Kinetic model of the action of oligomeric enzymes using phosphofructokinase as an example. II. General formulation of the hierarchical model

A general approach is suggested to describe the steady-state kinetics of the oligomeric enzymes on the base of the generalized statistical Ising model. Detailed analysis is given for the case of a oligomeric enzyme with a hierarchical supramolecular organization. A protomer of this enzyme composed of several equivalent subunits represents the quarternary level of structure. In their turn the finite or infinite number of protomers is associated into a oligomer thus creating a new "quinternary" level of the enzyme organization. The model accounts for the ligand-induced homotrophic cooperative interactions: firstly, between the neighbouring protomers and secondly, between the subunits of the same protomer. The influence of protomer conformation on the subunit state and the cooperativity induction caused by two-ligand binding are also taken into consideration. Monod-Wyman-Changeux's and Koshland's models are shown to be special limit cases of the suggested general theory.     

北京怀柔“4.23”急性可乐定中毒事件临床救治体会

本研究旨在观察群体性急性可乐定中毒的流行病学特点、临床表现及救治方法,尤其是评价血液灌流（hemoperfusion,HP）治疗急性可乐定中毒的有效性和安全性.通过对北京怀柔4.23急性可乐定中毒事件行流行病学调查,分析所有80例患者的所有流行病学资料,研究病情较重的34例患者的临床表现、治疗方案、预后情况.采用HA230树脂血液灌流器数次HP治疗前后血可乐定、尿可乐定浓度的变化,计算血可乐定浓度下降率,及与常规内科治疗相比HP的排毒效率.观察治疗前患者血压、心率及其他实验室指标如血小板、心肌酶谱、肝酶谱的变化并评价疗效及副作用.研究发现急性可乐定中毒具有隐蔽性强,发病潜伏期短,症状重等特点,HP治疗可显著降低血可乐定水平,短暂升高尿可乐定水平.患者临床症状亦显著改善,血可乐定的下降率为（81±12）%,所有患者经间断HP治疗1～3次后血、尿可乐定水平接近正常.随着患者血可乐定浓度渐趋正常,其临床症状及实验室指标亦能明显改善,短期HP治疗无明显副作用,随访观察半月余,未观察到后遗症.群体性可乐定中毒常常具有危害人群广,症状重风险大,诊治难度大的特点,重者致人死亡,或者造成社会极大恐慌.研究群体性可乐定中毒有浓厚的军事医学意义,HP是治疗可乐定中毒安全有效的治疗手段.     

The stay/switch model describes choice among magnitudes of reinforcers

The stay/switch model is an alternative to the generalized matching law for describing choice in concurrent procedures. The purpose of the present experiment was to extend this model to choice among magnitudes of reinforcers. Rats were exposed to conditions in which the magnitude of reinforcers (number of food pellets) varied for staying at alternative 1, switching from alternative 1, staying at alternative 2 and switching from alternative 2. A changeover delay was not used. The results showed that the stay/switch model provided a good account of the data overall, and deviations from fits of the generalized matching law to response allocation data were in the direction predicted by the stay/switch model. In addition, comparisons among specific conditions suggested that varying the ratio of obtained reinforcers, as in the generalized matching law, was not necessary to change the response and time allocations. Other comparisons suggested that varying the ratio of obtained reinforcers was not sufficient to change response allocation. Taken together these results provide additional support for the stay/switch model of concurrent choice.     

Generalized plasma skimming model for cells and drug carriers in the microvasculature

In microvascular transport, where both blood and drug carriers are involved, plasma skimming has a key role on changing hematocrit level and drug carrier concentration in capillary beds after continuous vessel bifurcation in the microvasculature. While there have been numerous studies on modeling the plasma skimming of blood, previous works lacked in consideration of its interaction with drug carriers. In this paper, a generalized plasma skimming model is suggested to predict the redistributions of both the cells and drug carriers at each bifurcation. In order to examine its applicability, this new model was applied on a single bifurcation system to predict the redistribution of red blood cells and drug carriers. Furthermore, this model was tested at microvascular network level under different plasma skimming conditions for predicting the concentration of drug carriers. Based on these results, the applicability of this generalized plasma skimming model is fully discussed and future works along with the model’s limitations are summarized.     

Heterozygote manifestation in recessive generalized myotonia

Summary The frequency of heterozygotes of recessive generalized myotonia may be estimated at about 1/108 in the German Federal Republic. Some heterozygotes can be identified by an EMG. However, apart from this, apparently 2%–5% of heterozygotes may show minor subclinical manifestations. Sporadic cases of myotonia with late onset and a history of preceding, extremely prolonged physical stress, undernourishment, and/or prolonged cold exposure may be due to heterozygote manifestations of this otherwise recessive gene. Late onset and sporadic appearance also are features in patients with myotonia associated with hypothyroidism. One male patient displayed myotonia after a protracted diabetic coma. In cases reported in the literature where myotonia developed in association with either propranolol (beta-adrenergic blocking agent) or fenoterolhydrobromide (stimulator of beta receptors) heterozygote manifestation of recessive generalized myotonia is suggested.     

TEMPORAL VARIATION IN ALLELE FREQUENCIES: TESTING THE RIGHT HYPOTHESIS

Although standard statistical tests (such as contingency chi-square or G tests) are not well suited to the analysis of temporal changes in allele frequencies, they continue to be used routinely in this context. Because the null hypothesis stipulated by the test is violated if samples are temporally spaced, the true probability of a significant test statistic will not equal the nominal α level, and conclusions drawn on the basis of such tests can be misleading. A generalized method, applicable to a wide variety of organisms and sampling schemes, is developed here to estimate the probability of a significant test statistic if the only forces acting on allele frequencies are stochastic ones (i.e., sampling error and genetic drift). Results from analyses and simulations indicate that the rate at which this probability increases with time is determined primarily by the ratio of sample size to effective population size. Because this ratio differs considerably among species, the seriousness of the error in using the standard test will also differ. Bias is particularly strong in cases in which a high percentage of the total population can be sampled (for example, endangered species). The model used here is also applicable to the analysis of parent-offspring data and to comparisons of replicate samples from the same generation. A generalized test of the hypothesis that observed changes in allele frequency can be satisfactorily explained by drift follows directly from the model, and simulation results indicate that the true α level of this adjusted test is close to the nominal one under most conditions.     

A Model for a Proportional Treatment Effect on Disease Progression

Treatments intended to slow the progression of chronic diseases are often hypothesized to reduce the rate of further injury to a biological system without improving the current level of functioning. In this situation, the treatment effect may be negligible for patients whose disease would have been stable without the treatment but would be expected to be an increasing function of the progression rate in patients with worsening disease. This article considers a variation of the Laird Ware mixed effects model in which the effect of the treatment on the slope of a longitudinal outcome is assumed to be proportional to the progression rate for patients with progressive disease. Inference based on maximum likelihood and a generalized estimating equations procedure is considered. Under the proportional effect assumption, the precision of the estimated treatment effect can be increased by incorporating the functional relationship between the model parameters and the variance of the outcome variable, particularly when the magnitude of the mean slope of the outcome is small compared with the standard deviation of the slopes. An example from a study of chronic renal disease is used to illustrate insights provided by the proportional effect model that may be overlooked with models assuming additive treatment effects.     

Characteristics of the meningococcal carrier state in organized collectives and its role in the development of generalized forms of meningococcal infection

Complex (epidemiological and bacteriological) investigations of the level and structure of meningococcal carriership among the members of organized collective bodies differing in the epidemiological situation with respect to meningococcal infection have been carried out. The absence of differences between the total level of meningococcal carriership and the morbidity rate with respect to the generalized forms of meningococcal infection has been shown. The presence of cases of meningococcal meningitis in the groups under study has been found to depend on the intensity of the circulation of certain meningococcal serogroups. The possibility of the ecological reservation of the causative agents of meningococcal infection as polyagglutinable forms has been suggested.     

Transactional skew and assured fitness return models fail to predict patterns of cooperation in wasps

Cooperative breeders often exhibit reproductive skew, where dominant individuals reproduce more than subordinates. Two approaches derived from Hamilton's inclusive fitness model predict when subordinate behavior is favored over living solitarily. The assured fitness return (AFR) model predicts that subordinates help when they are highly likely to gain immediate indirect fitness. Transactional skew models predict dominants and subordinates "agree" on a level of reproductive skew that induces subordinates to join groups. We show the AFR model to be a special case of transactional skew models that assumes no direct reproduction by subordinates. We use data from 11 populations of four wasp species (Polistes, Liostenogaster) as a test of whether transactional frameworks suffice to predict when subordinate behavior should be observed in general and the specific level of skew observed in cooperative groups. The general prediction is supported; in 10 of 11 cases, transactional models correctly predict presence or absence of cooperation. In contrast, the specific prediction is not consistent with the data. Where cooperation occurs, the model accurately predicts highly biased reproductive skew between full sisters. However, the model also predicts that distantly related or unrelated females should cooperate with low skew. This prediction fails: cooperation with high skew is the observed norm. Neither the generalized transactional model nor the special-case AFR model can explain this significant feature of wasp sociobiology. Alternative, nontransactional hypotheses such as parental manipulation and kin recognition errors are discussed.     

Effects of genomic imprinting on quantitative traits

Standard Mendelian genetic processes incorporate several symmetries, one of which is that the level of expression of a gene inherited from an organism’s mother is identical to the level should that gene have been inherited paternally. For a small number of loci in a variety of taxa, this symmetry does not hold; such genes are said to be “genomically imprinted” (or simply “imprinted”). The best known examples of imprinted loci come from mammals and angiosperms, although there are also cases from several insects and some data suggesting that imprinting exists in zebra fish. Imprinting means that reciprocal heterozygotes need not be, on average, phenotypically identical. When this difference is incorporated into the standard quantitative-genetic model for two alleles at a single locus, a number of standard expressions are altered in fundamental ways. Most importantly, in contrast to the case with euMendelian expression, the additive and dominance deviations are correlated. It would clearly be of interest to be able to separate imprinting effects from maternal genetic effects, but when the latter are added to the model, the well-known generalized least-squares approach to deriving breeding values cannot be applied. Distinguishing these two types of parent-of-origin effects is not a simple problem and requires further research.     

Predator interference emerging from trophotaxis in predator–prey systems: An individual-based approach

An individual-based model describing predator–prey interactions within a closed rectangular habitat was developed to study how different assumptions about the individual movements lead to the emergence at the population level of various kinds of prey- and predator-dependence in the spatially aggregated trophic function.In addition to random walk, both species are capable of directional movement, i.e., the model accounts for the predator prey-taxis and evasion of predators by prey individuals. The taxis stimulus of each species is the odour of the other species, which is distributed continuously in space. Spatial behaviour of individuals is determined by the specific response to the odour gradient and the tendency to maintain the taxis velocity.In order to facilitate the assessment of the trophic function, the model allows removing the effect of demographic density variations on the predator ration, keeping population sizes constant.Analyzing the dependence of the trophic function with the average predator density, we found that, depending on the intensity of taxis, the predator population exhibits various degrees of interference, from very low to very high values. In particular, a moderate taxis generates distinct levels of interference including the ratio-dependent case. The letter maximizes the average consumption rate.A new generalized function containing ratio-dependence and prey-dependence as special cases, at high and low population abundances, is suggested. This trophic function fits the simulated data better than the Hassell–Varley–Holling expression does.     

人工湿地去污模型的统一结构特征

通过对典型人工湿地去污模型的分析比较,提出了基于各模型微分方程而建立的统一去污模型。该模型能够将典型去污模型作为特例而导出,并能很好地解释这些模型之间的过渡关系。以潜流湿地中NH4^＋和BOD5的降解为例,对统一去污模型的应用情况进行了简单探讨,表明利用统一去污模型结构有助于深入揭示去污机理,从而提出更为精确的去污模型。     

Suction-assisted lipectomy for correction of 202 figure faults in 101 patients: indications, limitations, and applications

Since its introduction in the United States, suction-assisted lipectomy has proven to be a safe, effective technique for correction of figure faults. It has been greeted with considerable skepticism by many practitioners, however, owing to the poor results many have obtained in their initial attempts to apply similar techniques. Suction lipectomy using the blunt technique is a safe procedure that can yield consistently good results when appropriately applied. It is suggested that the principal reason others have had difficulty involves problems in patient selection. The technique may not be effective for the correction of generalized obesity and cannot be expected to dramatically alter overall appearance. Patients should be selected for treatment of specific "figure faults" and educated as to what may realistically be expected. The patient's emotional and psychological condition must be taken into consideration. We report a series of 101 patients treated with a total of 202 separate suction lipectomy procedures with good results and only two minor complications. A survey of patients treated by the method reveals a generally high level of satisfaction and some of the ambivalence that might be anticipated from such a technique.     

Towards a theory of insect epidemiology

An attempt is made to consolidate and extend some of our current thoughts on insect epidemiology using graphical reproduction models. Starting with a simple model with a single equilibrium point, the elementary hypothesis is proposed that epidemics erupt when this equilibrium point increases substantially through improvement of the insect's habitat. The extension of this model to more than one coincident equilibria, some of which may be locally stable, is discussed and generalized using the theory of habitat suitability. Use of equilibrium manifolds is suggested to permit greater dimensionality. Lastly, an explanation of insect epidemics, based on the effects of time delays in the response of density-dependent processes, is elaborated and generalized. The influence of spatial dimensions and insect dispersal on the theory is discussed.     

An Evaluation of Beta-Binomial and Dirichlet-Trinomial Models for the Analysis of Reproductive and Developmental Effects

The common endpoints for the evaluation of reproductive and developmental toxic effects are the number of dead/resorbed fetuses, the number of malformed fetuses, and the number of normal fetuses for each litter. The joint distribution of the three endpoints could be modelled by a Dirichlettrinomial distribution or by a product of two-beta-binomial distributions. A simulation experiment is used to investigate the biases of the maximum likelihood estimate (MLE) for the probability of adverse effects under the Dirichlet-trinomial model and the beta-binomial model. Also, the type I errors and powers of the likelihood ratio test for comparing the difference between treatment and control are evaluated for the two underlying models. In estimation, the two MLE's are comparable, the bias estimates are small. In testing, the likelihood ratio test is generally more powerful under the Dirichlet-trinomial model than the beta-binomial model. The type I error rate is greater than the nominal level using the Dirichlet-trinomial model in some cases, when the data are generated from the two-beta-binomial model, and it is less than the nominal level using the beta-binomial model in other cases, when the data are generated from the Dirichlet-trinomial model.     

Core mechanisms in generalized convulsions

A hypothetical model is proposed to account for the generalized convulsions observed in rats. Two versions of the hypothesis are discussed: an earlier, more specific formulation that accounts for kindled convulsions, and a later, general version that applies to generalized convulsions as a whole. Observations leading to the specific formulation of the model included: 1) kindling data that suggested a single downstream center responsible for kindled convulsions; 2) brain-stem stimulation data that indicated that the reticular core of that structure could initiate and maintain generalized convulsive behavior; and 3) spinal hemisection data that indicated that nonspecific systems in the cord could also maintain convulsions, even in the absence of direct input from the brain. The more specific version of the model suggests that kindled convulsions are nonspecific core seizures that occur when self-sustained epileptic activation spreads from forebrain foci to involve descending polysynaptic pathways in the nonspecific core of the brain stem and cord. Observations leading to a more general formulation of the model include the facts that: 1) maximal and submaximal convulsions in a variety of models resemble each other; and 2) they also resemble the maximal and submaximal seizures produced by direct stimulation of the brain stem and cord. The more general formulation of the nonspecific core hypothesis suggests that a wide variety of convulsions in rats may be nonspecific core seizures, differences in tonic-clonic and rostrocaudal configuration being related primarily to differences in the intensity of core activation.     

A bivariate joint frailty model with mixture framework for survival analysis of recurrent events with dependent censoring and cure fraction

In the study of multiple failure time data with recurrent clinical endpoints, the classical independent censoring assumption in survival analysis can be violated when the evolution of the recurrent events is correlated with a censoring mechanism such as death. Moreover, in some situations, a cure fraction appears in the data because a tangible proportion of the study population benefits from treatment and becomes recurrence free and insusceptible to death related to the disease. A bivariate joint frailty mixture cure model is proposed to allow for dependent censoring and cure fraction in recurrent event data. The latency part of the model consists of two intensity functions for the hazard rates of recurrent events and death, wherein a bivariate frailty is introduced by means of the generalized linear mixed model methodology to adjust for dependent censoring. The model allows covariates and frailties in both the incidence and the latency parts, and it further accounts for the possibility of cure after each recurrence. It includes the joint frailty model and other related models as special cases. An expectation-maximization (EM)-type algorithm is developed to provide residual maximum likelihood estimation of model parameters. Through simulation studies, the performance of the model is investigated under different magnitudes of dependent censoring and cure rate. The model is applied to data sets from two colorectal cancer studies to illustrate its practical value.     

Suggestions for a mathematical model of a pathological neuron with spontaneous repetitive discharges

A formal mathematical model is proposed for a spontaneously repetitively firing neuron. It is based on the assumption that an excitatory and inhibitory substance, possibly different from those involved in synaptic transmissions, is formed in the soma of everynormal neuron. Furthermore, the decay of the substances is ascribed to their combination with some other substances, present in healthy individuals. A generalized two factor system of differential equations is used. It is shown that when the normally present substances are absent, possibly due to genetic defects so that the decay constants become zero, the equations lead to undamped sinusoidal solutions of the difference between excitatory and inhibitory factors, thus producing a trulyspontaneous repetitive discharge, in the absence of external currents or other stimulation. It is suggested that convulsants may act by destroying the substances present in healthy individuals. It is further suggested that by administering to epileptics those substances, which are present in normal healthy persons, perhaps by using brain extracts fromhealthy higher animals which sometimes suffer from epilepsy, an actual cure rather than symptomatic treatment by anticonvulsants may be obtained.     

A covariance estimator for GEE with improved small-sample properties

In this paper, we propose an alternative covariance estimator to the robust covariance estimator of generalized estimating equations (GEE). Hypothesis tests using the robust covariance estimator can have inflated size when the number of independent clusters is small. Resampling methods, such as the jackknife and bootstrap, have been suggested for covariance estimation when the number of clusters is small. A drawback of the resampling methods when the response is binary is that the methods can break down when the number of subjects is small due to zero or near-zero cell counts caused by resampling. We propose a bias-corrected covariance estimator that avoids this problem. In a small simulation study, we compare the bias-corrected covariance estimator to the robust and jackknife covariance estimators for binary responses for situations involving 10-40 subjects with equal and unequal cluster sizes of 16-64 observations. The bias-corrected covariance estimator gave tests with sizes close to the nominal level even when the number of subjects was 10 and cluster sizes were unequal, whereas the robust and jackknife covariance estimators gave tests with sizes that could be 2-3 times the nominal level. The methods are illustrated using data from a randomized clinical trial on treatment for bone loss in subjects with periodontal disease.