Percutaneous Absorption of Benzoic Acid Across Human Skin. II. Prediction of an in Vivo,Skin-Flap System Using in Vitro Parameters

The possibility of predicting the behavior of in vivo systems based on physical and chemical parameters determined by in vitro experiments is examined using benzoic acid. The physical and chemical parameters governing percutaneous absorption of benzoic acid—permeability, partition coefficient, and skin thickness—were determined by in vitro experiments as described in Ref. 1. These parameters were used, in combination with benzoic acid elimination kinetics, to predict the results of in vivo experiments using a comprehensive mathematical model. The in vivo system consists of a congenitally athymic (nude) rat with a surgically constructed human skin sandwich (HSSF) flap on which a donor cell is placed. To apply the in vitro parameters to an in vivo system requires a suitable pharmacokinetic model describing distribution and elimination for benzoic acid in the nude rat. Blood concentrations of benzoic acid following a bolus intravenous injection are closely described by a two-compartment open pharmacokinetic model with elimination occurring from only one compartment. The mathematical model of the rat-donor cell system combines this two-compartment model of the rat with a percutaneous absorption model to provide useful estimates of the measured in vivo blood levels. Comparisons of predicted and measured results suggest that the parameters determined by in vitro experimentation can be used to predict the behavior of complex in vivo systems, if a suitable mathematical model is available.     

非线性部分最小二乘法在催化剂活性建模中的应用

结合统计回归与神经网络的优点，使用基于神经网络的非线性部分最小二乘回归法，建立了醋酸乙烯生产装置催化剂活性的非参数模型，模型的精度高且计算量较小。实际应用证明了方法的有效性。     

The Functional Organization of the Interictal Spike Complex in Benign Rolandic Epilepsy

Summary: Purpose : We studied the functional organization of the interictal epileptic spike complex in patients with benign rolandic epilepsy of childhood (BREC).
Methods : We recorded interictal epileptiform spikes and somatosensory evoked potentials after median nerve stimulation, providing a biologic marker for the location of the central sulcus in 12 patients with BREC. We used multiple dipole modeling to assess the number, the three-dimensional intracerebral location, and the time activity of the underlying neuronal sources.
Results : Although the interictal spike complex could be modeled by a single tangential dipolar source in seven patients (group 1), in the remaining five patients, two sources—a radial and a tangential dipole—were necessary adequately to explain the interictal spikes (group 2). The tangential source was located deeper than the radial source and was characterized by a frontal positivity and a centroparietal negativity with a phase reversal across the central sulcus, suggesting that the interictal spikes originated in the anterior wall of the central sulcus. The radial source showed a single electronegativity over the ipsilateral central region, which would be compatible with involvement of the top of either the pre- or postcentral gyrus. Both sources showed biphasic time patterns with an average latency difference of 30 ms.
Conclusions : Our results indicate that in some patients with typical BREC, the interictal epileptiform spike complex is generated by multiple, simultaneously active neuronal populations within the central region and that epileptiform activity is propagated between these two adjacent cortical areas.     

Postshock Potential Gradients and Dispersion of Repolarization in Cells Stimulated with Monophasic and Biphasic Waveforms

Effects of Monophasic and Biphasic Stimuli. Introduction: Even though the clinical advantage of biphasic defibrillation waveforms is well documented, the mechanisms that underlie this greater efficacy remain incompletely understood. It is established, though, that the response of relatively refractory cells to the shock is important in determining defibrillation success or failure. We used two computer models of an isolated ventricular cell to test the hypothesis that biphasic stimuli cause a more uniform response than the equivalent monophasic shocks, decreasing the likelihood that fibrillation will be reinduced. Methods and Results: Models of reciprocally polarized and uniformly polarized cells were used. Rapid pacing and elevated [K]_o were simulated, and either 10-nisec rectangular monophasic or 5-msec/5-msec symmetric biphasic stimuli were delivered in the relative refractory period. The effects of stimulus intensity and coupling interval on response duration and postshock transmembrane potential (V_m) were quantified for each waveform. With reciprocal polarization, biphasic stimuli caused a more uniform response than monophasic stimuli, resulting in fewer large gradients of V_m (only for shock strengths ≤ 1.25× threshold vs ≤ 2.125× threshold) and a smaller dispersion of repolarization (1611 msec² vs 1835 msec²). The reverse was observed with uniform polarization: monophasic pulses caused a more uniform response than did biphasic stimuli. Conclusion: These results show that the response of relatively refractory cardiac cells to biphasic stimuli is less dependent on the coupling interval and stimulus strength than the response to monophasic stimuli under conditions of reciprocal polarization. Because this may lead to fewer and smaller spatial gradients in V_m, these data support the hypothesis that biphasic defibrillation waveforms will be less likely to reinduce fibrillation. Further, published experimental results correlate to a greater degree with conditions of reciprocal polarization than of uniform polarization, providing indirect evidence that interactions between depolarized and hyper polarized regions play a role in determining the effects of defibrillation shocks on cardiac tissue.     

Age-dependent alterations of intestinal absorption. I. Theoretical aspects

To test the absorption of orally administered d-xylose in the upper small intestine its concentration in the blood plasma must be measured. Absorption is determined as a function of time by subtraction of the blood values found after intravenous administration, which would indicate the rates of metabolism and extraction of xylose by the body. It is suggested that comparison with the behavior of a proposed four compartment model may give a biological interpretation of the results.The possible dependence of amount and rate of absorption can be determined if the same time after feeding of the same diet is used in each absorption measurement. It is suggested that the time point to be used for administration be that time at which the highest concentration of xylose in the peripheral blood is found.     

Resistance to atracurium in rats with experimental inflammation: role of protein binchng

The influence of altered protein binding on the neuromuscular effect of atracurium has been studied in rats with experimental inflammation induced by subcutaneous injection of turpentine oil.
Doses of atracurium ranging from 0.45 to 1.5 mg·kg^-1 were administered to control (n = 30) and to experimental inflammation induced rats (n = 30). Neuromuscular transmission was monitored by recording the twitch tension of the tibialis-anterior muscle elicited by stimulation of the sciatic nerve. Three effect parameters were recorded: (i) intensity of the effect, measured as percentage depression of baseline twitch tension, (ii) duration of drug action (min) and (iii) recovery time (min).
The dose-intensity of the effect relationship was modelled using a sigmoid E _max model. The ED ₅₀ (effective dose eliciting 50% of the maximum effect) was significantly increased ( P <0.01) in the inflammation group as compared to the control group (0.94 vs. 0.68 mg·kg^-1). This change was reflected in a shift of the dose-response curve to the right in the pretrcated rats. For equipotent doses ED ₉₅ (defined as the effective dose eliciting 95% of maximum effect), no differences were found in recovery time and duration of action between the two groups of rats. Mucoproteins levels (index of α₁-acid glycoprotein (AAG)) and protein binding were significantly increased in rats with experimental inflammation as compared to control rats.
Based on these results, altered serum protein binding of atracurium appears to be responsible, at least in part, for the resistance to atracurium.     

Non-invasive localization of the epileptogenic focus by EEG dipole modeling

Localization of epileptogenic foci by traditional visual inspection of EEG traces is simplistic. Voltage topography and subsequent spatio-temporal multiple dipole modeling are new techniques to assess the character of cerebral generators of EEG spikes and seizure rhythms. These predictions have been validated by intracranial monitoring. Patients with mesial temporal seizures have ipsilateral spikes and early ictal rhythms with a strong tangential (vertical) dipole component that often leads any radial source activity. This suggests propagation from baso-mesial to lateral cortex. Those with infero-lateral temporal cortical seizures have similar findings, but tangential sources are synchronous with or lag radial sources. Patients with lateral temporal cortical seizures have spikes and ictal activity that are modeled principally by radial dipoles.     

基于受体结构的药物分子设计系统:维甲类分子与其结合蛋白之间相互作用的研究

大分子解剖程序,配体分子契合适配和DOCK程序,以及计算化学的其它程序等,已集成为基于受体结构和分子间相互作用的进行分子设计的软件系统,定名为BIOS(Biomolecularinteractionsandorientationsimulator)。BIOS软件可在普通的微机上运行。使用BIOS分别剥离了细胞浆维甲结合蛋白(CRBP)和副睾维甲酸结合蛋白(E-RABP)两种蛋白的配体结合腔,剥离是围绕配体以同样的分子距离进行的。从而得到了芳香性残基分布相似的两个结合腔,其结合位点的几何排布却有相当差别。揭示出的结合腔已用于一系列的维甲类化合物的DOCK研究。E-RABP的结合腔可做为设计新维甲类分子的模板。     

Molecular modeling of 5-HT3 receptor ligands.

Ligands of various chemical classes (e.g., indoles, indazoles, benzamides, carbazoles, and quinolines) have demonstrated high affinity for the 5-HT₃ receptor in radiolabeled ligand-binding studies, and have shown 5-HT₃ receptor antagonistic activity in functional assays which utilize the excitatory effects of 5-HT on enteric neurons and autonomic afferents. Several 5-HT₃ antagonists are currently being evaluated for potential use in the treatment of migraine, schizophrenia, and anxiety, and a few have already demonstrated high efficacy as antiemetics in cancer chemotherapy. The purpose of this presentation is to highlight the significant structure-affinity relationships (SAFIR) and common geometrical features among 5-HT₃ receptor ligands, and to describe the three-dimensional pharmacophore for the 5-HT₃ recognition site derived from computational techniques. The chemical template containing the recognition elements (functional groups) for the 5-HT₃ receptor are: an aromatic or heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center, interrelated by well-defined distances. Two “binding shapes” or “active shapes” for 5-HT₃ ligands have been identified from detailed conformational analyses.     

Physical Activity Monitors: Do More Sensors Mean Better Precision?

Physical activity is essential to health. Accelerometry-based activity monitors are widely used in clinical and epidemiological research settings; however, only measuring body movement may prohibit accurate prediction of energy expenditure. Recent technological advancements allow synchronous measurements of heart rate, body temperature, acceleration, and other physiological responses and record them in detail (every minute or finer precision). Current multisensor devices are small, wireless, and capable of continuously recording data over several days or weeks, making them readily applicable in the free-living environment. Future studies should focus on developing strategies to optimize sensor data for accurate and robust predictions of clinically pertinent outcome parameters, such as total daily energy expenditure and physical activity energy expenditure. There is also a need for calibration instruments to allow users to standardize devices in their own laboratory or clinic. We also call for more transparency in publishing sensor properties and modeling algorithms, rather than proprietary or “black-box” prediction approaches.