Pharmacodynamic modeling of the electroencephalographic effects of flumazenil in healthy volunteers sedated with midazolam

The purpose of this study was to model pharmacodynamically the reversal of midazolam sedation with flumazenil. Ten human volunteers underwent four different sessions. In session 1, individual midazolam pharmacokinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of sedation (20% or 80% of the maximal midazolam electroencephalographic effect) for a period of 210 minutes. After obtaining a stable electroencephalographic effect and constant midazolam plasma concentrations, a zero-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate because of the constant midazolam drug effect. The electroencephalographic response was measured during a 180-minute period and analyzed by aperiodic analysis and fast-Fourier transforms. In session 4, a midazolam plasma concentration corresponding to a deep level of sedation was targeted for 210 minutes to examine for the possible development of acute tolerance. No flumazenil was given in session 4. For a light sedation level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ml, the mean half-life of the equilibration rate constant of flumazenil reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentration causing 50% of Emax is 13.7 +/- 5.8 ng/ml. For a deep level of sedation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1.5 minutes, and the mean effect site concentration causing 50% of Emax is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magnitude of the blood/central nervous system equilibration delay for flumazenil antagonism of midazolam sedation and further defines the usefulness of the electroencephalogram as a measure of midazolam pharmacodynamic effect.     

rdgE: a novel retinal degeneration mutation in Drosophila melanogaster

We report isolating the Drosophila retinal degeneration E (rdgE) mutation. The hypomorphic rdgE1 allele causes rapid photoreceptor degeneration in light and a slower rate of degeneration when the flies are raised in constant darkness. The rdgE1 flies exhibited an electrophysiological light response that decreased with age, coinciding with the degeneration. This suggests that degeneration caused the loss of the light response. We determined that the ninaE (rhodopsin) mutation, but not norpA [phospholipase C (PLC)], slowed the rdgE-dependent degeneration. This was consistent with the light-enhanced degeneration, but revealed that the degeneration is independent of the PLC-mediated phototransduction cascade. Transmission electron microscopy revealed that rdgE1 photoreceptors exhibited a number of vesicular transport defects including unpacking/vesiculation of rhabdomeres, endocytosis of novel vesicles by photoreceptors, a buildup of very large multivesicular bodies, and an increased amount of rough endoplasmic reticulum. We determined that the rdgE null phenotype is a late embryonic lethality. Therefore, rdgE+ is required in cells outside of the retina, quite possibly in a large number of neurons. Thus, rdgE may define a mutational class that exhibits both light-enhanced retinal degeneration and a recessive null lethality by perturbing neuronal membrane biosynthesis and/or recycling.     

The effects of instructional match and content overlap on generalized reading performance

This study examined the effects of instructional match and content overlap on students' ability to generalize from passage reading instruction. Four students with mild disabilities served as participants. Using a multielement design, students were instructed with passages at two levels of text difficulty (instructionally matched vs. instructionally mismatched), and generalization was assessed with passages at two levels of similarity to those instructed (low vs. high content overlap). Results indicated that students' oral reading accuracy and fluency showed the greatest degree of generalization when instructional materials were matched to the students' skill level and assessment materials were similar to those used during instruction. Moreover, these results were maintained at 1-month follow-up. The implications of these findings for classroom reading instruction and the assessment of students' reading skills are discussed.     

Computer simulations of time-dependent suppression of EOF by polymer coatings

We use molecular dynamics simulations in order to investigate the time evolution of the effect of adsorbed polymer coatings on the electro-osmotic flow (EOF) in a capillary. Weakly adsorbed coatings show no time-dependent performance, but they do not strongly reduce the EOF. On the other hand, strongly adsorbed coatings made of longer polymer chains are often quenched in non-equilibrium conformations that can strongly reduce the EOF over extremely long periods of time. For intermediate adsorption strengths, we observe that the EOF increases as a function of time due to the relaxation of the coating layer. The concentration of polymers in solution and the length of the polymer chains also affect the time-dependence of the EOF. These results show that the quality of electrophoretic separations can depend on the waiting time between the formation of the coating and the beginning of the separation. We conclude by suggesting experimental tests of our predictions.     

Toxicoproteomics and its application to human health risk assessment

Toxicoproteomics is the use of proteomic technologies to better understand environmental and genetic factors, toxic mechanisms, and modes of action in response to acute exposure to toxicants and in the long-term development of diseases caused or influenced by these exposures. Use of toxicoproteomic technologies to identify key biochemical pathways, mechanisms, and biomarkers of exposure and toxicity will decrease the uncertainties that are associated with human health risk assessments. This review provides an overview of toxicoproteomics from human health risk assessment perspectives. Key toxicoproteomic technologies such as 2-D gel-based proteomic methods and toxicoproteomic approaches are described, and examples of applications of these technologies and methodologies in the risk assessment context are presented. The discussion includes a focus on challenges and future directions.     

设计灵感就在你的脑中

设计工程是一个以客户为中心的行业,其中新标准由终端客户的需求驱动.当演变到为电子工程设计和制造元器件时,它就再也不是一种产品适合所有应用的模式了.这就在国际上引发了一场工程师们观念上的革命.尽管在过去功能、成本控制和效率是工程师主要的着眼点,而现在一个元器件的外表形状正获得更高的关注度.     

手持终端设备电源管理系统的PPTC电路保护

着重介绍Raychem电路保护部的PolySwitch PPTC（聚合物正温度系数）元件在电源管理中提供电流过载和温度过载的保护过程。另外还介绍了电源适配器、CLA（点烟器）、移动电话设备及电池板的保护装置是如何进一步改善实际使用中的总体可靠性的。     

Inkjet Printed Large‐Area Flexible Few‐Layer Graphene Thermoelectrics

Graphene‐based organic nanocomposites have ascended as promising candidates for thermoelectric energy conversion. In order to adopt existing scalable printing methods for developing thermostable graphene‐based thermoelectric devices, optimization of both the material ink and the thermoelectric properties of the resulting films are required. Here, inkjet‐printed large‐area flexible graphene thin films with outstanding thermoelectric properties are reported. The thermal and electronic transport properties of the films reveal the so‐called phonon‐glass electron‐crystal character (i.e., electrical transport behavior akin to that of few‐layer graphene flakes with quenched thermal transport arising from the disordered nanoporous structure). As a result, the all‐graphene films show a room‐temperature thermoelectric power factor of 18.7 µW m^?1 K^?2, representing over a threefold improvement to previous solution‐processed all‐graphene structures. The demonstration of inkjet‐printed thermoelectric devices underscores the potential for future flexible, scalable, and low‐cost thermoelectric applications, such as harvesting energy from body heat in wearable applications.     

Removal of spurious coherence in MEG source-space coherence analysis

Source-space coherence analysis has become a popular method to estimate functional connectivity based on MEG/EEG. Source-space analysis involves solving the inverse problem, estimating the time courses of specific brain regions, and then examining the coherence between activities at different brain regions. However, source-space coherence analysis can be confounded by spurious coherence caused due to the leakage properties of the inverse algorithm employed. Such spurious coherence is typically manifested as an artifactual large peak around the seed voxel, called seed blur, in the resulting coherence images. This seed blur often obscures important details of brain interactions. This paper proposes the use of the imaginary part of the coherence to remove the spurious coherence caused by the leakage of an imaging algorithm. We present a theoretical analysis that explains how the use of imaginary part can remove this spurious coherence. We then present results from both computer simulations and experiments using resting-state MEG data which demonstrate the validity of our analysis.