CLEC19A overexpression inhibits tumor cell proliferation/migration and promotes apoptosis concomitant suppression of PI3K/AKT/NF-κB signaling pathway in glioblastoma multiforme.

BACKGROUND: GBM is the most frequent malignant primary brain tumor in humans. The CLEC19A is a member of the C-type lectin family, which has a high expression in brain tissue. Herein, we sought to carry out an in-depth analysis to pinpoint the role of CLEC19A expression in GBM. METHODS: To determine the localization of CLEC19A, this protein was detected using Western blot, Immunocytochemistry/Immunofluorescence, and confocal microscopy imaging. CLEC19A expression in glioma cells and tissues was evaluated by qRT-PCR. Cell viability, proliferation, migration, and apoptosis were examined through MTT assay, CFSE assay, colony formation, wound healing assay, transwell test, and flow cytometry respectively after CLEC19A overexpression. The effect of CLEC19A overexpression on the PI3K/AKT/NF-κB signaling pathway was investigated using Western blot. An in vivo experiment substantiated the in vitro results using the glioblastoma rat models. RESULTS: Our in-silico analysis using TCGA data and measuring CLEC19A expression level by qRT-PCR determined significantly lower expression of CLEC19A in human glioma tissues compared to healthy brain tissues. By employment of ICC/IF, confocal microscopy imaging, and Western blot we could show that CLEC19A is plausibly a secreted protein. Results obtained from several in vitro readouts showed that CLEC19A overexpression in U87 and C6 glioma cell lines is associated with the inhibition of cell proliferation, viability, and migration. Further, qRT-PCR and Western blot analysis showed CLEC19A overexpression could reduce the expression levels of PI3K, VEGFα, MMP2, and NF-κB and increase PTEN, TIMP3, RECK, and PDCD4 expression levels in glioma cell lines. Furthermore, flow cytometry results revealed that CLEC19A overexpression was associated with significant cell cycle arrest and promotion of apoptosis in glioma cell lines. Interestingly, using a glioma rat model we could substantiate that CLEC19A overexpression suppresses glioma tumor growth. CONCLUSIONS: To our knowledge, this is the first report providing in-silico, molecular, cellular, and in vivo evidences on the role of CLEC19A as a putative tumor suppressor gene in GBM. These results enhance our understanding of the role of CLEC19A in glioma and warrant further exploration of CLEC19A as a potential therapeutic target for GBM.

An application of dynamical directed connectivity of ictal intracranial EEG recordings in seizure onset zone localization.

BACKGROUND: Identification of the seizure onset zone (SOZ) is a challenging task in epilepsy surgery. Patients with epilepsy have an altered brain network, allowing connectivity-based analyses to have a great potential in SOZ identification. We investigated a dynamical directed connectivity analysis utilizing ictal intracranial electroencephalographic (iEEG) recordings and proposed an algorithm for SOZ identification based on grouping iEEG contacts. NEW METHODS: Granger Causality was used for directed connectivity analysis in this study. The intracranial contacts were grouped into visually detected contacts (VDCs), which were identified as SOZ by epileptologists, and non-resected contacts (NRCs). The intragroup and intergroup directed connectivity for VDCs and NRCs were calculated around seizure onset. We then proposed an algorithm for SOZ identification based on the cross-correlation of intragroup outflow and inflow of SOZ candidate contacts. RESULTS: Our results revealed that the intragroup connectivity of VDCs (VDC→VDC) was significantly larger than the intragroup connectivity of NRCs (NRC→NRC) and the intergroup connectivity between NRCs and VDCs (NRC→VDC) around seizure onset. We found that the proposed algorithm had 90.1 % accuracy for SOZ identification in the seizure-free patients. COMPARISON WITH EXISTING METHODS: The existing connectivity-based methods for SOZ identification often use either outflow or inflow. In this study, SOZ contacts were identified by integrating outflow and inflow based on the cross correlation between these two measures. CONCLUSIONS: The proposed group-based dynamical connectivity analysis in this study can aid our understanding of underlying seizure network and may be used to assist in identifying the SOZ contacts before epilepsy surgery.

Boswellia serrata extract shows cognitive benefits in a double-blind, randomized, placebo-controlled pilot clinical trial in individuals who suffered traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability. TBI can result in neuropsychiatric and cognitive problems as well as neurodegenerative pathologies that can appear right after or develop and persist years after injury. METHOD: We conducted a double-blind, randomized, placebo-controlled clinical trial on patients who suffered from TBI three months to three years ago. The patients were randomized to placebo (n = 34) or K-Vie™ group (n = 46) for a treatment period of 3 months. The main primary outcomes include cognitive assessment in the Rey Auditory Verbal Learning Test-Recognition Test (RAVLT), Wechsler adult intelligence Digit Symbol Substitution Test (DSST) and trail-making test part B (TMT-B). Assessments were performed at baseline and at the month 3 follow-up visit. Linear mixed models were carried out to evaluate cognitive changes from baseline across all cognitive assessment tests. RESULT: The current study showed significant (p < 0.05) improvement in cognitive function of patients who were given K-Vie™ compared with placebo across the RAVLT, DSST and TMT-B performance assessments. A larger cohort would be beneficial to further confirm the clinical utility of K-Vie™ and assess its effects in acute phases of TBI.

Placebo-controlled trial of oral amantadine and zolpidem efficacy on the outcome of patients with acute severe traumatic brain injury and diffuse axonal injury.

BACKGROUND: A constituent of diffuse axonal injury (DAI) is supposed to be present in about 1/3 of all severe traumatic brain injury (TBI) as specified by pathologic documents. Diffuse axonal injury is categorized by extensive injury to axons in the brain. A rise in the incidences of TBI, and the limited study to verified effect of drugs like amantadine and zolpidem in improving the consciousness levels of patients with acute traumatic brain injury with axonal injury enthused us to initiate this study in the acute TBI patients. METHODS: In our randomized, controlled trial involving patients with acute severe TBI, we studied 66 patients in 3 groups. Group 1 (n=22) received oral amantadine, Group 2 (n=22) received oral zolpidem, whereas group 3 (n=22) received placebo, the first 8 days after injury respectively. The primary outcome measures included GCS (Glashow coma scale) through the initial admission, a complete medical history was recorded, and each patient had a meticulous physical and neurological investigation. RESULTS: We found that the administration of amantadine in an acute phase after injury improved the rate of patients GCS and GOS (Glasgow Outcome Scale) compared with zolpidem and placebo groups, but without any significant statistical difference. CONCLUSION: Our results has emphasized that because amantadine has intense biochemical effects on several ways, it appears to be beneficial in acute period after DAI-associated TBI.

The phenotypic spectrum of PCDH12 associated disorders - Five new cases and review of the literature.

PCDH12 is a member of the non-clustered protocadherin family of calcium-dependent cell adhesion proteins, which are involved in the regulation of brain development and endothelial adhesion. To date, only 15 families have been reported with PCDH12 associated disease. The main features previously associated with PCDH12 deficiency are developmental delay, movement disorder, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications. Here, we report novel clinical features such as onset of epilepsy after infancy, episodes of transient developmental regression, and dysplasia of the medulla oblongata associated with three different novel truncating PCDH12 mutations in five cases (three children, two adults) from three unrelated families. Interestingly, our data suggests a clinical overlap with interferonopathies, and we show an elevated interferon score in two pediatric patients. This case series expands the genetic and phenotypic spectrum of PCDH12 associated diseases and highlights the broad clinical variability.

The Effect of Oral Simvastatin on the Clinical Outcome of Patients with Severe Traumatic Brain Injury: A Randomized Clinical Trial.

Background: Despite recent promising pharmacological and technological advances in neurosurgical intensive care, the overall TBI-related mortality and morbidity remain high and still pose a major clinical problem. The aim of this study was to evaluate the effect of oral simvastatin on the clinical outcome of patients with severe TBI. Methods: In a double-blind placebo-controlled randomized clinical trial a total of 98 patients with severe TBI in Imam Khomeini Hospital in Sari, Iran, were evaluated. Patients who meet the inclusion criteria were randomly allocated into two groups (n=49). In addition to supportive therapies, the intervention group received oral simvastatin (40 mg, daily) for 10 days, and the control group received the placebo (10 days). Patients' Glasgow coma scale (GCS) score, in hospital mortality, duration of mechanical ventilation and length of ICU and neurosurgery ward stay were evaluated during three-time intervals (T1: admission, T2: discharge and T3: one month after discharge). Results: The percentage of conscious patients was 18.9% (7 cases) in the simvastatin group and 3.1% (1 case) in controls (P=0.06) at T2. One month after discharge (T3) the proportion of conscious patients significantly increased in the simvastatin group compared to control group (64.9 % versus 28.1 %; P=0.002). There was no significant difference for the mean of GCS score between the simvastatin group and control group at T1 (6.41 ± 1.30 versus 6.41 ± 1.28, respectively; P = 0.98). However, the mean score of GCS in patients who received simvastatin was significantly greater than controls at T2 and T3 (p<0.05). There was no significant differences between two group in-terms of length of mechanical ventilation, ICU and neurosurgery ward stay. Conclusion: According to the results of this study it seems that using simvastatin may be an effective and promising therapeutic modality for improving GCS score during TBI recovery.

Idiopathic superficial siderosis of the central nervous system.

BACKGROUND: Regardless of the cause of the superficial siderosis (SS) disease, which is bleeding, the source of bleeding cannot be found in some cases. CASE PRESENTATION: In this article, we report two cases with idiopathic SS. Case 1 presented with bilateral hearing loss, cognitive impairment, sleep disturbances, and tremors. Case 2 presented with sensory neural hearing loss, ataxia, and spastic paraparesis. In both cases, brain MRI indicated evidence of SS. CT myelogram and SPECT with labeled RBC couldn't help finding the source of occult bleeding. CONCLUSION: SS is a rare central nervous system disease caused by the deposition of hemosiderin in the brain and spinal cord, which results in the progression of neurological deficits. The cause of this hemorrhage is often subarachnoid haemorrhage, intracranial surgery, carcinoma, arteriovenous malformation, nerve root avulsion, and dural abnormality. The condition progresses slowly and, by the time diagnosis is confirmed, the damage is often irreversible. In our cases, brain MRI clarified the definitive diagnosis, but we could not find the source of bleeding. SS should be considered in cases with ataxia and hearing loss, even if no source of bleeding is found.

Evaluation of subacute subarachnoid haemorrhage detection using a magnetic resonance imaging sequence: Double inversion recovery.

BACKGROUND AND OBJECTIVES: The diagnosis of subarachnoid hemorrhage (SAH) especially at the subacute stage is still a challenging issue using the conventional imaging modalities. Here we evaluated the role of double inversion recovery (DIR) sequence of MRI compared with the conventional gradient-recalled echo (GRE)-T2*-W and susceptibility-weighted imaging (SWI) sequences in the diagnosis of subacute SAH. MATERIALS AND METHODS: This prospective study was conducted on 21 patients with SAH, which were diagnosed using CT scan at the initial step. In the third week after the injury (14-20 days), all patients underwent a brain MRI exam that included T2*-W, SWI, and DIR imaging sequences. All images were independently read by two radiologists, who were blinded to the clinical history of the patients. The presence or absence of SAH was reviewed and assessed in 6 anatomical regions. RESULTS: On the DIR images, 20 patients were found to have at least one subarachnoid signal abnormality, while the SWI and T2*-W images identified SAH areas on 17 and 15 patients, respectively. The highest rate of inter-observer consensus by the DIR sequence was found in the interhemispheric fissure and perimesencephalic area (k = 1). Also, a highest rate of inter-observer consensus using SWI was found in the interhemispheric fissure and posterior fossa cistern area (k = 1). A weak agreement was found in frontal-parietal convexity using SWI (k = 0.447), and in posterior fossa cistern by the T2* sequence (k = 0.447). CONCLUSION: In conclusion, the DIR sequence was more reliable at identifying signal abnormalities in subacute SAH patients than the T2*-W and SWI sequence, and is suggested as a promising imaging technique for detecting hemorrhagic areas without considering the anatomical distribution of SAH.

Novel ABCD1 gene mutations in Iranian pedigrees with X-linked adrenoleukodystrophy.

Background X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the ABCD1 gene located on Xq28. X-ALD is characterized by a spectrum of different manifestations varying in patients and families. Methods Four pedigrees with X-ALD consisting of patients and healthy members were selected for investigation of ABCD1 gene mutations. The mutation analysis was performed by polymerase chain reaction (PCR) followed by direct sequencing of all exons. The identified mutations were investigated using bioinformatics tools to predict their effects on the protein product and also to compare the mutated sequence with close species. Results One previously known missense mutation (c.1978 C > T) and three novel mutations (c.1797dupT, c.879delC, c.1218 C > G) were identified in the ABCD1 gene, each in one family. Predicting the effects of the mutations on protein structure and function indicated the probable damaging effect for them with significant alterations in the protein structure. We found three novel mutations in the ABCD1 gene with damaging effects on its protein product and responsible for X-ALD.

Applications of End-Tidal Carbon Dioxide (ETCO2) Monitoring in Emergency Department; a Narrative Review.

Capnograph is an indispensable tool for monitoring metabolic and respiratory function. In this study, the aim was to review the applications of end-tidal carbon dioxide (ETCO2) monitoring in emergency department, multiple databases were comprehensively searched with combination of following keywords: "ETCO2", "emergency department monitoring", and "critical monitoring" in PubMed, Google Scholar, Scopus, Index Copernicus, EBSCO and Cochrane Database.

Propofol-fentanyl versus propofol-ketamine for procedural sedation and analgesia in patients with trauma.

OBJECTIVE: Many procedures performed in emergency department are stressful and painful, and creating proper and timely analgesia and early and effective assessment are the challenges in this department. This study has been conducted in order to compare the efficacy of propofol and fentanyl combination with propofol and ketamine combination for procedural sedation and analgesia (PSA) in trauma patients in the emergency department. METHOD: This is a randomized prospective double-blind clinical trial conducted in the emergency department of Imam Khomeini Hospital, a tertiary academic trauma center in northern Iran. Patients with trauma presenting to the emergency department who needed PSA were included in study. Patients were divided into two groups of propofol fentanyl (PF) and propofol ketamine (PK). Pain score and sedation depth were set as primary outcome measures and were recorded. RESULTS: Out of about 379 patients with trauma, who needed PSA, 253 met the criteria to be included in the study, 117 of which were excluded. The remaining 136 patients were randomly allocated to either PF group (n = 70) or PK group (n = 66). Pain management after drug administration was significantly different between the groups and the analgesia caused by fentanyl was significantly higher than ketamine. The sedation score after 15 min of PSA in the group PF was significantly higher than the group PK. CONCLUSION: It seems that regarding PSA in the emergency department, PF caused better analgesia and deeper sedation and it is recommended to use PF for PSA in the emergency departments.

Bilateral Abducent Nerve Palsy After Neck Trauma: A Case Report.

INTRODUCTION: The abducent nucleus is located in the upper part of the rhomboid fossa beneath the fourth ventricle in the caudal portion of the pons. The abducent nerve courses from its nucleus, to innervate the lateral rectus muscle. This nerve has the longest subarachnoid course of all the cranial nerves, it is the cranial nerve most vulnerable to trauma. It has been reported that 1% to 2.7% of all head injuries are followed by unilateral abducent palsy, but bilateral abducent nerve palsy is extremely rare. CASE PRESENTATION: A 65-year-old woman presented to the emergency department following a motor vehicle accident. A neurological assessment showed the patient's Glascow coma scale (GCS) to be 15. She complained of double vision, and we found lateral gaze palsy in both eyes. A hangman fracture type IIA (C2 fracture with posterior ligamentous C1 - C2 distraction) was found on the cervical CT scan. A three-month follow-up of the patient showed complete recovery of the abducent nerve. CONCLUSIONS: Conservative treatment is usually recommended for traumatic bilateral abducent nerve palsy. Our patient recovered from this condition after three months without any remaining neurological deficit, a very rare outcome in a rare case.

Safety of intramedullary autologous peripheral nerve grafts for post-rehabilitated complete motor spinal cord injuries: a phase I study.

Many experimental studies have reported behavioral improvement after transplantation of peripheral nerve tissue into the contused spinal cord, even in large animals. The safety of this treatment in human remains unknown. In this translational phase 1 study, safety of peripheral nerve grafting for chronic spinal cord injuries and possible outcomes are being reported. Twelve complete motor spinal cord injury patients, who had finished their rehabilitation program, were enrolled. There were 4 thoracic and 8 cervical cases. Patients underwent sural nerve preconditioning in the calf, followed 1 week later, by intramedullary transplantation of the harvested nerve fascicles. The patients were followed up for potential complications periodically, and final assessment by American Spinal Injury association (ASIA) and Spinal Cord Independence Measure (SCIM) III were reported after 2 years of follow-up. The median duration of the spinal cord injury was 31 months. At two years of follow up, out of 7 cases with ASIA Impairment Scale (AIS) A, 4(57.1%) cases improved to AIS B and 1 (14.3%) case became AIS C. There were 1 patient with transient increased spasm, one case of transient cystitis, 3 patients with transient increased neuropathic pain and 1 case with transient episode of autonomic dysreflexia, all being managed medically. There was no case of donor site infection. The above complications were transient as they responded to temporary medical treatment. It may be deduced that after two years follow-up of patients that the procedure may be safe, however further controlled studies are needed to prove its efficacy.

Coiling and migration of peritoneal catheter into the breast: a very rare complication of ventriculoperitoneal shunt.

Upward migration of distal catheter of a ventriculoperitoneal shunt with coiling is very rare. Pseudocyst and galactorrhea are known breast-related complications. Here, we report a 13-year-old girl, known case of myelomeningocele and shunted hydrocephalus, who presented with right breast pseudocyst due to distal tube migration and coiling of the catheter. Plain radiography was not diagnostic because of severe levoscoliosis, but chest computed tomography scan was confirmatory of shunt coiling lateral to the breast. The possible mechanisms causing this uncommon complication are described.

Primary intraosseous osteolytic meningioma of the skull: a case report.

Primary intraosseous meningiomas are uncommon. The osteolytic variants of these tumors are even rarer. When one reviews a bony skull lesion, the differential diagnosis is very wide and includes both malignant and benign diseases. In case of primary skull meningioma, correct diagnosis and total resection of the lesion ensures curative therapy. Presented is a case of osteolytic skull lesion not invading the dura that was proved to be a fibrillary meningioma with regions of syncitial pattern.