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PubMed2004

The etiopathogenesis of schizophrenias.

There is no generally accepted model explaining the aetiopathogenesis of schizophrenias. In recent years, hypotheses with a focus on single aspects of neurotransmission, single major genetic loci or single brain areas were predominating. Now, these different approaches converge to systemic models including neurotransmission, genetic changes and neurodevelopmental malformation of brain structures. Such systemic models will explain more aspects of schizophrenias than the recent confined hypotheses.

Animals↗

PubMed1998

Kinetics and energetics of subunit dissociation/unfolding of TIM: the importance of oligomerization for conformational persistence and chemical stability of proteins.

Kinetics of unfolding and refolding of rabbit muscle triosephosphate isomerase (TIM) were measured as a function of guanidine hydrochloride (GdnHCl) concentration. From the rate constants of these processes, the activation free-energy barriers (delta G++) were calculated using the Arrhenius equation. Assuming a linear dependence of delta G++ on the concentration of GdnHCl, activation energies in the absence of GdnHCl were estimated. The Gibbs free-energy change of dissociation/unfolding (delta G) was determined from GdnHCl unfolding curves in equilibrium. Using these data and the literature value for the bimolecular association rate constant of folded TIM monomers [Zabori, S., Rudolph, R., and Jaenicke, R. (1980) Z. Naturforsch. 35C, 999-1004], a model was developed that fully describes both kinetics and energetics of subunit dissociation/unfolding of TIM. Unfolded TIM monomers are susceptible to proteolytic digestion and thiol oxidation, while native TIM is resistant to both. The present model explains how the dimeric nature of TIM decreases the frequency of subunit unfolding by several orders of magnitude, thus increasing the chemical stability of the protein. Furthermore, the model also explains the recently demonstrated persistence (on a time scale of hours to days) of conformational heterogeneity of native TIM dimers [Rietveld, A. W. M., and Ferreira, S. T. (1996) Biochemistry 35, 7743-7751]. Again, it appears that the dimeric nature of TIM is essential for this behavior.

Animals↗

PubMed1996

Parenting predictors of early conduct problems in urban, high-risk boys.

OBJECTIVE: As part of a larger, prospective study, the authors examined concurrent and prospective relations among parenting and child antisocial behavior in inner-city boys at high risk for delinquent behavior. METHOD: One hundred twenty-six younger brothers (aged 6 to 10 years) of convicted delinquents in New York City and their parents were assessed; 15 months later 112 boys were reassessed. Demographics, parenting, and child diagnosis were examined as they relate to child externalizing behavior problems. Hierarchical multiple regression analyses predicted changes in Externalizing scores from year I parenting. RESULTS: At years I and II, 22% and 27% of boys, respectively, scored above the clinical cutoff for Externalizing. Controlling for earlier Externalizing, each of three domains of parenting still made significant independent contributions to later Externalizing scores, explaining 17% of the variance. Altogether this model explained 51% of the variance in year II Externalizing scores. CONCLUSIONS: Data support a cumulative risk model, whereby each of several adverse parenting factors further compounds the likelihood of child conduct problems.

Adolescent↗

PubMed2006

Mammalian cell killing by ultrasoft X rays and high-energy radiation: an extension of the MK model.

An alternate formulation of the microdosimetric-kinetic (MK) model is presented that applies to irradiation of mammalian cells with ultrasoft X rays as well as high-energy radiations of variable linear energy transfer (LET). Survival and DNA double-strand break measurements for V79 cells from the literature are examined to illustrate application of the model. It is demonstrated that the linear component of the linear-quadratic survival relationship (alpha) is enhanced because repairable potentially lethal lesions formed from a single ultrasoft X-ray energy deposition event, when closer on average than for a single high-energy radiation event, are more likely to combine to form a lethal lesion. The quadratic component (beta) of the linear-quadratic survival relationship is increased because the potentially lethal lesions formed by ultrasoft X rays are created with greater efficiency than those of high-energy radiation. In addition, potentially lethal lesions from very low-energy carbon K-shell X rays may be enriched in structural forms that favor combination to form lethal lesions instead of repair. These features account for the increased effectiveness of killing of V79 cells by ultrasoft X rays compared to cobalt-60 gamma radiation. The importance of pairwise combination of potentially lethal lesions to form exchange chromosome aberrations that become lethal lesions is discussed. The extended MK model explains and reconciles differences between the MK model and the theory of dual radiation action on the one hand, and on the other, the view that variation in the RBE with radiation quality is explained by differences in energy deposition in nanometer- rather than micrometer-size volumes.

Animals↗

PubMed2001

Light-triggered pH banding profile in Chara cells revealed with a scanning pH microprobe and its relation to self-organization phenomena.

When exposed to light, Characean cells develop a pattern of alternating alkaline and acid bands along the cell length. The bands were identified with a tip-sensitive antimony pH microelectrode positioned near one end of Chara internode at a distance of 50-100 microm from the cell wall. The stage with Chara cell was moved along its longitudinal axis at a computer-controlled speed (100 or 200 microm s(-1)) relative to the pH probe over a distance of 50 mm. Under sufficient uniform illumination of the cell (from 100 to 2.5 Wm(-2)), the homogeneous pH distribution becomes unstable and a banding pattern is formed, the spatial scale of which decreases with the light intensity. If the cell is locally illuminated, bands are formed only in the region of illumination. It is shown that the inhibition of cyclosis by cytochalasin B leads to the disappearance of the banding pattern. The addition of ammonium (weak base) inhibited the banding pattern, whereas acetate (weak acid) alleviated the inhibitory effect of ammonium and restored the pH banding. A model explaining the observed phenomena is formulated in terms of proton concentration outside and bicarbonate concentration inside the cell. It contains two diffusion equations for the corresponding ions with nonlinear boundary conditions determined by ion transport processes across the cell membrane. The model qualitatively explains most of the experimental observations. It describes the dependence of the pattern characteristics on the light intensity and reveals the role of cyclosis in this phenomenon.

Antimony↗

PubMed2004

Dynamic loads are determinants of peak bone mass.

This study investigated the association between non-invasive measurements of bone mass and markers of dynamic and static hip joint loads in subjects expected to be at peak bone mass. The bone mineral density (BMD) and bone mineral content (BMC) of three proximal femoral sites (neck, greater trochanter, and total) were measured by dual energy X-ray absorptiometry, and the peak external joint moments at the hip during walking and jogging were calculated from gait analyses of 31 normal human subjects ranging in age from 30 to 49 years (18 females, 13 males). Various multiple regression analyses were performed to determine how much of the variance in BMD and BMC was explained by height, body mass, and the peak hip joint moments. In total, the models explained up to 40% of the variance in BMD and 58% of the variance in BMC. Inclusion of height or body mass did not increase the explanatory power of the models for BMD and explained no more than 8% of the total variance in BMC once the joint moments from walking were allowed to enter the models. These data support the hypothesis that variance in peak bone mass is associated with variance in dynamic hip loads largely independent of the effect of static factors such as height and body mass.

Absorptiometry, Photon↗

PubMedDate not supplied

[Causality in urologic research].

Clinical-epidemiological research may orient us about the causes of disease, the relationships among them, and the relative magnitudes of their effects. The objective of this article is to link the notion of cause with the basic clinical-epidemiological parameters. There are different models explaining causality. All of them present the possible etiologic explanations for the diseases, taking into consideration the current knowledge at the time they have been posed. We start from a purely determinist conception, understanding causality as a constant connection between two factors x and y, unique, and perfectly predictable. Currently, this model is inadequate to be applied to many diseases. Many researchers have modified the determinist model to explain the multiple causality of disease, posing the existence of associations of causal factors, more than single factors, being these associations treated as sufficient cause (i.e. as a group of minimal conditions and events that inevitably produce the disease). That determinist concept of causality is supplemented with the probabilistic concept. The theory of probability is used in it, as well as the related statistical, methods, to empirically evaluate a possible association that is believed causal. As a consequence of the lack of certainty of the prediction at the individual level, the theoretical notion of cause is replaced by the empirical concept of risk factor, referring to a variable which is considered to be related to the probability that one individual develops the disease. Causal inference in epidemiology is the logic development of a theory, based on observations and arguments that attribute the presence (association) of a disease to one or more risk factors. We will follow the principles posed by B. Hill for the complex process called scientific generalization. To correctly perform this relationship between our ideas and are observations it is absolutely important to start from a correct election of the study design with which the research is undertaken.

Biomedical Research↗

PubMed1999

Statistical methodology: VIII. Using confirmatory factor analysis (CFA) in emergency medicine research.

How many underlying characteristics (or factors) does a set of survey questions measure? When subjects answer a set of self-report questions, is it more appropriate to analyze the questions individually, to pool responses to all of the questions to form one global score, or to combine subsets of related questions to define multiple underlying factors? Factor analysis is the statistical method of choice for answering such questions. When researchers have no idea beforehand about what factors may underlie a set of questions, they use exploratory factor analysis to infer the best explanatory model from observed data "after the fact." If, on the other hand, researchers have a hypothesis beforehand about the underlying factors, then they can use confirmatory factor analysis (CFA) to evaluate how well this model explains the observed data and to compare the model's goodness-of-fit with that of other competing models. This article describes the basic rules and building blocks of CFA: what it is, how it works, and how researchers can use it. The authors begin by placing CFA in the context of a common research application-namely, assessing quality of medical outcome using a patient satisfaction survey. They then explain, within this research context, how CFA is used to evaluate the explanatory power of a factor model and to decide which model or models best represent the data. The information that must be specified in the analysis to estimate a CFA model is highlighted, and the statistical assumptions and limitations of this analysis are noted. Analyzing the responses of 1,614 emergency medical patients to a commonly-used "patient satisfaction" questionnaire, the authors demonstrate how to: 1) compare competing factor-models to find the best-fitting model; 2) modify models to improve their goodness-of-fit; 3) test hypotheses about relationships among the underlying factors; 4) examine mean differences in "factor scores"; and 5) refine an existing instrument into a more streamlined form that has fewer questions and better conceptual and statistical precision than the original instrument. Finally, the role of CFA in developing new instruments is discussed.

Data Interpretation, Statistical↗

PubMed1999

Points of Zero Charge and Intrinsic Equilibrium Constants of Silica-Magnetite Composite Oxides.

A series of magnetic adsorbents (silica-magnetite composite oxides) containing 0, 20, 40, 60, 80, and 100 wt% magnetite were prepared via the sol-gel process, where 0.1-µm-radius magnetite particles were encased in a mesoporous silica matrix. The experimental pHpzc for each of the pure oxides and their mixtures was tested against two applicable models in the literature; neither model explained the observed behavior. One of the models did not account for the heterogeneous nature of the two distinct surfaces present in these silica-magnetite composite oxides, and neither model accounted for the possibility of the silica locally altering the behavior of the magnetite functional groups. The behavior was corroborated independently, however, based on an analysis carried out with the measured surface acidity constants. This work also showed that the total exchange capacity of each of the mixed oxides was dominated by the high surface area of the silica, and that the electrolyte species, Na+ or NO-3, did not completely complex with the surface of the oxides, as expected for weak binding ions. The chemical component of the free energy of adsorption of protons for the acid-base reactions also dominated the solvation and coulombic contributions for each of the pure oxides and their mixtures. Copyright 1999 Academic Press.

Journal Article↗

PubMed2004

Choline determination based on the intrinsic and the extrinsic (chemically modified) fluorescence of choline oxidase.

This paper describes two methods for the fluorometric determination of choline in serum by its reaction with the enzyme choline oxidase (ChOx). The first method, is based on changes in the intrinsic fluorescence of the enzyme (lambda(excitation)=28 nm and lambda(emission)=336 nm). The second method follows changes in the fluorescence intensity of a chemical modificant bonded to the enzyme (ChOx-FS), with excitation and emission maxima at 492 and 516 nm, respectively. Both methods have a similar response range (from 5 x 10(-7) to 10(-5) M or to 5 x 10(-5) M, depending on the analytical parameter) and precision (about 5%). The origin of the enzyme fluorescence changes has been elucidated and a mathematical model explaining the analytical signal is presented. This model can be applied to other enzymatic reactions based on flavin-containing enzymes and enables prediction of the sensitivity of new methods based on the Km values. Both methods have been applied to choline determination in synthetic serum samples. Moreover, the use of ChOx-FS avoids sample pretreatment.

Alcohol Oxidoreductases↗

PubMed2006

Body weight is a strong predictor of postural stability.

Proper balance control is a key aspect of acitivities of daily living. The aim of this study was to determine the contribution of body weight to predict balance stability. The balance stability of 59 male subjects with BMI ranging from 17.4 to 63.8kg/m(2) was assessed using a force platform. The subjects were tested with and without vision. A stepwise multiple regression analysis was used to determine the independent effect of body weight, age, body height and foot length on balance stability (i.e., mean speed of the center of foot pressure). With vision, the stepwise multiple regression revealed that body weight accounted for 52% of the variance of balance stability. The addition of age contributed a further 3% to explain balance control. Without vision, body weight accounted for 54% of the variance and the addition of age and body height added a further 8% and 1% to explain the total variance, respectively. The final model explained 63% of the variance. A decrease in balance stability is strongly correlated to an increase in body weight. This suggests that body weight may be an important risk factor for falling. Future studies should examine more closely the combined effect of aging and obesity on falling and injuries and the impact of obesity on the diverse range of activities of daily living.

Adult↗

PubMed2003

Molecular beacons for detecting DNA binding proteins: mechanism of action.

New methodology for detecting sequence-specific DNA binding proteins has been recently developed (T. Heyduk, and E. Heyduk, Nat. Biotechnol. 20 (2002) 171). The central feature of this assay is protein-dependent association of two DNA fragments, each containing about half of a DNA sequence-defining the protein binding site. In this report we propose a physical model explaining the functioning of the assay. The model involves two linked equilibria: association between the two DNA fragments and binding of the protein exclusively to the complex between the two DNA fragments. Equilibrium and kinetic experiments provided evidence supporting the proposed model and showed that the model was sufficient to describe the behavior of the assay under a variety of conditions. Kinetic data identified the association between the two DNA half-sites as the rate-limiting step of the assay. Theoretical simulations based on the proposed model were used to investigate parameters important for the maximal sensitivity of the assay. Physical understanding of the assay will provide means for rational design of the assay for a variety of target proteins.

Binding Sites↗

PubMed1995

Two classes of alamethicin transmembrane channels: molecular models from single-channel properties.

Molecular structures of transmembrane channels formed by alamethicin polypeptide aggregates were analyzed by measuring open-channel conductances and state-transition kinetics using voltage-clamp technique with artificial phospholipid bilayers isolated onto micropipettes by a novel solvent-free tip-dip method. Two distinct classes of alamethicin channels, each with a unique set of conductance states and kinetic properties, were identified. Alamethicin Rf50 at low temperatures forms mostly nonpersistent channels with lifetimes of < 1 min. Long-lasting persistent channels are formed by alamethicin Rf30 at all temperatures and by alamethicin Rf50 at room temperature. In the "modified barrel-stave" model for persistent channels based on the crystalline alamethicin secondary structure, the aqueous pore of the channel surrounded by parallel alamethicin monomers has a constriction generated by amino acid side chains protruding from the alamethicin helices into the pore. The model explains quantitatively the nonohmic channel conductance at high applied voltages and the conductance values and ion selectivities of various persistent channel states. The kinetic properties of nonpersistent channels are explained qualitatively by the "reversed-molecule" model in which nonpersistent channels differ from persistent channels by having one of the channel-forming alamethicin monomers oriented antiparallel to the others.

Alamethicin↗

PubMed2004

Inotropic effect of digoxin in humans: mechanistic pharmacokinetic/pharmacodynamic model based on slow receptor binding.

PURPOSE: The purpose of this study was to construct a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for digoxin that describes the relationship between plasma concentration and inotropic response. METHODS: On the basis of results obtained in the isolated perfused rat heart, a PK/PD model for digoxin in humans was developed. In fitting the model to previously published bolus dose and concentration clamp data (shortening of electromechanical systole), the plasma concentration-time curves were used as forcing functions in the computer program ADAPT II. RESULTS: The mechanistic approach allowed a modeling of digoxin pharmacodynamics which is consistent with available inotropic response data. The estimates of the receptor binding parameters were in the same order of magnitude as those measured in vitro for ouabain. The mechanistic model explained the parameters of the empirical link model (EC50, Emax and delay time tau) in terms of the underlying processes, suggesting that the long equilibration half-time of 13 h is due to slow receptor binding. The empirical link model, in contrast, is not compatible with a noninstantaneous receptor binding process and led to estimates of the delay time tau that were dependent on the digoxin administration schedule. CONCLUSIONS: The new, mechanistic model may provide a rationale for better understanding of digoxin pharmacodynamics and could become a tool to bridge the gap between in vitro and in vivo studies.

Animals↗

PubMed1999

Structural heterogeneity of the binding sites of HSA for phenyl-groups and medium-chain fatty acids. Demonstration of equilibrium between different binding conformations.

A new facet of the very heterogeneous albumin molecule is described. Chromatography at pH 6-9 of human serum albumin (HSA) on a phenyl-sepharose column separates it into two nonconvertible conformations that are, in turn, in equilibrium with its binding and nonbinding forms. The hydrophobic interaction of HSA with phenyl-sepharose depends on ionic strength, pH, and time of contact with the immobilized ligand. Binding as a function of pH shows a minimum at pH 6.5, and the binding profile at pH 7-9 fits the titration of a weak monoprotic acid with a pKa of 7.3. There was no observable difference in the CD spectra or the masses of the two forms. The equilibrium between the albumin forms was examined under defined conditions and cannot be explained by a simple two-state model. Thus rechromatography of the nonbinding fraction derived from a sample in which 50% of the protein was originally retained resulted only in 10-20% bound protein. Correspondingly only 70-80% of the binding form was retained. A model explaining the observations can be derived if two species, I and II, exist in the solution, both being in an equilibrium with a binding and a nonbinding form, but in which I is not in equilibrium with II. The rate of conversion between the binding and nonbinding conformations was determined to be faster than 15 s at room temperature.

Binding Sites↗

PubMed2006

New probabilistic network models and algorithms for oncogenesis.

Chromosomal aberrations in solid tumors appear in complex patterns. It is important to understand how these patterns develop, the dynamics of the process, the temporal or even causal order between aberrations, and the involved pathways. Here we present network models for chromosomal aberrations and algorithms for training models based on observed data. Our models are generative probabilistic models that can be used to study dynamical aspects of chromosomal evolution in cancer cells. They are well suited for a graphical representation that conveys the pathways found in a dataset. By allowing only pairwise dependencies and partition aberrations into modules, in which all aberrations are restricted to have the same dependencies, we reduce the number of parameters so that datasets sizes relevant to cancer applications can be handled. We apply our framework to a dataset of colorectal cancer tumor karyotypes. The obtained model explains the data significantly better than a model where independence between the aberrations is assumed. In fact, the obtained model performs very well with respect to several measures of goodness of fit and is, with respect to repetition of the training, more or less unique.

Algorithms↗

PubMed2001

Modeling women's quality of life after cardiac events.

Quality of life (QOL) is presented as a global, unidimensional, and subjective assessment of one's life. This study examined the impact of perceived health status, hope, and optimism on QOL in 93 women after suffering a cardiac event. Construct validity was examined by estimating a model where QOL was measured with four indicators, and perceived health was measured with the SF-36 Health Survey. Hope was measured with the Herth Hope Index and dispositional optimism was measured with the Life Orientation Test. The unidimensionality of QOL and its response to health status, hope, and optimism were tested. Fit indices suggested that the theoretical relations posited were compatible with the data, (chi 2(42) = 44.125, p = .382, RMSEA = .0001, GFI = .942). The model explained 66% of the variance in QOL. Modeling suggested the presence of a complex latent concept composed of hope and optimism that influenced QOL.

Aged↗

PubMedDate not supplied

Examining the care of patients with peripheral venous cannulas.

The purpose of this study was to examine nursing issues in the care of patients with peripheral venous cannulas (PVCs) with particular focus on duration of cannulation in order to minimize risk of infection. A tentative practice model evolved from this study. The research approach used involved qualitative methods utilizing grounded theory. Data analysis produced one tentative core category, 'effectiveness'. This allowed for the development of a 12-dimensional model explaining the nursing function against four interrelated models: development; practice; organizational support; effectiveness. Related to these four models were key professional aspects of 'autonomy-control' and 'knowledge-practice'. Interpretative findings from the study were plotted against this model, giving a graphic representation and highlighting strengths and weaknesses of nursing practice. Aspects requiring improvement included: PVC care as a syllabus subject; nursing practice; autonomy and control issues; shared responsibility problems; documentation systems; goal setting; outcomes. The policy, nurses' knowledge of PVC care and identification of critical issues were considered satisfactory. The model incorporates 12 important dimensions associated with effective practice that can be applied to nursing at different levels - clinical practice, education, management - and to other disciplines, providing a framework for narrowing the theory-practice gap and improving patient care.

Catheterization, Peripheral↗