小鼠卵细胞质内显微注入单精子受精的实验研究

为了探讨提高小鼠卵细胞质内单精子注入受精率的方法，选取鼠龄１２－１４周的健康昆明白小鼠作为精子和卵子的供体，受用ＩＣＳＩ技术，以受精后二细胞卵裂的形成率为指标，了解不同采卵时间，不同微注射针参数及不同培养液对细胞质单精子注入的影响。结果表明，ｈＣＧ注射后１８－１９ｈ采卵，用针尖内径为４－５μｍ，斜面角度为３５－４０度的微注射针进行ＩＣＳＩ操作受精后卵子置ＣＺＢ中培养可获得较多的２细胞胚，卵裂率明显     

Frequency-domain analysis of cerebral autoregulation from spontaneous fluctuations in arterial blood pressure

The dynamic relationship between spontaneous fluctuations of arterial blood pressure (ABP) and corresponding changes in crebral blood flow velocity (CBFV) is studied in a population of 83 neonates. Static and dynamic methods are used to identify two subgroups showing either normal (group A, n=23) or impaired (group B, n=21) cerebral autoregulation. An FFT algorithm is used to estimate the coherence and transfer function between CBFV and ABP. The significance of the linear dependence between these two variables in demonstrated by mean values of squared coherence >0.50 for both groups in the frequency range 0.02–0.50 Hz. However, group A has significanlty smaller coherences than group B in the frequency ranges 0.02–0.10 Hz and 0.33–0.49 Hz. The phase response of group A is also significantly more positive than that of group B, with slopes of 9.3±1.05 and 1.80±1.2 rad Hz⁻¹, respectively. The amplitude frequency response is also significantly smaller for group A in relation to group B for the frequency range 0.25–0.43 Hz. These results suggest that transfer function analysis may be able to identify different components of cerebral autoregulation and also provide a deeper understanding of recent findings by other investigators.     

Sonic phase delay from trachea to chest wall: spatial and inhaled gas dependency

A parametric phase delay estimation technique is used to determine the spatial and inhaled gas composition dependencies of sound propagation time through an intact human lung at frequencies of 150–1200 Hz. Noise transmission measurements from the mouth to the extrathoracic trachea and six sites on the posterior chest wall are performed in 11 healthy adult subjects at resting lung volume after equilibration with air, an 80% helium-20% oxygen mixture, and an 80% sulfurhexafluoride-20% oxygen mixture. The phase delay, τ(f), exhibits a bilateral asymmetry with relatively decreased delays to the left posterior chest as compared with the right. The phase delay to lower lung sites is greater than to upper sites at frequencies below 300 Hz; yet the opposite is found at higher frequencies, indicating changing propagation pathways with frequency. There is no measurable effect of inhaled gas composition on τ(f) below 300 Hz. At higher frequencies, changes in τ(f) that reflect the relative sound speed of the particular inhaled gas are observed. These findings support and extend previous measurements and hypotheses concerning the strong frequency dependence of the acoustical properties of the intact respiratory system.     

Phase shifts of circadian rhythms in activity entrained to food access

Rats anticipate daily 2 hr meals with a sharp increase in activity several hours prior to food availability. The present experiment examined the response to phase shifts of food access in rats with lesions of the suprachiasmatic nuclei (SCN). Following entrainment of activity to 2 hr of food per day, food access was phase delayed or phase advanced by 4, 6, or 8 hr. All rats responded to phase delays of 4 or 6 hr with an increase in the duration of anticipatory activity so that transients appeared mostly in activity onset. Following 8 hr phase delays, clear delaying transients in both activity onset and end were observed. Only a few rats showed advancing transients in activity after phase advances of food access. In response to 6 hr and 8 hr phase advances, 3 different responses occurred: (a) activity re-entrained to food access by the 2nd or 3rd day without clear intervening transients, (b) activity phase shifted by means of distinct delaying transients and (c) delaying transients occurred in one component of activity while a second component of activity appeared at the new phase position by the second or third day. These results provide further evidence that anticipation of food access is mediated by a circadian mechanism which is functionally independent of the SCN and illustrate some similarities as well as considerable differences between circadian rhythms entrained by feeding and those entrained by light-dark cycles.     

Phase-Field-Based Axisymmetric Lattice Boltzmann Method for Two-Phase Electro-Hydrodynamic Flows

In this work, a novel and simple phase-field-based lattice Boltzmann (LB) method is proposed for the axisymmetric two-phase electro-hydrodynamic flows. The present LB method is composed of three LB models, which are used to solve the axisymmetric Allen-Cahn equation for the phase field, the axisymmetric Poisson equation for the electric potential, and the axisymmetric Navier-Stokes equations for the flow field. Compared with the previous LB models for the axisymmetric Poisson equation, which can be viewed as the solvers to the convection-diffusion equation, the present model is a genuine solver to the axisymmetric Poisson equation. To test the capacity of the LB method, the deformation of a single leaky or perfect dielectric drop under a uniform electric field is considered, and the effects of electric strength, conductivity ratio, and permittivity ratio are investigated in detail. It is found that the present numerical results are in good agreement with some available theoretical, numerical and/or experimental data.     

Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials

Objective: Laboratory data are key evaluation procedures for Phase I clinical pharmacology for two reasons. Firstly, laboratory data are used within the screening process to exclude subjects with asymptomatic diseases, which could result in increased danger to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluation and in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common variation and a significant abnormality, which is considered to be a LAE. This report presents laboratory data distribution, reference values and reference changes and, based on previously published new methods, suggests inclusion limits at screening and laboratory adverse event limits for analysis during study implementation. Subjects and methods: Nine hundred and twenty-seven young healthy male volunteers were recruited in one centre (Association de Recherche Thérapeutique). A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed in the same conditions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting 2.5% and 97.5% of the distribution of data. Reference changes were also defined as the 2.5–97.5% interval of distribution of the variations between the end of treatment and baseline. Inclusion limit and LAE limit methods of determination used had been specified in previous articles. Results: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion limits and LAE limits are presented in tables with number of subjects, mean, median, standard deviation, minimal and maximal values and the 2.5–97.5% interval for each laboratory parameter. Conclusion: The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies. Received: 30 July 1998 / Accepted in revised form: 25 November 1998     

Leucovorin, 5-fluorouracil,and gemcitabine: A phase I study

Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU).The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0–2, and signed informed consent.Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m², 5FU 255 mg/m² and gemcitabine 600 mg/m². 5FU and gemcitabine were escalated in tandem to 340 mg/m² and 800 mg/m² and thereafter to 425 mg/m² and 1000 mg/m², respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1–32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses.The maximum tolerated dose is leucovorin 20 mg/m², 5FU 340 mg/m², and gemcitabine 800 mg/m². The impact of drug sequence remains undetermined.     

小儿缩窄性心包炎的临床和病理观察

对３０例小儿缩窄性心包炎进行了临床和病量分析。结果显示：临床症状及体征无显性差异。由金典色葡萄球菌引起的急性心包炎中在较短时间内形成缩窄。病理改变既有炎症反应,肉芽组织增生,又有纤维组织增生。     

Phase shift in temperature rhythm ffter transmeridian flight,as related to pre-flight phase angle

Summary Further analysis of temperature rhythms obtained in an earlier study of 38 subjects subjected to an 8-h eastward transmeridian flight showed that the extent to which the phase of the rhythm was shifted after the flight was related to the phase angle of the pre-flight rhythm. Late peakers shifted more than early peakers, and this difference between the two types was still as large after 12 days in the new time zone as on the first day. Because the phase-shift was an advance one, this meant that the pre-flight individual differences in phase-angle were abolished by the flight, and had not re-appeared by the end of the observation period. It is suggested that this may have been due to an increase in the rigidity of the routine in the post-flight stage of the study, and that a similar effect may also occur in a switch from day to shiftwork.     

A phase I study of 5-fluorouracil, leucovorin and levamisole

 Purpose: The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole may provide additional benefit in the treatment of colon cancer. Methods: A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed. Results: A group of 38 patients with incurable etastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU (375 mg/m² per day) and leucovorin (200 mg/m² per day) were administered intravenously (days 1–5). Levamisole was administered orally (days 1–3 and 15–17) at doses from 30 to 470 mg/m² per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles. All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m² per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as evidenced by release of neopterin from monocytes. Conclusion: With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m². However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate dose for further phase 11 studies. Received: 20 October 1995 / Accepted: 16 June 1996