Induction of specific brain oscillations may restore neural circuits and be used for the treatment of Alzheimer's disease.

Brain oscillations underlie the function of our brains, dictating how we both think and react to the world around us. The synchronous activity of neurons generates these rhythms, which allow different parts of the brain to communicate and orchestrate responses to internal and external stimuli. Perturbations of cognitive rhythms and the underlying oscillator neurons that synchronize different parts of the brain contribute to the pathophysiology of diseases including Alzheimer's disease, (AD), Parkinson's disease (PD), epilepsy and other diseases of rhythm that have been studied extensively by Gyorgy Buzsaki. In this review, we discuss how neurologists manipulate brain oscillations with neuromodulation to treat diseases and how this can be leveraged to improve cognition and pathology underlying AD. While multiple modalities of neuromodulation are currently clinically indicated for some disorders, nothing is yet approved for improving memory in AD. Recent investigations into novel methods of neuromodulation show potential for improving cognition in memory disorders. Here, we demonstrate that neuronal stimulation using audiovisual sensory stimulation that generated 40-HZ gamma waves reduced AD-specific pathology and improved performance in behavioural tests in mouse models of AD, making this new mode of neuromodulation a promising new avenue for developing a new therapeutic intervention for the treatment of dementia.

Development of a density-tapered capillary gas cell for laser wakefield acceleration.

A capillary gas cell for laser wakefield acceleration was developed with the aid of three-dimensional computational fluid dynamics simulations. The gas cell was specially designed to provide upward density tapering in the longitudinal direction, which is expected to suppress the dephasing problem in laser wakefield acceleration by keeping the accelerated electrons in the acceleration phase of the wake wave. The density-tapered capillary gas cell was fabricated by sapphire plates, and its performance characteristics were tested. The capillary gas cell was filled with a few hundred millibars of hydrogen gas, and a Ti:sapphire laser pulse with a peak power of 3.8 TW and a pulse duration of 40 fs (full width at half maximum) was sent through the capillary hole, which has a length of 7 mm and a square cross section of 350 × 350 µm2. The laser-produced hydrogen plasma in the capillary hole was then diagnosed two-dimensionally by using a transverse Mach-Zehnder interferometer. The capillary gas cell was found to provide an upward plasma density tapering in the range of 1018 cm-3-1019 cm-3, which has a potential to enhance the electron beam energy in laser wakefield acceleration experiments.

Deep neuromuscular blockade during spinal surgery reduces intra-operative blood loss: A randomised clinical trial.

BACKGROUND: Spinal surgery is usually performed in the prone position using a posterior approach. However, the prone position may cause venous engorgement in the back and thus increase surgical bleeding with interruption of surgery. The prone position also affects cardiac output since large vessels are compressed decreasing venous return to the heart. OBJECTIVE: We hypothesised that deep neuromuscular blockade would be associated with less surgical bleeding during spinal surgery in the prone position. DESIGN: Randomised, single blinded trial. SETTING: University teaching hospital. PARTICIPANTS: Eighty-eight patients in two groups. INTERVENTIONS: Patients were randomly assigned to moderate neuromuscular blockade or deep neuromuscular blockade. In the moderate neuromuscular blockade group, administration of rocuronium was adjusted such that the train-of-four count was one to two. In the deep neuromuscular blockade group, rocuronium administration was adjusted such that the train-of-four count was zero with a posttetanic count 2 or less. MAIN OUTCOME MEASURES: The primary outcome was the volume of intra-operative surgical bleeding. The surgeon's satisfaction with operating conditions, haemodynamic and respiratory status, and postoperative pain scores were evaluated. RESULTS: The median [IQR] volume of intra-operative surgical bleeding was significantly less in the deep neuromuscular blockade group than in the moderate neuromuscular blockade group; 300 ml [200 to 494] vs. 415 ml [240 to 601]; difference: 117 ml (95% CI, 9 to 244; P = 0.044). The mean ±â€ŠSD surgeon's satisfaction with the intra-operative surgical conditions was greater in the deep neuromuscular blockade group than in the moderate neuromuscular blockade group; 3.5 ±â€Š1.0 vs. 2.9 ±â€Š0.9 (P = 0.004). In intergroup comparisons of respiratory variables, peak inspiratory pressure was lower in the deep neuromuscular blockade group overall (P < 0.001). The median [IQR] postoperative pain score was lower in the deep neuromuscular blockade group than the moderate neuromuscular blockade group; 50 [36 to 60] vs. 60 [50 to 70], (P = 0.023). CONCLUSION: Deep neuromuscular blockade reduced intra-operative surgical bleeding in patients undergoing spinal surgery. This may be related to greater relaxation in the back muscles and lower intra-operative peak inspiratory pressure when compared with moderate neuromuscular blockade. TRIAL REGISTRATION: KCT0001264 (http://cris.nih.go.kr).

Interferometric analysis of sub-nanosecond laser-induced optical breakdown dynamics in the bulk of fused-silica glass.

Dynamics of laser-induced optical breakdown in the bulk of fused-silica glass irradiated by a sub-nanosecond laser pulse at a wavelength of 790 nm with a fluence of 522 J/cm2 was studied by the femtosecond time-resolved complex interferometry in Nomarski arrangement utilising a Fresnel bi-prism. Evolution of the plasma channel and the development of the free electron density were in focus of the investigation. The measured ultimate length of the plasma channel was equal to 30 µm and almost doubled the length estimated within the moving breakdown model. The history of the transient electron density distribution in the plasma was reconstructed from the phase shift maps using the inverse Abel transform and it revealed further deviation from this model. The core of the plasma channel exhibited at the last stages of the development a considerable level of the electron density up to 2.4×1020 cm-3. The signature of the pre-breakdown phase has been identified as radiation caused by ionization-released electrons interacting with ions and has been demonstrated in solids for the first time in this way. Origin of the discrepancy between the theoretical prediction of the moving breakdown model and the measured values of the channel length is discussed as well.

Sequencing-based counting and size profiling of plasma Epstein-Barr virus DNA enhance population screening of nasopharyngeal carcinoma.

Circulating tumor-derived DNA testing for cancer screening has recently been demonstrated in a prospective study on identification of nasopharyngeal carcinoma (NPC) among 20,174 asymptomatic individuals. Plasma EBV DNA, a marker for NPC, was detected using real-time PCR. While plasma EBV DNA was persistently detectable in 97.1% of the NPCs identified, ∼5% of the general population had transiently detectable plasma EBV DNA. We hypothesized that EBV DNA in plasma of subjects with or without NPC may have different molecular characteristics. We performed target-capture sequencing of plasma EBV DNA and identified differences in the abundance and size profiles of EBV DNA molecules within plasma of NPC and non-NPC subjects. NPC patients had significantly higher amounts of plasma EBV DNA, which showed longer fragment lengths. Cutoff values were established from an exploratory dataset and tested in a validation sample set. Adopting an algorithm that required a sample to concurrently pass cutoffs for EBV DNA counting and size measurements, NPCs were detected at a positive predictive value (PPV) of 19.6%. This represented superior performance compared with the PPV of 11.0% in the prospective screening study, which required participants with an initially detectable plasma EBV DNA result to be retested within 4 weeks. The observed differences in the molecular nature of EBV DNA molecules in plasma of subjects with or without NPC were successfully translated into a sequencing-based test that had a high PPV for NPC screening and achievable through single time-point testing.

A possible new target in lung-cancer cells: The orphan receptor, bombesin receptor subtype-3.

Human bombesin receptors, GRPR and NMBR, are two of the most frequently overexpressed G-protein-coupled-receptors by lung-cancers. Recently, GRPR/NMBR are receiving considerable attention because they act as growth factor receptors often in an autocrine manner in different lung-cancers, affect tumor angiogenesis, their inhibition increases the cytotoxic potency of tyrosine-kinase inhibitors reducing lung-cancer cellular resistance/survival and their overexpression can be used for sensitive tumor localization as well as to target cytotoxic agents to the cancer. The orphan BRS-3-receptor, because of homology is classified as a bombesin receptor but has received little attention, despite the fact that it is also reported in a number of studies in lung-cancer cells and has growth effects in these cells. To address its potential importance, in this study, we examined the frequency/relative quantitative expression of human BRS-3 compared to GRPR/NMBR and the effects of its activation on cell-signaling/growth in 13 different human lung-cancer cell-lines. Our results showed that BRS-3 receptor is expressed in 92% of the cell-lines and that it is functional in these cells, because its activation stimulates phospholipase-C with breakdown of phosphoinositides and changes in cytosolic calcium, stimulates ERK/MAPK and stimulates cell growth by EGFR transactivation in some, but not all, the lung-cancer cell-lines. These results suggest that human BRS-3, similar to GRPR/NMBR, is frequently ectopically-expressed by lung-cancer cells in which, it is functional, affecting cell signaling/growth. These results suggest that similar to GRPR/NMBR, BRS-3 should receive increased attention as possible approach for the development of novel treatments and/or diagnosis in lung-cancer.

Increased impedance near cut-off in plasma-like media leading to emission of high-power, narrow-bandwidth radiation.

Ultra-intense, narrow-bandwidth, electromagnetic pulses have become important tools for exploring the characteristics of matter. Modern tuneable high-power light sources, such as free-electron lasers and vacuum tubes, rely on bunching of relativistic or near-relativistic electrons in vacuum. Here we present a fundamentally different method for producing narrow-bandwidth radiation from a broad spectral bandwidth current source, which takes advantage of the inflated radiation impedance close to cut-off in a medium with a plasma-like permittivity. We find that by embedding a current source in this cut-off region, more than an order of magnitude enhancement of the radiation intensity is obtained compared with emission directly into free space. The method suggests a simple and general way to flexibly use broadband current sources to produce broad or narrow bandwidth pulses. As an example, we demonstrate, using particle-in-cell simulations, enhanced monochromatic emission of terahertz radiation using a two-colour pumped current source enclosed by a tapered waveguide.

Development of polymorphic microsatellite loci in Odontobutis obscura using Illumina paired-end sequencing and the test of cross-species amplification.

Odontobutis obscura is a bottom-dwelling freshwater fish native to East Asia. Its range encompasses southwest China, western Japan, and Geoje Island in South Korea. Despite its widespread range in China and Japan, only a small and spatially isolated population is found in South Korea. We developed a total of 23 novel and polymorphic microsatellite loci of O. obscura using Illumina paired-end shotgun sequencing and characterized them using 80 Japanese and Korean samples. An extensive genetic polymorphism was detected at these 23 loci, with the observed number of alleles at a locus ranging from 2 to 15 and expected and observed heterozygosities ranging from 0 to 0.656 and 0 to 0.547, respectively. Korean O. obscura exhibited a much lower level of genetic variability than the Japanese population did, probably as a result of long-term isolation combined with historical bottlenecks. The Japanese and Korean populations showed a high level of genetic differentiation with FST = 0.700 and RST = 0.913. Many of our primer sets were successfully transferable to congeneric O. interrupta and O. platycephala, which exhibited even greater polymorphism than Korean O. obscura. In conclusion, our study showed that these 23 microsatellite markers are useful for understanding the conservation biology and population genetic structure of O. obscura and other congeneric species.

Isolation and characterization of novel microsatellite loci in the wrinkled frog.

The wrinkled frog, Rana rugosa, is a species complex that inhabits plains and mountains near freshwater bodies throughout East Asia, encompassing China, Korea, Japan, and the Russian Primorye region. Although extensive efforts are required to estimate cryptic diversity in the R. rugosa complex, no specifically designed microsatellite loci are available. Here, novel and polymorphic microsatellites were isolated based on the construction of a microsatellite-enriched library and characterized using R. rugosa specimens collected on the Korean Peninsula. A total of 72 primer sets were designed from approximately 400 positive clones, and 22 were validated as being reliably amplified and polymorphic. Overall, high genetic variability was observed (mean number of alleles per locus = 22.23; mean observed and expected heterozygosities = 0.770 and 0.816, respectively) from a total of 60 individuals sampled from two geographically isolated localities. In the two sites analyzed, an extremely low level of relatedness was inferred from the estimation of pairwise relatedness, and no evidence of a genetic bottleneck was detected. The two sites showed a high level of genetic differentiation, suggesting a clear signature of isolation following colonization. With high statistical power in parentage and sibship exclusion, these microsatellite loci will be suitable for the identification of cryptic diversity and population structure as well as the recognition of individuals in social interaction and captive breeding practice.

Optical coherence tomography predicts visual outcome in acute central retinal vein occlusion.

PURPOSE: To investigate the clinical features of central retinal vein occlusion (CRVO) in relation to the presence of a prominent middle limiting membrane (p-MLM) sign on presenting optical coherence tomography, which may suggest macular ischemia and poor visual outcome. METHODS: Fifty consecutive eyes with acute CRVO of <1 month of symptom duration before presentation were retrospectively reviewed. A hyperreflective line located in the outer plexiform layer (p-MLM) in optical coherence tomography was used as a sign of acute ischemia. Cases with p-MLM were grouped and compared with the group of eyes with no p-MLM sign (non-MLM group) for clinical features including visual acuities, central fovea thickness, and CRVO types. RESULTS: Among the 50 eyes, 14 (28%) eyes showed a p-MLM sign, 21 (42%) eyes did not, and others had equivocal findings. Eyes with p-MLM sign presented worse initial and final best-corrected visual acuity compared with the non-MLM group (1.10 ± 0.72 vs. 0.47 ± 0.49 logMAR in the initial best-corrected visual acuity, P = 0.007; and 1.08 ± 0.86 vs. 0.32 ± 0.41 logMAR in the final best-corrected visual acuity, P = 0.044) in patients with a follow-up duration of 6 months or longer. The p-MLM group eyes showed a higher tendency toward being classified as ischemic type CRVO (57.1 vs. 4.8%, P = 0.001). CONCLUSION: Central retinal vein occlusion showing p-MLM on optical coherence tomography had worse visual outcome with higher incidence of being classified into ischemic type CRVO.

Preclinical evaluation of the mTOR-PI3K inhibitor BEZ235 in nasopharyngeal cancer models.

The dual PI3K-mTOR inhibitor BEZ235 was evaluated in preclinical models of nasopharyngeal carcinoma (NPC). The IC50 value of BEZ235 for growth was in the nanomolar range in vitro, induce G1 cycle arrest and apoptosis, and inhibited AKT and mTOR signaling in most NPC cell lines. No synergistic effect was observed when BEZ235 was combined with chemotherapy. BEZ235 increased MAPK activation in vitro but not in vivo. A daily schedule was more effective than a weekly schedule on tumor growth and inhibition of downstream mTOR signaling in vivo. The activity of BEZ235 maybe independent of the PIK3CA amplification and mutation status.

Effects of exercise program on appetite-regulating hormones, inflammatory mediators, lipid profiles, and body composition in healthy men.

AIM: Exercise can improve appetite, inflammatory mediators, lipid profiles, and body composition in overweight or obese patients. However, it has not yet been clearly elucidated how exercise affects healthy people in relation to these variables. Thus, we investigated the effects of an exercise program on appetite-regulating hormones, inflammatory mediators, lipid profiles, and body composition in healthy men. METHODS: Thirty sedentary men were recruited and randomly assigned to two groups (exercise group, EG, N.=15 and control group, CG, N.=15). Total plasma ghrelin, leptin, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were determined by radioimmunoassay and immunoassay. Total cholesterol (TC), triglyceride (TG), high- and low-density lipoprotein cholesterol (HDL-C and LDL-C) were determined by enzymatic assay. Body composition was determined by bioelectrical impedance analysis. RESULTS: After 8 weeks, the ghrelin and leptin levels of CG showed a tendency to increase, whereas those of EG were significantly decreased. Although TNF-α and CRP, except for IL-6, showed a tendency to increase in CG, all three tended to decrease in EG after 8 weeks. TG and LDL-C were significantly increased in CG. The TC, TG, and LDL-C levels of EG were remarkably decreased, whereas HDL-C was significantly increased. In EG, body weight, fat mass, percent fat, and waist/hip ratio were significantly decreased, whereas muscle mass was significantly increased after 8 weeks. CONCLUSION: The present study results have demonstrated the beneficial effects of an exercise program by altering appetite-regulating hormones, decreasing inflammatory factors, and improving lipid profiles and body composition in healthy young men.

Modeling the distribution of Culex tritaeniorhynchus to predict Japanese encephalitis distribution in the Republic of Korea.

Over 35,000 cases of Japanese encephalitis (JE) are reported worldwide each year. Culex tritaeniorhynchus is the primary vector of the JE virus, while wading birds are natural reservoirs and swine amplifying hosts. As part of a JE risk analysis, the ecological niche modeling programme, Maxent, was used to develop a predictive model for the distribution of Cx. tritaeniorhynchus in the Republic of Korea, using mosquito collection data, temperature, precipitation, elevation, land cover and the normalized difference vegetation index (NDVI). The resulting probability maps from the model were consistent with the known environmental limitations of the mosquito with low probabilities predicted for forest covered mountains. July minimum temperature and land cover were the most important variables in the model. Elevation, summer NDVI (July-September), precipitation in July, summer minimum temperature (May-August) and maximum temperature for fall and winter months also contributed to the model. Comparison of the Cx. tritaeniorhynchus model to the distribution of JE cases in the Republic of Korea from 2001 to 2009 showed that cases among a highly vaccinated Korean population were located in high-probability areas for Cx. tritaeniorhynchus. No recent JE cases were reported from the eastern coastline, where higher probabilities of mosquitoes were predicted, but where only small numbers of pigs are raised. The geographical distribution of reported JE cases corresponded closely with the predicted high-probability areas for Cx. tritaeniorhynchus, making the map a useful tool for health risk analysis that could be used for planning preventive public health measures.

Melanocytoma of the optic disk in the Korean population.

PURPOSE: To report on the clinical features and the natural course of optic disk melanocytoma in the Korean population. METHODS: A retrospective review of medical records was performed on 27 consecutive patients with optic disk melanocytoma. In cases with tumor enlargement, surface area and diameter of tumors were measured from fundus images using computer software. RESULTS: The median age at diagnosis was 46 years with a slight female predominance (63%). The median tumor diameter and height were 3.1 mm and 1.9 mm, respectively. There were no cases with tumor-related visual loss for a median follow-up of 2 years. Tumor enlargement was observed in 4 of 21 patients (19%) that had follow-up of 1 year or more with no malignant transformation. The mean change of tumor surface area was 2.4 mm (52% increase), and the mean change of tumor diameter was 1.8 mm over a mean follow-up of 53 months in 4 cases with tumor growth. Only tumor vascularization on fluorescent angiography correlated with tumor growth (Log-rank test; P = 0.049). Kaplan-Meier survival estimated that the tumor growth was 0% at 1 year, 14% at 5 years, and 57% at 8 years. CONCLUSION: Optic disk melanocytoma in the Korean population tends to be superiorly located in the optic disk, and visual prognosis was excellent. Periodic ocular examination is warranted because 57% of patients were estimated to show tumor enlargement by 8 years of follow-up.

A novel zebrafish jak2a(V581F) model shared features of human JAK2(V617F) polycythemia vera.

OBJECTIVE: The Janus kinase 2 (JAK2) is important for embryonic primitive hematopoiesis. A gain-of-function JAK2 (JAK2(V617F)) mutation in human is pathogenetically linked to polycythemia vera (PV). In this study, we generated a zebrafish ortholog of human JAK2(V617F) (referred herewith jak2a(V581F)) by site-directed mutagenesis and examined its relevance as a model of human PV. MATERIALS AND METHODS: Zebrafish embryos at one-cell stage were injected with jak2a(V581F) mRNA (200pg/embryo). In some experiments, the embryos were treated with a specific JAK2 inhibitor, TG101209. The effects of jak2a stimulation on hematopoiesis, jak/stat signaling, and erythropoietin signaling were evaluated at 18-somites. RESULTS: Injection with jak2a(V581F) mRNA significantly increased erythropoiesis, as enumerated by flow cytometry based on gfp(+) population in dissociated Tg(gata1:gfp) embryos. The response was reduced by stat5.1 morpholino coinjection (control: 4.37% +/- 0.08%; jak2a(V581F) injected: 5.71% +/- 0.07%, coinjecting jak2a(V581F) mRNA and stat5.1 morpholino: 4.66% +/- 0.13%; p<0.01). jak2a(V581F) mRNA also upregulated gata1 (1.83 +/- 0.08 fold; p=0.005), embryonic alpha-hemoglobin (1.61 +/- 0.12 fold; p=0.049), and beta-hemoglobin gene expression (1.65 +/- 0.13-fold; p=0.026) and increased stat5 phosphorylation. These responses were also ameliorated by stat5.1 morpholino coinjection or treatment with a specific JAK2 inhibitor, TG101209. jak2a(V581F) mRNA significantly reduced erythropoietin gene (0.24 +/- 0.03 fold; p=0.006) and protein expression (control: 0.633+/-0.11; jak2a(V581F) mRNA: 0.222+/-0.07 mIU/mL; p=0.019). CONCLUSION: The zebrafish jak2a(V581F) model shared many features with human PV and might provide us with mechanistic insights of this disease.

Combined delivery of heme oxygenase-1 gene and fibroblast growth factor-2 protein for therapeutic angiogenesis.

Ectopic expression of heme oxygenase-1 (HO-1) in ischemic tissue protects the tissue from apoptosis and necrosis and promotes angiogenesis. However, apoptosis and necrosis will decrease HO-1 gene transfection efficacy. We hypothesized that fibroblast growth factor-2 (FGF2) would attenuate ischemic damage during the incipient period, improve HO-1 gene transfection and, in turn, enhance neovascularization. To test this hypothesis, we employed a mouse model of hindlimb ischemia and treated the mice with HO-1 gene therapy alone, FGF2 alone, or HO-1 gene therapy plus FGF2. As controls, a group of mice was left untreated. At 12h, prior to the expression of exogenously delivered HO-1, apoptosis was significantly reduced in mice treated with FGF2, either alone or in combination with HO-1 gene therapy. At 3 days, HO-1 expression was greater in mice that also received FGF2 than in mice treated with HO-1 gene therapy alone. The expression of angiogenic growth factors and angiogenesis was greater in mice treated with HO-1 gene therapy plus FGF2 than in mice treated with HO-1 gene therapy alone. These data indicate that FGF2 rescued muscle necrosis prior to the exogenous expression of HO-1 and enhanced HO-1 gene transfection in ischemic murine limbs.

In vitro cardiomyogenic differentiation of adipose-derived stromal cells using transforming growth factor-beta1.

Transplanting stem cells differentiated towards a cardiac lineage can regenerate cardiac muscle tissues to treat myocardial infarction. In this study, we tested the hypothesis that transforming growth factor-beta1 (TGF-beta1) induces cardiomyogenic differentiation of adipose- derived stromal cells (ADSCs) in vitro. Rat ADSCs were cultured with TGF-beta1 (10 ng ml(-1)) for 2 weeks in vitro. ADSCs cultured without TGF-beta1 served as a control. The mRNA expression of cardiac-specific gene was induced by TGF-beta1, while the control culture did not show cardiac-specific gene expression. Immunocytochemical analyses showed that a small fraction of ADSCs cultured with TGF-beta1 for 2 weeks stained positively for cardiac myosin heavy chain (MHC) and alpha-sarcomeric actin. Flow cytometric analyses showed that the proportion of cells expressing cardiac MHC increased with TGF-beta1. However, no mesenchymal differentiation (e.g., osteogenic and adipogenic differentiation) was detected other than cardiomyogenic differentiation. These results showed that TGF-beta1 induce ADSC cardiomyogenic differentiation in vitro, which could be useful for myocardial infarction stem cell therapy.