Theoretical and practical applications of the intracerebroventricular route for CSF sampling and drug administration in CNS drug discovery research: a mini review

Clinically, central nervous system (CNS) disorders account for more hospitalisations and prolonged care than almost all other diseases combined. In the preclinical setting, the intracerebroventricular (ICV) route for cerebrospinal fluid (CSF) sampling or dose administration in rodent models of human CNS disorders has potential to provide key insight on the pathobiology of these conditions. Low level neuroinflammation is present in >40% of patients with severe depression or schizophrenia and so comparative assessment of CSF composition between patients and rodent models of CNS disorders is potentially invaluable for hypothesis generation and for assessing rodent model validity. As molecules in the CSF have relatively low protein binding and are freely exchanged into the extracellular fluid of the brain parenchyma, supraspinal drug administration into the CSF can produce therapeutic drug concentrations in the brain. Direct administration of investigational agents into the CSF of the lateral ventricle of the brain enables intrinsic efficacy and adverse effect profiles to be evaluated without the confounding effects of drug metabolism, due to the low capacity of the CNS to metabolise exogenous compounds. It is our view that the ICV route for CSF sampling and for administration of novel drugs in development is under-utilised in preclinical research on CNS disorders. This is due to the high degree of technical skill and low margin for error associated with correct ICV guide cannula implantation in the rat. However, these technical challenges can be overcome by using standardised procedures and attention to detail during surgery and in the post-operative period. (C) 2014 Elsevier B.V. All rights reserved

The Effects Of Direction Of Electronic Word-Of-Mouth And Tie Strength On Purchase Decisions: Self-Construal As The Moderator

Electronic Word-of-Mouth (eWOM) has become an important communication method and has received considerable interest. This study examined how direction of eWOM (positive vs. negative) and tie strength influence consumers’ online purchase decision making and how the relationships are moderated by self-construal of online consumers. The empirical results showed that the effects of eWOM direction on intention to click, attitude toward the product ad, product attitude, and purchase intention were stronger for consumers with interdependent self-construal than for those with independent self-construal. Besides, the results also showed that the effects of tie strength between reviewer and consumer on intention to click, attitude toward the product ad, product attitude and purchase intention were stronger for interdependent consumers than for independent consumers when receiving eWOM from their strong ties; whereas, the effects were stronger for independent consumers than for interdependent consumers when receiving eWOM from their weak ties. The findings of this study offer insights for advertiser to develop effective online marketing strategy on social networking sites

A Reduced-Complexity Fast Algorithm for Software Implementation of the IFFT/FFT in DMT Systems

The discrete multitone (DMT) modulation/demodulation scheme is the standard transmission technique in the application of asymmetric digital subscriber lines (ADSL) and very-high-speed digital subscriber lines (VDSL). Although the DMT can achieve higher data rate compared with other modulation/demodulation schemes, its computational complexity is too high for cost-efficient implementations. For example, it requires 512-point IFFT/FFT as the modulation/demodulation kernel in the ADSL systems and even higher in the VDSL systems. The large block size results in heavy computational load in running programmable digital signal processors (DSPs). In this paper, we derive computationally efficient fast algorithm for the IFFT/FFT. The proposed algorithm can avoid complex-domain operations that are inevitable in conventional IFFT/FFT computation. The resulting software function requires less computational complexity. We show that it acquires only 17% number of multiplications to compute the IFFT and FFT compared with the Cooly-Tukey algorithm. Hence, the proposed fast algorithm is very suitable for firmware development in reducing the MIPS count in programmable DSPs

Transcriptional regulation of FoxO3 gene by glucocorticoids in murine myotubes.

Glucocorticoids and FoxO3 exert similar metabolic effects in skeletal muscle. FoxO3 gene expression was increased by dexamethasone (Dex), a synthetic glucocorticoid, both in vitro and in vivo. In C2C12 myotubes the increased expression is due to, at least in part, the elevated rate of FoxO3 gene transcription. In the mouse FoxO3 gene, we identified three glucocorticoid receptor (GR) binding regions (GBRs): one being upstream of the transcription start site, -17kbGBR; and two in introns, +45kbGBR and +71kbGBR. Together, these three GBRs contain four 15-bp glucocorticoid response elements (GREs). Micrococcal nuclease (MNase) assay revealed that Dex treatment increased the sensitivity to MNase in the GRE of +45kbGBR and +71kbGBR upon 30- and 60-min Dex treatment, respectively. Conversely, Dex treatment did not affect the chromatin structure near the -17kbGBR, in which the GRE is located in the linker region. Dex treatment also increased histone H3 and/or H4 acetylation in genomic regions near all three GBRs. Moreover, using chromatin conformation capture (3C) assay, we showed that Dex treatment increased the interaction between the -17kbGBR and two genomic regions: one located around +500 bp and the other around +73 kb. Finally, the transcriptional coregulator p300 was recruited to all three GBRs upon Dex treatment. The reduction of p300 expression decreased FoxO3 gene expression and Dex-stimulated interaction between distinct genomic regions of FoxO3 gene identified by 3C. Overall, our results demonstrate that glucocorticoids activated FoxO3 gene transcription through multiple GREs by chromatin structural change and DNA looping

Prediction of stable walking for a toy that cannot stand

Previous experiments [M. J. Coleman and A. Ruina, Phys. Rev. Lett. 80, 3658 (1998)] showed that a gravity-powered toy with no control and which has no statically stable near-standing configurations can walk stably. We show here that a simple rigid-body statically-unstable mathematical model based loosely on the physical toy can predict stable limit-cycle walking motions. These calculations add to the repertoire of rigid-body mechanism behaviors as well as further implicating passive-dynamics as a possible contributor to stability of animal motions.Comment: Note: only corrections so far have been fixing typo's in these comments. 3 pages, 2 eps figures, uses epsf.tex, revtex.sty, amsfonts.sty, aps.sty, aps10.sty, prabib.sty; Accepted for publication in Phys. Rev. E. 4/9/2001 ; information about Andy Ruina's lab (including Coleman's, Garcia's and Ruina's other publications and associated video clips) can be found at: http://www.tam.cornell.edu/~ruina/hplab/index.html and more about Georg Bock's Simulation Group with whom Katja Mombaur is affiliated can be found at http://www.iwr.uni-heidelberg.de/~agboc

Significant association of hematinic deficiencies and high blood homocysteine levels with burning mouth syndrome

Background/PurposeBurning mouth syndrome (BMS) is characterized by a burning sensation of the oral mucosa in the absence of clinically apparent mucosal alterations. In this study, we evaluated whether there was an intimate association of the deficiency of hemoglobin (Hb), iron, vitamin B12, or folic acid; high blood homocysteine level; and serum gastric parietal cell antibody (GPCA) positivity with BMS.MethodsBlood Hb, iron, vitamin B12, folic acid, and homocysteine concentrations and the serum GPCA level were measured in 399 BMS patients and compared with the corresponding levels in 399 age- and sex-matched healthy control individuals.ResultsWe found that 89 (22.3%), 81 (20.3%), 10 (2.5%), and six (1.5%) BMS patients had deficiencies of Hb (men: <13 g/dL, women: <12 g/dL), iron (<60 μg/dL), vitamin B12 (<200 pg/mL), and folic acid (<4 ng/mL), respectively. Moreover, 89 (22.3%) BMS patients had abnormally high blood homocysteine level and 53 (13.3%) had serum GPCA positivity. BMS patients had a significantly higher frequency of Hb, iron, or vitamin B12 deficiency; of abnormally elevated blood homocysteine level; or of serum GPCA positivity than the healthy control group (all p < 0.001 except for vitamin B12 deficiency, for which p = 0.004). However, no significant difference in frequency of folic acid deficiency (p = 0.129) was found between BMS patients and healthy control individuals.ConclusionWe conclude that there is a significant association of deficiency of Hb, iron, and vitamin B12; abnormally high blood homocysteine level; and serum GPCA positivity with BMS

Anatomical variations of the ethmoid sinuses and their association with health or pathology of the ethmoid and maxillary sinuses in a Southern Chinese population: An analysis using cone-beam computed tomography.

Purpose The aim of this study was to evaluate the prevalence of clinically relevant anatomical variations of the ethmoid sinuses and their potential association with ethmoid and maxillary sinus pathologies on cone-beam computed tomography (CBCT) scans. Additionally, potential associations with different sides and demographic factors, including age and sex, were evaluated. Materials and Methods In total, 273 CBCT scans with complete ethmoid and maxillary sinuses were analyzed to determine the prevalence of Agger nasi cell, supraorbital ethmoid cell, Haller cell, Onodi cell, and ethmomaxillary sinus. In addition, the health or pathology of the ethmoid and maxillary sinuses was also recorded to assess correlations with the aforementioned variations. Results The prevalence of Agger nasi cell was found to be the highest (95.6%) in this study, followed by Onodi cell (60.4%), Haller cell (29.3%), and supraorbital ethmoid cell (19.4%). Ethmomaxillary sinus was the least common finding (16.5%). Males and persons above 61 years of age had a significantly higher frequency of supraorbital ethmoid cell and Onodi cell, respectively. However, no significant relationships were noted between anatomical variations of the ethmoid sinus and pathologies of the ethmoid or maxillary sinus. Conclusion There was a high prevalence of ethmoid sinus variations in this Southern Chinese population. The prevalence of Agger nasi cell and Onodi cell was higher than that of other anatomical variations of the ethmoid sinuses. Anatomical variations of the ethmoid sinuses were not associated with ethmoid or maxillary sinus pathologies in this patient cohort

Acupuncture as a new cultural tourism product in Greater Bay Area – Stakeholders’ perspectives

Qi is a body network other than blood, nerve and lymph network being recognized by western medication and is identified by Chinese in thousand years ago. However, Qi network still remains relatively vague in the eyes of many scientists and people nowadays, despite the fact that Americans are adopting acupuncture as one of the medical treatments. Presently, a growing number of international tourists were found to be interested in learning more about the Chinese culture, particularly the Qi and acupuncture. It is conceivable that a combination of Qi knowledge and therapy devices can turn into an additional tourism attraction in China for international tourists. Interviews with specialists were conducted to receive valuable stakeholders’ viewpoints about the barriers and alternatives to develop the proposed tourism product

Current understanding and quantification of clouds in the changing climate system and strategies for reducing critical uncertainties

To date, no observation-based proxy for climate change has been successful in quantifying the feedbacks between clouds and climate. The most promising, yet demanding, avenue to gain confi dence in cloud–climate feedback estimates is to utilize observations and large-eddy simulations (LES) or cloud-resolving modeling (CRM) to improve cloud process parameterizations in large-scale models. Sustained and improved satellite observations are essential to evaluate large-scale models. A reanalysis of numerical prediction models with assimilation of cloud, aerosol, and precipitation observations would provide a valuable dataset for examining cloud interactions. The link between climate modeling and numerical weather prediction (NWP) may be exploited by evaluating how accurate cloud characteristics are represented by the parameterization schemes in NWP models. A systematic simplifi cation of large-scale models is an important avenue to isolate key processes linked to cloud–climate feedbacks and would guide the formulation of testable hypotheses for fi eld studies. Analyses of observation-derived correlations between cloud and aerosol properties in combination with modeling studies may allow aerosol–cloud interactions to be detected and quantifi ed. Reliable representations of cloud dynamic and physical processes in large-scale models are a prerequisite to assess aerosol indirect effects on a large scale with confi dence. To include aerosol indirect effects in a consistent manner, we recommend that a “radiative fl ux perturbation” approach be considered as a complement to radiative forcing