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OBJECTIVE: To investigate the differences in exposure to medications in a cohort of multi-ethnic pregnant women. METHODS: Six hundred and forty-one pregnant women of Western, Arab/Turkish and "other origins" participated in this cross-sectional study using a questionnaire in a university hospital in Brussels, Belgium. Assessment of the drug safety was done using the food and drug administration (FDA) risk classification system. Data analysis was performed using SPSS (Chicago, IL). RESULTS: In overall cohort, 83.8% used at least one preparation (including multivitamins) during pregnancy and 37.0% of women used at least one drug (excluding multivitamins). Significantly more Western women (43.7%) used one or more medications compared to Arab/Turkish women (28.7%; p = 0.000). This difference in exposure was most pronounced for over-the-counter (OTC) drugs for occasional and pregnancy-related complaints, and was observed for potentially unsafe drugs or drugs with unknown safety. None of the women reported use of FDA X category drugs. CONCLUSIONS: The use of drugs known to be harmful was not observed, but a higher prevalence of exposure to potentially harmful drugs (FDA C/D) was found among Western women who also consumed more OTC drugs. This highlights the need for cautious prescribing for women in the fertile age in general and for continuous monitoring of medication use during pregnancy.

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The use of chromatographic descriptors as alternative for Caco-2 permeability in drug absorption screening was evaluated. Therefore, retentions were measured on 17 Reversed-Phase Liquid Chromatographic systems, considered to be orthogonal or dissimilar, and an Immobilized Artificial Membrane (IAM) system. Retentions on a Micellar Liquid Chromatography system were taken from the literature. From this set of systems, those found dissimilar for the used data set were selected. The retention factors on these systems were then used as descriptors in QSAR modelling. Modelling was performed using Stepwise Multiple Linear Regression. This resulted in a model using only two chromatographic systems with good descriptive and acceptable predictive properties. A high qualitative model was obtained by combining both chromatographic systems selected in the previous model with a lipophilicity parameter (the squared Moriguchi n-octanol/water partition coefficient) and the molecular volume.

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Recent studies emphasize a key role of controlled operations, such as set-shifting and inhibition, in the occurrence of freezing of gait (FOG) in Parkinson's disease (PD). However, FOG can also be characterized as a de-automatization disorder, showing impairments in both the execution and acquisition of automaticity. The observed deficits in automaticity and executive functioning indicate that both processes are malfunctioning in freezers. Therefore, to explain FOG from a cognitive-based perspective, we present a model describing the pathways involved in automatic and controlled processes prior to a FOG episode. Crucially, we focus on disturbances in automaticity and control, regulated by the frontostriatal circuitry. In complex situations, non-freezing PD patients may compensate for deficits in automaticity by switching to increased cognitive control. However, as both automatic and controlled processes are more severely impaired in freezers, this hampers cognitive compensation in FOG, resulting in a potential breakdown. Future directions for cognitive rehabilitation are proposed, based on the cognitive model we put forward.

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Classification trees built with the Classification And Regression Tree algorithm were evaluated for modelling infrared spectroscopic data in order to discriminate between genuine and counterfeit drug samples and to classify counterfeit samples in different classes following the RIVM classification system. Models were built for two data sets consisting of the Fourier Transformed Infrared spectra, the near infrared spectra and the Raman spectra for genuine and counterfeit samples of respectively Viagra(®) and Cialis(®). Easy interpretable models were obtained for both models. The models were validated for their descriptive and predictive properties. The predictive properties were evaluated using both cross validation as an external validation set. The obtained models for both data sets showed a 100% correct classification for the discrimination between genuine and counterfeit samples and 83.3% and 100% correct classification for the counterfeit samples for the Viagra(®) and the Cialis(®) data set respectively.

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OBJECTIVES: To investigate the anemia prevalence during pregnancy and the use of and response to iron supplementation in a multi-ethnic population as well as the possible association between anemia and birth outcomes (pregnancy duration, birth weight). METHODS: Cross-sectional study conducted in a university hospital (Brussels, Belgium) in 341 women. Hemoglobin, ferritin and iron prescription data were extracted from the patients' electronic dossiers; a questionnaire was used to assess iron intake during pregnancy. RESULTS: Anemia prevalence was higher during the 3rd trimester (24.3%) than in the 1st trimester (6.2%). Arab/Turkish women had a higher prevalence of anemia (9.1%) in the 1st trimester compared to Western women (2.4%; p = 0.044). The frequency of iron prescription was significantly higher among Arab/Turkish (43.7%) compared to Western women (27.9%; p = 0.006). A significantly lower mean birth weight was found among women presenting with anemia in the 1st trimester (3166 g) compared to non anemic women (3442 g; p = 0.036) but no significant difference was detected in mean pregnancy duration between both groups (p = 0.804). CONCLUSIONS: Anemia was more prevalent among Arab/Turkish women in spite of receiving more iron prescriptions than Western women. Efficient iron therapy and intensive follow-up are warranted to decrease the anemia prevalence during pregnancy, especially among non-Western women.

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The use of some unconventional non-linear modeling techniques, i.e. classification and regression trees and multivariate adaptive regression splines-based methods, was explored to model the blood-brain barrier (BBB) passage of drugs and drug-like molecules. The data set contains BBB passage values for 299 structural and pharmacological diverse drugs, originating from a structured knowledge-based database. Models were built using boosted regression trees (BRT) and multivariate adaptive regression splines (MARS), as well as their respective combinations with stepwise multiple linear regression (MLR) and partial least squares (PLS) regression in two-step approaches. The best models were obtained using combinations of MARS with either stepwise MLR or PLS. It could be concluded that the use of combinations of a linear with a non-linear modeling technique results in some improved properties compared to the individual linear and non-linear models and that, when the use of such a combination is appropriate, combinations using MARS as non-linear technique should be preferred over those with BRT, due to some serious drawbacks of the BRT approaches.

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In general, linear modelling techniques such as multiple linear regression (MLR), principal component regression (PCR) and partial least squares (PLS), are used to model QSAR data. This type of data can be very complex and linear modelling techniques often model only a limited part of the information captured in the data. In this study, it was tried to combine linear techniques with the flexible non-linear technique multivariate adaptive regression splines (MARS). Models were built using an MLR model, combined with either a stepwise procedure or a genetic algorithm for variable selection, a PCR model or a PLS model as starting points for the MARS algorithm. The descriptive and predictive power of the models was evaluated in a QSAR context and compared to the performances of the individual linear models and the single MARS model. In general, the combined methods resulted in significant improvements compared to the linear models and can be considered valuable techniques in modelling complex QSAR data. For the used data set the best model was obtained using a combination of PLS and MARS. This combination resulted in a model with a Pearson correlation coefficient of 0.90 and a cross-validation error, evaluated with 10-fold cross-validation of 9.9%, pointing at good descriptive and high predictive properties.

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In order to select chromatographic starting conditions to be optimized during further method development of the separation of a given mixture, so-called generic orthogonal chromatographic systems could be explored in parallel. In this paper the use of univariate and multivariate regression trees (MRT) was studied to define the most orthogonal subset from a given set of chromatographic systems. Two data sets were considered, which contain the retention data of 68 structurally diversive drugs on sets of 32 and 38 chromatographic systems, respectively. For both the univariate and multivariate approaches no other data but the measured retention factors are needed to build the decision trees. Since multivariate regression trees are used in an unsupervised way, they are called auto-associative multivariate regression trees (AAMRT). For all decision trees used, a variable importance list of the predictor variables can be derived. It was concluded that based on these ranked lists, both for univariate and multivariate regression trees, a selection of the most orthogonal systems from a given set of systems can be obtained in a user-friendly and fast way.

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Multivariate adaptive regression splines (MARS) and a derived method two-step MARS (TMARS) were used for modelling the gastro-intestinal absorption of 140 drug-like molecules. The published absorption values for these molecules were used as response variable and calculated molecular descriptors as potential explanatory variables. Both methods were compared and their potential use in quantitative structure-activity relationship (QSAR) context evaluated. The predictive abilities of the models were studied using different sequences of Monte Carlo cross validation (MCCV). It was shown that both types of models had good predictive abilities and that for the data used, MARS gave better results than TMARS. It could be concluded that both methods could be valuable for QSAR modelling.

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Classification and regression trees (CART) were evaluated for their potential use in a quantitative structure-activity relationship (QSAR) context. Models were build using the published absorption values for 141 drug-like molecules as response variable and over 1400 molecular descriptors as potential explanatory variables. Both the role of two- and three-dimensional descriptors and their relative importance were evaluated. For the used dataset, CART models showed high descriptive and predictive abilities. The predictive abilities were evaluated based on both cross-validation and an external test set. Application of the variable ranking method to the models showed high importances for the n-octanol/water partition coefficient (logP) and polar surface area (PSA). This shows that CART is capable of selecting the most important descriptors, as known from the literature, for the absorption process in the intestinal tract.

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The use of the classification and regression tree (CART) methodology was studied in a quantitative structure-retention relationship (QSRR) context on a data set consisting of the retentions of 83 structurally diverse drugs on a Unisphere PBD column, using isocratic elutions at pH 11.7. The response (dependent variable) in the tree models consisted of the predicted rention factor (log kw) of the solutes, while a set of 266 molecular descriptors was used as explanatory variables in the tree building. Molecular descriptors related to the hydrophobicity (log P and Hy) and the size (TPC) of the molecules were selected out of these 266 descriptors in order to describe and predict retention. Besides the above mentioned, CART was also able to select hydrogen-bonding and molecular complexity descriptors. Since these variables are expected from QSRR knowledge, it demonstrates the potential of CART as a methodology to understand retention in chromatographic systems. The potential of CART to predict retention and thus occasionally to select an appropriate system for a given mixture was also evaluated. Reasonably good prediction, i.e. only 9% serious misclassification, was observed. Moreover, some of the misclassifications probably are inherent to the data set applied.

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The use of non-linear mixed effects models to describe dissolution data has been evaluated. A theoretical part is included to introduce this approach to scientists who are not familiar with this type of statistics. The standard settings of the statistical software package (S-plus) are used as much as possible. Several mathematical functions like the Weibull, logistic, first-order and Gompertz are employed as basis for the non-linear mixed effects models. Examples are given using dissolution data of immediate and extended release tablets. The results are compared with those obtained using linear mixed effects models.

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The performance of linear mixed effects models for the comparison of dissolution profiles is examined. This type of model is frequently used by statisticians, but is rather unknown to people that work in dissolution laboratories. Hence, an extensive theoretical part was introduced to make the methodology more accessible. Firstly, repeated measures ANOVA is discussed, followed by the "real" linear mixed effects models. The theory is applied to two types of dissolution data: one corresponding to an immediate and another to a slow release formulation. We tried to use as much as possible the standard settings of the statistical software (S-plus). Suggestions are given to solve problems encountered during model fitting. It was found that the statistical limits are much more discriminative than the similarity factor.

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Two successive acid etch biopsies were performed on the permanent maxillary right central incisors of two age groups of children resident in an urban area in Belgium. Lead was determined in the biopsy solutions and the concentrations were related to etch depths, which were calculated from the calcium and phosphorus concentrations in the biopsy solutions. The mean lead concentration in the first enamel biopsy layer was five times higher than in the second biopsy. A strong correlation was observed between the two biopsies. It was shown that calibration of the lead values with respect to etch depths and Ca/P ratio was desirable and that a robust regression analysis approach was needed instead of classical more reliable calibration. In this study no age related increase in the surface enamel lead concentration could be demonstrated. Therefore, it was concluded that for these children the presence of lead in surface enamel had to be attributed primarily to pre-eruptive uptake.

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The rehardening of surface-softened and surface-etched enamel was investigated in vitro and by intraoral exposure. Surface-softened enamel was obtained by treatment with 0.1 M acetic acid buffer solution (pH = 5.5) for 3 h. Surface-etched enamel was obtained by the acid etch procedure used in clinical situations (37% phosphoric acid gel, 30 s). The enamel lesions were treated in vitro, with calcifying solutions for 8 h or were carried for 48 h in an intraoral appliance. Changes at the enamel surfaces were investigated by surface microhardness measurements. Following the treatment with calcifying solutions a significantly greater indentation length was observed in surface-etched than in surface-softened enamel. No significant difference in indentation length between both types of enamel lesions was observed following intraoral exposure. It was concluded that the initial rate of rehardening between both types of enamel lesions is comparable. At his stage remineralization occurs in microspaces created in the slightly destroyed enamel structures. The influence of the etch pits on the indentation length becomes dominating when remineralization continues. An obliteration of etch pits was observed in enamel samples treated with the calcifying solution with the highest degree of saturation. It was suggested that freshly prepared highly supersaturated calcifying solutions can be used to enhance mineral appositions in accidental etch pits.

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The load dependency of hardness measurements was investigated on sound and demineralized enamel samples. For all samples investigated, the Knoop hardness number (KHN) varied as a function of the applied load. Higher loads enhanced indenter penetration into the test surface. The variation in KHN values observed in demineralized enamel, both surface-softened and surface-etched, was explained by a decrease in porosity as a function of depth. The reading error for indentations made on surface enamel etched with 37% phosphoric acid gel for 30 s was found to be slightly elevated compared to indentations made on a polished sound enamel surface. It was concluded that the surface microhardness technique can be used for the longitudinal investigation of etched surface enamel.

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The in-vitro and in-vivo fluoride release of bioadhesive, slow-release tablets prepared from a mixture of polyethylene glycol polymers, containing 0.1 mg of fluoride as NaF was studied, and their ability to sustain fluoride levels in saliva were compared with conventional fluoride tablets with the same fluoride content. In-vitro release experiments showed that the bioadhesive tablets needed 8 h to release all their fluoride compared with less than 1 h for the conventional fluoride tablets. In-vivo, the bioadhesive tablets had a retention period of 6 h and could sustain a salivary fluoride level of more than 10 microM above the baseline for 7 h. The conventional fluoride tablets achieved a peak concentration of 0.5 mM directly after dissolution in the mouth, but the fluoride level could not be sustained for longer than 1 h. A good agreement was found between the in-vitro swelling behaviour of the bioadhesive tablets and their in-vitro and in-vivo release characteristics and their in-vivo retention time.

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Three studies (84, 140, and 200 d) were performed to examine the effect of injecting dairy cows with various doses (0, 320, 640, or 960 mg/28 d; 0 or 640 mg/28 d; 0, 320 mg/14 d, or 320 or 640 mg/28 d) of bST on milk production, composition, and manufacturing properties. Mean bST response among studies on milk production varied from 0 (trial 1) to 7.3% (trial 2) and from 8.5 to 14.2% (trial 3) in relation to feeding conditions. Neither milk fat nor protein percentages in milk at time of maximum response were affected by the use of bST. Distribution of casein and protein in the whey was not affected by the treatments at any time. The nature of fatty acids varied more with time after injection than with bST doses. Neither coagulation time, standard curd firmness, nor soft or pressed cheese yields were affected by the treatments.

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Two groups of schoolchildren between seven and 12 years old residing in the vicinity of a non-ferrous industrial plant and exposed to lead (Pb) at a concentration that could cause health problems, were monitored. Concentrations of Pb in blood (blood-Pb), which were determined at regular six monthly intervals, were related to the Pb concentrations in surface tooth enamel (enamel-Pb). Acid etch biopsy samples of surface enamel were taken at the end of the five year study period in the first group (A) and after two years in the second group (B). Salivary Pb (saliva-Pb) concentrations were determined for the first study group on the same day that the enamel biopsies were performed. Calibration of the data was necessary--that is, blood-Pb concentration with respect to age and sex and enamel-Pb concentration with respect to etch depth and age. The blood-Pb concentrations declined with time. Surface enamel Pb concentrations correlated with blood-Pb concentration for the period starting with the pre-eruptive development of the incisors, related to blood-Pb concentration for a long time, and corresponded partly to the exposure at the time of pre-eruptive development and/or eruption. Through the correlation with enamel-Pb concentration, the seasonal behaviour of blood-Pb concentration became apparent. Saliva-Pb concentrations related to blood-Pb concentrations only in the short term.

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