A high-throughput method for assessing chemical toxicity using a Caenorhabditis elegans reproduction assay

The National Research Council has outlined the need for non-mammalian toxicological models to test the potential health effects of a large number of chemicals while also reducing the use of traditional animal models. The nematode Caenorhabditis elegans is an attractive alternative model because of its well-characterized and evolutionarily conserved biology, low cost, and ability to be used in high-throughput screening. A high-throughput method is described for quantifying the reproductive capacity of C. elegans exposed to chemicals for 48 h from the last larval stage (L4) to adulthood using a COPAS Biosort. Initially, the effects of exposure conditions that could influence reproduction were defined. Concentrations of DMSO vehicle ≤ 1% did not affect reproduction. Previous studies indicated that C. elegans may be influenced by exposure to low pH conditions. At pHs greater than 4.5, C. elegans reproduction was not affected; however below this pH there was a significant decrease in the number of offspring. Cadmium chloride was chosen as a model toxicant to verify that automated measurements were comparable to those of traditional observational studies. EC₅₀ values for cadmium for automated measurements (176-192 µM) were comparable to those previously reported for a 72-h exposure using manual counting (151 µM). The toxicity of seven test toxicants on C. elegans reproduction was highly correlative with rodent lethality suggesting that this assay may be useful in predicting the potential toxicity of chemicals in other organisms.     

INFLUENCE OF 3-PPP, A SIGMA RECEPTOR LIGAND, ON THE ANTICONVULSIVE ACTION OF CONVENTIONAL ANTIEPILEPTIC DRUGS

(+)-3-(3-Hydroxyphenyl)-N-(1-propyl)-piperidine (3-PPP; a sigma receptor ligand), administered at 30 mg kg-1, 30 min before the test, significantly decreased the electroconvulsive threshold in mice, being ineffective in lower doses. 3-PPP (20 mg kg-1) diminished the protective activity of diphenylhydantoin, phenobarbital and valproate, but not that of carbamazepine against maximal electroshock. The effect of 3-PPP upon the electroconvulsive threshold and the 3-PPP-induced inhibition of the protective action of antiepileptics was reversed by haloperidol (0.5 mg kg-1). Moreover, 3-PPP did not alter the total and free plasma levels of antiepileptic drugs, so a pharmacokinetic interaction is not probable. The combined treatment of 3-PPP with antiepileptic drugs, providing a 50% protection against maximal electroshock, did not affect motor performance in mice, although resulted in significant long-term memory deficits. Our data indicate that sigma receptor-mediated events may play some role in seizure processes in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs.     

IPG-Ⅲ阻抗静脉血流仪的研制

本文报道了IPG-Ⅲ阻抗静脉血流仪的研制及临床应用。该仪器检测深静脉血栓等静脉疾患灵敏、可靠、无损伤,可多次重复并操作简便。阻抗静脉血流图与静脉造影符合率达96.4％接近国外同类产品的水平。     

Spontaneous versus controlled ventilation in anaesthetized children with congenital cardiac malformations

The effects of intermittent positive pressure ventilation on gas exchange were studied in 12 children with congenital cardiac malformation. Six children (b.w. 3.7-16 kg) had a left-to-right shunt (Group LR) resulting in overperfused lungs, while six others (b.w. 3.4-12 kg) had a right-to-left shunt (Group RL) with oligaemic lungs. Measurements, prior to surgery, were done during spontaneous breathing (SB) and controlled mechanical ventilation (CMV) with a short (25%) and a long (55%) duration of inspiration. In children with oligaemic lungs P(a-E')CO2 differences and VD/VT ratios were greater and PaO2 was lower than in those with overperfused lungs, indicating a less efficient ventilation. In Group RL, ventilation and gas exchange during SB were similar at the two settings of CMV. In Group LR, however, VD/VT was reduced during CMV, with the lowest VD/VT ratio at the longer inspiration time. It is concluded that in children with an oligaemic lung perfusion, either of the two ventilator settings could be used. When controlled ventilation is to be used in children with overperfused lungs, the longer duration of inspiration seems to be preferable.     

Clinical benefit in Phase-I trials of novel molecularly targeted agents: does dose matter?

Phase-I trials traditionally involve dose-escalation to determine the maximal tolerated dose (MTD). With conventional chemotherapy, efficacy is generally deemed to be dose-dependent, but the same may not be applicable to molecularly targeted agents (MTAs). We analysed consecutive patients included in Phase-I trials at the Royal Marsden Hospital from 5 January 2005 to 6 June 2006. We considered only trials of monotherapy MTAs in which the MTD was defined. Three patient cohorts (A, B, and C) were identified according to the dose received as a percentage of the final trial MTD (0–33%, 34–65%, >66%). Potential efficacy was assessed using the non-progression rate (NPR), that is, complete/partial response or stable disease for at least 3 months by RECIST. A total of 135 patients having progressive disease before enrolment were analysed from 15 eligible trials. Median age was 57 years (20–86); male : female ratio was 1.8 : 1. Cohort A, B, and C included 28 (21%), 22 (16%), and 85 (63%) patients; NPR at 3 and 6 months was 21% and 11% (A), 50% and 27% (B), 31% and 14% (C), respectively, P=0.9. Median duration of non-progression (17 weeks; 95% CI=13–22) was not correlated with the MTD level, P=0.9. Our analysis suggests that the potential for clinical benefit is not confined to patients treated at doses close to the MTD in Phase-I trials of MTAs.     

Enantioselective Actions of Tocainide on the Electrophysiologic Properties of the Guinea Pig Papillary Muscle

Enantioselective Electrophysiologic Actions of Tocainide. The electrophysiologic effects of the R (?) and S(+) enantiomers of tocainide, a Class IB antiarrhythmic drug, were studied in the guinea pig papillary muscle, using the standard microelectrode technique. The results can be summarized as follows: (1) R(?) tocainide HCI, 100 mg/L (437 μM), was more potent in reducing the maximal rate of depolarization (τ_max) than S(+) tocainide HCl. At a stimulation frequency of 1 Hz, in the presence of 5.4 mM external K⁺, τ_max was reduced an average of 44% in the presence of R(?) tocainide while only 26% in the presence of S(+) tocainide. The inhibition was mainly due to tonic block. The amount of tonic block, as well as phasic block, were different for both enantiomers. (2) The recovery of drug-occupied channels during the diastolic interval was slower in the presence of R(?) tocainide (τ= 491 msec) than in the presence of S(+) tocainide (τ= 241 msec). Decreasing the stimulation interval caused proportionally more reduction of V_max in the presence of R(?) tocainide than in the presence of S(+) tocainide. (3) Voltage dependence of block of τ_max was also more pronounced with R(?) tocainide. Inactivation curves were shifted toward more negative potentials of 14 mV in the presence of R(?) tocainide, while S(+) tocainide provoked a shift of only 7 mV.     

从南丁格尔贡献中得到的启示

论述了从南丁格尔在护理实践、护理教育、护理研究和护理管理各个护理学领域的贡献中得到的几点启示,包括南丁格尔从整体的、发 展的眼光创建了《护理学》;南丁格尔注重循证护理,并用证据体现护理的价值;南丁格尔注重学科间的合作,寻求共同发展。     

Reference values for cardiopulmonary exercise testing in healthy subjects – an updated systematic review

Introduction: Reference values for cardiopulmonary exercise testing (CPET) parameters provide the comparative basis for answering important questions concerning the normalcy of exercise responses in patients, and significantly impacts the clinical decision-making process.

Areas covered: The aim of this study was to provide an updated systematic review of the literature on reference values for CPET parameters in healthy subjects across the life span.

A systematic search in MEDLINE, Embase, and PEDro databases were performed for articles describing reference values for CPET published between March 2014 and February 2019.

Expert opinion: Compared to the review published in 2014, more data have been published in the last five years compared to the 35 years before. However, there is still a lot of progress to be made. Quality can be further improved by performing a power analysis, a good quality assurance of equipment and methodologies, and by validating the developed reference equation in an independent (sub)sample. Methodological quality of future studies can be further improved by measuring and reporting the level of physical activity, by reporting values for different racial groups within a cohort as well as by the exclusion of smokers in the sample studied. Normal reference ranges should be well defined in consensus statements.     

Development of an automatic Doppler flow signal detection system: variability of pulmonary and aortic peak flow velocity

Purpose Automatic Doppler flow signal detection systems can provide beat-to-beat information for large blood vessels. We have developed new equipment for automatic measurement of Doppler flow signals. The reliability of the system was examined, and the variability of aortic and pulmonary peak flow velocity was determined. Methods We measured peak flow velocity using a newly developed system in healthy volunteers and patients with atrial fibrillation. Analysis of variability of peak flow velocity was performed with maximal entropy methods. Results In Bland–Altman plots, the mean and standard deviation (SD) of differences in aortic peak flow velocities between the automatic and manual measurements were 0.22 ± 0.75 cm/s and 0.85 ± 0.38 cm/s, respectively, in five normal volunteers. Moreover, less than 5% of the plotted points were beyond ± 2 SD of the differences. Furthermore, good reproducibility was demonstrated using Bland–Altman plots and Pearson's correlation analysis. Identical reliability was obtained in patients with atrial fibrillation. The same results were obtained for pulmonary peak flow velocity. In five healthy subjects, aortic and pulmonary peak flow showed standard deviations of 7.2 ± 2.4 and 3.8 ± 0.6 cm/s, respectively, and coefficients of variation of 6.1% ± 1.0% and 5.1% ± 1.1%, respectively, in time-domain variability. Similarly, frequency-domain variability was obtained for both peak flow velocities. Conclusion The present study demonstrated the reliability of a newly developed automatic Doppler flow signal detection system. Using this system, the present study demonstrated for the first time aortic and pulmonary peak flow velocity variability. The present analytical methods may have considerable potential for studying aortic and/or pulmonary flow variability in connection with cardiac performance and prognosis of cardiac disease.     

中重度慢阻肺患者气流阻塞的影响因素与康复

目的 :探讨中、重度慢阻肺 (COPD)患者气流阻塞的影响因素及康复治疗的指导意义。方法 :分别测定 10 1例中、重度慢阻肺患者的最大呼气流量 容积曲线并进行相关分析。结果 :中度COPD患者FEV1%仅与Vmax50 %呈正相关 (r=0 .4 76 ,P <0 .0 0 1) ;重度COPD患者FEV1%则与Vmax75%、Vmax50 %和Vmax2 5%皆呈正相关 (依次r =0 .70 5 ,P <0 .0 0 1;r =0 .5 6 9,P <0 .0 0 1;r =0 .4 2 1,P <0 .0 0 1)。另对 2 8例吸烟者FEV1%与吸烟时间、日吸烟量和戒烟时间所作的相关分析表明 ,FEV1%与这些因素都无明显的相关性。结论 :中度COPD的气流阻塞仅与小气道阻塞有关 ,缓解期的康复治疗保持气道的通畅至为重要 ;重度COPD的气流阻塞不但同时与大、小气道阻塞有关 ,还可能与呼吸肌的功能状态有关 ,其缓解期的康复治疗不但要保持气道的通畅 ,还需要进行呼吸肌的康复锻炼和配合营养支持 ,但仅有FEV1%数据也无法给患者提供有效的指导 ,呼吸肌功能测定极为必需 ,有必要将呼吸肌功能测定列入COPD诊治指南内