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PubMed2004

Robustness of chlorzoxazone as an in vivo measure of cytochrome P450 2E1 activity.

AIMS: Chlorzoxazone is metabolized by cytochrome P450 2E1 (CYP2E1) to a single oxidized metabolite, 6-hydroxychlorzoxazone. The aim of the study was to test the robustness of chlorzoxazone as an in vivo probe of CYP2E1 activity in humans, with emphasis on investigating short-term and long-term intra-individual variabilities and effects of different doses of the drug. In addition, the influences of body build, drug metabolizing enzyme genotype, blood sampling time, and moderate recent ethanol intake were investigated. METHODS: The 6-hydroxychlorzoxazone:chlorzoxazone (metabolic) ratio in plasma was measured at 2 h in 28 male and nine female volunteers following a single oral dose of 500 mg chlorzoxazone. Similarly, the metabolic ratios at 4 h and 6 h were measured in 20 of the males. The metabolic ratio at 2 h was also determined 1.5 and 2.5 years later in 13 and seven males, respectively, and weekly for 3 weeks in seven males, after a dose of 500 mg, once at higher (750 mg) and lower (250 mg) doses, and once (500 mg) following moderate ethanol intake (0.5 g kg(-1) body weight) the preceding evening. Genotypes were determined for CYP2E1 as well as for N-acetyltransferase 2 and glutathione transferase M1. RESULTS: Excluding an outlier (ratio = 1.6) the metabolic ratio at 2 h ranged from 0.12 to 0.61 (n = 36). A positive correlation with body weight (r = 0.61, P < 0.001) suggested dose-dependent metabolism of chlorzoxazone. The metabolic ratio decreased with increasing chlorzoxazone dose (P = 0.01), again suggesting dose-dependent metabolism. Long-term (yearly intervals) and short-term (weekly intervals) intra- and interindividual variabilities in metabolic ratio were similar (30% and 63%vs 28% and 54%, respectively). Both inter- and intra-individual variabilities tended to decrease with increasing dose of chlorzoxazone. There was no significant influence of moderate ethanol intake the preceding evening, or of CYP2E1 genotype on the metabolic ratio. CONCLUSIONS: The relatively low intra-individual variability in the metabolism of chlorzoxazone suggests that a single-sample procedure may suffice to assess CYP2E1 activity in vivo. However, chlorzoxazone metabolism is dose-dependent at commonly used doses and it is therefore advisable to adjust the dose for body weight. Moderate intake of ethanol the preceding evening did not significantly affect the chlorzoxazone metabolic ratio.

Adult↗
PubMed2007

Robust association of the APOE epsilon4 allele with premature myocardial infarction especially in patients without hypercholesterolaemia: the Aachen study.

BACKGROUND: Genetic influence on the manifestation of coronary artery disease (CAD) and myocardial infarction (MI) has been shown previously. From many candidate genes the APOE (apolipoprotein E) with the major alleles epsilon2/epsilon3/epsilon4 is in the focus of interest. MATERIALS AND METHODS: In 1817 patients admitted for their first left heart catheterization at a premature age (males < 55 and females < 65) the association of APOE alleles with MI was analysed. Genotyping was done by 5' exonuclease assay (TaqMan). RESULTS APOE was significantly associated with hypercholesterolaemia (epsilon4 72% vs. epsilon3 66% vs. epsilon2 51%; P < 0.0001), and premature MI (epsilon4 57% vs. epsilon3 50% vs. epsilon2 41%; P < 0.0001; hazard ratio 1.41, 95%CI 1.14-1.75). In patients without hypercholesterolaemia, the APOE allele epsilon4 was highly predictive for the presence of premature MI (epsilon4 55% vs. epsilon3 45% vs. epsilon2 28%; P < 0.0001; hazard ratio 1.75, 95%CI 1.19-2.57). CONCLUSION: The APOEepsilon4 allele shows a robust association with premature MI independent of hypercholesterolaemia.

Adult↗
PubMed2004

Increased breakthrough bleeding during prophylaxis with B-domain deleted factor VIII--a robust meta-analytic finding.

Meta-analyses of observational studies have become increasingly common to support evidence-based clinical decisions. We analyzed currently available clinical studies of full-length factor VIII (FL-FVIII) vs. B-domain deleted recombinant factor VIII (BDD-rFVIII) using a random effects model to investigate possible differences in clinical efficacy in patients treated during prophylaxis. Some studies reported breakthrough bleeding incidence as mean annual total bleeds, whereas others reported median bleeds. In accord with the consensus recommendations by the Meta-analysis of Observational Studies in Epidemiology (MOOSE) group, all available studies where included. For analysis, data were combined by converting median to mean annual total bleeds using a conversion factor of 2.6, based on clinical data previously compiled by the Universal Data Collection Program of the U.S. Centers for Disease Control and Prevention. To evaluate the sensitivity of our model upon the choice of conversion factor, we re-estimated incidence rate ratios for breakthrough bleeding over a wide range of conversion factors from 1.4-2.6. Even at the lowest extreme conversion factor of 1.4, bleeding incidence was statistically higher in patients treated with BDD-rFVIII compared with FL-FVIII. We also examined the impact of reported patient age on our multivariate model. Exposure to BDD-rFVIII remained an independent predictor of bleeding, regardless of patient age at start or mean age during prophylaxis. These analyses further support the robustness of our meta-analysis and its conclusions.

Age Factors↗
PubMed2006

What do we know about partnership with service users and carers in social work education and how robust is the evidence base?

Partnership work with service users and carers in social work education is a policy requirement, and it is also central to the anti-oppressive and rights-based values of social work. This paper reports research findings which are drawn from an educational context, but are also relevant to the wider field of health and social care. The research team undertook a systematic knowledge review using the Evidence for Policy and Practice Information and Coordinating Centre system, which had been used in health and education, but which had not previously been used in social care and social work. This involved an extensive search of electronic databases and rigorous screening to identify studies which had sufficient relevance to be subjected to detailed analysis. The research team also undertook a practice survey of the teaching, learning and assessment of partnership in prequalifying programmes in England, Wales and Northern Ireland. This involved three stages: a document search; telephone interviews; and focus groups held with students, academic staff, and service users and carers. Throughout the research process, the interdisciplinary team was advised and supported by a stakeholder group which consisted of service users and carers, students, and employer representatives. In the second part of the paper, subsequent discussion explores key findings from the research, including the disputed nature of the concept of partnership, models of partnership work within social work education and the dearth of research on partnership outcomes. Five related questions are identified as a means of interrogating the robustness of the research process and findings. The paper concludes by arguing for work to be done to theorise partnership, and to develop effective strategies for improving the quality of partnership working in education, and health and social care practice.

Caregivers↗
PubMed2006

Robust salivary gland-specific transgene expression in Anopheles stephensi mosquito.

Malaria sporozoites invade the mosquito salivary glands and wait in the salivary duct until the next blood feeding. The mechanisms of the process and molecules involved in the salivary gland invasion remain largely unknown. To establish a robust salivary gland-specific transgene expression in Anopheles stephensi, we obtained a salivary gland-specific promoter for a gene encoding anopheline antiplatelet protein (AAPP). The aapp promoter is a female salivary gland-specific and blood meal-inducible strong promoter. Using this promoter, we generated a transgenic An. stephensi expressing abundant Discosoma sp. red fluorescent protein (DsRed) in the distal-lateral lobes of the glands, where the sporozoites invade preferentially. These results open up the possibilities of elucidating salivary gland-parasite interactions and generating transgenic mosquitoes refractory to parasites.

Animals↗
PubMed2006

Robust hierarchical state-space models reveal diel variation in travel rates of migrating leatherback turtles.

1. Biological and statistical complexity are features common to most ecological data that hinder our ability to extract meaningful patterns using conventional tools. Recent work on implementing modern statistical methods for analysis of such ecological data has focused primarily on population dynamics but other types of data, such as animal movement pathways obtained from satellite telemetry, can also benefit from the application of modern statistical tools. 2. We develop a robust hierarchical state-space approach for analysis of multiple satellite telemetry pathways obtained via the Argos system. State-space models are time-series methods that allow unobserved states and biological parameters to be estimated from data observed with error. We show that the approach can reveal important patterns in complex, noisy data where conventional methods cannot. 3. Using the largest Atlantic satellite telemetry data set for critically endangered leatherback turtles, we show that the diel pattern in travel rates of these turtles changes over different phases of their migratory cycle. While foraging in northern waters the turtles show similar travel rates during day and night, but on their southward migration to tropical waters travel rates are markedly faster during the day. These patterns are generally consistent with diving data, and may be related to changes in foraging behaviour. Interestingly, individuals that migrate southward to breed generally show higher daytime travel rates than individuals that migrate southward in a non-breeding year. 4. Our approach is extremely flexible and can be applied to many ecological analyses that use complex, sequential data.

Animal Migration↗
PubMed1978

The estimation of neuronal population density by a robust distance method.

A new "nearest-neighbour" or "distance" method of estimating neurone population density is introduced. The method was originally developed for ecological studies but can be imported into histology without significant modification; changes in population density can be estimated by inverting the measure of area per unit cell (the so-called mean area). Its advantages include tests of randomness for the spatial distribution of the cells at issue and a robustness which can tolerate some departure from a random distribution pattern. To illustrate how the method is applied estimates of neurone density, in terms of "mean area" per cell-point, are made on a montage tracing of the human cerebellar dentate nucleus.

Cell Count↗
PubMed2005

The robustness of learning through overhearing.

Two studies examined the robustness of vocabulary learning through overhearing by testing 48 2-year-olds in contexts in which a potentially distracting activity was present (Studies 1 and 2) and in which the novel word was embedded in a directive rather than a labeling statement (Study 2). The children were equally good at learning a novel object label when there was no distracting activity as when there was. They were also able to learn the word when the object was not explicitly labeled. These findings suggest that young children are keen observers of third-party interactions and that their linguistic input consists of more than just speech directly addressed to them.

Attention↗
PubMed1996

Assessing genetic linkage and association with robust components of variance approaches.

Simulation studies are used to explore the properties of procedures for estimating components of variance and constructing test statistics in genetic linkage studies of quantitative traits. We evaluated the bias and median squared error of estimates of the linked additive genetic variance obtained by regression, maximum likelihood and quasilikelihood estimation procedures. The quasilikelihood and regression procedures provided unbiased estimates of the additive component of variance. Maximum likelihood procedures that assumed multivariate normality were biased for most sample sizes considered but had more precision for most generating models than regression or quasilikelihood methods did. Wald tests derived from quasilikelihood procedures had similar or greater power than Wald tests based upon estimators from maximum likelihood analyses. Quasilikelihood estimation may therefore be preferable whenever there is uncertainty about the generating distribution for the error variance, but the robustness of this approach is offset by its required computational complexity.

Age Factors↗
PubMed2007

Efficacy and feasibility of a novel tri-modal robust exercise prescription in a retirement community: a randomized, controlled trial.

OBJECTIVES: To test the feasibility and efficacy of current guidelines for multimodal exercise programs in older adults. DESIGN: Randomized, controlled trial. SETTING: Retirement village. PARTICIPANTS: Thirty-eight subjects (14 men and 24 women) aged 76.6 +/- 6.1. INTERVENTION: A wait list control or 10 weeks of supervised exercise consisting of high-intensity (80% of one-repetition maximum (1RM)) progressive resistance training (PRT) 3 days per week, moderate-intensity (rating of perceived exertion 11 to 14/20) aerobic training 2 days per week, and progressive balance training 1 day per week. MEASUREMENTS: Blinded assessments of dynamic muscle strength (1RM), balance, 6-minute walk, gait velocity, chair stand, stair climb, depressive symptoms, self-efficacy, and habitual physical activity level. RESULTS: Higher baseline strength and psychological well-being were associated with better functional performance. Strength gains over 10 weeks averaged 39+/-31% in exercise, versus 21+/-24% in controls (P=.10), with greater improvements in hip flexion (P=.01), hip abduction (P=.02), and chest press (P=.04) in the exercise group. Strength adaptations were greatest in exercises in which the intended continuous progressive overload was achieved. Stair climb power (12.3+/-15%, P=.002) and chair stand time (-7.1+/-15%, P=.006) improved significantly and similarly in both groups. Reduction in depressive symptoms was significantly related to compliance (attendance rate r=-0.568, P=.009, PRT progression in loading r=-0.587, P=.02, and total volume of aerobic training r=-0.541, P=.01), as well as improvements in muscle strength (r=-0.498, P=.002). CONCLUSION: Robust physical and psychological adaptations to exercise are linked, although volumes and intensities of multiple exercise modalities sufficient to cause significant adaptation appear difficult to prescribe and adhere to simultaneously in older adults.

Aged↗
PubMed2005

Doubly robust estimation in missing data and causal inference models.

The goal of this article is to construct doubly robust (DR) estimators in ignorable missing data and causal inference models. In a missing data model, an estimator is DR if it remains consistent when either (but not necessarily both) a model for the missingness mechanism or a model for the distribution of the complete data is correctly specified. Because with observational data one can never be sure that either a missingness model or a complete data model is correct, perhaps the best that can be hoped for is to find a DR estimator. DR estimators, in contrast to standard likelihood-based or (nonaugmented) inverse probability-weighted estimators, give the analyst two chances, instead of only one, to make a valid inference. In a causal inference model, an estimator is DR if it remains consistent when either a model for the treatment assignment mechanism or a model for the distribution of the counterfactual data is correctly specified. Because with observational data one can never be sure that a model for the treatment assignment mechanism or a model for the counterfactual data is correct, inference based on DR estimators should improve upon previous approaches. Indeed, we present the results of simulation studies which demonstrate that the finite sample performance of DR estimators is as impressive as theory would predict. The proposed method is applied to a cardiovascular clinical trial.

Antidepressive Agents↗
PubMed2006

Bayesian robust inference for differential gene expression in microarrays with multiple samples.

We consider the problem of identifying differentially expressed genes under different conditions using gene expression microarrays. Because of the many steps involved in the experimental process, from hybridization to image analysis, cDNA microarray data often contain outliers. For example, an outlying data value could occur because of scratches or dust on the surface, imperfections in the glass, or imperfections in the array production. We develop a robust Bayesian hierarchical model for testing for differential expression. Errors are modeled explicitly using a t-distribution, which accounts for outliers. The model includes an exchangeable prior for the variances, which allows different variances for the genes but still shrinks extreme empirical variances. Our model can be used for testing for differentially expressed genes among multiple samples, and it can distinguish between the different possible patterns of differential expression when there are three or more samples. Parameter estimation is carried out using a novel version of Markov chain Monte Carlo that is appropriate when the model puts mass on subspaces of the full parameter space. The method is illustrated using two publicly available gene expression data sets. We compare our method to six other baseline and commonly used techniques, namely the t-test, the Bonferroni-adjusted t-test, significance analysis of microarrays (SAM), Efron's empirical Bayes, and EBarrays in both its lognormal-normal and gamma-gamma forms. In an experiment with HIV data, our method performed better than these alternatives, on the basis of between-replicate agreement and disagreement.

Bayes Theorem↗
PubMed2006

Robust semiparametric microarray normalization and significance analysis.

Microarray technology allows the monitoring of expression levels of thousands of genes simultaneously. A semiparametric location and scale model is proposed to model gene expression levels for normalization and significance analysis purposes. Robust estimation based on weighted least absolute deviation regression and significance analysis based on the weighted bootstrap are investigated. The proposed approach naturally combines normalization and significance analysis, and incorporates the variations due to normalization into the significance analysis properly. A small simulation study is used to compare finite sample performance of the proposed approach with alternatives. We also demonstrate the proposed method with a real dataset.

Biometry↗
PubMed1986

Clinical methods in psychiatric genetics. I. Robustness of genetic marker investigative strategies.

Population stratification, secondary effects of illness or treatment, biological heterogeneity of a clinical syndrome, or complex biology underlying a syndrome (where only one component is measured) are conditions which may obscure the association of a genetic risk factor with a clinical syndrome. We consider several investigative strategies under each of these conditions. Only segregation-based paradigms are robust to genetic heterogeneity and population stratification. But secondary effects on the risk factor produced by illness or treatment require other strategies for their detection.

Chromosome Aberrations↗
PubMed2005

A robust homogeneous binding assay for alpha4beta2 nicotinic acetylcholine receptor.

AIM: To develop a homogeneous high-throughput screening (HTS) assay based on scintillation proximity assay (SPA) technology for identification of novel alpha4beta2 nicotinic acetylcholine receptor (nAChR) modulators. METHODS: Membrane preparation of HEK293 cells expressing alpha4beta2 nAChR, [(3)H]cytisine and wheat germ agglutinin (WGA)-coupled microbeads were used to develop an HTS assay based on SPA technology. This method was validated against a conventional filter binding approach and applied to large-scale screening of a library containing 32 000 synthetic compounds. Intracellular calcium measurement was carried out to verify the bioactivities of the hits found by the SPA assay. RESULTS: IC(50) values of 2 reference compounds (epibatidine and RJR 2403) determined by SPA and filter binding methods were comparable and consistent with those reported elsewhere. A total of 54 compounds, showing more than 60% competitive inhibition on [(3)H]cytisine binding to alpha4beta2 nAChR, were identified initially following an HTS campaign. Secondary screening confirmed that 17 compounds with novel chemical structures possessed relatively high binding affinity to alpha4beta2 nAChR (K(i)<2 micromol/L). Eight compounds displayed antagonistic effects with >50% inhibition on ABT-594-induced calcium mobilization while none showed any agonist activity. CONCLUSIONS: This homogeneous binding assay is a highly efficient, amenable to automation and robust tool to screen potential alpha4beta2 nAChR modulators in an HTS setting. Its application may be expanded to other membrane receptors and ion channels.

Alkaloids↗
PubMed2006

Cyclothiazide induces robust epileptiform activity in rat hippocampal neurons both in vitro and in vivo.

Cyclothiazide (CTZ) is a potent blocker of AMPA receptor desensitization. We have recently demonstrated that CTZ also inhibits GABA(A) receptors. Here we report that CTZ induces robust epileptiform activity in hippocampal neurons both in vitro and in vivo. We first found that chronic treatment of hippocampal cultures with CTZ (5 microM, 48 h) results in epileptiform activity in the majority of neurons (80%). The epileptiform activity lasts more than 48 h after washing off CTZ, suggesting a permanent change of the neural network properties after CTZ treatment. We then demonstrated in in vivo recordings that injection of CTZ (5 micromol in 5 microl) into the lateral ventricles of anaesthetized rats also induces spontaneous epileptiform activity in the hippocampal CA1 region. The epileptogenic effect of CTZ is probably due to its enhancing glutamatergic neurotransmission as shown by increasing the frequency and decay time of mEPSCs, and simultaneously inhibiting GABAergic neurotransmission by reducing the frequency of mIPSCs. Comparing to a well-known epileptogenic agent kainic acid (KA), CTZ affects neuronal activity mainly through modulating synaptic transmission without significant change of the intrinsic membrane excitability. Unlike KA, which induces significant cell death in hippocampal cultures, CTZ treatment does not result in any apparent neuronal death. Therefore, the CTZ-induced epilepsy model may provide a novel research tool to elucidate the molecular and cellular mechanisms of epileptogenesis without any complication from drug-induced cell death. The long-lasting epileptiform activity after CTZ washout may also make it a very useful model in screening antiepileptic drugs.

Animals↗
PubMedDate not supplied

Robust nonlinear autoregressive moving average model parameter estimation using stochastic recurrent artificial neural networks.

In this study, we introduce a new approach for estimating linear and nonlinear stochastic autoregressive moving average (ARMA) model parameters, given a corrupt signal, using artificial recurrent neural networks. This new approach is a two-step approach in which the parameters of the deterministic part of the stochastic ARMA model are first estimated via a three-layer artificial neural network (deterministic estimation step) and then reestimated using the prediction error as one of the inputs to the artificial neural networks in an iterative algorithm (stochastic estimation step). The prediction error is obtained by subtracting the corrupt signal of the estimated ARMA model obtained via the deterministic estimation step from the system output response. We present computer simulation examples to show the efficacy of the proposed stochastic recurrent neural network approach in obtaining accurate model predictions. Furthermore, we compare the performance of the new approach to that of the deterministic recurrent neural network approach. Using this simple two-step procedure, we obtain more robust model predictions than with the deterministic recurrent neural network approach despite the presence of significant amounts of either dynamic or measurement noise in the output signal. The comparison between the deterministic and stochastic recurrent neural network approaches is furthered by applying both approaches to experimentally obtained renal blood pressure and flow signals.

Algorithms↗
PubMed2001

Design and analysis of robust total joint replacements: finite element model experiments with environmental variables.

Computer simulation of orthopaedic devices can be prohibitively time consuming, particularly when assessing multiple design and environmental factors. Chang et al. (1999) address these computational challenges using an efficient statistical predictor to optimize a flexible hip implant, defined by a midstem reduction, subjected to multiple environmental conditions. Here, we extend this methodology by: (1) explicitly considering constraint equations in the optimization formulation, (2) showing that the optimal design for one environmental distribution is robust to alternate distributions, and (3) illustrating a sensitivity analysis technique to determine influential design and environmental factors. A thin midstem diameter with a short stabilizing distal tip minimized the bone remodeling signal while maintaining satisfactory stability. Hip joint force orientation was more influential than the effect of the controllable design variables on bone remodeling and the cancellous bone elastic modulus had the most influence on relative motion, both results indicating the importance of including uncontrollable environmental factors. The optimal search indicated that only 16 to 22 computer simulations were necessary to predict the optimal design, a significant savings over traditional search techniques.

Arthroplasty, Replacement, Hip↗