γ-secretase inhibitors, DAPT and RO4929097, promote the migration of Human Glioma Cells via Smad5-downregulated E-cadherin Expression.

Malignant gliomas are a type of central nervous system cancer with extremely high mortality rates in humans. γ-secretase has been becoming a potential target for cancer therapy, including glioma, because of the involvement of its enzymatic activity in regulating the proliferation and metastasis of cancer cells. In this study, we attempted to determine whether γ-secretase activity regulates E-cadherin to affect glioma cell migration. The human glioma cell lines, including LN18 and LN229, and the γ-secretase inhibitors, including N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) and RO4929097, were used in this study. It was shown that γ-secretase activity inhibition by DAPT and RO4929097 could promote LN18 and LN229 glioma cell migration via downregulating E-cadherin mRNA and protein expressions, but not via affecting E-cadherin protein processing. In addition, γ-secretase activity inhibition was regulated by bone morphogenetic proteins-independent Smad5 activation in glioma cells. Moreover, endogenous Smad1 in glioma cells was found to play an important role in regulating E-cadherin expression and subsequent cell migration but did not affect DAPT-stimulated effects. These results help further elucidate the molecular mechanisms of γ-secretase activity regulation involved in controlling glioma cell malignancy. Information about a potential role for Smad1/5 activity upregulation and subsequent E-cadherin downregulation during inhibition of γ-secretase activity in the development of gliomas is therefore relevant for future research.

The risk of cardiac mortality in patients with status epilepticus: A 10-year study using data from the Centers for Disease Control and Prevention (CDC).

OBJECTIVE: To explore whether status epilepticus affected cardiac mortality. METHODS: We used the 2008-2017 multicause mortality data of the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiological Research. The status epilepticus group included patients whose death certificates mentioned status epilepticus as contributing to death. The non-status epilepticus group included patients whose death certificates mentioned epilepsy, other and unspecified convulsions, febrile convulsions, or post-traumatic seizures, as contributing to death. The outcomes for evaluation were death certificates that indicated that myocardial infarction, arrhythmia, heart failure, or cardiac arrest (CA) was the immediate cause of death. The numbers of deaths and population sizes by categorical demographics were recorded and subjected to multiple logistic regression analysis. RESULTS: Among the 14,487 death certificates in status epilepticus group; 3080 patients (21.3%) died of CA. When clinical records were compared to autopsy data, females were at a lower risk of myocardial infarction (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.51-0.61). Patients aged 45-65 years and older than 65 years were at a higher risk of developing all four cardiac complications. Status epilepticus was associated with higher risks of arrhythmia (OR: 1.55, 95% CI: 1.11-2.15) and CA (OR: 4.34, 95% CI: 3.49-5.39) but a reduced risk of myocardial infarction (OR: 0.42, 95% CI: 0.30-0.57) as the cause of immediate death. CONCLUSION: The frequency of CA in patients with status epilepticus increased between 2008 and 2017. Male and elderly patients were at a higher risk of cardiogenic mortality.

Risk of Cardiac Morbidities and Sudden Death in Patients With Epilepsy and No History of Cardiac Disease: A Population-Based Nationwide Study.

OBJECTIVE: To investigate the impact of epilepsy on secondary cardiac morbidities and sudden death in patients with epilepsy. PATIENTS AND METHODS: The present cohort study evaluated data obtained from a subset of adult patients listed in the Taiwan National Health Insurance Research Database with an International Classification of Diseases, Ninth Revision, diagnosis code of epilepsy from January 1, 1997, to December 31, 2013; the date of epilepsy diagnosis or antiepilepsy drug prescription was defined as the index date. Patients with cardiac disease prior to the index date were excluded, and the remaining patients were categorized into epilepsy and nonepilepsy groups. Frequency matching was performed to balance the covariates across groups for the comparison of outcomes. The development of myocardial infarction (MI) and arrhythmia and/or the occurrence of sudden death were the outcomes for evaluation. A Cox proportional hazards regression model and competing risk analysis were used to compare the risks of cardiac morbidities and sudden death between groups. RESULTS: The final analysis included a total of 5411 patients with epilepsy and 21,644 participants without epilepsy. The epilepsy group had significantly higher risks for development of MI (hazard ratio [HR], 1.71; 95% CI, 1.62 to 1.81; P<.001) and arrhythmia (HR, 2.11; 95% CI, 1.97 to 2.25; P<.001) and the occurrence of sudden death (HR, 1.83; 95% CI, 1.53 to 2.18; P<.001) compared with the nonepilepsy group. CONCLUSION: Our results indicate that the risks for development of MI and arrhythmia and the occurrence of sudden death were higher in patients with epilepsy. These findings support the hypothesis that epilepsy may lead to secondary cardiac dysfunction and increases the risk of sudden death.

Effect of valproic acid on overall survival in patients with high-grade gliomas undergoing temozolomide: A nationwide population-based cohort study in Taiwan.

High-grade gliomas (HGGs) are a rapidly progressive and highly recurrent group of primary brain tumors. Despite aggressive surgical resection with chemoradiotherapy, prognoses remained poor. Valproic acid (VPA), a histone deacetylase inhibitor has shown the potential to inhibit glioma cell growth in vitro through several diverse mechanisms. However clinical studies regarding the effect of VPA on HGGs are limited. This study aimed to investigate whether using VPA in patients with HGGs under temozolomide (TMZ) would lead to a better overall survival (OS).We used the Taiwan National Health Insurance Research database to conduct this population-based cohort study. A total of 2379 patients with HGGs under TMZ treatment were included and were further classified into VPA (n = 1212, VPA ≥ 84 defined daily dose [DDD]) and non-VPA (n = 1167, VPA < 84 DDD) groups. Each patient was followed from 1998 to 2013 or until death. A Cox proportional hazard regression was performed to evaluate the effect of VPA and OS.The VPA group had a longer mean OS time compared with the non-VPA group (OS: 50.3 ±â€Š41.0 vs 42.0 ±â€Š37.2 months, P < .001). In patients between 18 and 40 years old, the difference is most significant (OS: 70.5 ±â€Š48.7 vs 55.1 ±â€Š46.0, P = .001). The adjusted hazard ratio is 0.81 (95% confidence interval, 0.72-0.91) for the VPA group relative to the non-VPA group.VPA at over 84 DDD improved OS in HGGs TMZ treatment.

Intracranial aneurysms formation after radiotherapy for head and neck cancer: a 10-year nationwide follow-up study.

BACKGROUND: Intracranial aneurysms after radiotherapy (RT) have previously been reported. However, the majority of studies were case reports. Therefore, we performed a nationwide study to explore the risk of radiation-induced intracranial aneurysms. METHODS: This study included patients diagnosed with head and neck cancer (ICD9: 140-149, 161). Intracranial aneurysms formation was identified using the following ICD9 codes: nonruptured cerebral aneurysm (ICD9:4373), aneurysm clipping (ICD9:3951). Patients who did not receive curative treatment and those with intracranial aneurysms before the diagnosis of head and neck cancer were excluded. RESULTS: In total, 70,691 patients were included in the final analysis; they were categorized into the following three groups: nasopharyngeal carcinoma (NPC) with RT, non-NPC with RT, and non-NPC without RT. Patients in the NPC with RT group had the highest risk of developing intracranial aneurysms (hazard ratio (HR) 2.57; P <  0.001). In addition, hypertension was also a risk factor of developing intracranial aneurysms (HR 2.14; P <  0.01). The mean time interval from cancer diagnosis to intracranial aneurysm formation in the NPC with RT group was 4.3 ± 3.1 years. CONCLUSIONS: Compared with the non-NPC with RT and the non-NPC without RT groups, patients with NPC who received RT had a higher risk of developing intracranial aneurysms.

Evaluation of Cardiac Complications Following Hemorrhagic Stroke Using 5-Year Centers for Disease Control and Prevention (CDC) Database.

Literature regarding cardiac deaths in hemorrhagic stroke patients is few. The aim of this study was to investigate the incidence and risk factors of cardiac death in hemorrhagic stroke patients. We used the multiple causes of death database from the Centers for Disease Control and Prevention Wide-ranging Online Data of the United States. We identified death certificates from 2006 to 2010 with hemorrhagic stroke (International Classification of Disease, Tenth Revision (ICD-10) code I60-62), or ischemic stroke (ICD-10 code I63), and evaluated the frequency and risk factors of reporting MI (ICD-10 code I20-25) or arrhythmias (ICD-10 code I44-45, I47-49) as the main cause of death in these populations. Over the five-year period, 224,359 death certificates that mentioned hemorrhagic stroke were identified, and the cause of death was MI in 8.95% and arrhythmia in 7.28% patients. With autopsy confirmation, the incidences of MI and arrhythmias in the hemorrhagic stroke group were still lower than the ischemic group. The odds ratio of reporting arrhythmias as a cause of death in hospitalized population was higher. A substantial percentage of hemorrhagic stroke patients had cardiac death. Greater efforts are needed to closely monitor high-risk groups such as females and the elderly.

Cell Subpopulations Overexpressing p75NTR Have Tumor-initiating Properties in the C6 Glioma Cell Line.

BACKGROUND/AIM: Glioma is the most common and lethal primary brain tumor. Even with the development of multidisciplinary treatment approaches, results are disappointing because of the unavoidable tumor recurrence, which may be caused by the existence of tumor-initiating cells. The p75 neurotrophin receptor (p75NTR), which belongs to the tumor necrosis factor receptor superfamily, is not only involved in various cellular functions but also related to tumor growth. This study is focused, on the possible role of p75NTR in glioma tumor initiation. MATERIALS AND METHODS: C6 cells with high and low expression of p75NTR were sorted using flow cytometry. The neurosphere characteristics and properties of these two subpopulations were assessed and compared with those of parental cells. Radiation and chemotherapy sensitivity was also analyzed in these cell populations. Finally, in vivo tumorigenicity of cells was tested in a rat model. RESULTS: Cells overexpressing p75NTR (C6p75+++ cells) demonstrated greater ability of neurosphere formation, colony proliferation, and certain stem cell marker overexpression than cells with low p75NTR expression (C6p75+) and parental cells. In addition, following irradiation or temozolomide treatment, more viable C6p75+++ cells remained, and they proliferated into more colonies. In vivo, C6p75+++ cell implantation in Sprague Dawley rats reduced the survival time. CONCLUSION: Cells with p75NTR overexpression demonstrated certain unique characteristics of tumor-initiating cells, such as neurosphere formation, high colony proliferation, and resistance to radio- and chemotherapy. With regard to the heterogeneous composition of glioma cells, p75NTR can be used as an alternative marker to identify a glioma subpopulation with tumor-initiating properties.

Fusion Techniques Are Related to a Lower Risk of Reoperation in Lumbar Disc Herniation: A 5-Year Observation Study of a Nationwide Cohort in Taiwan.

OBJECTIVE: Lumbar disc herniation (LDH) is a common spinal problem, with reoperation rates of 6%-24%. Although different surgical techniques are used for treatment, there is still debate regarding whether fusion techniques can reduce the reoperation rate in patients with LDH. METHODS: This retrospective study used a 5-year nationwide database to analyze reoperation rates in Taiwan. Patient age groups (≥20 and <90 years) treated by index surgery and reoperation for LDH were identified. Four surgical procedures were included in the analysis: discectomy (DC), anterior lumbar fusion with DC (FA + DC), posterior lumbar fusion (FP), and posterior lumbar fusion with DC (FP + DC). RESULTS: There were 1743 index surgeries between 2008 and 2012, with 184 (10.56%) reoperations. Index surgery DC had the highest reoperation rate (n = 121, 20%). The reoperation risk was significantly lower for patients undergoing fusion procedures (FA + DC vs. DC [hazard ratio (HR), 0.24; 95% confidence interval (CI), 0.12-0.47; P < 0.01], FP versus DC [HR, 0.17; 95% C, 0.09-0.33; P <0.01], FP + DC versus DC [HR, 0.31; 95% CI, 0.22-0.44; P < 0.01]). Fusion procedures had significantly higher treatment costs compared with DC (FA + DC vs. FP vs. FP + DC vs. DC: 5851.74 ± 4808.94 vs. 5116.88 ± 3428.97 vs. 4782.16 ± 2902.19 vs. 3846.79 ± 3584.45 U.S. dollars/patient, respectively; P < 0.0001). CONCLUSIONS: Among surgical procedures for LDH, fusion techniques are related to lower reoperation rates compared with discectomy, but at the expense of higher medical costs.

Percutaneous dorsal root ganglion block for treating lumbar compression fracture-related pain.

BACKGROUND: The pain of acute compression fracture in the lumbar spine may be refractory to conservative treatment, and surgery is not an optimal choice for the elderly or infirm individuals. Moreover, even vertebroplasty can cause many side effects such as chemical leak, adjacent segment instability, and residual pain. Percutaneous dorsal root ganglion block (PDRGB) possibly is an alternative therapeutic option. In this study, we evaluated the efficacy of pain relief and the rate of adjacent level compression fracture in patients with acute compression fracture of the lumbar spine. METHODS: We retrospectively reviewed 40 patients with lumbar compression fracture from 2013 to 2015. The patients were treated with navigation-assisted CT-guided PDRGB with steroid at the pathological level and at the adjacent level above and below. Therapeutic response was evaluated using the Numerical Rating Scale (NRS); and an optimal, acceptable, and unfavorable outcome were analyzed. RESULTS: Among the 40 patients treated, initial pain relief on the first day was dramatic, and the average NRS did not change significantly up to the first-year follow-up. The highest percentage of a good outcome, at 90% (37.5% with an optimal outcome, 52.5% with an acceptable outcome), was reported at 1 week postoperatively. The percentage of optimal outcomes increased even at the 1-year follow-up. No adjacent compression fracture was found in the group treated with PDRGB alone at the 1-year follow-up. CONCLUSIONS: PDRGB is a simple, safe, and minimally invasive procedure that showed immediate and prolonged improvement of pain in lumbar osteoporotic compression fracture patients who failed conservative treatment or had residual pain after vertebroplasty. However, continuous medication for osteoporosis was still required.

Rapid M1 Hemoclips Arteriotomy Repair After Emergency Coil Embolectomy.

BACKGROUND: The vascular closure staple clips have been studied in animal models and shown to have comparable results with sutured repair when it comes to the healing process, degree of vessel narrowing, and risk of thrombosis. However, they are clearly superior when the speed of application is taken into account, and they were clinically used in many vascular repair processes. Nevertheless, their usefulness in intracranial vascular surgery has not been described. OBJECTIVE: To describe the usefulness of hemoclips in fast and efficient repair of medium-sized and large intracranial vessels. METHODS: Two female patients diagnosed with giant symptomatic cavernous sinus aneurysms were undergoing elective endovascular procedures that were complicated by the dislodgement of coils into the M1 segment of the middle cerebral artery. Both patients were treated performing M1 arteriotomies and coil embolectomy. To avoid prolonged temporary occlusion in the M1 perforator's territory, the arteriotomies were repaired using microhemoclips in less than 10 min with re-establishment of flow. RESULTS: In both patients, flow was re-established in the M1 segments. In 1 patient, the coils extended to the temporal M2 causing intimal injury and leading to diminished flow. M1 segments in both patients were patent on later angiographic studies. CONCLUSION: We describe the advantage of emergent cerebrovascular arteriotomy and embolectomy in a rapid repair process that helped avoid massive ischemic injury. We believe this technique should be added to the armamentarium of neurosurgical cerebrovascular options.

Biocompatible Amniotic Sac Implant Maintains a Scar-Free Brain Surface During Recurrent Glioma Surgery.

BACKGROUND: Dissection of brain surface adhesions during recurrent glioma surgery carries a risk of injury to cortical vessels and important surface vessels. We present our experience with the use of BioD film, a biocompatible amniotic membrane implant, to help prevent postoperative adhesions. We describe a novel method for preventing postoperative adhesions after high-grade glioma surgery using BioD film. METHODS: Amniotic sac implants were laid on the brain surface after resection of gliomas located near major surface arteries (sylvian fissure) and major veins (parasagittal convexity). Seven cases involved reoperation for tumor recurrence. RESULTS: In all 7 of the cases requiring reoperation, a new arachnoid-like surface layer was formed without any dural adhesions. The newly formed layer allowed for easy and simple dissection and mobilization of surface vessels while avoiding any trauma to the cortex. CONCLUSIONS: Amniotic sac implants have a promising role in preventing most surgical brain adhesions associated with recurrent glioma surgery, reducing the risks of cortical vessel and tissue injury.

Salvage of postcranioplasty implant exposure using free tissue transfer.

BACKGROUND: Refractory implant exposure is frustrating after cranioplasty. The purpose of this study was for the authors to present their experience with free tissue transfer for salvage of postcranioplasty implant exposure. METHODS: A retrospective medical chart review was conducted on all free tissue transfers performed for exposed implant coverage after cranioplasty between January 2004 and February 2016. RESULTS: Twelve free flaps were performed in 11 patients who underwent postcranioplasty with implant exposure, and whose attempted implant coverage using locoregional flaps had failed. The free flaps used included anterolateral thigh flap, radial forearm flap, anteromedial thigh and rectus femoris chimeric flap, latissimus dorsi flap, gracilis flap, and Juri flap. The flap survival rate was 100%, and 10 of 11 implants (91%) were salvaged without removal. CONCLUSIONS: Free tissue transfer should be considered as the preferred reconstructive option for postcranioplasty exposed implant salvage. High rate of implant salvage (>90%) is possible even with chronic implant exposure (>3 months).

Endocrine dysfunction following traumatic brain injury: a 5-year follow-up nationwide-based study.

Post-traumatic endocrine dysfunction is a complication of traumatic brain injury (TBI). However, there is lack of long-term follow-up and large sample size studies. This study included patients suffering from TBI registered in the Health Insurance Database. Endocrine disorders were identified using the ICD codes: 244 (acquired hypothyroidism), 253 (pituitary dysfunction), 255 (disorders of the adrenal glands), 258 (polyglandular dysfunction), and 259 (other endocrine disorders) with at least three outpatient visits within 1 year or one admission diagnosis. Overall, 156,945 insured subjects were included in the final analysis. The 1- and 5-year incidence rates of post-traumatic endocrinopathies were 0.4% and 2%, respectively. The risks of developing a common endocrinopathy (p < 0.001) or pituitary dysfunction (P < 0.001) were significantly higher in patients with a TBI history. Patients with a skull bone fracture had a higher risk of developing pituitary dysfunction at the 1-year follow up (p value < 0.001). At the 5-year follow up, the association between intracranial hemorrhage and pituitary dysfunction (p value: 0.002) was significant. The risk of developing endocrine dysfunction after TBI increased during the entire 5-year follow-up period. Skull bone fracture and intracranial hemorrhage may be associated with short and long-term post-traumatic pituitary dysfunction, respectively.

Characterization of highly proliferative secondary tumor clusters along host blood vessels in malignant glioma.

The aim of the present study was to investigate the extensive invasion of tumor cells into normal brain tissue, a life­threatening feature of malignant gliomas. How invasive tumor cells migrate into normal brain tissue and form a secondary tumor structure remains to be elucidated. In the present study, the morphological and phenotypic changes of glioma cells during invasion in a C6 glioma model were investigated. C6 glioma cells were stereotactically injected into the right putamen region of adult Sprague­Dawley rats. The brain tissue sections were then subjected to hematoxylin and eosin, immunohistochemical or immunofluorescent staining. High magnification views of the tissue sections revealed that C6 cells formed tumor spheroids following implantation and marked invasion was observed shortly after spheroid formation. In the later stages of invasion, certain tumor cells invaded the perivascular space and formed small tumor clusters. These small tumor clusters exhibited certain common features, including tumor cell multilayers surrounding an arteriole, which occurred up to several millimeters away from the primary tumor mass; a high proliferation rate; and similar gene expression profiles to the primary tumor. In conclusion, the present study revealed that invading tumor cells are capable of forming highly proliferative cell clusters along arterioles near the tumor margin, which may be a possible cause of the recurrence of malignant glioma.

Edge promoted ultrasensitive electrochemical detection of organic bio-molecules on epitaxial graphene nanowalls.

We report the simultaneous electrochemical detection of dopamine (DA), uric acid (UA) and ascorbic acid (AA) on three dimensional (3D) unmodified 'as-grown' epitaxial graphene nanowall arrays (EGNWs). The 3D few layer EGNWs, unlike the 2D planar graphene, offers an abundance of vertically oriented nano-graphitic-edges that exhibit fast electron-transfer kinetics and high electroactive surface area to geometrical area (EAA/GA≈134%), as evident from the Fe(CN)6(3-/4-) redox kinetic study. The hexagonal sp(2)-C domains, on the basal plane of the EGNWs, facilitate efficient adsorption via spontaneous π-π interaction with the aromatic rings in DA and UA. Such affinity together with the fast electron kinetics enables simultaneous and unambiguous identification of individual AA, DA and UA from their mixture. The unique edge dominant EGNWs result in an unprecedented low limit of detection (experimental) of 0.033 nM and highest sensitivity of 476.2 µA/µM/cm(2), for UA, which are orders of magnitude higher than comparable existing reports. A reaction kinetics based modeling of the edge-oriented 3D EGNW system is proposed to illustrate the superior electro-activity for bio-sensing applications.

Comparison of surface markers between human and rabbit mesenchymal stem cells.

This study investigated whether there are marked differences in surface markers between rabbit and human mesenchymal stem cells (MSCs). Murine and rabbit MSCs have been reported to be CD90-negative. Rat MSCs have been reported to be CD71-negative. Our previous study also shows that rabbit MSCs are CD29-negative. However, human MSCs are generally considered to be CD29-, CD71-, and CD90-positive. Therefore, the surface markers of human MSCs might differ from those of other species. Rabbit bone marrow MSCs were obtained that had a multi-differentiation potential. The phenotype of these cells was studied using flow cytometry antibodies for 25 rabbit surface markers, namely, CD13, CD14, CD29, CD31, CD34, CD44, CD45, CD49d, CD49f, CD51, CD54, CD59, CD71, CD73, CD90, CD105, CD106, CD133, CD166, MHC I, MHC II, α-smooth muscle actin (α-SMA), cytokeratin, desmin, and vimentin. The phenotype of commercially available human MSCs was similarly studied using antibodies for human surface markers. CD14, CD31, CD34, CD45, CD49d, CD49f, CD51, CD54, CD71, CD106, CD133, MHC II, and cytokeratin were absent from both rabbit and human MSCs, while CD44, α-SMA, and vimentin were present on both cell lines. CD13, CD29, CD59, CD73, CD90, CD105, CD166, and MHC I were present on human MSCs, but not on rabbit MSCs. However, desmin was present on rabbit MSCs, but not on human MSCs. In total, the surface expression of nine markers differed between human and rabbit MSCs, whereas the surface expression of 16 markers was the same in the two cell lines.

Band gap engineering of chemical vapor deposited graphene by in situ BN doping.

Band gap opening and engineering is one of the high priority goals in the development of graphene electronics. Here, we report on the opening and scaling of band gap in BN doped graphene (BNG) films grown by low-pressure chemical vapor deposition method. High resolution transmission electron microscopy is employed to resolve the graphene and h-BN domain formation in great detail. X-ray photoelectron, micro-Raman, and UV-vis spectroscopy studies revealed a distinct structural and phase evolution in BNG films at low BN concentration. Synchrotron radiation based XAS-XES measurements concluded a gap opening in BNG films, which is also confirmed by field effect transistor measurements. For the first time, a significant band gap as high as 600 meV is observed for low BN concentrations and is attributed to the opening of the π-π* band gap of graphene due to isoelectronic BN doping. As-grown films exhibit structural evolution from homogeneously dispersed small BN clusters to large sized BN domains with embedded diminutive graphene domains. The evolution is described in terms of competitive growth among h-BN and graphene domains with increasing BN concentration. The present results pave way for the development of band gap engineered BN doped graphene-based devices.

Pial arteriovenous fistula: a review of literature.

Pial arteriovenous fistula (AVF) is a rare vascular lesion, with less than 120 reported cases in the English literatures (Hoh et al., Neurosurgery 2001;49(6):1351). The angio-architecture, clinical course and therapeutic options are all different from arteriovenous malformation (AVM), dural AVM or other intracranial vascular lesions. A review of literatures to analyse the clinical course of pial AVF was carried out. The presence of varix dictates the clinical course and presentation. Paediatric type had high percentage of varix, and mass effect as clinical presentation while the adult type usually manifest by haemorrhage. Disconnection of direct shunting, either by endovascular or surgically, is sufficient to achieve successful treatment; therefore, total resection of the lesion is unnecessary.