Calcineurin, Calcium-Dependent Serine-Threonine Phosphatase Activation by Prion Peptide 106-126 Enhances Nuclear Factor-κB-Linked Proinflammatory Response through Autophagy Pathway.

Prion diseases are mortal neurodegenerative pathologies that are caused by the accumulation of abnormal prion protein (PrPSc) in the brain. Recent advances reveal that calcineurin may play a critical role in regulating nuclear factor kappa B (NF-κB) in the calcium-calmodulin pathway. However, the exact mechanism by calcineurin remains unclear. In the present study, we observed that the prion peptide induces calcineurin and autophagy activation. Also, NF-κB and proinflammatory cytokines like interleukin (IL)-6 and tumor necrosis factor (TNF)-α are upregulated upon exposure to prion peptide in human neuroblastoma. The results show that the prion peptide induces calcineurin activation, leading to the activation of NF-κB transcription factor via autophagy signaling. Expression of TNF-α and IL-6 was increased by calcineurin activation and blocked by calcineurin inhibitor and autophagy inhibitor treatments. Collectively, these findings indicate that calcineurin activation mediated by prion protein induces NF-κB-driven neuroinflammation via autophagy pathway, suggesting that calcineurin and autophagy may be possible therapeutic targets for neuroinflammation in neurodegeneration diseases including prion disease.

Predicting long-term outcomes after cardiac arrest by using serum neutrophil gelatinase-associated lipocalin.

OBJECTIVES: Neutrophil gelatinase-associated lipocalin (NGAL) is secreted by various tissues in pathologic states. Previous studies reported that post-cardiac arrest serum NGAL levels correlate with short-term neurologic outcomes and survival. The aim of this study was to examine the associations between NGAL levels post-cardiac arrest and long-term outcomes and survival. METHODS: This prospective observational study and retrospective review included adult out-of-hospital cardiac arrest survivors who were treated by hypothermia-targeted temperature management. Serum NGAL was assessed at 0, 24, 48, and 72h after return of spontaneous circulation. The primary outcome was poor outcome at six months after cardiac arrest, defined as cerebral performance category score of 3-5. The secondary outcome was six-month mortality. RESULTS: In total, 76 patients were analyzed. The patients with poor outcomes showed significantly higher NGAL levels at 24, 48 and 72h after cardiac arrest than the patients with good outcomes. Long-term survival rates were significantly lower in the high-NGAL group than in the low-NGAL group at each time point. Subgroup analysis of patients who survived 72h showed that only serum NGAL 72h after cardiac arrest had prognostic value for long-term outcomes (area under the receiver operating characteristic curve=0.72; p=0.02). CONCLUSIONS: Post-cardiac arrest serum NGAL is associated with long-term outcomes and survival; particularly, three days post-cardiac arrest is the optimal time point for predicting long-term outcomes. However, the predictive power of NGAL is unsatisfactory, and it should be regarded as an additional prognostic modality.

Usefulness of titanium mesh cage for posterior C1-C2 fixation in patients with atlantoaxial instability.

The aim of this study was to investigate the usefulness of titanium mesh cage as an interlaminar spacer combined with nitinol shape memory loop fixation in patients with atlantoaxial instability.From April 2009 to March 2017, among the patients with atlantoaxial instability, a total of 30 patients were treated by nitinol shape memory loop fixation combined with titanium mesh cage as a spacer. We retrospectively reviewed 30 enrolled patients. Successful fusion was determined as improvement of symptoms and radiologic findings of bone fusion. We also reviewed surgical complications, instrumentation failure, bony fusion rate, and posterior atlantodental interval (PADI).After surgery, the symptoms of all patients significantly improved. Successful fusion was documented throughout the follow-up period. Evidence of solid bridging bone was found, and no instability was seen on flexion-extension radiographs and callus formation on 3D cervical spine computed tomography (CT) 6 months postoperatively in all cases. No surgical complications were observed. No cases of instrumentation failure were observed. The mean PADI also improved significantly to 22.45 ±â€Š1.11 mm 6 months postoperatively compared with the preoperative value of 18.37 ±â€Š1.16 mm (P < .05).We obtained a good fusion rate by using titanium mesh cage spacer with nitinol shape memory alloy loop in patients with atlantoaxial instability. This technique can help surgeons in avoiding vertebral artery injury and reducing bleeding and operation time. Therefore, we suggest that titanium mesh cage spacer combined with nitinol shape memory alloy loop can be a good substitute of autograft for C1-C2 fusion in treating atlantoaxial instabilities.

A Randomized Comparison Simulating Face to Face Endotracheal Intubation of Pentax Airway Scope, C-MAC Video Laryngoscope, Glidescope Video Laryngoscope, and Macintosh Laryngoscope.

OBJECTIVES: Early airway management is very important for severely ill patients. This study aimed to investigate the efficacy of face to face intubation in four different types of laryngoscopes (Macintosh laryngoscope, Pentax airway scope (AWS), Glidescope video laryngoscope (GVL), and C-MAC video laryngoscope (C-MAC)). METHOD: Ninety-five nurses and emergency medical technicians were trained to use the AWS, C-MAC, GVL and Macintosh laryngoscope with standard airway trainer manikin and face to face intubation. We compared VCET (vocal cord exposure time), tube pass time, 1st ventilation time, VCET to tube pass time, tube pass time to 1st ventilation time, and POGO (percentage of glottis opening) score. In addition, we compared success rate according to the number of attempts and complications. RESULT: VCET was similar among all laryngoscopes and POGO score was higher in AWS. AWS and Macintosh blade were faster than GVL and C-MAC in total intubation time. Face to face intubation success rate was lower in GVL than other laryngoscopes. CONCLUSION: AWS and Macintosh were favorable laryngoscopes in face to face intubation. GVL had disadvantage performing face to face intubation.

GlideScope video laryngoscopy versus direct laryngoscopy in the emergency department: a propensity score-matched analysis.

OBJECTIVE: To evaluate whether the use of a GlideScope video laryngoscope (GVL) improves first-attempt intubation success compared with the Macintosh laryngoscope (MAC) in the emergency department (ED). DESIGN: A propensity score-matched analysis of data from a prospective multicentre ED airway registry-the Korean Emergency Airway Management Registry (KEAMR). SETTING: 4 academic EDs located in a metropolitan city and a province in South Korea. PARTICIPANTS: A total of 4041 adult patients without cardiac arrest who underwent emergency intubation from January 2007 to December 2010. OUTCOME MEASURES: The primary and secondary outcomes were successful first intubation attempt and intubation failure, respectively. To reduce the selection bias and potential confounding effects, we rigorously adjusted for the baseline differences between two groups using a propensity score matching. RESULTS: Of the 4041 eligible patients, a GVL was initially used in 540 patients (13.4%). Using 1:2 propensity score matching, 363 and 726 patients were assigned to the GVL and MAC groups, respectively. The adjusted relative risks (95% CIs) for the first-attempt success rates with a GVL compared with a MAC were 0.76 (0.56 to 1.04; p=0.084) and the respective intubation failure rates 1.03(0.99 to 1.07; p=0.157). Regarding the subgroups, the first-attempt success of the senior residents and attending physicians was lower with the GVL (0.47 (0.23 to 0.98), p=0.043). In the patients with slight intubation difficulty, the first-attempt success was lower (0.60 (0.41 to 0.88), p=0.008) and the intubation failure was higher with the GVL (1.07 (1.02 to 1.13), p=0.008). CONCLUSIONS: In this propensity score-matched analysis of data from a prospective multicentre ED airway registry, the overall first-attempt intubation success and failure rates did not differ significantly between GVL and MAC in the ED setting. Further randomised controlled trials are needed to confirm our findings.

Pyogenic pancreatic abscess mimicking pancreatic neoplasm: a four-case series.

A pyogenic pancreatic abscess mimicking pancreatic neoplasm in the absence of acute pancreatitis is rare. We report four patients who each presented with a pancreatic mass at the pancreas head or body without acute pancreatitis. The presenting symptoms were abdominal pain, fever, or weight loss. Abdominal CT scans showed low-density round masses at the pancreas head or body with/without lymphadenopathy. In each case, a PET-CT scan showed a mass with a high SUV, indicating possible malignancy. Comorbid diseases were identified in all patients: chronic pancreatitis and thrombus at the portal vein, penetrating duodenal ulcer, distal common bile duct stenosis, and diabetes mellitus. Diagnoses were performed by laparoscopic biopsy in two patients and via EUS fine needle aspiration in one patient. One patient revealed a multifocal microabscess at the pancreatic head caused by a deep-penetrating duodenal ulcer. He was treated with antibiotics and a proton-pump inhibitor. The clinical symptoms and pancreatic images of all the patients were improved using conservative management. Infective causes should be considered for a pancreatic mass mimicking malignancy.

Combination treatment with 17ß-estradiol and therapeutic hypothermia for transient global cerebral ischemia in rats.

OBJECTIVE: Therapeutic hypothermia is now regarded as the only effective treatment of global ischemic injury after cardiac arrest. Numerous studies of the neuroprotective effects of 17ß-estradiol have yielded conflicting results depending on administration route and dose. Herein, we investigated the neuroprotective effect of postischemic 17ß-estradiol administration combined with therapeutic hypothermia. METHODS: Twenty-one rats were randomly divided into 4 groups: control (group I), therapeutic hypothermia (group II), 17ß-estradiol treatment (group III), and therapeutic hypothermia combined with 17ß-estradiol treatment (group IV). One rat was assigned to a sham operation group. With the exception of the sham-operated rat, all animals underwent transient global cerebral ischemia for 20 minutes by the 4-vessel occlusion method. Hypothermia was maintained at 33°C for 2 hours in groups II and IV, and 17ß-estradiol (10 µg/kg) was intraperitoneally administered to rats in groups III and IV. Neurologic deficit scores and hippocampal cornu ammonis 1 neuronal injury were assessed 72 hours postischemia. RESULTS: The neurologic deficit score was not significantly different among the groups. The percentage of normal neurons in the hippocampal cornu ammonis 1 was 7.32% ± 0.88% in group I, 53.65% ± 2.52% in group II, 51.6% ± 3.44% in group III, and 79.79% ± 1.6% in group IV. The neuroprotective effect in the combined treatment group was markedly greater than in the single treatment groups, which suggests that hypothermia and 17ß-estradiol work synergistically to exert neuroprotection. CONCLUSION: Postischemic administration of low-dose 17ß-estradiol appears to be neuroprotective after transient global ischemia, and its effect is potentiated by therapeutic hypothermia.

Notch1 counteracts WNT/ß-catenin signaling through chromatin modification in colorectal cancer.

Crosstalk between the Notch and wingless-type MMTV integration site (WNT) signaling pathways has been investigated for many developmental processes. However, this negative correlation between Notch and WNT/ß-catenin signaling activity has been studied primarily in normal developmental and physiological processes in which negative feedback loops for both signaling pathways are intact. We found that Notch1 signaling retained the capability of suppressing the expression of WNT target genes in colorectal cancers even when ß-catenin destruction by the adenomatous polyposis coli (APC) complex was disabled. Activation of Notch1 converted high-grade adenoma into low-grade adenoma in an Apcmin mouse colon cancer model and suppressed the expression of WNT target genes in human colorectal cancer cells through epigenetic modification recruiting histone methyltransferase SET domain bifurcated 1 (SETDB1). Extensive microarray analysis of human colorectal cancers also showed a negative correlation between the Notch1 target gene, Notch-regulated ankyrin repeat protein 1 (NRARP), and WNT target genes. Notch is known to be a strong promoter of tumor initiation, but here we uncovered an unexpected suppressive role of Notch1 on WNT/ß-catenin target genes involved in colorectal cancer.

Moyamoya syndrome following growth hormone-secreting pituitary adenoma.

We report a case of Moyamoya syndrome developing in association with growth hormone-secreting pituitary adenoma. A 31-year-old female presented with acromegalic features. Magnetic resonance imaging revealed a 1 × 2 cm tumor in the sella turcica and MR angiography demonstrated unremarkable findings. Blood growth hormone and insulin-like growth factor I levels were elevated to 74.1 ng/ml and over 1 575 ng/ml, respectively. The diagnosis was growth hormone-secreting pituitary adenoma, and the tumor was removed through a transsphenoidal approach. Four years after surgery, she visited the outpatient department due to left side weakness for 2 months. Magnetic resonance images showed acute and old infarcted lesions in the basal ganglia and subcortical area and residual small pituitary adenoma in the sellar area. MR angiography demonstrated stenosis of the bilateral distal internal carotid arteries with basal collateral vessels. Conventional cerebral angiography showed complete obstruction in the right internal carotid artery and severe stenosis of the left internal carotid artery, middle cerebral artery, and anterior cerebral artery with basal collateral vessels. Her blood growth hormone and insulin-like growth factor I levels were 15.3 ng/ml and 1 055 ng/ml, respectively. We believe that excess systemic exposures of growth hormone and insulin-like growth factor I may participate in the development of Moyamoya syndrome.

Identification of co-occurring transcription factor binding sites from DNA sequence using clustered position weight matrices.

Accurate prediction of transcription factor binding sites (TFBSs) is a prerequisite for identifying cis-regulatory modules that underlie transcriptional regulatory circuits encoded in the genome. Here, we present a computational framework for detecting TFBSs, when multiple position weight matrices (PWMs) for a transcription factor are available. Grouping multiple PWMs of a transcription factor (TF) based on their sequence similarity improves the specificity of TFBS prediction, which was evaluated using multiple genome-wide ChIP-Seq data sets from 26 TFs. The Z-scores of the area under a receiver operating characteristic curve (AUC) values of 368 TFs were calculated and used to statistically identify co-occurring regulatory motifs in the TF bound ChIP loci. Motifs that are co-occurring along with the empirical bindings of E2F, JUN or MYC have been evaluated, in the basal or stimulated condition. Results prove our method can be useful to systematically identify the co-occurring motifs of the TF for the given conditions.

Endotracheal intubation using a GlideScope video laryngoscope by emergency physicians: a multicentre analysis of 345 attempts in adult patients.

OBJECTIVE: To investigate the use and success rates of the GlideScope (GVL) by emergency physicians (EPs) during the initial two years after its introduction. METHODS: We performed an observational study using registry data of five emergency departments. The success rates in adult patients were evaluated and compared with those of conventional laryngoscope (CL). RESULTS: The GVL was used in 345 (10.7%) of 3233 intubation attempts by EPs. The overall success rate of the GVL was not higher than a CL (79.1% vs 77.6%, p=0.538). The success rate for the patients with difficult airway was higher in the GVL than a CL (80.0% vs 50.4%, p<0.001). CONCLUSION: The GVL was not used frequently by EPs during the initial two years after its introduction. Although the GVL provides a better glottic view, the overall success rates were similar to a CL. The GVL may be useful in patients with difficult airway.

Prediction and experimental validation of novel STAT3 target genes in human cancer cells.

The comprehensive identification of functional transcription factor binding sites (TFBSs) is an important step in understanding complex transcriptional regulatory networks. This study presents a motif-based comparative approach, STAT-Finder, for identifying functional DNA binding sites of STAT3 transcription factor. STAT-Finder combines STAT-Scanner, which was designed to predict functional STAT TFBSs with improved sensitivity, and a motif-based alignment to minimize false positive prediction rates. Using two reference sets containing promoter sequences of known STAT3 target genes, STAT-Finder identified functional STAT3 TFBSs with enhanced prediction efficiency and sensitivity relative to other conventional TFBS prediction tools. In addition, STAT-Finder identified novel STAT3 target genes among a group of genes that are over-expressed in human cancer cells. The binding of STAT3 to the predicted TFBSs was also experimentally confirmed through chromatin immunoprecipitation. Our proposed method provides a systematic approach to the prediction of functional TFBSs that can be applied to other TFs.

Language Lateralization in Patients with Temporal Lobe Epilepsy : A Comparison between Volumetric Analysis and the Wada Test.

OBJECTIVE: Determining language lateralization is important for the presurgical evaluation of patients with medically intractable epilepsy. The Wada test has been the gold standard for lateralization of language dominance before epilepsy surgery. However, it is an invasive test with risk, and have some limitations. METHODS: We compared the volumetric analysis with Wada test, and studied the clinical potential of volumetric analysis to assess language laterality in large surgical candidates with temporal lobe epilepsy (TLE). To examine the efficacy of volumetric analysis to determine language lateralization during presurgical evaluation, we compared the volumetric analysis of the bilateral planum temporale with the results of Wada test in 59 patients with chronic intractable TLE (rTLE, n=32; lTLE, n=27) who underwent epilepsy surgery. We measured the gray matter volumes of planum temporale (PT) of each patients using the VoxelPlus2 program (Mevisys, Daejeon, Korea). RESULTS: Overall congruence of the volumetric analysis with the Wada test was 97.75% in rTLE patients and 81.5% in lTLE patients. There were more significant leftward asymmetry of the PT in rTLE patients than lTLE patients. In lTLE patients, relatively high proportion (37%) of the patients showed bilateral or right hemispheric language dominance. CONCLUSION: These results provide evidence that the volumetric analysis of the PT could be used as an alternatives in language lateralization. Also, the results of the Wada test suggested that there was considerable plasticity of language representation in the brains of patients with intractable TLE and it was associated with an earlier age of brain injury.

Posterior arch defects of the cervical spine: a comparison between absent pedicle syndrome and spondylolysis.

BACKGROUND CONTEXT: Abnormalities of the posterior arch are rare entities that are usually found incidentally on neck radiographs. Their radiographic appearance may cause them to be confused with more serious entities such as fractures, locked facets, and tumor-induced bony erosions. It is important to distinguish these posterior arch abnormalities from the other entities because the treatment is very different. PURPOSE: Posterior arch defects of the cervical spine, including cervical spondylolysis and absent pedicle syndrome, occur rarely. In this case report, we describe three cases of posterior arch defects and present a review of the literature concerning the distinguishing features between spondylolysis and absent pedicle syndrome. STUDY DESIGN: A case report and literature review of the posterior arch defects. METHODS: Two patients are presented who developed posterior neck pain after trauma. They had no neurologic deficits, but cervical radiographs suggested that they had a traumatic injury. Cervical spine computed tomography (CT) revealed absent pedicle syndrome and they were treated conservatively. Another patient is presented who developed worsening posterior neck pain and left shoulder pain. She had no history of significant neck injury. Cervical radiographs and CT showed bilateral spondylolysis of C6 vertebra and subluxation of C6 on C7. Because her symptoms were not relieved by conservative measures, we performed anterior cervical discectomy and fusion. RESULTS: We treated two patients with absent pedicle syndrome by conservative measures and one patient with cervical spondylolyis by surgical treatment. CONCLUSIONS: Posterior arch defects were often confused with other disease entities. But, they have some distinctive features and such distinctive features may be helpful in confirming diagnosis and planning treatment. Furthermore, three-dimensional CT scan reconstruction provides comprehensive anatomic evaluation of the structures with an absent pedicle and the associated bony abnormalities.

Midline glioblastoma multiforme with bilateral symmetric cysts.

Cystic glioblastoma multiforme (GBM) is a rare disease. Its exact prevalence has not yet been reported. Also, the mechanism of cyst formation remains to be elucidated. We report a case of GBM with a large peripheral cyst. A 43-year-old woman visited our clinic with a 3-month history of severe headache, memory impairment and general weakness. T1-weighted gadolinium-enhanced magnetic resonance (MR) image revealed a midline enhanced solid mass and bilateral symmetric banana-shaped peripheral cysts. A centrally enhanced mass was measured 2x4 cm in size and both mass and cysts as 7x7 cm. Both the frontal lobe and the frontal horn were severely compressed inferiorly and posteriorly. We resected a midline solid tumor and cysts via the bilateral interhemispheric transcortical approach. Histopathologic examination revealed GBM. The patient was subsequently treated with fractionated conventional brain radiation therapy, followed by temozolomide chemotherapy. Eighteen months later, there was no tumor recurrence and no neurological deficits were noted. Our patient showed no tumor recurrence and a long survival at a long follow-up.

Effect of vagus nerve stimulation in post-traumatic epilepsy and failed epilepsy surgery : preliminary report.

OBJECTIVE: Vagus nerve stimulation (VNS) has been used in epilepsy patients refractory to standard medical treatments and unsuitable candidates for resective or disconnective surgery. In this study, we investigated the efficacy of VNS to patients who had refractory result to epilepsy surgery and patients with post-traumatic epilepsy. METHODS: We analyzed the effect of VNS in 11 patients who had undergone previous epilepsy surgery and patients with intractable post-traumatic epilepsy associated with brain injury. All patients underwent VNS implantation between October 2005 and December 2006. RESULTS: We evaluated seizure frequency before and after implantation of VNS and maximum follow up period was 24 months. In the first 6 months, 11 patients showed an average of 74.3% seizure reduction. After 12 months, 10 patients showed 85.2% seizure reduction. Eighteen months after implantation, 9 patients showed 92.4% seizure reduction and 7 patients showed 97.2% seizure reduction after 24 months. Six patients were seizure-free at this time. CONCLUSION: We conclude that the VNS is a helpful treatment modality in patients with surgically refractory epilepsy and in patients with post-traumatic epilepsy due to severe brain injury.