乳腺增生病动物模型的实验研究

目的探索建立与人类乳腺增生病相类似动物模型的最佳方法。方法采用手术、己烯雌酚、黄体酮处理动物。检测血液中雌二醇(E2)、黄体酮(P)、促卵泡生成激素(FSH)、促黄体生成激素(LH)水平;乳腺组织作组织形态学观察与评价。结果与对照组比较,各实验组动物的乳腺组织切片均有典型的乳腺增生;血清中各激素的水平也有不同的变化。结论采用“己烯雌酚 黄体酮”方法,以家兔为实验对象,建立乳腺增生病的动物模型是目前最好的方法。     

Model Studies of the Dynamics of Bacterial Flagellar Motors

The bacterial flagellar motor is a rotary molecular machine that rotates the helical filaments that propel swimming bacteria. Extensive experimental and theoretical studies exist on the structure, assembly, energy input, power generation, and switching mechanism of the motor. In a previous article, we explained the general physics underneath the observed torque-speed curves with a simple two-state Fokker-Planck model. Here, we further analyze that model, showing that 1), the model predicts that the two components of the ion motive force can affect the motor dynamics differently, in agreement with latest experiments; 2), with explicit consideration of the stator spring, the model also explains the lack of dependence of the zero-load speed on stator number in the proton motor, as recently observed; and 3), the model reproduces the stepping behavior of the motor even with the existence of the stator springs and predicts the dwell-time distribution. The predicted stepping behavior of motors with two stators is discussed, and we suggest future experimental procedures for verification.     

Lattice Model for QSAR Studies

A system of lattice models that takes into account the structures of molecules, their form, stereochemical features and their interaction with the enclosing space, is proposed. The local, integral and field structural parameters of molecules (more than 20 thousand per compound) are estimated within the proposed framework. An investigation of the utility of these parameters in Quantitative Structure-Activity Relationships (QSAR) has been made using several statistical methods (multiple regression analysis, partial least squares (PLS), trend-vector procedure). The efficiency of the proposed approach has been examined using a data set derived from the formation of charge-transfer complexes of monosubstituted bezens with 1,3,5-trinitrobenzene.     

Evolutionary Studies Illuminate the Structural-Functional Model of Plant Phytochromes

A synthesis of insights from functional and evolutionary studies reveals how the phytochrome photoreceptor system has evolved to impart both stability and flexibility. Phytochromes in seed plants diverged into three major forms, phyA, phyB, and phyC, very early in the history of seed plants. Two additional forms, phyE and phyD, are restricted to flowering plants and Brassicaceae, respectively. While phyC, D, and E are absent from at least some taxa, phyA and phyB are present in all sampled seed plants and are the principal mediators of red/far-red–induced responses. Conversely, phyC-E apparently function in concert with phyB and, where present, expand the repertoire of phyB activities. Despite major advances, aspects of the structural-functional models for these photoreceptors remain elusive. Comparative sequence analyses expand the array of locus-specific mutant alleles for analysis by revealing historic mutations that occurred during gene lineage splitting and divergence. With insights from crystallographic data, a subset of these mutants can be chosen for functional studies to test their importance and determine the molecular mechanism by which they might impact light perception and signaling. In the case of gene families, where redundancy hinders isolation of some proportion of the relevant mutants, the approach may be particularly useful.     

Information-Theoretic Model Selection and Model Averaging for Closed-Population Capture-Recapture Studies

Specification of an appropriate model is critical to valid statistical inference. Given the “true model” for the data is unknown, the goal of model selection is to select a plausible approximating model that balances model bias and sampling variance. Model selection based on information criteria such as AIC or its variant AIC_c, or criteria like CAIC, has proven useful in a variety of contexts including the analysis of open-population capture-recapture data. These criteria have not been intensively evaluated for closed-population capture-recapture models, which are integer parameter models used to estimate population size (N), and there is concern that they will not perform well. To address this concern, we evaluated AIC, AIC_c, and CAIC model selection for closed-population capture-recapture models by empirically assessing the quality of inference for the population size parameter N. We found that AIC-, AIC_c-, and CAIC-selected models had smaller relative mean squared errors than randomly selected models, but that confidence interval coverage on N was poor unless unconditional variance estimates (which incorporate model uncertainty) were used to compute confidence intervals. Overall, AIC and AIC_c outperformed CAIC, and are preferred to CAIC for selection among the closed-population capture-recapture models we investigated. A model averaging approach to estimation, using AIC, AIC_c, or CAIC to estimate weights, was also investigated and proved superior to estimation using AIC-, AIC_c-, or CAIC-selected models. Our results suggested that, for model averaging, AIC or AIC_c should be favored over CAIC for estimating weights.     

Model Studies of the Iron-Catalysed Haber-Weiss Cycle and the Ascorbate-Driven Fenton Reaction

Complementary hydroxylation assays and stopped-flow e.s.r. techniques have been employed in the investigation of the effect of various iron chelators (of chemical, biological and clinical importance) on hydroxyl-radical generation via the Haber-Weiss cycle and the ascorbate-driven Fenton reaction.

Chelators have been identified which selectively promote or inhibit various reactions involved in hydroxyl-radical generation (for example, NTA and EDTA promote all the reactions of both the Haber-Weiss cycle and the ascorbate-driven Fenton reaction, whereas DTPA and phytate inhibit the recycling of iron in these reactions). The biological chelators succinate and citrate are shown to be relatively poor catalysts of the Haber-Weiss cycle, whereas they are found to be effective catalysts of ·OH generation in the ascorbate-driven Fenton reaction.

It is also suggested that continuous redox-cycling reactions between iron, oxygen and ascorbate may represent an important mechanism of cell death in biological systems.     

Model Studies of the Iron-Catalysed Haber-Weiss Cycle and the Ascorbate-Driven Fenton Reaction

Complementary hydroxylation assays and stopped-flow e.s.r. techniques have been employed in the investigation of the effect of various iron chelators (of chemical, biological and clinical importance) on hydroxyl-radical generation via the Haber-Weiss cycle and the ascorbate-driven Fenton reaction.

Chelators have been identified which selectively promote or inhibit various reactions involved in hydroxyl-radical generation (for example, NTA and EDTA promote all the reactions of both the Haber-Weiss cycle and the ascorbate-driven Fenton reaction, whereas DTPA and phytate inhibit the recycling of iron in these reactions). The biological chelators succinate and citrate are shown to be relatively poor catalysts of the Haber-Weiss cycle, whereas they are found to be effective catalysts of ·OH generation in the ascorbate-driven Fenton reaction.

It is also suggested that continuous redox-cycling reactions between iron, oxygen and ascorbate may represent an important mechanism of cell death in biological systems.     

通便化痔颗粒对痔疮模型大鼠的疗效

目的对酸灼伤大鼠皮肤能否行成痔疮模型进行方法学研究及通便化痔颗粒对此模型的药理作用。方法采用10 mol/L盐酸灼伤人工划伤的大鼠肛门周围皮肤及肛门内侧的黏膜,连续灌胃给予通便化痔颗粒10 d后,进行肉眼观察及光镜观察评分。通便化痔颗粒能使被盐酸灼伤并发生病理性改变的皮肤得到有效地恢复。结果病理结果显示痔疮模型成功;通便化痔颗粒在大、中剂量下能使大鼠被盐酸灼伤发生病理性改变的皮肤得到有效地恢复。结论酸灼伤大鼠皮肤模拟痔疮模型成立;通便化痔颗粒能够有效恢复大鼠痔疮模型皮肤组织。     

Kinetic Model Development for Accelerated Stability Studies

Accelerated stability coupled with modeling to predict the stability of compounds, blends, and products at long-term storage conditions provides significant benefits in science-based decision-making throughout drug substance and drug product development. The study can often be completed, including data analysis in the space of three working weeks, and the information gathered and learning made in this time period can rival years of traditional analysis. The speed of the studies allows an earlier assessment of risk to quality enabling appropriate risk mitigation strategies to be implemented in a timely manner. The scientific foundation is based upon Arrhenius kinetic equations that can be linear or nonlinear in time, and can be based upon water vapor pressure or liquid water activity (relative humidity). A variety of kinetic models are evaluated, and the best model is chosen based upon both Bayesian information criteria and an automated assessment of kinetic model parameters fitting within acceptable ranges. Confidence intervals are estimated based upon a bootstrapping approach. Moisture vapor transmission rate models are applied on top of the resulting kinetic models in order to simulate different packaging types and the use of desiccant. The kinetic models are integrated with the prediction of packaging humidity over time to create a long-term prediction of impurities and other phenomena. The resulting models have been shown to be useful for not only the prediction of drug product impurities in long-term storage but other physical phenomena as well such as hydrate development and solvate loss.     

Interaction between Protein Subunits from Model Studies

A molecular model of hemoglobin was constructed which made it possible to visualize the relation between various amino acid residues in the molecule. The model indicates that electrostatic forces might play a significant role in holding the subunits of hemoglobin together. This would explain why myoglobin does not form a tetramer while four β-chains, which are structurally similar to myoglobin, do assemble into a hemoglobin H molecule. Also, as far as the primary structures of hemoglobin chains of various species are known, the proposed ionic links between subunits are consistent with the fact that mammalian hemoglobins form stable tetramers while the peptide chains of lamprey hemoglobin are only weakly associated. The different behavior of hemoglobin H and of normal hemoglobin upon oxygen uptake is briefly discussed in terms of allosteric effects.     

Model Studies of the Role of Mechano-sensitive Currents in the Generation of Cardiac Arrhythmias

Mechano-electrical feedback is studied by incorporating linear, instantaneously activating mechano-sensitive conductances into single cardiac cell models, as well as one- and two-dimensional cardiac network models. The models qualitatively reproduce effects of maintained mechanical stretch on experimentally measured action potential characteristics such as amplitude, maximum diastolic potential, peak upstroke velocity, and conduction velocity. Models are also used to simulate stretch-induced depolarizations, action potentials, and arrhythmias produced by pulsatile volume changes in left ventricle of dog. The mechano-sensitive conductance threshold for a stretch-induced action potential is closely related to the magnitude of the time-independent K⁺current,I_K1, which offsets inward mechano-sensitive current. Activation of mechano-sensitive conductances in small, spatially localized region of cells can evoke graded depolarizations, propagating ectopic beats, and if timed appropriately, spiral reentrant waves. Mechano-sensitive conductance changes required to evoke these responses are well within the physiologically plausible range. Results therefore indicate that many mechano-electrical feedback effects can be modeled using linear, instantaneously activating mechano-sensitive conductances. As an example of how stretch can occur in real human hearts, magnetic resonance images with saturation tagging are used to reconstruct the three-dimensional left ventricular wall motion. In patients with infarcts or recent ischemic events, “paradoxical deformation” is observed in that regions of myocardium are stretched rather than contracted during systole. In contrast, normal hearts contract uniformly with no stretch during systole. Paradoxical deformations in ischemic hearts may therefore present one possible substrate for the mechanically induced arrhythmias modeled above.     

Studies on the Behavior of 14C-chlorpyrifos in a Model Rice Ecosystem

Fate of ¹⁴C-chlorpyrifos was studied in a model rice ecosystem. The level of ¹⁴C-residues in floodwater showed initially a rapid decline in first 10 days. These residues were observed till 30 days. The insecticide residues in soil did not show any appreciable build-up, thereby indicating that the residue levels of this insecticide may not be significant. Extractable residues were formed up to 10–13% of the applied ¹⁴C-activity during the period of 136 days, while the bound fraction of ¹⁴C-residues reached a maximum of 2.9% after 92 days. Algae and rice plants showed ¹⁴C-residues to the extent of only 0.01% of the applied ¹⁴C-activity. Rice grains did not show any residues at all. These results indicate that chlorpyrifos undergoes considerable degradation in rice soils and does not leave residues, which may be of environmental concern.     

Cross-Protection Studies with Three Serotypes of Pasteurella haemolytica in the Goat Model

Cross-protection studies employing three serotypes of Pasteurella haemolytica (Ph) were performed in goats, with challenge exposure by transthoracic injection. Indirect hemagglutination (IHA) serum titers showed that the herd had been naturally infected with Ph biovar A, serovar 2 (PhA2) prior to the study. Sixty-four weanling male Spanish goats were randomly allotted to 16 groups. Fifteen goats were given two transthoracic injections into the lungs 21 days apart with live Pasteurella haemolytica biovar A, serovar 1 (PhA1) in agar beads. Fifteen goats were given two transthoracic injections into the lungs 21 days apart with live PhA2 in agar beads. Sixteen goats were given two transthoracic injections into the lungs 21 days apart with live P. haemolytica biovar A, serovar 6 (PhA6) in agar beads. Eighteen control (CON) goats were given two transthoracic injections into the lungs 21 days apart with agar beads alone. Fourteen days after the second injection, goats were challenge-exposed to either live PhA1, PhA2, or PhA6 by transthoracic injection into the lung, and 4 days later, all goats were euthanatized and necropsied. Serum antibody to P. haemolytica antigens was measured throughout the experiment. Mean volumes of consolidated lung tissue for the CON goats challenged with PhA1, PhA2, and PhA6 were 28.29 cm³, 8.36 cm³, and 16.29 cm³, respectively. Mean volumes of consolidated lung tissue for the PhA1-immunized goats challenged with PhA1, PhA2, and PhA6 were 4.38 cm³, 0.25 cm³, and 1.90 cm³, respectively. Mean volumes of consolidated lung tissue for the PhA2-immunized goats challenged with PhA1, PhA2, and PhA6 were 9.68 cm³, 0.05 cm³, and 3.39 cm³, respectively. Mean volumes of consolidated lung tissue for the PhA6-immunized goats challenged with PhA1, PhA2, and PhA6 were 14.05 cm³, 1.27 cm³, and 4.53 cm³, respectively. These data demonstrate protection in immunized goats challenged with the homologous serotype of P. haemolytica. PhA1-immunized animals were protected against serotype 2 challenge as well as against serotype 6 challenge. PhA2-immunized animals were not protected against serotype 1 challenge, but were protected against transthoracic PhA6 challenge. PhA6-immunized animals were not protected against serotype 1 challenge, but were protected against transthoracic PhA2 challenge. There appears to be some cross-protection among the P. haemolytica serotypes, and this fact should be taken into consideration when developing vaccines against this organism. Received: 13 June 1997 / Accepted: 6 October 1997     

Goodness-of-Fit Tests for the Logistic Regression Model for Matched Case-Control Studies

A number of statistics have recently been proposed to asssess the fit of the multiple logistic regression model in both prospective and retrospective studies involving two independent samples as well as in cross sectional studies. These statistics are not appropriate for assessing fit with matched case-control studies. This paper presents methods for assessing fit for matched case-control studies. Both parametric and nonparametric approaches are suggested even though none are directly analogous to the statistics proposed in the unmatched situation. Several examples are included to illustrate the methods.     

Use of Polytomous Logistic Model in Matched Case-Control Studies

Binary logistic model has been found useful for estimating odds ratio in case of dichotomous exposure variable under matched case-control retrospective design. We describe the use of polytomous logistic model for estimating odds ratios when the exposure of prime interests, relative to disease incidence, has more than two levels. An illustrative example is presented and discussed.     

A Statistical Model for Regional Tornado Climate Studies

Tornado reports are locally rare, often clustered, and of variable quality making it difficult to use them directly to describe regional tornado climatology. Here a statistical model is demonstrated that overcomes some of these difficulties and produces a smoothed regional-scale climatology of tornado occurrences. The model is applied to data aggregated at the level of counties. These data include annual population, annual tornado counts and an index of terrain roughness. The model has a term to capture the smoothed frequency relative to the state average. The model is used to examine whether terrain roughness is related to tornado frequency and whether there are differences in tornado activity by County Warning Area (CWA). A key finding is that tornado reports increase by 13% for a two-fold increase in population across Kansas after accounting for improvements in rating procedures. Independent of this relationship, tornadoes have been increasing at an annual rate of 1.9%. Another finding is the pattern of correlated residuals showing more Kansas tornadoes in a corridor of counties running roughly north to south across the west central part of the state consistent with the dryline climatology. The model is significantly improved by adding terrain roughness. The effect amounts to an 18% reduction in the number of tornadoes for every ten meter increase in elevation standard deviation. The model indicates that tornadoes are 51% more likely to occur in counties served by the CWAs of DDC and GID than elsewhere in the state. Flexibility of the model is illustrated by fitting it to data from Illinois, Mississippi, South Dakota, and Ohio.     

Studies on the electroretinogram. II. Model of an a-wave regenerator mechanism

A model is proposed to relate the regeneration of the ERGa-wave after partial light adaptation to the level of the light adaptation. The model assumes that thea-wave amplitude is a function of some reactive substance associated with ana-wave generator. The maximuma-wave amplitude occurs when the eye is fully dark adapted, and thea-wave generator initiator concentration is at a maximum. Thea-wave generator initiator concentration can be decreased by interacting with a product of the rhodopsin-light energy reaction, and increased by removal of this inhibitor. The removal of the inhibitor depends upon the isomerization of the all-trans-retinene to the 11-cis form. An excess of inhibitory material overa-wave generator initiator would cause a delay in the appearance of thea-wave until the excess inhibitory material is removed. This delay is a linear function of the logarithm of the adapting energy. The agreement of this model with the experimental ERG data is very good. Supported in whole by Public Health Service Research Grant No. NB-02522, from the National Institute of Neurological Diseases and Blindness, Bethesda, Maryland.