopharyngiomas With Predominantly Ventricular Involvement: An Endoscopic Endonasal Series Based on Histopathological Assessment.

OBJECTIVE: Craniopharyngiomas (CPs) predominantly involving the third ventricle were commonly termed "intraventricular" lesions. The aim of this study was to clarify the anatomical relationship between the tumor and the third ventricle by both surgical and histological investigation. METHODS: A retrospective review of primarily resected CPs by endoscopic endonasal surgery was performed. CPs with predominantly ventricular involvement were selected for study inclusion by preoperative imaging. The surgical procedure of each case was reviewed. The wholly removed tumor specimens were histologically analyzed, in all cases, to investigate the tumor-third ventricle relationship using hematoxylin and eosin, immunochemical, and immunofluorescence staining. RESULTS: Twenty-six primary CPs predominantly involving the third ventricle were selected from our series of 223 CPs treated by endoscopic endonasal surgery between January 2017 and March 2021. Gross-total resection was achieved in 24 (92.3%) of 26 patients, with achievement of near-total resection in the remaining patients. A circumferential layer of stretched third ventricle floor was identified surrounding the tumor capsule, which could be peeled off easily from the ventricle floor remnants at most areas of the plane of tumor attachment. Some portions of the tumor capsule tightly adhered to the third ventricle floor were removed together with the floor. A breach of various size was observed at the third ventricle floor after tumor removal in most cases, the floor remaining intact in only two cases (7.7%). Histological examination on marked portions of tumor capsule showed that the pia mater was frequently detected at most of the tumor-brain interface, except at the antero-frontal border of tumor contacting with the third ventricle floor. At this point, a layer of gliosis with various thickness was observed between the tumor and the neural tissue of the third ventricle floor. CONCLUSION: CPs with predominantly ventricular involvement should be considered as lesions with an extraventricular, epi-pia topography rather than "intraventricular" or "subpial" topography. Accurate understanding of the relationship between the third ventricle and such tumors would predict the circumferential cleavage plane of dissection, and remind neurosurgeons of performing dissection along the safe surgical plane to achieve total tumoral resection with minimizing hypothalamic damage.

Clinical impact of craniopharyngioma classification based on location origin: a multicenter retrospective study.

BACKGROUND: An assessment of the clinical impact for craniopharyngiomas (CPs) classification based on origin location has not been reported. The aim of this study was to determine the clinical impact of the site of tumor origin in primary CPs. METHODS: Patients from six national institutions who had undergone resection for primary CP were enrolled. Based on the point of origin and surrounding membranous structures, the location of the tumor origin was labelled as Q, S, or T, where Type Q CPs originated below the diaphragmatic area; Type S CPs originated from Rathke's pouch precursor cells; and Type T CPs originated from the Rathke's pouch precursor cells located above the pars tuberalis. Clinical characteristics, surgical approach, and outcome were evaluated according to the location of the tumor origin. RESULTS: Among the 529 patients with primary CP, symptoms, age, histopathology type, tumor size, the incidence of hydrocephalus, survival rates, and recurrence-free survival rates were significantly different among tumors originating in different locations. Patients with type T CPs had higher symptom rates of intracranial hypertension and hypothalamic dysfunction, while those with type Q CPs had higher rates of hormone deficits during pre-and post-operative management. Type S CPs were correlated with better outcomes and lower recurrence rates. The location of origin and primary therapy with survival and recurrence in CP were independent factors for survival and recurrence in multivariate analysis. CONCLUSIONS: The identification of the different location of origin of CPs is of great significance in understanding the relationship between tumors and peripheral tissues. The origin of tumors effects the choice of surgical approach and prognosis.

Pharmacokinetics of Linezolid Dose Adjustment for Creatinine Clearance in Critically Ill Patients: A Multicenter, Prospective, Open-Label, Observational Study.

PURPOSE: The aim of this study is to use a population pharmacokinetic (PK) approach to evaluate the optimal dosing strategy for linezolid (LNZ) in critically ill patients. METHODS: This multicenter, prospective, open-label, observational study was conducted in 152 patients, and 117 of them were included in the PK model, whereas the rest were in the validation group. The percentage of therapeutic target attainment (PTTA) comprising two pharmacodynamic indices and one toxicity index was used to evaluate dosing regimens based on Monte Carlo simulations stratified by low, normal, and high renal clearance for MICs of 0.25-4 mg/L. RESULTS: A single-compartment model with a covariate creatinine clearance (CrCL) was chosen as the final model. The PK parameter estimates were clearance of 5.60 L/h, with CrCL adjustment factor of 0.386, and a distribution volume of 43.4 L. For MIC ≤2 mg/L, the standard dosing regimen (600 mg q12h) for patients with severe renal impairment (CrCL, 40 mL/min) and standard dosing or 900 mg q12h for patients with normal renal functions (CrCL, 80 mL/min) could achieve PTTA ≥74%. The dose of 2400 mg per 24-h continuous infusion was ideal for augmented renal clearance (ARC) with MIC ≤1 mg/L. For MICs >2 mg/L, rare optimal dose regimens were found regardless of renal function. CONCLUSION: In critically ill patients, the standard dose of 600 mg q12h was sufficient for MIC ≤2 mg/L in patients without ARC. Moreover, a 2400 mg/day 24-h continuous infusion was recommended for ARC patients.

Incidence and Possible Predictors of Sodium Disturbance After Craniopharyngioma Resection Based on QST Classification.

OBJECTIVE: Serum sodium abnormalities are one of the most common manifestations after radical craniopharyngioma (CP) excision. The aim of this study was to report the incidence and possible predictors of serum sodium disturbance and explore features of sodium destabilization manifestation among QST classification results after CP resection. METHODS: A retrospective analysis was performed of clinical, biochemical, radiologic, and operative data for 134 successive patients who underwent primary CP removal between September 2016 and March 2018. Univariate and multivariate analyses were conducted to determine predictors. RESULTS: Sixty patients (44.8%) experienced hyponatremia and 67 patients (50%) hypernatremia; the median time of onset was 6 days and the first day after surgery, respectively. The incidence, onset, severity, and type of sodium disturbance among different types of CP differed significantly based on statistical tests (P < 0.05). Sodium disturbance was more common and severe in patients with type T tumors (P < 0.05). Age, tumor type, and preoperative diabetes insipidus were independent prognostic factors for obvious disorders of serum sodium. CONCLUSIONS: Hyponatremia/hypernatremia is common after primary CP resection. The site of tumor origin has a direct effect on the growth pattern of CP, which may serve as a useful index for anticipating sodium perturbation after surgery. The level of sodium in children and patients with type T tumors, preoperative diabetes insipidus should be monitored closely throughout hospitalization.

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.

Endoscopic endonasal versus transcranial surgery for primary resection of craniopharyngiomas based on a new QST classification system: a comparative series of 315 patients.

OBJECTIVE: An assessment of the transcranial approach (TCA) and the endoscopic endonasal approach (EEA) for craniopharyngiomas (CPs) according to tumor types has not been reported. The aim of this study was to evaluate both surgical approaches for different types of CPs. METHODS: A retrospective review of primary resected CPs was performed. A QST classification system based on tumor origin was used to classify tumors into 3 types as follows: infrasellar/subdiaphragmatic CPs (Q-CPs), subarachnoidal CPs (S-CPs), and pars tuberalis CPs (T-CPs). Within each tumor type, patients were further arranged into two groups: those treated via the TCA and those treated via the EEA. Patient and tumor characteristics, surgical outcomes, and postoperative complications were obtained. All variables were statistically analyzed between surgical groups for each tumor type. RESULTS: A total of 315 patients were included in this series, of whom 87 were identified with Q-CPs (49 treated via TCA and 38 via EEA); 56 with S-CPs (36 treated via TCA and 20 via EEA); and 172 with T-CPs (105 treated via TCA and 67 via EEA). Patient and tumor characteristics were equivalent between both surgical groups in each tumor type. The overall gross-total resection rate (90.5% TCA vs 91.2% EEA, p = 0.85) and recurrence rate (8.9% TCA vs 6.4% EEA, p = 0.35) were similar between surgical groups. The EEA group had a greater chance of visual improvement (61.6% vs 35.8%, p = 0.01) and a decreased risk of visual deterioration (1.6% vs 11.0%, p < 0.001). Of the patients with T-CPs, postoperative hypothalamic status was better in the TCA group than in the EEA group (p = 0.016). Postoperative CSF leaks and nasal complication rates occurred more frequently in the EEA group (12.0% vs 0.5%, and 9.6% vs 0.5%; both p < 0.001). For Q-CPs, EEA was associated with an increased gross-total resection rate (97.4% vs 85.7%, p = 0.017), decreased recurrence rate (2.6% vs 12.2%, p = 0.001), and lower new hypopituitarism rate (28.9% vs 57.1%, p = 0.008). The recurrence-free survival in patients with Q-CPs was also significantly different between surgical groups (log-rank test, p = 0.037). The EEA required longer surgical time for T-CPs (p = 0.01). CONCLUSIONS: CPs could be effectively treated by radical surgery with favorable results. Both TCA and EEA have their advantages and limitations when used to manage different types of tumors. Individualized surgical strategies based on tumor growth patterns are mandatory to achieve optimal outcomes.

Long intergenic non-protein coding RNA 00475 silencing acts as a tumor suppressor in glioma under hypoxic condition by impairing microRNA-449b-5p-dependent AGAP2 up-regulation.

OBJECTIVE: Long non-coding RNAs have been demonstrated to be involved in the progression of a variety of cancers, including glioma. Through microarray analyses, long intergenic non-protein coding RNA 00475 (LINC00475) was identified in the glioma development. However, its potential role remains incompletely understood. This study aimed to elucidate the effect of LINC00475 on the development of glioma under hypoxic conditions. METHODS: Glioma cells underwent hypoxic treatment and were collected. The functional role of LINC00475 and AGAP2 in glioma was determined using ectopic expression, depletion, and reporter assay experiments. Then, the expression of LINC00475, microRNA (miR)-449b-5p, AGAP2, FAK, and HIF-1α was determined. In addition, cell migration and invasion were examined. Finally, a tumor xenograft was carried out in nude mice to explore the role of LINC00475 on oxidation in vivo. RESULTS: LINC00475 was identified to be overexpressed in hypoxic glioma samples, which was further observed to bind to and down-regulate miR-449b-5p, and negatively targeted AGAP2. Moreover, we also revealed a positive correlation between LINC00475 and AGAP2 expression in glioma. In addition, silencing of LINC00475 decreased the extent of FAK phosphorylation and reduced the expression of HIF-1α and AGAP2. It was also observed that LINC00475 silencing suppressed glioma cell proliferation, migration, and invasion, and promoted cell apoptosis. Moreover, oxidation of nude mice was promoted by LINC00475 silencing. CONCLUSION: Taken together, LINC00475 silencing exerted an inhibitory effect on glioma under hypoxic conditions by down-regulating AGAP2 via up-regulation of miR-449b-5p.

Risk Factors of Acute Gastrointestinal Failure in Critically Ill Patients With Traumatic Brain Injury.

OBJECTIVE: To assess the risk factors associated with acute gastrointestinal failure (AGF) in critically ill patients with traumatic brain injury (TBI). METHODS: Prospective, observational study was conducted in NanFang Hospital, Southern Medical University. All patients admitted to the Department of Critical Care Medicine and Department of Neurosurgery from June 1, 2017 to December 1, 2018 with TBI were enrolled. RESULTS: Overall, 199 patients were enrolled. About 62 episodes (31%) of AGF were diagnosed. In the multivariate analysis, women, severe Glasgow Coma Scale (GCS) classification, frontal lobe injury, abnormal serum sodium, pulmonary infection, and intracranial infection are significantly associated with developing AGF, independent of other prognostic factors. CONCLUSION: The AGF occurs frequently in intensive care unit patients who are suffering from TBI. In critically ill patients with TBI, women, severe GCS classification, frontal lobe injury, abnormal serum sodium, pulmonary infection, and intracranial infection are independent risk factors for AGF.

Interleukin-1α leads to growth hormone deficiency in adamantinomatous craniopharyngioma by targeting pericytes: implication in pituitary fibrosis.

BACKGROUND: The incidence of growth hormone deficiency (GHD) in adamantinomatous craniopharyngioma (aCP) is significantly higher than in other sellar region tumors, but the possible mechanism is still elusive. A high level of inflammatory responses is another feature of aCP. We investigated the internal connection between interleukin-1α (IL-1α) and GHD, while focusing on its biological activities in pituitary fibrosis. MATERIALS AND METHODS: To diagnosis of GHD, the Body Mass Index (BMI), Insulin Like Growth Factor-1(IGF-1) and peak growth hormone (GH) values after insulin stimulation test of 15 aCP patients were recorded. Histological staining was performed on the aCP samples. Levels of 9 proinflammatory cytokines in tumor tissue and cell supernatant were detected using Millipore bead arrays. The effect of IL-1α on GH secretion was evaluated in vivo and in vitro. Western blot, qRT-PCR and cell functional assays were used to explore the potential mechanism through which IL-1α acts on GH secretion. The stereotactic ALZET osmotic pump technique was used to simulate aCP secretion of proinflammatory cytokines in rats. Recombinant IL-1α (rrIL-1α) and conditioned media (CM) prepared from the supernatant of aCP cells was infused directly into the intra-sellar at a rate of 1 µl/h over 28 days, and then the effects of IL-1α treatment on pathological changes of pituitary gland and GH secretion were measured. To further confirm whether IL-1α affects GH secretion through IL-1R1, an IL-1R1 blocker (IL-1R1a, 10 mg/kg body weight, once daily) was administered subcutaneously from the first day until day 28. RESULTS: There was a significant positive correlation between pituitary fibrosis and GHD (rS = 0.756, P = 0.001). A number of cytokines, in particular IL-1α, interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), were elevated in tumor tissue and cell supernatant. Only IL-1α showed a significant difference between the GHD group and the No-GHD group (P < 0.001, F = 6.251 in tumor tissue; P = 0.003, F = 1.529 in cell supernatant). IL-1α significantly reduced GH secretion in coculture of GH3 and pericytes. The activation of pericytes induced by IL-1α was mediated by the IL-1R1 signaling pathway. In vivo, IL-1α induces pituitary fibrosis, further leading to a decreased level of GH. This pathological change was antagonized by IL-1R1a. CONCLUSION: This study found that the cross talk between aCP cells and stroma cells in the pituitary, i.e. pericytes, is an essential factor in the formation of GHD, and we propose that neutralization of IL-1α signaling might be a potential therapy for GHD in aCP.

Exosomes derived from microRNA-199a-overexpressing mesenchymal stem cells inhibit glioma progression by down-regulating AGAP2.

Accumulating evidence has implied that microRNAs (miRNAs) are implicated in glioma progression, and genetically engineered mesenchymal stem cells can help to inhibit tumor growth of glioma. Herein we hypothesized that miR-199a could be delivered by mesenchymal stem cells to glioma cells through exosomes and thus prevent the glioma development by down-regulating ArfGAP with GTPase domain, ankyrin repeat and PH domain 2 (AGAP2). The expression pattern of miR-199a and AGAP2 was characterized in glioma tissues and cells using RNA polymerase chain reaction quantification, immunohistochemical staining and Western blot assays. Mesenchymal stem cells transfected with miR-199a mimic or their derived exosomes were co-cultured with U251 cells. The biological behaviors as well as chemosensitivity of U251 cells were assessed to explore the involvement of miR-199a/AGAP2 in glioma. MiR-199a was poorly expressed in glioma tissue and cells while AGAP2 was highly expressed. Mesenchymal stem cells delivered miR-199a to the glioma cells via the exosomes, which resulted in the suppression of the proliferation, invasion and migration of glioma cells. Besides, mesenchymal stem cells over-expressing miR-199a enhanced the chemosensitivity to temozolomide and inhibited the tumor growth in vivo. Taken together, mesenchymal stem cell-derived exosomal miR-199a can inhibit the progression of glioma by down-regulating AGAP2.

An improved method of culturing somatotropic cells from rat adenohypophysis.

This study aimed to propose a simple and practical method for culturing primary rat somatotropic cells in vitro free of pericytes contamination. Rat adenohypophyses were randomly divided into two groups. An improved method was used in group A (digesting adenohypophysis with 0.25% trypsin-EDTA, followed by removing pericytes by double filtration and using serum-free medium for culturing somatotropic cells). The traditional method was used in group B (digesting adenohypophysis with 0.35% collagenase, using serum medium for culturing somatotropic cells, and removing pericytes by changing the culture dish). The numbers and viability of somatotropic cells were higher in group A than in group B after 6 days. GH secretion of somatotropic cells was also higher in group A than in group B. Besides, the pericytes grew rapidly only in group B after 3 days. α-SMA, type I collagen, and type III collagen had weaker expression in group A. Also, the viability of pericytes decreased in group A. The improved method could solve the problem of pericytes contamination, and the culture of primary rat somatotropic cells in vitro was successful. This method can be used for other primary cultures with pericytes contamination.

Prediction of Minimally Conscious State With Brain Stem Reflexes in Unconscious Patients After Traumatic Brain Injury.

OBJECTIVE: To evaluate the predictive power of the brain stem reflexes (BSRs) for minimally conscious state in unconscious patients after traumatic brain injury. MATERIALS AND METHODS: A total of 120 patients with duration of unconsciousness were enrolled in this study. BSRs were recorded 14 days after Traumatic brain injury, and classified into 3 grades. Predictors including BSRs, age, sex, Glasgow Coma Scale (GCS), and cause of injury were also analyzed, respectively. The outcome was divided into 2 groups including unconscious group and minimally conscious state (MCS) group. RESULTS: Seventy-two of 120 were minimally conscious and 48 of 120 were unconscious at 6 months from the onset of injury. The BSRs outmatched the predictive accuracy of the GCS for outcome (AUROC, 0.853; 95% confidence interval, 0.753-0.953; and AUROC, 0.655; 95% confidence interval, 0.512-0.799, respectively). BSRs grade (P < 0.001) and GCS (P < 0.05) were significantly associated with the outcome. The accuracy of the whole regression model for predicting unconscious and MCS was 91.7% and 79.2%, respectively. CONCLUSION: The BSRs grade shows a significantly higher accuracy for prediction of MCS compared with the GCS. BSRs grade is a simple, yet reliable and stratification tool for early decision making.

Traumatic brain injury in China.

China has more patients with traumatic brain injury (TBI) than most other countries in the world, making this condition a major public health concern. Population-based mortality of TBI in China is estimated to be approximately 13 cases per 100 000 people, which is similar to the rates reported in other countries. The implementation of various measures, such as safety legislation for road traffic, establishment of specialised neurosurgical intensive care units, and the development of evidence-based guidelines, have contributed to advancing prevention and care of patients with TBI in China. However, many challenges remain, which are augmented further by regional differences in TBI care. High-level care, such as intracranial pressure monitoring, is not universally available yet. In the past 30 years, the quality of TBI research in China has substantially improved, as evidenced by an increasing number of clinical trials done. The large number of patients with TBI and specialised trauma centres offer unique opportunities for TBI research in China. Furthermore, the formation and development of research collaborations between China and international groups are considered essential to advancing the quality of TBI care and research in China, and to improve quality of life in patients with this condition.

Endoplasmic reticulum stress induces apoptosis of arginine vasopressin neurons in central diabetes insipidus via PI3K/Akt pathway.

AIMS: Central diabetes insipidus (CDI), a typical complication caused by pituitary stalk injury, often occurs after surgery, trauma, or tumor compression around hypothalamic structures such as the pituitary stalk and optic chiasma. CDI is linked to decreased arginine vasopressin (AVP) neurons in the hypothalamic supraoptic nucleus and paraventricular nucleus, along with a deficit in circulating AVP and oxytocin. However, little has been elucidated about the changes in AVP neurons in CDI. Hence, our study was designed to understand the role of several pathophysiologic changes such as endoplasmic reticulum (ER) stress and apoptosis of AVP neurons in CDI. METHODS: In a novel pituitary stalk electric lesion (PEL) model to mimic CDI, immunofluorescence and immunoblotting were used to understand the underlying regulatory mechanisms. RESULTS: We reported that in CDI condition, generated by PEL, ER stress induced apoptosis of AVP neurons via activation of the PI3K/Akt and ERK pathways. Furthermore, application of N-acetylcysteine protected hypothalamic AVP neurons from ER stress-induced apoptosis through blocking the PI3K/Akt and ERK pathways. CONCLUSION: Our findings showed that AVP neurons underwent apoptosis induced by ER stress, and ER stress might play a vital role in CDI condition through the PI3K/Akt and ERK pathways.

A rat model for pituitary stalk electric lesion-induced central diabetes insipidus: application of 3D printing and further outcome assessments.

A stable and reproducible rat injury model is not currently available to study central diabetes insipidus (CDI) and the neurohypophyseal system. In addition, a system is needed to assess the severity of CDI and measure the accompanying neurobiological alterations. In the present study, a 3D-printed lesion knife with a curved head was designed to fit into the stereotaxic instrument. The neuro-anatomical features of the brain injury were determined by in vivo magnetic resonance imaging (MRI) and arginine vasopressin (AVP) immunostaining on brain sections. Rats that underwent pituitary stalk electrical lesion (PEL) exhibited a tri-phasic pattern of CDI. MRI revealed that the hyperintenseT1-weighted signal of the pituitary stalk was interrupted, and the brain sections showed an enlarged end proximal to the injury site after PEL. In addition, the number of AVP-positive cells in supraoptic nucleus (SON) and paraventricular nucleus (PVN) decreased after PEL, which confirmed the success of the CDI model. Unlike hand-made tools, the 3D-printed lesion knives were stable and reproducible. Next, we used an ordinal clustering method for staging and the k-means' clustering method to construct a CDI index to evaluate the severity and recovery of CDI that could be used in other multiple animals, even in clinical research. In conclusion, we established a standard PEL model with a 3D-printed knife tool and proposed a CDI index that will greatly facilitate further research on CDI.