Choroid plexus immune cell response in murine hydrocephalus induced by intraventricular hemorrhage.

BACKGROUND: Intraventricular hemorrhage (IVH) and associated hydrocephalus are significant complications of intracerebral and subarachnoid hemorrhage. Despite proximity to IVH, the immune cell response at the choroid plexus (ChP) has been relatively understudied. This study employs CX3CR-1GFP mice, which marks multiple immune cell populations, and immunohistochemistry to outline that response. METHODS: This study had four parts all examining male adult CX3CR-1GFP mice. Part 1 examined naïve mice. In part 2, mice received an injection 30 µl of autologous blood into right ventricle and were euthanized at 24 h. In part 3, mice underwent intraventricular injection of saline, iron or peroxiredoxin 2 (Prx-2) and were euthanized at 24 h. In part 4, mice received intraventricular iron injection and were treated with either control or clodronate liposomes and were euthanized at 24 h. All mice underwent magnetic resonance imaging to quantify ventricular volume. The ChP immune cell response was examined by combining analysis of GFP(+) immune cells and immunofluorescence staining. RESULTS: IVH and intraventricular iron or Prx-2 injection in CX3CR-1GFP mice all induced ventriculomegaly and activation of ChP immune cells. There were very marked increases in the numbers of ChP epiplexus macrophages, T lymphocytes and neutrophils. Co-injection of clodronate liposomes with iron reduced the ventriculomegaly which was associated with fewer epiplexus and stromal macrophages but not reduced T lymphocytes and neutrophils. CONCLUSION: There is a marked immune cell response at the ChP in IVH involving epiplexus cells, T lymphocytes and neutrophils. The blood components iron and Prx-2 may play a role in eliciting that response. Reduction of ChP macrophages with clodronate liposomes reduced iron-induced ventriculomegaly suggesting that ChP macrophages may be a promising therapeutic target for managing IVH-induced hydrocephalus.

Opinions over targets for blood pressure control after mechanical thrombectomy in patients with acute ischemic stroke: baseline survey for the ENCHANTED2/MT trial in China.

BACKGROUND: Although guidelines recommend a target blood pressure 185-180/105-110 mmHg after mechanical thrombectomy for acute ischemic stroke (AIS), there is limited randomized evidence to support this level. We surveyed candidate institutions about the approach to blood pressure management in this patient group in preparation for inviting them to participate in the Enhanced Blood Pressure Control after Endovascular Thrombectomy for the Acute Ischemic Stroke Trial (ENCHANTED2/MT). METHODS: Physicians from a professional network of institutions that met mechanical thrombectomy qualification requirements were invited to participate in an online questionnaire covering basic clinical information as well as questions on blood pressure management. RESULTS: We invited 88 sites to participate with 44 (50%) ultimately joining the trial, and a total of 88 physicians finished the survey. The median number of annual mechanical thrombectomy cases performed per site was 89 [IQR 65-150]. Only 38 (43%) institutions strictly adhere to guidelines when managing the blood pressure of mechanical thrombectomy patients. The most popular blood pressure target for reperfusion patients was 140-160 mmHg (n=47, 53%), and <120 mmHg (n=28, 32%). Fewer hospital stroke beds (40 [21-57] vs. 60 [39-110], p = 0.01) and lower proportion of elevated blood pressure after mechanical thrombectomy (25% [10%-50%] vs. 50% [20%-70%], p = 0.02) were related to a more aggressive blood pressure target (<120 mmHg). Urapidil (n=82, 93%) and calcium channel blockers (CCBs) (n = 87, 99%), were the most widely used antihypertensive drugs, respectively. CONCLUSIONS: According to the survey, unstandardized blood pressure management protocols are performed in mechanical thrombectomy patients at institutions across China, which is different from prior survey from another country. More high-quality studies are needed to guide clinical practice.

Comparison of remimazolam and propofol combined with low dose esketamine for pediatric same-day painless bidirectional endoscopy: a randomized, controlled clinical trial.

Background: Remimazolam has shown similar or even superior properties to propofol in procedural sedation in adults, but few studies have been conducted in pediatric populations. Thus, we aimed to compare the effect and safety of remimazolam and propofol combined with low dose esketamine for pediatric same-day bidirectional endoscopy (BDE). Methods: Pediatrics <18 years scheduled for elective BDE under sedation were included and randomly assigned to remimazolam group (R group) or propofol group (P group). The primary outcome was the success rate of sedation. Secondary outcomes include sedation-related information and adverse events. Mean arterial pressure (MAP), heart rate (HR), and perfusion index (PI) were recorded during sedation. Results: A total of 106 patients were enrolled and analyzed. The success rate of sedation was 100% in both groups. Compared with the P group, the induction time of the R group was significantly prolonged (p < 0.001), and the incidence of injection pain, intraoperative respiratory depression, hypotension and bradycardia was significantly lower (p < 0.001). The changes in MAP, HR and PI were relatively stable in the R group compared with the P group. Additionally, awake time significantly decreased with age by approximately 1.12 index points for each increase in age in the P group (p = 0.002) but not in the R group (p > 0.05). Furthermore, the decline in PI and PI ratio during BDE was related to body movement in the P group. Conclusion: Remimazolam combined with low dose esketamine has a non-inferior sedative effect than propofol for pediatric BDE, with no injection pain, less respiratory depression, more stable hemodynamics. Moreover, early detection of the decline in PI may avoid harmful stimulation under light anesthesia. Clinical trial registration: https://www.clinicaltrials.gov/study/NCT05686863?id=NCT05686863&rank=1, NCT05686863.

Minocycline attenuates hydrocephalus and inhibits iron accumulation, ependymal damage and epiplexus cell activation after intraventricular hemorrhage in aged rats.

Intracerebral hemorrhage is primarily a disease of the elderly and it is frequently accompanied by intraventricular hemorrhage (IVH) which can lead to posthemorrhagic hydrocephalus and poor prognosis. Red blood cell iron has been implicated in brain injury after cerebral hemorrhage. The current study examined using T2* magnetic resonance imaging (MRI) to detect periventricular iron deposition after IVH and investigated the effects of minocycline on hydrocephalus in an aged rat IVH model. It had three parts. In part 1, male aged rats received a 200 µl injection of saline or autologous blood into the lateral ventricle and were euthanized at day 14. In parts 2 and 3, aged IVH rats were treated with vehicle or minocycline and euthanized at day 7 or 14. Rats underwent MRI to quantify hydrocephalus and iron deposition followed by brain histology and immunohistochemistry. Periventricular iron overload was found after IVH using T2* MRI and confirmed by histology. IVH also caused ventricular wall damage and increased the number of CD68(+) choroid plexus epiplexus cells. Minocycline administration reduced iron deposition and ventricular volume at days 7 and 14 after IVH, as well as ventricle wall damage and epiplexus cell activation. In summary, IVH-induced hydrocephalus is associated with periventricular iron deposition, ependymal damage and choroid plexus epiplexus cell activation in aged rats. Minocycline attenuated those effects and might be a potential treatment for posthemorrhagic hydrocephalus in the elderly.

Iron-Induced Hydrocephalus: the Role of Choroid Plexus Stromal Macrophages.

Evidence indicates that erythrocyte-derived iron and inflammation both play a role in intraventricular hemorrhage-induced brain injury including hydrocephalus. Many immune-associated cells, primarily stromal macrophages, reside at the choroid plexus where they are involved in inflammatory responses and antigen presentation. However, whether intraventricular iron impacts those stromal cells is unknown. The aim of this study was to evaluate the relationship between choroid plexus stromal macrophages and iron-induced hydrocephalus in rats and the impact of minocycline and clodronate liposomes on those changes. Aged (18-month-old) and young (3-month-old) male Fischer 344 rats were used to study choroid plexus stromal macrophages. Rats underwent intraventricular iron injection to induce hydrocephalus and treated with either minocycline, a microglia/macrophage inhibitor, or clodronate liposomes, a macrophage depleting agent. Ventricular volume was measured using magnetic resonance imaging, and stromal macrophages were quantified by immunofluorescence staining. We found that stromal macrophages accounted for about 10% of the total choroid plexus cells with more in aged rats. In both aged and young rats, intraventricular iron injection resulted in hydrocephalus and increased stromal macrophage number. Minocycline or clodronate liposomes ameliorated iron-induced hydrocephalus and the increase in stromal macrophages. In conclusion, stromal macrophages account for ~10% of all choroid plexus cells, with more in aged rats. Treatments targeting macrophages (minocycline and clodronate liposomes) are associated with reduced iron-induced hydrocephalus.

Brain edema formation and therapy after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) accounts for about 10% of all strokes in the United States of America causing a high degree of disability and mortality. There is initial (primary) brain injury due to the mechanical disruption caused by the hematoma. There is then secondary injury, triggered by the initial injury but also the release of various clot-derived factors (e.g., thrombin and hemoglobin). ICH alters brain fluid homeostasis. Apart from the initial hematoma mass, ICH causes blood-brain barrier disruption and parenchymal cell swelling, which result in brain edema and intracranial hypertension affecting patient prognosis. Reducing brain edema is a critical part of post-ICH care. However, there are limited effective treatment methods for reducing perihematomal cerebral edema and intracranial pressure in ICH. This review discusses the mechanisms underlying perihematomal brain edema formation, the effects of sex and age, as well as how edema is resolved. It examines progress in pharmacotherapy, particularly focusing on drugs which have been or are currently being investigated in clinical trials.

Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.

BACKGROUND: The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. METHODS: We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target <120 mm Hg) or less intensive treatment (target 140-180 mm Hg) to be achieved within 1 h and sustained for 72 h. The primary efficacy outcome was functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days. Analyses were done according to the modified intention-to-treat principle. Efficacy analyses were performed with proportional odds logistic regression with adjustment for treatment allocation as a fixed effect, site as a random effect, and baseline prognostic factors, and included all randomly assigned patients who provided consent and had available data for the primary outcome. The safety analysis included all randomly assigned patients. The treatment effects were expressed as odds ratios (ORs). This trial is registered at ClinicalTrials.gov, NCT04140110, and the Chinese Clinical Trial Registry, 1900027785; recruitment has stopped at all participating centres. FINDINGS: Between July 20, 2020, and March 7, 2022, 821 patients were randomly assigned. The trial was stopped after review of the outcome data on June 22, 2022, due to persistent efficacy and safety concerns. 407 participants were assigned to the more intensive treatment group and 409 to the less intensive treatment group, of whom 404 patients in the more intensive treatment group and 406 patients in the less intensive treatment group had primary outcome data available. The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common OR 1·37 [95% CI 1·07-1·76]). Compared with the less intensive treatment group, the more intensive treatment group had more early neurological deterioration (common OR 1·53 [95% 1·18-1·97]) and major disability at 90 days (OR 2·07 [95% CI 1·47-2·93]) but there were no significant differences in symptomatic intracerebral haemorrhage. There were no significant differences in serious adverse events or mortality between groups. INTERPRETATION: Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion. FUNDING: The Shanghai Hospital Development Center; National Health and Medical Research Council of Australia; Medical Research Futures Fund of Australia; China Stroke Prevention; Shanghai Changhai Hospital, Science and Technology Commission of Shanghai Municipality; Takeda China; Hasten Biopharmaceutic; Genesis Medtech; Penumbra.

The association between functional status and physical pain with depressive symptoms after a stroke event: A cross-sectional analysis of the China Health and Retirement Longitudinal Study 2018.

Background: Stroke is a major cause of mortality and long-term physical and cognitive impairment. This study aims to: (1) examine the prevalence of depressive symptoms, disability and pain among Chinese adults with stroke; (2) test the associations of functional limitations and body pain with occurrence of depressive symptoms; (3) investigate gender and urban-rural disparities in these associations. Methods: This study utilized the data from the China Health and Retirement Longitudinal Study in 2018, involving 969 patients with stroke among 17,970 participants aged ≥ 45 years. Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression (CES-D) Scale. We performed multivariable logistic regression models to estimate the associations between activities of daily life (ADL), instrumental activities of daily life (IADL) and pain with depressive symptoms. Results: Depressive symptoms were found among 40.2% of stroke patients, with a higher prevalence in females (48.2%) than males (32.7%). Prevalence of ADL limitations, IADL limitations and pain among stroke patients were 39.2, 49.8 and 14.0%, respectively. ADL and IADL limitations and pain were more prevalent among females and residents in rural areas. Multivariable regression analyses showed a significant association between ADL limitation (OR = 1.535, 95% CI = 1.168, 2.018), IADL limitation (OR = 1.666, 95% CI = 1.260, 2.203) and pain (OR = 2.122, 95% CI = 1.466, 3.073) with depressive symptoms. Stratified analyses revealed stronger associations among urban residents. Females had a higher association of ADL and IADL with depressive symptoms but similar in that of pain to the males. The impact of ADL and IADL in male patients is higher than in females, but the impact of pain on depressive symptoms is higher in female patients. Conclusion: Depressive symptoms are common amongst post-stroke patients in China and are significantly associated with functional disability and physical pain. Our findings have implications for practitioners on the early assessment of pain and depression after stroke. Future research should explore effective intervention measures for physical-mental stroke complications.

Effects of aging on hydrocephalus after intraventricular hemorrhage.

BACKGROUND: Hydrocephalus is a common and major complication that affects outcome after intraventricular hemorrhage (IVH). While aging impacts the occurrence of hydrocephalus in patients with IVH this and the underlying mechanisms have received little attention. The present investigation, therefore, studied the impact of aging on hydrocephalus after IVH in a rat model. METHODS: Young and aged (3 and 18 months old, respectively) male Fischer 344 rats had an intraventricular injection of 200 µl autologous blood or saline. Ventricular volume was estimated using magnetic resonance imaging (MRI), while ventricular wall damage, heme oxygenase-1 (HO-1) and epiplexus cell activation were quantified by histological staining and Western blot. Additionally, the impact of intraventricular iron injection was examined in young and aged rats. RESULTS: Intraventricular injection of autologous blood induced hydrocephalus in both young and aged rats but ventricular volumes were larger in aged rats compared to young rats from day 3 to day 14 followed IVH. In addition, ventricular wall damage and periventricular HO-1 upregulation were greater in aged versus young rats on day 1 after IVH. Aged rats also had more choroid plexus epiplexus cells on day 14 after IVH. Additionally, organized hematomas were observed in 23% (3/13) of aged rats but not in young rats after IVH. Organized hematomas in aged rats showed larger T2* lesions on MRI compared to rats with non-organized hematomas. Similar to the effects of IVH, intraventricular injection of iron resulted in more epiplexus cells activation and more severe hydrocephalus in aged compared to young rats. CONCLUSIONS: IVH causes more severe hydrocephalus in aged compared to young rats. Enhanced ventricular wall damage, epiplexus cell activation and iron overload may contribute to this aggravated hydrocephalus development in aged animals.

Clinical characteristic of 15 cases of cryptococcal meningitis treated with Ommaya reservoir.

Cryptococcal meningitis is a severe subacute fungal meningoencephalitis. Intracerebroventricular (ICV) injection of antifungal medication and aspiration of cerebrospinal fluid (CSF) through Ommaya reservoir were reported to be useful cryptococcal meningitis treatment method. We want to evaluate the role of Ommaya reservoir in the treatment of refractory cryptococcal meningitis. We retrospectively analyzed clinical records and data of 15 refractory cryptococcal meningitis patients who were treated with Ommaya reservoir in Sir Run Run Shaw hospital from June 2013 to June 2017. Fifteen patients who underwent Ommaya reservoir implanted surgery include eight women and seven men. Headache and fever were the common clinical symptoms. Underlying diseases mainly include diabetes mellitus and hypertension. Three patients occurred renal dysfunction and four patients experienced liver damage. Thirteen patients recovered completely, whereas two patients died. Implant Ommaya reservoir which can serial extract CSF and ICV injection of Amphotericin B is a valuable approach in the treatment of Cryptococcal meningitis, especially for patients with refractory intracranial hypertension.

Activation of epiplexus macrophages in hydrocephalus caused by subarachnoid hemorrhage and thrombin.

AIMS: We have found that hydrocephalus development in spontaneously hypertensive rats was associated with activation of epiplexus cells. The current study examined whether epiplexus cell activation occurs in a rat subarachnoid hemorrhage (SAH), whether activation would be greater in a subset of rats that developed hydrocephalus and the potential role of thrombin in epiplexus cell activation. METHODS: There were two parts in this study. First, an endovascular perforation was performed in rats to induce SAH. Second, rats received an intraventricular infusion of either thrombin or saline. Magnetic resonance imaging was used to measure the ventricular volumes. Immunofluorescence and immunohistochemistry were used to study epiplexus cell activation. RESULTS: Iba-1, OX-6, and CD68 were expressed in the epiplexus cells of the choroid plexus in sham-operated rats. SAH increased Iba-1 and CD68 immunoreactivity in epiplexus cells in addition to an increase in Iba-1-positive cell soma size. Those effects were greater in rats that developed hydrocephalus. Intraventricular thrombin mimicked the effects of SAH on epiplexus cell activation and hydrocephalus. CONCLUSION: This study supports the concept that epiplexus cell activation is associated with hydrocephalus development. Epiplexus cell activation may be in response to thrombin production after hemorrhage, and it may be a therapeutic target.

Single Versus Double Burr Hole Craniostomy in Surgical Treatment of Chronic Subdural Hematoma: A Meta-Analysis.

BACKGROUND: Chronic subdural hematoma (cSDH) is one of the most common illnesses seen in neurosurgery departments worldwide. For surgical treatment, some neurosurgeons prefer single burr hole craniostomy (SBHC), whereas others prefer double burr hole craniostomy (DBHC). We performed a meta-analysis to investigate whether DBHC is associated with increased risks of recurrence, complications and mortality compared with SBHC in patients with cSDH. METHODS: Retrospective observational trial or randomized controlled trial (RCT) studies concerning burr hole craniostomy to treat cSDH were systematically identified through a search of electronic databases: PubMed, Web of Science, Embase, and Cochrane. Inclusion and exclusion criteria were defined for the eligible studies. The random fixed-effects model was used when heterogeneity was indicated; otherwise, a fixed-effects model was adopted. RESULTS: This meta-analysis included 12 studies, 3 of which were RCTs. Our findings can be summarized as follows. First, SBHC did not increase the risk of recurrence compared with DBHC in patients with cSDH (odds ratio [OR], 1.28; 95% confidence interval [CI], 0.92-1.78; P =0.07). Second, DBHC was not associated with an increased complication rate compared with SBHC in patients with cSDH (OR, 0.74; 95% CI, 0.20-2.76; P = 0.11). Third, DBHC did not increase mortality compared with SBHC in patients with cSDH (OR, 1.38; 95% CI, 0.55-3.46; P = 0.58). CONCLUSIONS: This meta-analysis demonstrates that there are no significant differences in recurrence rate, complication rate, and morbidity between SBHC and DBHC in the treatment of patients with cSDH.

Calcium-sensing receptor antagonist NPS2390 attenuates neuronal apoptosis though intrinsic pathway following traumatic brain injury in rats.

Traumatic brain injury (TBI) initiates a complex cascade of neurochemical and signaling changes that leads to neuronal apoptosis, which contributes to poor outcomes for patients with TBI. Previous study indicates that calcium-sensing receptor (CaSR) activation contributes to neuron death in focal cerebral ischemia-reperfusion mice, however, its role in neuronal apoptosis after TBI is not well-established. Using a controlled cortical impact model in rats, the present study was designed to determine the effect of CaSR inhibitor NPS2390 upon neuronal apoptosis after TBI. Rats were randomly distributed into three groups undergoing the sham surgery or TBI procedure, and NPS2390 (1.5 mg/kg) was infused subcutaneously at 30 min and 120 min after TBI. All rats were sacrificed at 24 h after TBI. Our data indicated that NPS2390 significantly reduced the brain edema and improved the neurological function after TBI. In addition, NPS2390 decreased caspase-3 levels and the number of apoptotic neurons. Furthermore, NPS2390 up-regulated anti-apoptotic protein Bcl-2 expression and down-regulated pro-apoptotic protein Bax, and reduced subsequent release of cytochrome c into the cytosol. In summary, this study indicated that inhibition of CaSR by NPS2390 attenuates neuronal apoptosis after TBI, in part, through modulating intrinsic apoptotic pathway.

The Comparison Between Surgical Procedure and Conservative Treatment in the Management of Traumatic Subdural Effusion.

AIM: Traumatic subdural effusion (TSE) occurs following traumatic brain injury and may be treated by either conservative methods or surgical procedure commonly according to the patients' clinical information. We aimed to compare the effective rate of effusion removal and the standardized morbidity ratio of poor prognosis of the two different treatments, and to discuss the future treatment methods possible. MATERIAL AND METHODS: We reviewed the clinical records of patients who were divided into two groups according to the treatment choices in our center, and the effective rate of effusion removal and the standardized morbidity ratio of poor prognosis were compared. RESULTS: Eighty patients were identified, and divided into two groups: conservative treatment and surgical procedure group. The mean CRASH-CT predicted risk of mortality in two weeks and unfavorable outcome at six months was higher in the surgical procedure group compared with the conservative treatment group. Effective rate of effusion removal was observed in 57.1 % of conservative treatment group versus 88.5% of surgical procedure group (p=0.002). The standardized morbidity ratio of poor prognosis (observed/expected poor prognosis) was 0.56 (95 % CI: 0.32-0.80) for the conservative treatment group versus 0.25 (95 % CI: 18 0.08-0.42) for the surgical procedure group. CONCLUSION: Conservative treatment and surgical procedure are used for the management of traumatic subdural effusion, and the former is used more commonly to treat the mildly affected patients than the latter one, but a surgical procedure may be more effective for the patients in poor clinical condition. Adequate evidence is required to clear the indications.

Clinical characteristics of 15 cases of chronic subdural hematomas due to spontaneous intracranial hypotension with spinal cerebrospinal fluid leak.

The etiology of chronic subdural hematoma (CSDH) in patients is diverse. The primary objective of this article was to discuss one of the causes, spontaneous intracranial hypotension with spinal cerebrospinal fluid (CSF) leak, which is usually neglected by the neurosurgeon. All the consecutive 15 patients who underwent operation for CSDHs between June 2012 and June 2014 at Sir Run Run Shaw Hospital of Zhejiang University were included in this retrospective cohort study. The clinical and imaging data of these patients with CSDHs due to spinal CSF leak were retrospectively studied. Fifteen patients, with a mean age of 53.8 ± 8.3 years, underwent operations for CSDH. Hematomas were unilateral in 4 patients and bilateral in 11 patients. Among these patients, eight patients had recurrence of hematomas after operation due to neglect of spinal CSF leak. All patients had fully recovery. Spinal CSF leak is a cause of cSDH, which is overlooked by the doctor.

Norcantharidin blocks Wnt/ß-catenin signaling via promoter demethylation of WIF-1 in glioma.

Glioma is one of the most common primary intracranial tumors, and the prognosis is poor even though much treatment management is employed. Wnt/ß-catenin signaling has been reported to be associated with glioma. Norcantharidin (NCTD) is the demethylated analog of cantharidin isolated from blister beetles, and it is reported to possess anticancer activity but less nephrotoxicity than cantharidin. Accordingly, we aimed to investigate NCTD as an anti-neoplastic drug that inhibits the Wnt/ß­catenin pathway via promoter demethylation of Wnt inhibitory factor-1 (WIF-1) in glioma growth in vitro. In the present study, we report that NCTD inhibited cell proliferation, induced apoptosis and cell cycle arrest, and suppressed cell migration and invasion in vitro. Moreover, we observed that the expression levels of WIF-1 mRNA and protein in the NCTD-treated cells were increased significantly compared with these levels in the negative control (NC) cells. Promoter demethylation was observed in the NCTD­treated cells. In contrast, aberrant methylation was observed in the NC cells. Additionally, more investigation revealed that NCTD suppressed activity of Wnt/ß-catenin signaling and transcription of ß-catenin/TCF-4. Furthermore, the expression of apoptosis-related proteins Bcl-2 and cleaved caspase-3 indicated significant cell apoptosis. We provide initial evidence that NCTD reactivates WIF-1 from a methylation state, and downregulates canonical Wnt/ß-catenin signaling. Our findings revealed that NCTD is effective for glioma in vitro and may be a new therapeutic option in vivo.

Neuroendocrine dysfunction and insomniain in mild traumatic brain injury patients.

Mild traumatic brain injury (mTBI) has been a growing public health concern in the worldwide. To investigate the subjective and objective characteristics of insomnia following mTBI and the association between insomnia and hypothalamic-pituitary-adrenal (HPA) function of mTBI patients, 59 patients with mTBI (mTBI group) were compared with 50 healthy participants (control group) in the present study. The subjective and objective measures of insomnia were respectively obtained from Pittsburgh Sleep Quality (PSQI) and polysomnography (PSG). HPA function was measured with low-dose short synacthen test (LDSST). According to the comparative and correlation analysis of the two groups, for PSQI, the scores of sleep syndrome, sleep latency, sleep efficiency, overall sleep quality and daytime dysfunction of mTBI patients were all higher, however only sleep efficiency and daytime dysfunction of mTBI patients were related with peak cortisol on lDSST; while for PSG, sleep efficiency (SE) was lower and wake after sleep onset (WASO) was longer in mTBI patients, moreover SE and WASO of mTBI patients were correlated with peak cortisol on LDSTT; for HPA function indexes, only peak cortisol on LDSST was lower in mTBI patients. These findings suggested that mTBI patients experienced more serious subjective insomnia symptoms than objective measurement, which were associated with HPA dysfunction. This study may contribute to identifying better treatment for mTBI patients with insomnia.

Effect of CDKN2A/B rs4977756 polymorphism on glioma risk: a meta-analysis of 16 studies including 24077 participants.

So far, epidemiological studies have been performed to investigate the association of CDKN2A/B rs4977756 polymorphism and glioma risk. However, the results from different studies remain inconsistent. To clarify these conflicts and to quantitatively evaluate the effect of rs4977756 polymorphism on glioma risk, a meta-analysis was conducted using relevant published clinical studies about rs4977756 polymorphisms and glioma risk. Relevant studies concerning the association between rs4977756 polymorphism and risk of glioma were included in this meta-analysis. Odds ratio (OR) and 95 % confidence interval (CI) were calculated under fixed or random effects models when appropriate. Subgroup analyses were performed by race. This meta-analysis included 13 studies with a total of 8129 cases and 15,858 controls. The pooled results showed that there was an obvious association of CDKN2A/B rs4977756 polymorphism with risk of glioma in all four comparison models (dominant model/AG + GG vs. AA: OR = 1.36, 95 %CI = 1.20-1.54, p < 0.01; heterozygote comparison/AG vs. AA: OR = 1.31, 95 %CI = 1.12-1.53, p < 0.01; homozygote comparison/GG versus AA: OR = 1.49, 95 %CI = 1.36-1.64, p < 0.01; additive model/G vs. A: OR = 1.23, 95 %CI = 1.18-1.28, p < 0.01, respectively). For the subgroup analyses of ethnicities, similar results were observed in Caucasians. However, the association was not found between rs4977756 polymorphism and the risk of glioma in all models for the Asian studies. The CDKN2A/B rs4977756 polymorphism is obvious increase the risk of glioma in Caucasians. Future studies are needed to confirm the results in other ethnic populations.