The design and protocol of acupuncture for migraine prophylaxis: A multicenter randomized controlled trial

Background: Many studies have already reported encouraging results in the prophylactic therapy of migraine by acupuncture, but there seems to be a lack of high quality randomized controlled trials from China. We design and perform a randomized controlled clinical trial to evaluate the efficacy of acupuncture compared with flunarizine in the prophylactic therapy of patients with migraine without aura in China. Methods: This trial is a multicenter, prospective, randomized controlled clinical trial. The 140 migraine patients are randomly allocated to two different groups. The acupuncture groups (n = 70) is treated with acupuncture and placebo medicine; while the control group (n = 70) is treated with sham acupuncture and medicine (Flunarizine). Both Flunarizine and placebo are taken 10 mg once per night for the first 2 weeks and then 5 mg once per night for the next 2 weeks. Patients in both groups receive 12 sessions of verum/sham acupuncture in 4 weeks. Discussion: The study design and the long term clinical practice of acupuncturists guarantee a high external validity for the results. The results of our trial will be helpful to supply the evidence on the efficacy of acupuncture for migraine prophylaxis in China. Trial Registration: The trial is registered at Controlled Clinical Trials: ISRCTN49839714.Medicine, Research & ExperimentalSCI(E)0ARTICLEnull1

Regulation of DNA Repair Mechanism in Human Glioma Xenograft Cells both In Vitro and In Vivo in Nude Mice

Glioblastoma Multiforme (GBM) is the most lethal form of brain tumor. Efficient DNA repair and anti-apoptotic mechanisms are making glioma treatment difficult. Proteases such as MMP9, cathepsin B and urokinase plasminogen activator receptor (uPAR) are over expressed in gliomas and contribute to enhanced cancer cell proliferation. Non-homologous end joining (NHEJ) repair mechanism plays a major role in double strand break (DSB) repair in mammalian cells.Here we show that silencing MMP9 in combination with uPAR/cathepsin B effects NHEJ repair machinery. Expression of DNA PKcs and Ku70/80 at both mRNA and protein levels in MMP9-uPAR (pMU) and MMP9-cathepsin B (pMC) shRNA-treated glioma xenograft cells were reduced. FACS analysis showed an increase in apoptotic peak and proliferation assays revealed a significant reduction in the cell population in pMU- and pMC-treated cells compared to untreated cells. We hypothesized that reduced NHEJ repair led to DSBs accumulation in pMU- and pMC-treated cells, thereby initiating cell death. This hypothesis was confirmed by reduced Ku70/Ku80 protein binding to DSB, increased comet tail length and elevated γH2AX expression in treated cells compared to control. Immunoprecipitation analysis showed that EGFR-mediated lowered DNA PK activity in treated cells compared to controls. Treatment with pMU and pMC shRNA reduced the expression of DNA PKcs and ATM, and elevated γH2AX levels in xenograft implanted nude mice. Glioma cells exposed to hypoxia and irradiation showed DSB accumulation and apoptosis after pMU and pMC treatments compared to respective controls.Our results suggest that pMU and pMC shRNA reduce glioma proliferation by DSB accumulation and increase apoptosis under normoxia, hypoxia and in combination with irradiation. Considering the radio- and chemo-resistant cancers favored by hypoxia, our study provides important therapeutic potential of MMP9, uPAR and cathepsin B shRNA in the treatment of glioma from clinical stand point

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Nutrient Intakes Linked to Better Health Outcomes Are Associated with Higher Diet Costs in the US

Degrees of nutrient intake and food groups have been linked to differential chronic disease risk. However, intakes of specific nutrients may also be associated with differential diet costs and unobserved differences in socioeconomic status (SES). The present study examined degrees of nutrient intake, for every key nutrient in the diet, in relation to diet cost and SES.Socio-demographic data for a stratified random sample of adult respondents in the Seattle Obesity Study were obtained through telephone survey. Dietary intakes were assessed using food frequency questionnaire (FFQ) (n = 1,266). Following standard procedures, nutrient intakes were energy-adjusted using the residual method and converted into quintiles. Diet cost for each respondent was estimated using Seattle supermarket retail prices for 384 FFQ component foods.Higher intakes of dietary fiber, vitamins A, C, D, E, and B12, beta carotene, folate, iron, calcium, potassium, and magnesium were associated with higher diet costs. The cost gradient was most pronounced for vitamin C, beta carotene, potassium, and magnesium. Higher intakes of saturated fats, trans fats and added sugars were associated with lower diet costs. Lower cost lower quality diets were more likely to be consumed by lower SES.Nutrients commonly associated with a lower risk of chronic disease were associated with higher diet costs. By contrast, nutrients associated with higher disease risk were associated with lower diet costs. The cost variable may help somewhat explain why lower income groups fail to comply with dietary guidelines and have highest rates of diet related chronic disease

Mitochondrial Oxidative Stress Causes Hyperphosphorylation of Tau

Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD): tau phosphorylation, and ß-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau) in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a well-characterized mouse model of AD (Tg2576) with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Aß load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD

Towards a resolution of some outstanding issues in transitive research: an empirical test on middle childhood

Transitive Inference (deduce B > D from B > C and C > D) can help us to understand other areas of sociocognitive development. Across three experiments, learning, memory, and the validity of two transitive paradigms were investigated. In Experiment 1 (N = 121), 7-year-olds completed a three-term nontraining task or a five-term task requiring extensive-training. Performance was superior on the three-term task. Experiment 2 presented 5–10-year-olds with a new five-term task, increasing learning opportunities without lengthening training (N = 71). Inferences improved, suggesting children can learn five-term series rapidly. Regarding memory, the minor (CD) premise was the best predictor of BD-inferential performance in both task-types. However, tasks exhibited different profiles according to associations between the major (BC) premise and BD inference, correlations between the premises, and the role of age. Experiment 3 (N = 227) helped rule out the possible objection that the above findings simply stemmed from three-term tasks with real objects being easier to solve than computer-tasks. It also confirmed that, unlike for five-term task (Experiments 1 & 2), inferences on three-term tasks improve with age, whether the age range is wide (Experiment 3) or narrow (Experiment 2). I conclude that the tasks indexed different routes within a dual-process conception of transitive reasoning: The five-term tasks indexes Type 1 (associative) processing, and the three-term task indexes Type 2 (analytic) processing. As well as demonstrating that both tasks are perfectly valid, these findings open up opportunities to use transitive tasks for educability, to investigate the role of transitivity in other domains of reasoning, and potentially to benefit the lived experiences of persons with developmental issues

Small-Animal PET Imaging of Amyloid-Beta Plaques with [11C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease

In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice

Right hemisphere has the last laugh: neural dynamics of joke appreciation

Understanding a joke relies on semantic, mnemonic, inferential, and emotional contributions from multiple brain areas. Anatomically constrained magnetoencephalography (aMEG) combining high-density whole-head MEG with anatomical magnetic resonance imaging allowed us to estimate where the humor-specific brain activations occur and to understand their temporal sequence. Punch lines provided either funny, not funny (semantically congruent), or nonsensical (incongruent) replies to joke questions. Healthy subjects rated them as being funny or not funny. As expected, incongruous endings evoke the largest N400m in left-dominant temporo-prefrontal areas, due to integration difficulty. In contrast, funny punch lines evoke the smallest N400m during this initial lexical–semantic stage, consistent with their primed “surface congruity” with the setup question. In line with its sensitivity to ambiguity, the anteromedial prefrontal cortex may contribute to the subsequent “second take” processing, which, for jokes, presumably reflects detection of a clever “twist” contained in the funny punch lines. Joke-selective activity simultaneously emerges in the right prefrontal cortex, which may lead an extended bilateral temporo-frontal network in establishing the distant unexpected creative coherence between the punch line and the setup. This progression from an initially promising but misleading integration from left frontotemporal associations, to medial prefrontal ambiguity evaluation and right prefrontal reprocessing, may reflect the essential tension and resolution underlying humor