不同致伤条件撞击对兔钝性胸部创伤伤情影响的实验研究

探讨不同致伤参数对兔钝性胸部创伤后胸部筘器官伤情的影响。方法采用兔钝性胸部创伤型,设置不同的致伤参数,观察其对胸部各器 伤情影响及其对死亡率的影响。结果驱动压力越大,胸部各器官伤情越重;撞击面积越大,对胸壁和肺的损伤较重,但心脏伤情并不随之加重;收缩末期撞击对心脏的损伤较重,舒张末期撞击大血管系统的影响较大,死亡率与驱动压力、撞击面积成正;舒张末期撞击死亡率上升。结论致伤参数不同,对钝化胸部创伤后     

Determination of microviscosity and location of 1,3-Di(1-pyrenyl)propane in brain membranes

We determined the microviscosity of synaptosomal plasma membrane vesicles (SPMV) isolated from bovine cerebral cortex and liposomes of total lipids (SPMTL) and phospholipids (SPMPL) extracted from SPMV. Changes in the microviscosity induced by the range and rate of lateral diffusion were measured by the intramolecular excimerization of 1,3-di(1-pyrenyl)-propane (Py-3-Py). The microviscosity values of the direct probe environment in SPMV, SPMTL and SPMPL were 38.17, 31.11 and 27.64 cP, respectively, at 37°C and the activation energies (E_a) of the excimer formation of Py-3-Py in SPMV, SPMTL and SPMPL were 8.236, 7.448 amd 7.025 kcal/mol, respectively. Probe location was measured by polarity and polarizability parameters of the probe Py-3-Py and probe analogues, pyrene, 1-pyrenenonanol and 1-pyrenemethyl-3β-hydroxy-22,23-bisnor-5-cholenate (PMC), incorporated into membranes or solubilized in reference solvents. There existed a good linear relationship between the first absorption peak of the¹L_a band and the polarizability parameter (n ²−1)/(2n ²+1). The calculated refractive index values for SPMV, SPMTL and SPMPL were close to 1.50, which is higher than that of liquid paraffin (n=1.475). The probe location was also determined by using a polarity parameter (f−1/2f¹). Here f=(ε−1)/(2ε+1) is the dielectric constant function and f'=(n ²−1)/(2n ²+1) is the refractive index function. A correlation existed between the monomer fluorescence intensity ratio and the solvent polarity parameter. The probes incorporated in SPMV, SPMTL, and SPMPL report a polarity value close to that of 1-hexanol (ε=13.29). In conclusion, Py-3-Py is located completely inside the membrane, not in the very hydrophobic core, but displaced toward the polar head groups of phospholipid molecules, e.g., central methylene region of aliphatic chains of phospholipid molecules.     

Classification of normal and pathological tremors using a multidimensional electromagnetic system

A new multidimensional movement analysis system was used to record limb tremor over six degrees-of-freedom, and signal processing techniques were explored to develop a suitable classification method to distinguish between different types of tremor. The specific aims were to investigate the ability of the system to screen for differences between normal subjects and a group of neurological patients, and then to differentiate between three diagnostic groups of patients.

Postural tremor at the hand was recorded in normal subjects (n=24) and patients with essential tremor (n=21), multiple sclerosis (n=17) and parkinsonism (n=19). Data were collected using a 3Space Fastrak^® (Polhemus, Inc.) over six degrees-of-freedom (three translational directions and three rotations). Spectral estimates produced measures of tremor frequency and amplitude. Mathematical models of the data, using autoregressive modelling and K-nearest neighbour classification, produced parameters used to classify, (1) the normal subjects and 24 patients (using the three rotational movements), and (2) the three patient groups (using all six movement directions). Results were given in terms of the probability of each subject belonging to the groups being classified.

Tremor frequency and amplitude showed large overlap between the groups. The screening classification produced high probabilities of correctly classifying normal subjects (>70%) and patients (>70%). The diagnostic classification produced clear differences between the patient groups (60% for essential tremor, 80% for multiple sclerosis and 60% for parkinsonism).

The ability of this assessment technique to distinguish between postural tremor in normal subjects and neurological patients suggests that it could be developed as a screening tool. Classification of tremors between the patients groups, with a high degree of sensitivity, indicates the potential for further development of the system as a diagnostic aid.     

Pharmacokinetics of methotrexate in leukemia cells: Effect of dose and mode of injection

A lumped compartmental model has been derived to predict methotrexate concentration as a function of time for L1210 cells in BD2F ₁ female mice at doses ranging from 3 mg/kg to 400 mg/kg. Using standard methods of parameter estimation as well as experimental determinations, an integrated approach was derived to account for the differences between the subcutaneous (s.c.) and intraperitoneal (i.p.) modes of injection. It was found that a single generalized forcing function can be used to fit plasma concentration after s.c. injection for all doses. Adequate fits (average error<20% while the standard deviation of experimental determinations was±22%) of L1210 cell data after s.c. injection were obtained. The best results were for a maximum facilitated influx constant V_max of 0.424 g/min/ml, a Michaelis influx constant K_m of 1,42 g/ml, and a first-order efflux constant of 0.047 min^–1.The model simulations were not sensitive to V_max, K_m,and so long as the ratio V_max/was approximately 9g/ml. The values of V _max ,K _m ,and which were obtained from our analysis of the in vivodata can be explained on the basis of previously performed in vitroexperiments. The parameters obtained from modeling the s.c. data were then applied for i.p. injection data. The resulting fits were adequate (average error<20% while the standard deviation of experimental determinations was±22%). A single generalized forcing function for drug concentration in the peritoneal cavity after i.p. injection for all doses was derived. The application of these results enables the prediction of methotrexate concentration in neoplastic cells at other doses after either s.c. or i.p. injection.     

Affected kin-pair IBD methods: genetic models.

Cases of interest using affected sib-pair methods to distinguish between recessive and additive (dominant) modes of inheritance of a disease-predisposing gene involve goodness-of-fit tests with a small expected number in the "share-zero parental haplotypes" category, as well as an unknown parameter, the frequency of the disease-predisposing allele. Our simulations demonstrate that the real significance level of the chi-square test using the three-haplotype-sharing IBD values (share 2, 1, and 0 parental haplotypes) is close to the assumed (.05) level in these cases, so that the haplotype-sharing classes do not have to be lumped, which would leave no degrees of freedom for a statistical test. The validity of the chi-square approximation in cases of small expected frequencies has previously been described, but the situations that have been considered do not cover the very small values in the share-zero category that are often expected in the affected sib-pair analysis, nor do they involve estimation of an unknown parameter. Although including IBD values from affected kin pairs other than sibs can be a very powerful tool in demonstrating linkage of a marker and disease, these pairs do not add power, in fact they reduce the power, of the chi-square tests of goodness-of-fit of modes of inheritance.     

The importance of employing stringent methods to recruit fertile male controls

Two methods of recruiting fertile male controls were evaluated and compared. The first group was recruited from the partners of women attending an antenatal clinic without obtaining details of their reproductive history. The second group was recruited after obtaining a detailed reproductive history from the couple and employing stringent entry criteria. Entry criteria for the second group included a length of exposure to the risk of pregnancy of not more than 12 months and no previous episode of involuntary infertility for either partner. There were significant differences between the distributions of semen parameters obtained from the two groups, indicating that the selection criteria for "fertile" men significantly influence results obtained and therefore that it is important to employ stringent criteria for the recruitment of fertile male controls. The group which was recruited by stringent criteria (mean length of exposure to the risk of pregnancy of 3 months) was characterised by a significantly higher median concentration of spermatozoa which exhibited slow linear or nonlinear motility. This confirms the findings of a previous study which suggested that slow linear or nonlinear motility are superior forms of spermatozoal motion.     

Receptor-recycling model of clearance and distribution of insulin in the perfused mouse liver

Summary After perfusion of mouse livers with A₁₄-¹²⁵I-insulin for designated intervals, an acid-wash technique was employed to separately measure the surface-bound (X_s) and intracellular (X_i) A₁₄-¹²⁵I-insulin, as well as intracellular degradation products (X_deg) of labelled insulin. From the perfusate concentrations (C_p) of A₁₄-¹²⁵I-insulin, the apparent intrinsic hepatic clearance of labelled insulin at a high dose (0.2 nmol/l) was shown to be 60% smaller than that at a low dose (0.018 nmol/l), indicating that the cellular uptake of insulin is remarkably nonlinear at the concentration range examined. From the time courses of C_p, X_s, X_i and X_deg, the hepatic insulin disposition was shown to be largely accounted for by the receptor-mediated endocytosis. The observed data at the low dose were analysed to estimate biochemical parameters, (i.e., total receptor number, endocytotic rate constant and intracellular degradation rate constant) according to receptor-recycling and non-receptor-recycling models, using a computer-aided optimization procedure. The receptor-recycling model could not only adequately explain the C_p, X_s, X_i and X_deg at the low dose, but also predict the C_p at the high dose. On the other hand, a non-receptor-recycling model, in which recycling of receptors was not assumed, could also explain the observed data at the low dose, but failed to predict the C_p at the high dose, indicating that the receptor recycling process is necessary to explain the hepatic insulin clearance at high insulin concentrations, at which hepatic insulin clearance should be limited by the rate of receptor recycling. However, the applicability of our model might be limited within the physiologic insulin concentrations, because of the negative co-operativity of insulin-receptor interaction and a high-capacity, non-degradative and more rapidly recycling pathway for receptors that may occur at high concentrations of insulin. In conclusion, we have developed a mathematical model of hepatic insulin clearance and distribution under physiological conditions, including receptor binding, receptor-mediated endocytosis and receptor recycling, which has been so far demonstrated using isolated hepatocytes.     

美托洛尔两种光学异构体代谢的酶动力学研究

目的：建立一种用AUC对酶动力学模型参数进行估算的方法，用酶动力学模型对美托洛尔（Met）两种光学异构体在大鼠肝脏的药物代谢进行研究。方法：用数学方法推导参数估算法公式；用大鼠肝切片孵育技术，对Met两种光学异构体的三种不同剂量（5、10、30μmol.L^-1）的药物浓度进行分析。并用本的参数估算法求出各自的酶动力学参数。结果：两种异构体，三种不同剂量的AUC有显性的统计学意义（P＜0．01），R－（＋）－Met的Vm,Km值分别为5．7471μmol.L^-1.h^-1和6．7724μmol.L^-1，S－（－）－Met的Vm,Km值分别为6．4350μmol.L^-1.h^-1和18．3404μmol.L^-1。结论：酶动力学模型适用于脏代谢的药动学研究。两种异构体的代谢具有明显差异。存在代谢的右旋异构体选择性。     

Pharmacokinetics of paclitaxel-containing liposomes in rats

In animal models, liposomal formulations of paclitaxel possess lower toxicity and equal antitumor efficacy compared with the clinical formulation, Taxol. The goal of this study was to determine the formulation dependence of paclitaxel pharmacokinetics in rats, in order to test the hypothesis that altered biodistribution of paclitaxel modifies the exposure of critical normal tissues. Paclitaxel was administered intravenously in either multilamellar (MLV) liposomes composed of phosphatidylglycerol/phosphatidylcholine (L-pac) or in the Cremophor EL/ethanol vehicle used for the Taxol formulation (Cre-pac). The dose was 40 mg/kg, and the infusion time was 8 to 9 minutes. Animals were killed at various times, and pharmacokinetic parameters were determined from the blood and tissue distribution of paclitaxel. The area under the concentration vs time curve (AUC) for blood was similar for the 2 formulations (L-pac: 38.1±3.32 μg-h/mL; Cre-pac: 34.5±0.994 μg-h/mL), however, the AUC for various tissues was formulation-dependent. For bone marrow, skin, kidney, brain, adipose, and muscle tissue, the AUC was statistically higher for Cre-pac. For spleen, a tissue of the reticuloendothelial system that is important in the clearance of liposomes, the AUC was statistically higher for L-pac. Apparent tissue partition coefficients (K_p) also were calculated. For bone marrow, a tissue in which paclitaxel exerts significant toxicity, K_p was 5-fold greater for paclitaxel in Cre-pac. The data are consistent with paclitaxel release from circulating liposomes, but with efflux delayed sufficiently to retain drug to a greater extent in the central (blood) compartment and reduce penetration into peripheral tissues. These effects may contribute to the reduced toxicity of liposomal formulations of paclitaxel.     

大肠癌巨─微血管构筑的临床研究

为了探讨大肠癌和其间质血管的关系，我们研究了48例大肠癌标本不同部位的巨─-微血管构筑。方法：用癌瘤标本造影摄X线片、立体显微镜和微机图象定量分析。结果显示：癌中心血管稀疏或为无血管的坏死区及血管破坏；癌远近端瘤组织内血管增多增粗，畸形及紊乱；其血管定量参数与癌中心和癌远近端肠粘膜相比有显著差异（P＜O．05，P＜0．01）。结论：①大肠癌的发生发展依赖于血管形成和细胞增殖。②在理论上解释了大肠癌的临床病理过程。③大肠癌的恶性程度与其血管密度间似有负相关的趋势。④探讨了其临床应用价值。