Voluntary activation in the triceps brachii at short and long muscle lengths

The aim was of this study was to determine whether voluntary activation calculated using the interpolated twitch technique (ITT) would be underestimated by muscle length–induced changes in the twitch amplitude evoked at rest after maximum voluntary contraction (MVC) in the elbow extensors. In 12 healthy men, calculated voluntary activations were compared at short (20° of elbow flexion) and long muscle lengths (120°) using the actual post‐MVC doublet, and the predicted post‐MVC doublet estimated from linear or nonlinear extrapolations. Actual post‐MVC doublet amplitudes were smaller at 20° versus 120°. At 20°, the predicted post‐MVC doublet obtained from nonlinear extrapolation was larger, and voluntary activation values improved by 5–33% at the submaximal voluntary contraction intensities (≤80% of MVC). When voluntary drive is compromised, this method of extrapolation is useful to account for mechanical limitations that blunt the actual post‐MVC doublet, which otherwise leads to underestimation of voluntary activation. Muscle Nerve, 2010     

Interocular Transfer: The Dichoptic Flash-Lag Effect in Controls and Amblyopes

PurposeThe mammalian brain can take into account the neural delays in visual information transmission from the retina to the cortex when accurately localizing the instantaneous position of moving objects by motion extrapolation. In this study, we wanted to investigate whether such extrapolation mechanism operates in a comparable fashion between the eyes in normally sighted and amblyopic observers.MethodsTo measure interocular extrapolation, we adapted a dichoptic version of the flash-lag effect (FLE) paradigm, in which a flashed bar is perceived to lag behind a moving bar when their two positions are physically aligned. Twelve adult subjects with amblyopia and 12 healthy controls participated in the experiment. We measured the FLE magnitude of the subjects under binocular, monocular, and dichoptic conditions.ResultsIn controls, the FLE magnitude of binocular condition was significantly smaller than that of monocular conditions (P ≤ 0.023), but there was no difference between monocular and dichoptic conditions. Subject with amblyopia exhibited a smaller FLE magnitude in the dichoptic condition when the moving bar was presented to the amblyopic eye and the flash to the fellow eye (DA condition) compared to the opposite way around (DF condition), consistent with a delay in the processing of the amblyopic eye (P = 0.041).ConclusionsOur observations confirm that trajectory extrapolation mechanisms transfer between the eyes of normal observers. However, such transfer may be impaired in amblyopia. The smaller FLE magnitude in DA compared to DF in patients with amblyopia could be due to an interocular delay in the amblyopic visual system. The observation that normal controls present a smaller FLE in binocular conditions raises the question whether a larger FLE is or is not an indicator of better motion processing and extrapolation.     

紫杉醇种属间药动学相关性的荟萃分析

 目的 应用基于模型化的荟萃分析的方法,建立紫杉醇种属间相关性的定量评价方法,为新药研发的种属间外推与剂量确定提供参考。 方法 以紫杉醇药动学为关键词,检索Pub-Med、中国知网（CNKI）、万方等数据库建库相关文献。按照纳入排除标准对检索文献进行筛选,并按种属进行分类,摘录每篇文献的血药浓度数据,应用非线性混合效应模型法（NONMEM）分别对人、大鼠、小鼠进行建模。采用正态化预测分布误差（normalized prediction distribution errors,NPDE）法对建立的模型进行验证,并依据相关生长规律法对药物种属间相关系数进行计算。 结果 通过非线性混合效应模型法法模型化,人、大鼠、小鼠的药动学行为均符合二室模型,与文献检索结果一致。正态化预测分布误差对最终模型结果进行可视化检验,模型结果准确可靠。依据相关生长规律法（allometric scaling）对3个种属的清除率CL和总表观分布容积V_total的相关系数进行计算,结果分别为r²=0.997 4和r²=0.937 2,种属间相关系数的线性关系良好。 结论 以紫杉醇为例,成功地建立了基于模型的Meta分析方法,能够定量的评价和预测种属间相关性。     

The frequency of U-shaped dose responses in the toxicological literature.

Hormesis has been defined as a dose-response relationship in which there is a stimulatory response at low doses, but an inhibitory response at high doses, resulting in a U- or inverted U-shaped dose response. To assess the proportion of studies satisfying criteria for evidence of hormesis, a database was created from published toxicological literature using rigorous a priori entry and evaluative criteria. One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria. Subsequent application of evaluative criteria revealed that 245 (37% of 668) dose-response relationships from 86 articles (0.4% of 20,285) satisfied requirements for evidence of hormesis. Quantitative evaluation of false-positive and false-negative responses indicated that the data were not very susceptible to such influences. A complementary analysis of all dose responses assessed by hypothesis testing or distributional analyses, where the units of comparison were treatment doses below the NOAEL, revealed that of 1089 doses below the NOAEL, 213 (19.5%) satisfied statistical significance or distributional data evaluative criteria for hormesis, 869 (80%) did not differ from the control, and 7 (0.6%) displayed evidence of false-positive values. The 32.5-fold (19.5% vs 0.6%) greater occurrence of hormetic responses than a response of similar magnitude in the opposite (negative) direction strongly supports the nonrandom nature of hormetic responses. This study, which provides the first documentation of a data-derived frequency of hormetic responses in the toxicologically oriented literature, indicates that when the study design satisfies a priori criteria (i.e., a well-defined NOAEL, > or = 2 doses below the NOAEL, and the end point measured has the capacity to display either stimulatory or inhibitory responses), hormesis is frequently encountered and is broadly represented according to agent, model, and end point. These findings have broad-based implications for study design, risk assessment methods, and the establishment of optimal drug doses and suggest important evolutionarily adaptive strategies for dose-response relationships.     

Sodium fluoride is a less efficient human cell mutagen at low concentrations

Sodium fluoride was found to induce gene-locus mutations at the thymidine kinase (tk) and hypoxanthine guanine phosphoribosyl transferase (hgprt) loci in human lymphoblastoid cells. A single, 28 hr exposure to up to 600 micrograms/ml sodium fluoride induced a concentration-dependent increase in mutant fraction at both gene loci and reduced cell survival to 12% relative to negative control cultures. When cells were exposed to sodium fluoride concentrations that were only minimally toxic using a 20 day treatment protocol, no detectable induction of mutation was ob-served at the hgprt locus, and induction of mutation was observed at the tk locus only for treatment with 65 micrograms/ml sodium fluoride; exposure to 50 and 35 micrograms/ml sodium fluoride did not induce detectable mutation. The assay protocol used was of sufficient statistical sensitivity to detect the level of mutation predicted based on a linear extrapolation of data obtained from a 28 hour exposure. The implications of these observations with regard to the extrapolability of mutagenicity data to low concentrations are discussed.     

N1 Latencies of the Slow Auditory Evoked Potential

Several studies have been published concerning the relation between stimulus level and amplitude of the slow auditory evoked response. Little attention has, however, been given to the relation between level and latency of the N₁ component (100-200 ms). A mathematical model of such a relation is proposed based on the assumption of an exponential relationship. The model has been tested on normally hearing subjects as well as on patients with sensorineural lesions, cochlear as well as retrocochlear. The results indicate that the proposed method of evaluating the slow evoked responses offers a way of threshold extrapolation with rather good accuracy. It also appears to be useful in determining the type of hearing loss     

Comments on the health effects institute-asbestos research (HEI-AR) report: “Asbestos in public and commercial buildings,” with emphasis on risk assessment methods used

A Health Effects Institute—Asbestos Research Report calculates the risk of exposure to environmental asbestos fibers (EAF) by downward extrapolation from the mortality of workers exposed for 20 years. This extrapolation is improper because 1) relative risks of asbestos exposure very likely are not linearly progressive; 2) the composition of EAF may not be equivalent to that in mining or fabricating; 3) the same environmental asbestos concentration probably represents different exposure doses for different populations; and 4) health effects of asbestos exposure on children, seniors, patients, the institutionalized, the handicapped, and the chronically ill may not be the same as those of healthy workers. Evidence of asbestos-related disease among family members of exposed workers demonstrates that the risk observed for EAF is substantially larger than that estimated from downward extrapolation and suggests a basis for an alternative approach to estimating asbestos-related health risks. Such epidemiologic procedures are well established and ought to form the basis for detecting the health effects of EAF. It is also unclear which industry supports HEI-AR. © 1993 Wiley-Liss, Inc.     

Prediction of in vivo drug clearance from in vitro data. II: Potential inter-ethnic differences

Potential differences in drug clearance between Japanese and Caucasians were investigated by integrating data on demography, liver size, the abundance of the major cytochromes P450 and in vitro metabolic parameters. Eleven drugs (alprazolam, caffeine, chlorzoxazone, cyclosporine, midazolam, omeprazole, sildenafil, tolbutamide, triazolam, S-warfarin and zolpidem) fulfilled the entry criteria of the study (i.e. the necessary in vitro metabolism data were available and clearance values had been reported both in Caucasians and Japanese). Values of relevant biological variables were obtained from the literature, and clearance predictions were made using the Simcyp® Population-Based ADME Simulator. The ratios of observed oral clearance (CL_p.o.) values in Caucasians compared with Japanese ranged from 0.6 to 2.8 (integrating data from 82 sources). The CL_p.o. values for alprazolam, caffeine and zolpidem were not statistically different between Caucasian and Japanese (p?>?0.05), whereas those for chorzoxazone, cyclosporine, omeprazole, tolbutamide and triazolam were higher in Caucasians (p?S-warfarin were higher in Japanese (p?p.o. values, predicted from in vitro data, were within 3-fold of observed in vivo values for seven of the 11 drugs in Japanese. Values for the predicted ratios ranged from 1.6 to 4.9. The predicted ratios were not significantly different from observed ratios for cyclosporine, omeprazole, tolbutamide and triazolam. Only partial success in predicting ethnic differences in clearance indicates the need for larger and more reliable databases on relevant variables. With such information, in silico predictions might be used with more confidence to decrease the need for repeating pharmacokinetic studies in different ethnic groups.     

Swimming navigation,open-field activity,and extrapolation behavior of two inbred mouse strains with Robertsonian translocation of chromosomes 8 and 17

Female mice from inbred strains carrying a Robertsonian translocation (nine CBARb and eight C57BL/6Rb) were compared with animals from their respective strains (seven CBA and nine C57BL/6) first in open-field activity (two exposures of 10-min duration), then during 5 days (with six trials each) in Morris' swimming navigation test, and finally, in their ability to extrapolate the future position of a food reward being moved slowly out of their reach. ANOVA (strain and translocation) revealed significant effects of Robertsonian translocations (Rb) in swimming navigation,Rb mice being impaired primarily in the initial phases of acquisition and during the first trials of platform reversal and the impairment being stronger in C57BL/6 mice. In the open field,Rb mice were as active as the normal strains but showed significantly increased path tortuosity and moved slightly faster. In the extrapolation task,Rb mice showed above-chance levels in moving to the target indicated by the disappearance of the stimulus, while normal mice chose at chance levels, but the translocation effects were not statistically significant. These data indicate that telocentric fusion of chromosomes may entail behavioral alterations, perhaps by subtle changes in neurotransmitters or limbic circuitry. The expression of such alterations, however, can be remarkably strain dependent.