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Articles by Angélique Bordey in JoVE

 JoVE Neuroscience

Preparation of Acute Subventricular Zone Slices for Calcium Imaging

1Department of Neurosurgery and Cellular & Molecular Physiology, Yale University School of Medicine


JoVE 4071

A method to load subventricular zone (SVZ) cells with calcium indicator dyes for recording calcium activity is described. The postnatal SVZ contains tightly packed cells including neural progenitor cells and neuroblasts. Rather than using bath loading we injected the dye by pressure inside the tissue allowing better dye diffusion.

 JoVE Neuroscience

Neonatal Subventricular Zone Electroporation

1Department of Neurosurgery and Cellular & Molecular Physiology, Yale University School of Medicine


JoVE 50197

We demonstrate a minimally invasive technique referred to as neonatal subventricular zone electroporation. The technique consists of injecting plasmid DNA into the lateral ventricles of neonatal pups and applying electrical current to deliver and genetically manipulate neural stem cells

Other articles by Angélique Bordey on PubMed

Telestroke: Rapid Treatment of Acute Ischemic Stroke Patients Using Telemedicine in a Singapore Emergency Department

STUDY OBJECTIVE: In recent years, telemedicine technology has allowed hospitals without an in-house neurology service access to 24-h neurology consultation from specialized centers, thus paving the way for these hospitals to offer thrombolysis treatment for stroke patients. This article will describe the experience of the study hospital's emergency department (ED) in its use of telemedicine technology to facilitate the rapid treatment of acute ischemic stroke patients. METHODS: The ED records, in-patient records, and paramedic records of all patients who presented to the study hospital's ED and received thrombolytic treatment for ischemic strokes were retrospectively reviewed. RESULTS: From 25 October 2010 to 25 May 2011, using the telemedicine system, a total of 18 patients received thrombolytic treatment for acute ischemic strokes. The overall mean door to needle time was 92.7 min (95% CI 80.0 to 105.5), median 86.0 min. The mean onset of symptoms to needle (OTN) time was 154.9 min (95% CI 136.7 to 173.2), median 148 min. Factors such as presentation during office hours, brought in by ambulances as standby cases, and direct management by senior doctors were associated with shorter door to needle times. CONCLUSION: Telemedicine is an invaluable tool that enables hospitals without 24-h onsite neurology service to offer emergency thrombolysis to eligible stroke patients, who otherwise will not be able to benefit from this therapy.

Acute Cholangitis Secondary to a Recently Migrated Cystic Duct Clip, 15 Years After Cholecystectomy

Ultrasound-Enhanced Monoclonal Antibody Production

With the rapidly growing demand for monoclonal antibody (mAb)-based products, new technologies are urgently needed to increase mAb production while reducing manufacturing costs. To solve this problem, we report our research findings of using low-intensity pulsed ultrasound (LIPUS) to enhance mAb production. LIPUS with frequency of 1.5 MHz and pulse repetition frequency of 1 kHz, as well as duty cycle of 20%, was used to stimulate hybridoma cells to enhance the production of mAb, anti-CD4 (hybridoma GK1.5). The enzyme-linked immunosorbent assay results show a 60.42 ± 7.63% increase of mAb expression in hybridoma cells. The evidence of structural changes of the cellular outer membrane in both transmission electron microscopy and scanning electron microscopy images and the more than 20% lactate dehydrogenase release indicates that the increased mAb production is related to the increased cell permeability induced by LIPUS. This value-added ultrasound technology provides a potential cost-effective solution for pharmaceutical companies to manufacture mAb-based drugs. The technology, in turn, can reduce the drug manufacturing costs and decrease health care spending.

Co-aggregation of RNA Binding Proteins in ALS Spinal Motor Neurons: Evidence of a Common Pathogenic Mechanism

While the pathogenesis of amyotrophic lateral sclerosis (ALS) remains to be clearly delineated, there is mounting evidence that altered RNA metabolism is a commonality amongst several of the known genetic variants of the disease. In this study, we evaluated the expression of 10 ALS-associated proteins in spinal motor neurons (MNs) in ALS patients with mutations in C9orf72 (C9orf72(GGGGCC)-ALS; n = 5), SOD1 (mtSOD1-ALS; n = 9), FUS/TLS (mtFUS/TLS-ALS; n = 2), or TARDBP (mtTDP-43-ALS; n = 2) and contrasted these to cases of sporadic ALS (sALS; n = 4) and familial ALS without known mutations (fALS; n = 2). We performed colorimetric immunohistochemistry (IHC) using antibodies against TDP-43, FUS/TLS, SOD1, C9orf72, ubiquitin, sequestosome 1 (p62), optineurin, phosphorylated high molecular weight neurofilament, peripherin, and Rho-guanine nucleotide exchange factor (RGNEF). We observed that RGNEF-immunoreactive neuronal cytoplasmic inclusions (NCIs) can co-localize with TDP-43, FUS/TLS and p62 within spinal MNs. We confirmed their capacity to interact by co-immunoprecipitations. We also found that mtSOD1-ALS cases possess a unique IHC signature, including the presence of C9orf72-immunoreactive diffuse NCIs, which allows them to be distinguished from other variants of ALS at the level of light microscopy. These findings support the hypothesis that alterations in RNA metabolism are a core pathogenic pathway in ALS. We also conclude that routine IHC-based analysis of spinal MNs may aid in the identification of families not previously suspected to harbor SOD1 mutations.

A Comparison of Electronic Radial and Curvilinear Endoscopic Ultrasonography in the Detection of Pancreatic Malignant Tumor

Abstract Objective. There is no comparative study of electronic radial endoscopic ultrasonography (ER-EUS) and electronic curvilinear EUS (EC-EUS). The aim of this study was to compare the accuracy of ER-EUS and EC-EUS for detecting pancreatic malignancies. Methods. This was a retrospective review of the patients who had EUS assessment from September 2008 to December 2011 for suspicious pancreatic tumors. Sensitivity, specificity, and area under the ROC curve to detect pancreatic malignancies were calculated and compared between the ER-EUS and EC-EUS cohort. The final diagnosis of pancreatic malignancy was based on pathology, or the consensus of patient's clinical course and multimodal imaging tests. Results. Two hundred twenty-one patients were included and divided into two cohorts: ER-EUS (n = 139) and EC-EUS (n = 82) cohorts. With propensity score matching method, 70 cases in each cohort were selected for the comparison. There was no significant difference in sensitivity, specificity, and area under the ROC curve to detect pancreatic malignancy between ER-EUS and EC-EUS cohort (88.5 vs. 100%, 88.6 vs. 90.9%, 0.8855 vs. 0.9545). Conclusion: ER-EUS and EC-EUS provided similar accuracy for the detection of pancreatic malignancies. In view of similar diagnostic results of ER-EUS and EC-EUS for the detection of pancreatic malignancy, and the advantage of being able to perform FNA with EC-EUS, EC-EUS may be the preferred choice.

Urinary α-carboxyethyl Hydroxychroman Can Be Used As a Predictor of α-tocopherol Adequacy, As Demonstrated in the Energetics Study

BACKGROUND: Other than the in vitro erythrocyte hemolysis test, no valid biomarkers of vitamin E status currently exist. OBJECTIVE: We hypothesized that the urinary vitamin E metabolite α-carboxyethyl hydroxychroman (α-CEHC) could serve as a biomarker. DESIGN: The relations between urinary α-CEHC, plasma α-tocopherol, and vitamin E intakes were assessed by using a previously validated multipass, Web-based, 24-h self-administered dietary recall, and we concurrently collected plasma and 24-h urine samples from 233 participants of both sexes. RESULTS: Median vitamin E intakes were 9.7 mg α-tocopherol/d. Intakes were correlated with plasma α-tocopherol (R = 0.40, P < 0.001) and urinary α-CEHC (R = 0.42, P < 0.001); these correlations were essentially unchanged after multivariate adjustments. On the basis of multiple regression analysis, urinary α-CEHC excretion increased by ∼0.086 μmol/g creatinine (95% CI: 0.047, 0.125) for every 1-mg (2.3-μmol) increase in dietary α-tocopherol. Urinary α-CEHC excretion remained at a plateau (median: 1.39 μmol/g creatinine) until dietary intakes of α-tocopherol exceeded 9 mg α-tocopherol/d. The inflection point at which vitamin E metabolism increased was estimated to be at an intake of 12.8 mg α-tocopherol/d. Daily excretion of >1.39 μmol α-CEHC/g creatinine is associated with a greater than adequate α-tocopherol status, as evidenced by increased vitamin E metabolism and excretion. CONCLUSION: Thus, urinary α-CEHC is a valid biomarker of α-tocopherol status that can be used to set a value for the Estimated Adequate Requirement of vitamin E.

Neuropathology of Temporal Lobe Epilepsy

Pathologic findings in surgical resections from patients with temporal lobe epilepsy include a wide range of diagnostic possibilities that can be categorized into different groups on the basis of etiology. This paper outlines the various pathologic entities described in temporal lobe epilepsy, including some newly recognized epilepsy-associated tumors, and briefly touch on the recent classification of focal cortical dysplasia. This classification takes into account coexistent pathologic lesions in focal cortical dysplasia.

Optometry-based General Population Survey of Pupil Ruff Atrophy and Ocular Hypertension

BACKGROUND: To evaluate and describe the pupil ruff changes and relationship to intraocular pressure (IOP), pseudoexfoliation syndrome (PXF) and glaucoma status in an optometric population in New Zealand DESIGN: Prospective cross-sectional survey of an optometric population PARTICIPANTS: 620 subjects over 50 years old routinely attending the participating optometry practices. Exclusion criteria included previous intraocular surgery, ophthalmic laser, uveitis, iris neovascularization, angle closure on gonioscopy and secondary glaucoma. METHODS: Multi-center study involving 11 optometry practices in the Wellington region, New Zealand. The pupillary ruff and associated gonioscopy findings of study participants were graded based on the previously published Pupil Ruff Atrophy (PRA) grading system. Parameters evaluated include pupillary ruff absence and abnormality, PXF material, and trabecular meshwork pigmentation. MAIN OUTCOME MEASURES: Correlations between inter-eye PRA grading differences and inter-eye IOP and CDR differences. RESULTS: 620 subjects were included, with a mean age of 62.2 ± 9.1 years and mean IOP of 14.8 ± 3.4 mmHg. 414 (66.8%) had bilateral pupil ruff changes and 12 (1.5%) had PXF. Inter-eye IOP asymmetry was significantly correlated with amount of missing pupillary ruff (r = 0.111; P = 0.022) and trabecular meshwork pigmentation (r = 0.147; P = 0.002). Inter-eye CDR asymmetry was not correlated with any of the PRA grading parameters. CONCLUSIONS: Asymmetry of pupillary ruff absence and trabecular meshwork pigmentation was correlated with IOP asymmetry (but not with CDR asymmetry) in a general optometric population setting in New Zealand. Further study will be required to determine the clinical relevance of this finding.

Elucidation of the Effect of Ionic Liquid Pretreatment on Rice Husk Via Structural Analyses

ABSTRACT: BACKGROUND: In the present study, three ionic liquids, namely 1-butyl-3-methylimidazolium chloride ([BMIM]Cl), 1-ethyl-3-methylimidazolium acetate ([EMIM]OAc), and 1-ethyl-3-methylimidazolium diethyl phosphate ([EMIM]DEP), were used to partially dissolve rice husk, after which the cellulose were regenerated by the addition of water. The aim of the investigation is to examine the implications of the ionic liquid pretreatments on rice husk composition and structure. RESULTS: From the attenuated total reflectance Fourier transform-infrared (ATR FT-IR) spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM) results, the regenerated cellulose were more amorphous, less crystalline, and possessed higher structural disruption compared with untreated rice husk. The major component of regenerated cellulose from [BMIM]Cl and [EMIM]DEP pretreatments was cellulose-rich material, while cellulose regenerated from [EMIM]OAc was a matrix of cellulose and lignin. Cellulose regenerated from ionic pretreatments could be saccharified via enzymatic hydrolysis, and resulted in relatively high reducing sugars yields, whereas enzymatic hydrolysis of untreated rice husk did not yield reducing sugars. Rice husk residues generated from the ionic liquid pretreatments had similar chemical composition and amorphousity to that of untreated rice husk, but with varying extent of surface disruption and swelling. CONCLUSIONS: The structural architecture of the regenerated cellulose and rice husk residues showed that they could be used for subsequent fermentation or derivation of cellulosic compounds. Therefore, ionic liquid pretreatment is an alternative in the pretreatment of lignocellulosic biomass in addition to the conventional chemical pretreatments.

Common Variants at the MHC Locus and at Chromosome 16q24.1 Predispose to Barrett's Esophagus

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P(combined) = 4.09 × 10(-9); odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P(combined) = 2.74 × 10(-10); OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

[Impact of Liver Steatosis on Antiviral Effects of Pegylated Interferon-alpha in Patients with Chronic Hepatitis B]

To investigate the impact of hepatic steatosis on virologic response in chronic hepatitis B (CHB) patients treated with pegylated interferon-alpha (PEG-IFNa).

Association of Common Genetic Variants with Breast Cancer Risk and Clinicopathological Characteristics in a Chinese Population

Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations, and thus GWAS-identified single nucleotide polymorphisms (SNPs) in one population may not be of significance in another population. In order to explore the role of breast cancer susceptibility variants in a Chinese population of Southern Chinese descent, we analyzed 22 SNPs for 1,191 breast cancer cases and 1,534 female controls. Associations between the SNPs and clinicopathological features were also investigated. In addition, we evaluated the combined effects of associated SNPs by constructing risk models. Eight SNPs were associated with an elevated breast cancer risk. Rs2046210/6q25.1 increased breast cancer risk via an additive model [per-allele odds ratio (OR) = 1.43, 95 % confidence interval (CI) = 1.26-1.62], and was associated with estrogen receptor (ER)-positive (per-allele OR = 1.39, 95 % CI = 1.20-1.61) and ER-negative (per-allele OR = 1.55, 95 % CI = 1.28-1.89) disease. Rs2046210 was also associated with stage 1, stage 2, and stage 3 disease, with per-allele ORs of 1.38 (1.14-1.68), 1.48 (1.25-1.74), and 1.58 (1.28-1.94), respectively. Four SNPs mapped to 10q26.13/FGFR2 were associated with increased breast cancer risk via an additive model with per-allelic risks (95 % CI) of 1.26 (1.12-1.43) at rs1219648, 1.22 (1.07-1.38) at rs2981582, 1.21 (1.07-1.36) at rs2981579, and 1.18 (1.04-1.35) at rs11200014. Variants of rs7696175/TLR1, TLR6, rs13281615/8q24, and rs16886165/MAP3K1 were also associated with increased breast cancer risk, with per-allele ORs (95 % CI) of 1.16 (1.00-1.34), 1.15 (1.02-1.29), and 1.15 (1.01-1.29), respectively. Five SNPs associated with breast cancer risk predominantly among ER-positive tumors (rs2981582/FGFR2, rs4415084/MRPS30, rs1219648/FGFR2, rs2981579/FGFR2, and rs11200014/FGFR2). Among our Chinese population, the risk of developing breast cancer increased by 90 % for those with a combination of 6 or more risk alleles, compared to patients with ≤3 risk alleles.

Reduced Graphene Oxide for Catalytic Oxidation of Aqueous Organic Pollutants

We discovered that chemically reduced graphene, with an ID/IG >1.4 (defective to graphite) can effectively activate peroxymonosulfate (PMS) to produce active sulfate radicals. The produced sulfate radicals (SO4•-) are powerful oxidizing species with a high oxidative potential (2.5 - 3.1 V vs. 2.7 V of hydroxyl radical), and can effectively decompose various aqueous contaminants. Graphene demonstrated a higher activity than several carbon allotropes, such as activated carbon (AC), graphite powder (GP), graphene oxide (GO), and multiwall carbon nanotube (MWCNT). Kinetic study of graphene catalyzed activation of PMS was carried out. It was shown that graphene catalysis is superior to that on transition metal oxide (Co3O4) in degradation of phenol, 2,4-dichlorophenol (DCP) and a dye (methylene blue, MB) in water, therefore providing a novel strategy for environmental remediation.

Genetic Variants Near PDGFRA Are Associated with Corneal Curvature in Australians

PURPOSE. Irregularity in corneal curvature (CC) is highly associated with various eye disorders such as keratoconus and myopia. Our sample had limited power to find genome-wide significant (5 × 10 -8) hits but good power for replication. Thus, we attempted to test whether alleles in the FRAP1 and PDGFRA genes, recently found to be associated with CC in Asian populations, also influence CC in Australians of North European ancestry. We also report initial GWAS results for CC in Australians. METHODS. Two population-based cohorts of 1788 Australian twins and their families, as well as 1013 individuals from a birth cohort from Western Australia were genotyped using genome-wide arrays. Following separate individual analysis and quality control, the results from each cohort underwent meta-analysis. RESULTS. Meta-analysis revealed significant replication of association between rs2114039 and corneal curvature (P = 0.0045). The SNP rs2114039 near PDGFRA has been previously implicated in Asians. No SNP at the FRAP1 locus was found to be associated in our Australian samples. No SNP surpassed the genome wide significance threshold of 5×10-8. The SNP with strongest association was rs2444240 has (p=3.658 × 10-07), which is 31kb upstream to the TRIM29 gene. CONCLUSIONS. This study confirms a significant role of the PDGFRA gene in determining corneal curvature in the Australian population. It also highlights the putative association of the TRIM29 locus with CC.

Tissue-based Approaches to Study Pharmacodynamic Endpoints in Early Phase Oncology Clinical Trials

Anti-cancer clinical drug development is currently costly and slow with a high attrition rate. There is thus an urgent and unmet need to integrate pharmacodynamic biomarkers into early phase clinical trials in the framework provided by the "pharmacologic audit trail" in order to overcome this challenge. This review discusses the rationale, advantages and disadvantages, as well as the practical considerations of various tissue-based approaches to perform pharmacodynamic studies in early phase oncology clinical trials using case histories of molecular targeting agents such as PI3K, m-TOR, HSP90, HDAC and PARP inhibitors. These approaches include the use of normal "surrogate" tissues such as peripheral blood mononuclear cells, platelet-rich plasma, plucked hair follicles, skin biopsies, plasma-based endocrine assays, proteomics, metabolomics and circulating endothelial cells. In addition the review discusses the use of neoplastic tissues including tumor biopsies, circulating tumor DNA and tumor cells and metabolomic approaches. The utilization of these tissues and technology platforms to study biomarkers will help accelerate the development of molecularly targeted agents for the treatment of cancer.

Patterns of Disease Recurrence Following Treatment of Oropharyngeal Cancer With Intensity Modulated Radiation Therapy

PURPOSE: To report mature results of a large cohort of patients diagnosed with squamous cell carcinoma of the oropharynx who were treated with intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: The database of patients irradiated at The University of Texas, M.D. Anderson Cancer Center was searched for patients diagnosed with oropharyngeal cancer and treated with IMRT between 2000 and 2007. A retrospective review of outcome data was performed. RESULTS: The cohort consisted of 776 patients. One hundred fifty-nine patients (21%) were current smokers, 279 (36%) former smokers, and 337 (43%) never smokers. T and N categories and American Joint Committee on Cancer group stages were distributed as follows: T1/x, 288 (37%); T2, 288 (37%); T3, 113 (15%); T4, 87 (11%); N0, 88(12%); N1/x, 140 (18%); N2a, 101 (13%); N2b, 269 (35%); N2c, 122 (16%); and N3, 56 (7%); stage I, 18(2%); stage II, 40(5%); stage III, 150(19%); and stage IV, 568(74%). Seventy-one patients (10%) presented with nodes in level IV. Median follow-up was 54 months. The 5-year overall survival, locoregional control, and overall recurrence-free survival rates were 84%, 90%, and 82%, respectively. Primary site recurrence developed in 7% of patients, and neck recurrence with primary site control in 3%. We could only identify 12 patients (2%) who had locoregional recurrence outside the high-dose target volumes. Poorer survival rates were observed in current smokers, patients with larger primary (T) tumors and lower neck disease. CONCLUSIONS: Patients with oropharyngeal cancer treated with IMRT have excellent disease control. Locoregional recurrence was uncommon, and most often occurred in the high dose volumes. Parotid sparing was accomplished in nearly all patients without compromising tumor coverage.

Highly Electrically Conductive Layered Carbon Derived from Polydopamine and Its Functions in SnO(2)-based Lithium Ion Battery Anodes

Thin carbonized polydopamine (C-PDA) coatings are found to have similar structures and electrical conductivities to those of multilayered graphene doped with heteroatoms. Greatly enhanced electrochemical properties are achieved with C-PDA-coated SnO(2) nanoparticles where the coating functions as a mechanical buffer layer and conducting bridge.

Leader-Member Exchange (LMX) and Culture: A Meta-Analysis of Correlates of LMX Across 23 Countries

This study extends leader-member exchange (LMX) research by meta-analyzing the role of national culture in moderating relationships between LMX and its correlates. Results based on 282 independent samples (N = 68,587) from 23 countries and controlling for extreme response style differences indicate that (a) relationships of LMX with organizational citizenship behavior, justice perceptions, job satisfaction, turnover intentions, and leader trust are stronger in horizontal-individualistic (e.g., Western) contexts than in vertical-collectivistic (e.g., Asian) contexts; and (b) national culture does not affect relationships of LMX with task performance, organizational commitment, and transformational leadership. These findings highlight that although members are universally sensitive to how their leaders treat them, members' responses in Asian contexts may also be influenced by collective interests and role-based obligations. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Photoswitchable Supramolecular Catalysis by Interparticle Host-Guest Competitive Binding

On and off: Ester hydrolysis catalyzed by a Zn(II) -coordinated β-cyclodextrin dimer can be switched on and off using light in the presence of gold nanoparticles with azobenzene units displayed on their surfaces. Under visible light, the azobenzene units are trans and bind tightly to the dimer, thus leading to reduced catalysis. Under UV light, the azobenzene units are cis and bind loosely to the dimer, thus allowing substrates to bind and hydrolysis to occur.

Contrast-enhanced Ultrasonography Assessment of Gastric Cancer Response to Neoadjuvant Chemotherapy

To quantitatively assess the ability of double contrast-enhanced ultrasound (DCUS) to detect tumor early response to pre-operative chemotherapy.

Online Semi-supervised Learning with KL Distance Weighting for Motor Imagery-based BCI

Studies had shown that Motor Imagery-based Brain Computer Interface (MI-based BCI) system can be used as a therapeutic tool such as for stroke rehabilitation, but had shown that not all subjects could perform MI well. Studies had also shown that MI and passive movement (PM) could similarly activate the motor system. Although the idea of calibrating MI-based BCI system from PM data is promising, there is an inherent difference between features extracted from MI and PM. Therefore, there is a need for online learning to alleviate the difference and improve the performance. Hence, in this study we propose an online batch mode semi-supervised learning with KL distance weighting to update the model trained from the calibration session by using unlabeled data from the online test session. In this study, the Filter Bank Common Spatial Pattern (FBCSP) algorithm is used to compute the most discriminative features of the EEG data in the calibration session and is updated iteratively on each band after a batch of online data is available for performing semi-supervised learning. The performance of the proposed method was compared with offline FBCSP, and results showed that the proposed method yielded slightly better results in comparison with offline FBCSP. The results also showed that the use of the model trained from PM for online session-to-session transfer compared to the use of the calibration model trained from MI yielded slightly better performance. The results suggest that using PM, due to its better performance and ease of recording is feasible and performance can be improved by using the proposed method to perform online semi-supervised learning while subjects perform MI.

Utilization of Temporal Information for Intracranial Pressure Development Trend Forecasting in Traumatic Brain Injury

Objective. Our primary objective is to demonstrate and statistically justify that forecasting models that utilize temporal information of the historical readings of ICP and related parameters are superior, in terms of performance, compared with models that do not make use of temporal information.

Omitting the Intra-session Calibration in EEG-based Brain Computer Interface Used for Stroke Rehabilitation

Brain-computer interface (BCI) as a rehabilitation tool has been used in restoring motor functions in patients with moderate to sever stroke impairments. To achieve the best possible outcome in such an application, it is highly desirable to have a stable and accurate operation of BCI. However, since electroencephalogram (EEG) signals considerably vary between sessions of even the same user, typically a long calibration session is recorded at the beginning of each session. This process is time-consuming and inconvenient for stroke patients who undergo long-term BCI sessions with repeating same mental tasks. This paper investigates the possibility of omitting the intra-session calibration for BCI-based stroke rehabilitation when large data recorded from the same user are available. For this purpose, a large dataset of EEG signals from 11 stroke patients performing 12 BCI-based stroke rehabilitation sessions over one month is used. Our offline results suggest that after recording a number of stroke rehabilitation sessions, the patient does not require calibration any more. The experimental results show that combining 11 sessions, which each session comprises minimum 60 trials per class, yields a model that averagely outperforms the standard calibration model trained by the data recorded directly before the test session.

Transcranial Direct Current Stimulation and EEG-based Motor Imagery BCI for Upper Limb Stroke Rehabilitation

Clinical studies had shown that EEG-based motor imagery Brain-Computer Interface (MI-BCI) combined with robotic feedback is effective in upper limb stroke rehabilitation, and transcranial Direct Current Stimulation (tDCS) combined with other rehabilitation techniques further enhanced the facilitating effect of tDCS. This motivated the current clinical study to investigate the effects of combining tDCS with MI-BCI and robotic feedback compared to sham-tDCS for upper limb stroke rehabilitation. The stroke patients recruited were randomized to receive 20 minutes of tDCS or sham-tDCS prior to 10 sessions of 1-hour MI-BCI with robotic feedback for 2 weeks. The online accuracies of detecting motor imagery from idle condition were assessed and offline accuracies of classifying motor imagery from background rest condition were assessed from the EEG of the evaluation and therapy parts of the 10 rehabilitation sessions respectively. The results showed no evident differences between the online accuracies on the evaluation part from both groups, but the offline analysis on the therapy part yielded higher averaged accuracies for subjects who received tDCS (n=3) compared to sham-tDCS (n=2). The results suggest towards tDCS effect in modulating motor imagery in stroke, but a more conclusive result can be drawn when more data are collected in the ongoing study.

Prefrontal Cortical Activation During Arithmetic Processing Differentiated by Cultures: A Preliminary FNIRS Study

Understanding the neural basis of arithmetic processes could play an important role in improving mathematical education. This study investigates the prefrontal cortical activation among subjects from different cultural backgrounds while performing two difficulty levels of mental arithmetic tasks. The prefrontal cortical activation is measured using a high density 206 channels fNIRS. 8 healthy subjects, consisting of 5 Asians and 3 Europeans, are included in this study. NIRS-SPM is used to compute hemoglobin response changes and generate brain activation map based on two contrasts defined as Easy versus Rest and Hard versus Rest. Differences between the Asian group and the European group are found in both contrasts of Easy versus Rest and Hard versus Rest. The results suggest people with different cultural backgrounds engage different neural pathways during arithmetic processing.

Targeted Agents and Systemic Therapy in Hepatocellular Carcinoma

Cytotoxic chemotherapy, hormonal agents, and immunotherapy have been tested in hepatocellular cancer (HCC) with marginal efficacy to date. Recent insights into the molecular pathogenesis of HCC have identified several aberrant signaling pathways that have served as targets for novel therapeutic agents. These discoveries have been translated into the clinical realm with the use of the antiangiogenic and the Raf kinase inhibitor, sorafenib, and have revealed the potential of targeted agents to produce clinically meaningful survival benefits in patients with advanced HCC. Efforts continue in the quest to improve the outcome of HCC patients through the development and evaluation of other targeted agents, and to better understand the interactions between the underlying disease biology and response to therapy. Several pathways are now implicated in hepatocarcinogenesis and agents that target these pathways continue to be developed.

Factors Determining Diagnostic Yield of Endoscopic Ultrasound Guided Fine-Needle Aspiration for Pancreatic Cystic Lesions: A Multicentre Asian Study

BACKGROUND AND AIM: The purpose of this study was to determine (1) the diagnostic yield for endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in patients with pancreatic cystic lesions, (2) additional value of EUS-FNA over EUS alone in the diagnosis of pancreatic cysts, and (3) diagnostic sensitivity and specificity of EUS and EUS-FNA in the subset of patients where histopathology of surgical specimens were available. METHODS: All patients who underwent EUS examination for the evaluation of pancreatic cystic lesions in six Asian centres were included in the study. RESULTS: Of 298 patients with pancreatic cysts who underwent EUS, 132 (44.3 %) underwent FNA. In the entire cohort, pseudocysts and intraductal papillary mucinous neoplasm (IPMN) were the predominant cystic lesions. The cytologic yield of EUS-FNA was 47 %. On univariate analysis, factors associated with higher cytologic yield included vascular involvement on EUS, presence of solid cystic component, and increased number of needle passes during EUS-FNA. On multivariate analysis, presence of solid cystic components and increased number of needle passes during EUS-FNA were associated with higher diagnostic yield of EUS-FNA. For pancreatic cysts with a solid component, the diagnostic yield of EUS-FNA increased significantly from 44 % with one pass to 78 % with more than one pass (p = 0.016). In the absence of a solid component, the diagnostic yield was 29 % with one pass and was not significantly different from the diagnostic yield of 50 % with more than one pass, p = 0.081. CONCLUSION: The cytologic yield of EUS-FNA was 47 %. When a solid component was present in the cyst, doing more than one pass during EUS-FNA increased its diagnostic yield.

Filtration of Sea Louse, Lepeophtheirus Salmonis, Copepodids by the Blue Mussel, Mytilus Edulis, and the Atlantic Sea Scallop, Placopecten Magellanicus, Under Different Flow, Light and Copepodid-density Regimes

Population management of Lepeophtheirus salmonis in Canada currently relies on chemotherapeutants to remove attached stages of the ectoparasite. However, some populations of L. salmonis are developing resistance to chemotherapeutants making alternate management measures necessary. This article explores the ability of filter-feeding shellfish [i.e. blue mussels (Mytilus edulis) and Atlantic sea scallops (Placopecten magellanicus)] to consume the copepodid stages of L. salmonis in the laboratory under static and flowing water conditions, with variable copepodid densities, and with the aid of a light attractant. Mytilus edulis consumed copepodids under both static and flowing water conditions, and the proportion of individuals ingested was similar at low and high copepodid densities, suggesting that M. edulis was not saturated at the concentrations tested. Also, M. edulis consumed more copepodids when a light attractant was present, suggesting that lights may be useful to concentrate widely dispersed copepodids around cultured shellfish in the field. Finally, P. magellanicus consumed the same number of copepodids as an equivalent total wet weight of M. edulis. During each of the four separate experiments, shellfish consumed between 18 and 38% of the copepodids presented per hour, suggesting that both species are well suited for low level removal of copepodids over time.

The Global Spread of Healthcare-Associated Multidrug-Resistant Bacteria: a Perspective from Asia

Since antibiotics were first used, each new introduced class has been followed by a global wave of emergent resistance, largely originating in Europe and North America where they were first used. MRSA spread from the UK and North America across Europe and then Asia over more than a decade. VRE and KPC-producing Klebsiella pneumoniae followed a similar path some 20 years later. Recently however, metallo-beta-lactamases have originated in Asia. NDM-1 was found in almost every continent within a year of its emergence in India. MBL enzymes are encoded on highly transmissible plasmids that spread rapidly between bacteria, rather than relying on clonal proliferation. Global air travel may have helped facilitate rapid dissemination. As the antibiotic pipeline offers little in the short term, our most important tools against the spread of antibiotic resistant organisms are intensified infection control, surveillance and antimicrobial stewardship.

3H-1,2,4-Dithiazol-3-one Compounds As Novel Potential Affordable Antitubercular Agents

Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette-Guérin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor. Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1,2,4-dithiazol-3-one, and also fifteen 1,3,4-oxathiazol-2-one molecules in order for potency comparison and structure-activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before. All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method. Among the tested compounds, 3H-1,2,4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC(90) value of 1μg/mL. Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method. Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100μM, indicating its better safety profile.

PIK3CA-AKT Pathway Mutations in Micropapillary Breast Carcinoma

Micropapillary carcinoma of the breast is associated with increased rates of lymph node metastasis and lymphovascular invasion. While activating point mutations in PIK3CA (encoding phosphatidylinositol-3-kinase catalytic subunit) or AKT1 are found in 25% to 30% of invasive ductal carcinomas, the mutational profile of invasive micropapillary carcinomas has not been characterized in detail. Micropapillary carcinomas, concurrent metastatic and precursor breast lesions from 19 patients were identified. Lesional tissue was punched from paraffin-tissue blocks, and genomic DNA was extracted and screened for a large panel of known hotspot mutations using multiplex polymerase chain reaction and mass-spectroscopy analysis (643 mutations in 53 genes). Hotspot point mutations were identified in 35% (7/20) of micropapillary breast carcinomas, including PIK3CA exons 7, 9 and 20 hotspots, as well as the AKT1 plekstrin homology domain mutation (E17K); mutations in TP53 and KRAS were each found in a single patient. In 6 patients, micropapillary and non-micropapillary components of the same tumor were separately tested, yielding concordant results in five; one had a wild type micropapillary component, but a PIK3CA mutation in the invasive ductal component. Concurrent lymph node metastases were mostly wild type (2/8 mutant). Accompanying ductal carcinoma in situ had point mutations in 45% (5/11), mostly concordant with invasive carcinoma; however, mutational status of other breast proliferative lesions was generally discordant with accompanying carcinoma. The rate of PIK3CA mutations in this series of micropapillary carcinomas is similar to invasive ductal carcinomas; however, there may be an enrichment of AKT1 mutations (10%). The non-micropapillary components and precursor lesions occasionally had different mutations.

Novel Agmatine Dipeptide Inhibitors Against the West Nile Virus NS2B/NS3 Protease: A P3 and N-cap Optimization Study

This communication describes the synthesis and inhibitory activities of thirty-seven novel C-terminal agmatine dipeptides used as screening compounds to study the structure-activity relationship between active-site peptidomimetics and the West Nile virus (WNV) NS2B/NS3 serine protease. Our efforts lead to the discovery of a novel agmatine dipeptide inhibitor (compound 33, IC(50) 2.6 ± 0.3 μM) with improved inhibitory activity in comparison to the most potent inhibitor described in our recent report [IC(50) 4.7 ± 1.2 μM; Lim et al., Eur. J. Med. Chem. 46 (2011) 3130-3134]. In addition, our study cleared the contention surrounding the previous X-ray co-crystallization study and an enzyme inhibition report on the binding conformation adopted by active-site peptide aldehydes. Our data should provide valuable insights into the design of future peptidomimetic antivirals against WNV infections.

Outcomes and Patterns of Care of Patients with Locally Advanced Oropharyngeal Carcinoma Treated in the Early 21st Century

ABSTRACT: BACKGROUND: We performed this study to assess outcomes of patients with oropharyngeal cancer treated with modern therapy approaches. METHODS: Demographics, treatments and outcomes of patients diagnosed with Stage 3- 4B squamous carcinoma of the oropharynx, between 2000 -- 2007 were tabulated and analyzed. RESULTS: The cohort consisted of 1046 patients. The 5- year actuarial overall survival, recurrence-free survival and local-regional control rates for the entire cohort were 78%, 77% and 87% respectively. More advanced disease, increasing T-stage and smoking were associated with higher rates of local-regional recurrence and poorer survival. CONCLUSIONS: Patients with locally advanced oropharyngeal cancer have a relatively high survival rate. Patients' demographics and primary tumor volume were very influential on these favorable outcomes. In particular, patients with small primary tumors did very well even when treatment was not intensified with the addition of chemotherapy.

Endoscopic Ultrasound

Multiplex Electrochemical Genosensor for Identifying Toxigenic Vibrio Cholerae Serogroups O1 and O139

We developed a multiplex enzyme-based electrochemical genosensor for sequence-specific detection of multiplex linear-after-the-exponential-PCR amplicons that targeted toxigenic Vibrio cholerae O1 and O139 using novel screen-printed gold electrode bisensors.

Repeatability of Primary Selective Laser Trabeculoplasty in Patients with Primary Open-angle Glaucoma

To determine if primary selective laser trabeculoplasty (SLT) can be repeated with clinical benefit in patients with primary open-angle glaucoma (POAG). Forty-two eyes of 42 patients with POAG were studied. All patients underwent primary SLT treatment of 40-50 shots to the trabecular meshwork over 360°. The treatment response at the initial post-SLT visit (4 weeks), and second post-SLT visit (mean 4 months), clinical success and duration of clinical success were measured. SLT was repeated in all patients after failure to maintain target intraocular pressure (IOP). The same parameters were measured after repeat SLT. The main outcome measures were success of treatment (as defined by reduction of IOP by at least 20 % and below an individually determined target pressure), duration of treatment success and reduction in IOP. No significant difference between initial and repeat treatments was found for mean reduction in IOP or success rate, or duration of success. Survival analysis found significantly longer benefit for repeat treatment compared to initial treatment (P < 0.01). Repeat SLT treatment in eyes with POAG has similar efficacy to primary SLT treatment with respect to reduction in IOP and success rates, produces a longer duration of treatment success.

A Preliminary Study of Complementary and Alternative Medicine (CAM) Practitioners in Singapore

To investigate the profile and health attitudes of complementary and alternative medicine (CAM) practitioners in Singapore.

Sleeping Beauty System to Redirect T-cell Specificity for Human Applications

The Sleeping Beauty (SB) transposon/transposase DNA plasmid system is used to genetically modify cells for long-term transgene expression. We adapted the SB system for human application and generated T cells expressing a chimeric antigen receptor (CAR) specific for CD19. Electrotransfer of CD19-specific SB DNA plasmids in peripheral blood mononuclear cells and propagation on CD19 artificial antigen presenting cells was used to numerically expand CD3 T cells expressing CAR. By day 28 of coculture, >90% of expanded CD3 T cells expressed CAR. CAR T cells specifically killed CD19 target cells and consisted of subsets expressing biomarkers consistent with central memory, effector memory, and effector phenotypes. CAR T cells contracted numerically in the absence of the CD19 antigen, did not express SB11 transposase, and maintained a polyclonal TCR Vα and TCR Vβ repertoire. Quantitative fluorescence in situ hybridization revealed that CAR T cells preserved the telomere length. Quantitative polymerase chain reaction and fluorescence in situ hybridization showed CAR transposon integrated on average once per T-cell genome. CAR T cells in peripheral blood can be detected by quantitative polymerase chain reaction at a sensitivity of 0.01%. These findings lay the groundwork as the basis of our first-in-human clinical trials of the nonviral SB system for the investigational treatment of CD19 B-cell malignancies (currently under 3 INDs: 14193, 14577, and 14739).

Method for Real-time Critical Dimensions Signature Monitoring and Control: Sensor, Actuator, and Experimental Results

We present in this paper a system and method for real-time monitoring and control of critical dimensions (CD) signature profile in lithography. The proposed system involves the development and integration of a scatterometry system, a programmable multi-zone thermal processing system, and control system software. Based on scatterometry, the intensity and phase of the reflected light from the resist film are measured at a fixed incident angle and across multiple wavelengths. A programmable thermal processing system is then used to adjust the processing temperature during post-exposure baking in lithography to achieve the desired CD signature profile. Experimental results demonstrate the feasibility of the proposed approach. An improvement of CD signature control of 85% is achieved in terms of the mean square error with and without control.

Development of a Genomic Metric That Can Be Rapidly Used to Predict Clinical Outcome in Severely Injured Trauma Patients

OBJECTIVE:: Many patients have complicated recoveries following severe trauma due to the development of organ injury. Physiological and anatomical prognosticators have had limited success in predicting clinical trajectories. We report on the development and retrospective validation of a simple genomic composite score that can be rapidly used to predict clinical outcomes. DESIGN:: Retrospective cohort study. SETTING:: Multi-institutional level 1 trauma centers. PATIENTS:: Data were collected from 167 severely traumatized (injury severity score >15) adult (18-55 yr) patients. METHODS:: Microarray-derived genomic data obtained from 167 severely traumatized patients over 28 days were assessed for differences in messenger RNA abundance among individuals with different clinical trajectories. Once a set of genes was identified based on differences in expression over the entire study period, messenger RNA abundance from these subjects obtained in the first 24 hrs was analyzed in a blinded fashion using a rapid multiplex platform, and genomic data reduced to a single metric. RESULTS:: From the existing genomic dataset, we identified 63 genes whose leukocyte expression differed between an uncomplicated and complicated clinical outcome over 28 days. Using a multiplex approach that can quantitate messenger RNA abundance in less than 12 hrs (nanoString Technologies, Seattle, WA), we reassessed total messenger RNA abundance from the first 24 hrs after trauma and reduced the genomic data to a single composite score using the difference from reference. This composite score showed good discriminatory capacity to distinguish patients with a complicated outcome (area under a receiver-operator curve, 0.811, p < 0.001). This was significantly better than the predictive power of either Acute Physiology and Chronic Health Evaluation II or new injury severity score scoring systems. CONCLUSIONS:: A rapid genomic composite score obtained in the first 24 hrs after trauma can retrospectively identify trauma patients who are likely to develop complicated clinical trajectories. A novel platform is described in which this genomic score can be obtained within 12 hrs of blood collection, making it available for clinical decision making.

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