Rational redesign of inhibitors of furin／kexin processing proteases by electrostatic mutations

AIM:Tomodelthethree-dimensionalstructureandinvestigatetheinteractionmechanismoftheproproteinconvertasefurin/kexinandtheirinhibitors(eglincmutants).METHODS:Thethree-dimensionalcomplexstructuresoffurin/kexinwithitsinhibitors,eglincmutants,weregeneratedbymodellerprogramusingthenewlypublishedX-raycrystallographicalstructuresofmousefurinandyeastkexinastemplates.Theelectrostaticinteractionenergyofeachcomplexwascalculatedandtheresultswerecomparedwiththeexperimentallydeterminedinhibitioncon-stants…     

Advances in modeling of biomolecular interactions

Modeling of molecular interactions is increasingly used in life science research and biotechnology development. Examples are computer aided drug design, prediction of protein interactions with other molecules, and simulation of networks of biomolecules in a particular process in human body. This article reviews recent progress in the related fields and provides a brief overview on the methods used in molecular modeling of biological systems.     

Is depression related to subsequent diabetes mellitus?

OBJECTIVE: To compare the risk of developing diabetes mellitus (DM) in the general population between subjects who had a depression and subjects who never had a depression. METHOD: Retrospective cohort design. People with depression were diagnosed with a depression between 1975 and 1990; controls never had a depression. Both groups were followed for a diagnosis of type II diabetes until 2000. Data on 1334 depressed and 66 670 non-depressed subjects were available from a large general practice-based database. RESULTS: No overall relation was found, but among males below age 50 there was a 78% increase in the rate of development of DM compared with non-depressed patients (hazard ratio 1.78, 95% CI: 1.21-2.62). CONCLUSION: Depression in males between the age of 20 and 50 years is related to an increased risk of developing DM.     

Optimizing the novel formulation of liposome-polycation-dna complexes (lpd) by central composite design

LPD vectors are non-viral vehicles for gene delivery comprised of polycation-condensed plasmid DNA and liposomes. Here, we described a novel anionic LPD formulation containing protamine-DNA complexes and pH sensitive liposomes composed of DOPE and cholesteryl hemisuccinate (Chems). Central composite design (CCD) was employed to optimize stable LPD formulation with small particle size. A three factor, five-level CCD design was used for the optimization procedure, with the weight ratio of protamine/DNA (X1), the weight ratio of Chems/ DNA (X2) and the molar ratio of Chems/DOPE in the anionic liposomes (X3) as the independent variables. LPD size (Y1) and LPD protection efficiency against nuclease (Y2) were response variables. Zeta potential determination was utilized to define the experimental design region. Based on experimental design, responses for the 15 formulations were obtained. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The mathematical model predicted optimized X1-X3 levels that achieve the desired particle size and the protection efficiency against nuclease. According to these levels, an optimized LPD formulation was prepared, resulting in a particle size of 185.3 nm and protection efficiency of 80.22%.     

Nonresponse bias in a general population survey of eating-disordered behavior

OBJECTIVE: To investigate nonresponse bias in a two-phase epidemiologic study of eating-disordered behavior. METHOD: Self-report questionnaires were delivered to a community sample of women aged 18-45 drawn from the electoral roll. Follow-up interviews were completed with a subgroup of respondents. Eating disorder psychopathology, general physical and mental health, and sociodemographic characteristics were compared among early (n = 259) and late (n = 71) respondents at the first phase of the study and among individuals with whom interviews were completed (n = 208) and individuals declining to be interviewed (n = 63) at the second phase. RESULTS: With respect to levels of eating disorder psychopathology, and on all other measures, individuals who responded at the first phase of the study only after repeated reminders did not differ from those who responded to the initial mailout, and individuals who declined to be interviewed did not differ from individuals with whom interviews were completed. CONCLUSIONS: Nonresponse bias among individuals declining to be interviewed is unlikely to pose a problem in two-phase epidemiologic studies of eating disorders. Further research is needed to examine the characteristics of nonrespondents at the first phase of such studies.     

Optimal designs for Michaelis-Menten kinetic studies

Many reactions in enzymology are governed by the Michaelis-Menten equation. Characterising these reactions requires the estimation of the parameters K(M) and V(max) which determine the Michaelis-Menten equation and this is done by observing rates of reactions at a set of substrate concentrations. The choice of substrate concentrations is investigated by determining Bayesian D-optimal designs for a model in which residuals have a normal distribution with constant variance. Designs which focus on alternative quantities, such as K(M) or the ratio V(max)/K(M) are also considered. The effect on the optimal designs of alternative error distributions is also considered.     

Quantile estimation following non-parametric phase I clinical trials with ordinal response

A non-parametric multi-dimensional isotonic regression estimator is developed for use in estimating a set of target quantiles from an ordinal toxicity scale. We compare this estimator to the standard parametric maximum likelihood estimator from a proportional odds model for extremely small data sets. A motivating example is from phase I oncology clinical trials, where various non-parametric designs have been proposed that lead to very small data sets, often with ordinal toxicity response data. Our comparison of estimators is performed in conjunction with three of these non-parametric sequential designs for ordinal response data, two from the literature and a new design based on a random walk rule. We also compare with a non-parametric design for binary response trials, by keeping track of ordinal data for estimation purposes, but dichotomizing the data in the design phase. We find that a multidimensional isotonic regression-based estimator far exceeds the others in terms of accuracy and efficiency. A rule by Simon et al. (J. Natl. Cancer Inst. 1997; 89:1138-1147) yields particularly efficient estimators, more so than the random walk rule, but has higher numbers of dose-limiting toxicity. A small data set from a leukemia clinical trial is analysed using our multidimensional isotonic regression-based estimator.     

Changing education,changing assessment,changing research?

BACKGROUND: In medical education, assessment of medical competence and performance, important changes have taken place in the last 5 decades. These changes have affected the basic concepts in all 3 domains. DEVELOPMENTS IN EDUCATION AND ASSESSMENT: In education constructivism has provided a completely new view on how students learn best. In assessment the change from trait-orientated to competency- or role-orientated thinking has given rise to a whole range of new approaches. Certain methods of education, such as problem-based learning (PBL), and assessment, however, are often seen as almost synonymous with the underlying concepts, and one tends to forget that it is the concept that is important and that a particular method is but 1 way of using a concept. When doing this, one runs the risk of confusing means and ends, which may hamper or slow down new developments. LESSONS FOR RESEARCH: A similar problem seems to occur often in research of medical education. Here too, methods--or, rather, methodologies--are confused with research questions. This may lead to an overemphasis on research that fits well known methodologies (e.g. the randomised controlled trial) and neglect of what are sometimes even more important research questions because they do not fit well known methodologies. CONCLUSION: In this paper we advocate a return to the underlying concepts and a careful reflection of their use in various situations.     

Estimating Non-Response Bias in Family Studies: Application to Mental Health and Lifestyle

Non-response to mailed surveys reduces the effective sample size and may introduce bias. Non-response has been studied by (1) comparison to available data in population based registers, (2) directly contacting non-respondents by telephone or single-item reply cards, and (3) longitudinal repetition of the survey. The goal of this paper was to propose an additional method to study non-response bias: when the variable of interest has a familial component, data from respondents can be used as proxy for the data from their non-responding family members. This approach was used with data on smoking, alcohol consumption, physical activity, coffee- and tea-use, education, body mass index, religion, burnout, life events, personality and mental health in large number of siblings and DZ twins registered with the Netherlands Twin Register. In addition, for smoking behavior, we also used the second strategy by sending a reply card. Results show that scores of members from less cooperative families or incomplete twin pairs tended to be more unfavorable than the scores from highly cooperative families or complete twin pairs. For example, family members from less cooperative families cycled less often and scored higher on anxious depression and neuroticism. For smoking, both the results of the reply card and the results of the additional method suggested a higher percentage smokers among the non-respondents but this was only significant with reply card method. In general, differences between highly/less cooperative families and complete/incomplete DZ twins were small. Results suggest that, even for studies with moderate response rates, data collected on health, personality and lifestyle are relatively unbiased.     

Gold is not always good enough: the shortcomings of randomization when evaluating interventions in small heterogeneous samples

The three criteria for valid inference in therapeutic intervention evaluation are achieving control, avoiding systematic error, and minimizing random error. The randomized, double-blind, controlled trial has appropriately been accepted as the methodological gold standard because it is the only method with the potential to avoid systematic error resulting from unbalanced distributions of recognized and unrecognized determinants of outcome. This potential is not always realized, however, particularly with small, heterogeneous patient samples—which undermines the rationale for randomization in these circumstances. Minimization is one possible strategy to attain validity in such circumstances, but the acceptability of nonrandomized strategies is currently hampered by deference to the concept of randomization. For each intervention evaluation, research design should be considered afresh, focusing on the criteria determining validity rather than particular methodological elements.