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PubMed1992

Utilization of maternal health-care services in Peru: the role of women's education.

This article explores the hypothesis that formal education of women influences the use of maternal health-care services in Peru, net of the mother's childhood place of residence, household socioeconomic status and access to health-care services. The findings are consistent with the hypothesis; both cross-sectional and fixed-effects logit models yield quantitatively important and statistically reliable estimates of the positive effect of maternal schooling on the use of prenatal care and delivery assistance. In addition, large differentials were found in the utilization of maternal health-care services by place of residence, suggesting that much greater efforts on the part of the government are required if modern maternal health-care services are to reach women in rural areas.

Adult↗
PubMed1999

Heritability of cellular radiosensitivity: a marker of low-penetrance predisposition genes in breast cancer?

Many inherited cancer-prone conditions show an elevated sensitivity to the induction of chromosome damage in cells exposed to ionizing radiation, indicative of defects in the processing of DNA damage. We earlier found that 40% of patients with breast cancer and 5%-10% of controls showed evidence of enhanced chromosomal radiosensitivity and that this sensitivity was not age related. We suggested that this could be a marker of cancer-predisposing genes of low penetrance. To further test this hypothesis, we have studied the heritability of radiosensitivity in families of patients with breast cancer. Of 37 first-degree relatives of 16 sensitive patients, 23 (62%) were themselves sensitive, compared with 1 (7%) of 15 first-degree relatives of four patients with normal responses. The distribution of radiosensitivities among the family members showed a trimodal distribution, suggesting the presence of a limited number of major genes determining radiosensitivity. Segregation analysis of 95 family members showed clear evidence of heritability of radiosensitivity, with a single major gene accounting for 82% of the variance between family members. The two alleles combine in an additive (codominant) manner, giving complete heterozygote expression. A better fit was obtained to a model that includes a second, rarer gene with a similar, additive effect on radiosensitivity, but the data are clearly consistent with a range of models. Novel genes involved in predisposition to breast cancer can now be sought through linkage studies using this quantitative trait.

Alleles↗
PubMed2002

A critical assessment of the secondary structure alpha-helices and their termini in proteins.

Secondary structure prediction from amino acid sequence is a key component of protein structure prediction, with current accuracy at approximately 75%. We analysed two state-of-the-art secondary structure prediction methods, PHD and JPRED, comparing predictions with secondary structure assigned by the algorithms DSSP and STRIDE. The specific focus of our study was alpha-helix N-termini, as empirical free energy scales are available for residue preferences at N-terminal positions. Although these prediction methods perform well in general at predicting the alpha-helical locations and length distributions in proteins, they perform less well at predicting the correct helical termini. For example, although most predicted alpha-helices overlap a real alpha-helix (with relatively few completely missed or extra predicted helices), only one-third of JPRED and PHD predictions correctly identify the N-terminus. Analysis of neighbouring N-terminal sequences to predicted helical N-termini shows that the correct N-terminus is often within one or two residues. More importantly, the true N-terminal motif is, on average, more favourable as judged by our experimentally measured free energies. This suggests a simple, but powerful, strategy to improve secondary structure prediction using empirically derived energies to adjust the predicted output to a more favourable N-terminal sequence.

Algorithms↗
PubMed2003

Alcohol consumption and fatal accidents in Canada, 1950-98.

AIMS: To evaluate the effects of changes in aggregate alcohol consumption on overall fatal accidents, motor vehicle accidents, fatal falling accidents and drowning accidents in Canadian provinces after 1950. DESIGN: Time-series analysis of annual mortality rates (15-69 years) in relation to per capita alcohol consumption, utilising the Box-Jenkins technique. All series were differenced to remove long-term trends. MEASUREMENTS: Gender-specific and age-adjusted mortality rates for the age group 15-69 years were calculated on the basis of mortality data for 5-year age groups, using a standard population. Data on per capita alcohol consumption was converted to consumption per inhabitant 15 years and older. In the analysis of motor vehicle accidents, the number of motor vehicles was used as a control variable. FINDINGS: Statistically significant associations between alcohol consumption and overall fatal accident rates were uncovered in all provinces for males, and in all provinces except Ontario for females. For Canada at large, an increase in per capita alcohol consumption of 1 litre was accompanied by an increase in accident mortality of 5.9 among males and 1.9 among females per 100,000 inhabitants. Among males there was a significant association with alcohol for both falling accidents, motor vehicle accident and other accidents, but the association was insignificant for drowning accidents. Among females, the association with falling accidents and other accidents was significant. CONCLUSION: Changes in alcohol consumption have had substantial effects on most of the main types of fatal accidents in Canada during the second half of the 20th century. The size of the association is comparable to the one previously reported from Northern Europe.

Accidental Falls↗
PubMed2003

Characterization of monoclinic crystals in tablets by pattern-fitting procedure using X-ray powder diffraction data.

The purpose of this study is to characterize the monoclinic crystals in tablets by using X-ray powder diffraction data and to evaluate the deformation feature of crystals during compression. The monoclinic crystals of acetaminophen and benzoic acid were used as the samples. The observed X-ray diffraction intensities were fitted to the analytic expression, and the fitting parameters, such as the lattice parameters, the peak-width parameters, the preferred orientation parameter and peak asymmetric parameter were optimized by a non-linear least-squares procedure. The Gauss and March distribution functions were used to correct the preferred orientation of crystallites in the tablet. The March function performed better in correcting the modification of diffraction intensity by preferred orientation of crystallites, suggesting that the crystallites in the tablets had fiber texture with axial orientation. Although a broadening of diffraction peaks was observed in acetaminophen tablets with an increase of compression pressure, little broadening was observed in the benzoic tablets. These results suggest that "acetaminophen is a material consolidating by fragmentation of crystalline particles and benzoic acid is a material consolidating by plastic deformation then occurred rearrangement of molecules during compression". A pattern-fitting procedure is the superior method for characterizing the crystalline drugs of monoclinic crystals in the tablets, as well as orthorhombic isoniazid and mannitol crystals reported in the previous paper.

Acetaminophen↗
PubMed2003

A chemometric approach for brain tumor classification using magnetic resonance imaging and spectroscopy.

A new classification approach was developed to improve the noninvasive diagnosis of brain tumors. Within this approach, information is extracted from magnetic resonance imaging and spectroscopy data, from which the relative location and distribution of selected tumor classes in feature space can be calculated. This relative location and distribution is used to select the best information extraction procedure, to identify overlapping tumor classes, and to calculate probabilities of class membership. These probabilities are very important, since they provide information about the reliability of classification and might provide information about the heterogeneity of the tissue. Classification boundaries were calculated by setting thresholds for each investigated tumor class, which enabled the classification of new objects. Results on histopathologically determined tumors are excellent, demonstrated by spatial maps showing a high probability for the correctly identified tumor class and, moreover, low probabilities for other tumor classes.

Aspartic Acid↗
PubMed1999

New models for pharmacokinetic data based on a generalized Weibull distribution.

We consider the development of the concentration of a drug in the blood after single oral or intravenous administration. We introduce a new nonlinear model capable of describing concentration-time curves following intravenous administration. A similar model is proposed for oral data. Both models have four parameters, of which two regulate the shape of the curve and two determine the scale of the time and concentration axes. All the parameters are closely related to geometric properties of the curve. The scale parameters determine a point in the curve, and the shape parameters can be calculated by using numerical integration. The models can be used when the object of the analysis is to quantify the shape of a concentration-time curve. We discuss the usefulness of the models in bioequivalency trials, in clinical safety and efficacy trials, and in population pharmacokinetics. The models are applied to two previously presented data sets. To reduce the number of parameters, the shape parameters are assumed common for all individuals. Encouraging results are obtained. We also present a new four-parameter Michaelis-Menten model.

Administration, Oral↗
PubMed2005

A class of goodness of fit tests for a copula based on bivariate right-censored data.

The copula of a bivariate distribution, constructed by making marginal transformations of each component, captures all the information in the bivariate distribution about the dependence between two variables. For frailty models for bivariate data the choice of a family of distributions for the random frailty corresponds to the choice of a parametric family for the copula. A class of tests of the hypothesis that the copula is in a given parametric family, with unspecified association parameter, based on bivariate right censored data is proposed. These tests are based on first making marginal Kaplan-Meier transformations of the data and then comparing a non-parametric estimate of the copula to an estimate based on the assumed family of models. A number of options are available for choosing the scale and the distance measure for this comparison. Significance levels of the test are found by a modified bootstrap procedure. The procedure is used to check the appropriateness of a gamma or a positive stable frailty model in a set of survival data on Danish twins.

Algorithms↗
PubMed2006

On the application of the von Mises distribution and angular regression methods to investigate the seasonality of disease onset.

This paper describes an approach to summarize the data arising from studies investigating the pattern of disease onset within a calendar year. Such data have been traditionally summarized into monthly counts summated over the complete years studied and patterns often examined by use of Pearson's chi(2) tests with 11 degrees of freedom. This test and others commonly used in practice are reviewed. As an alternative, we suggest that by first representing the date of onset for an individual as a point on a unit circle that the von Mises distribution with a single peak may provide a useful description of such data. Further an extension to angular regression including covariates, analogous to that used routinely in other areas of clinical research, potentially allows a more systematic and detailed investigation of possible seasonal patterns in patient subgroups. The methodology is applied to examples from the date of onset of primary angle-closure glaucoma and date of diagnosis of acute lymphoblastic leukaemia and examines in both situations how the peak onset varies with covariates. Difficulties associated with convergence to the maximum likelihood estimates of the associated parameters are described. Finally, we emphasize the need for individualized (rather than grouped) patient data to be available for study, a clear specification of the particular 'onset' time studied, and suggest that further case studies are required to evaluate the approach.

Adult↗
PubMed2006

Epidemiology of the size distribution of intracranial bifurcation aneurysms: smaller size of distal aneurysms and increasing size of unruptured aneurysms with age.

OBJECTIVE: To explore the epidemiology of the size distribution of intracranial bifurcation aneurysms at different locations and to specifically test the hypothesis that distal vessels develop, on average, smaller aneurysms. METHODS: A database detailing all aneurysm cases admitted to Massachusetts General Hospital from 1991 to 2003 was reviewed. Aneurysms were classified by location and size. The distribution of aneurysms by sizes at differing origin sites was then compared. RESULTS: We identified 1673 aneurysms for study; 854 were ruptured and 819 were unruptured; 58 lesions were classified as distal middle cerebral artery and anterior cerebral artery, of which 26 were unruptured and 32 were ruptured. Analysis of the kernel density estimates for the distribution of aneurysm sizes revealed that aneurysms at distal locations and the posterior-inferior cerebellar artery location were smaller than those at other locations in the circle of Willis. The mean size of ruptured distal aneurysms at 5.7 mm (95% confidence interval 4.8-6.5), or ruptured posterior-inferior cerebellar artery aneurysms at 7.1 mm (95% confidence interval 6.3-7.8) was smaller than the average size for basilar, middle cerebral artery, or ICA aneurysms occurring proximally in the Circle of Willis. The decrease in the mean size of the distal lesions is caused by a relative paucity of aneurysms above 10 mm in size. Although ruptured aneurysms showed no change in size with age, unruptured lesions at most intracranial locations increased in size with age. CONCLUSION: The distribution of aneurysm sizes differs according to location in the intracranial vasculature in this single institution series. Smaller aneurysm sizes are observed for "distal" aneurysms than at other locations in the Circle of Willis. We hypothesize that this may be related to Laplace's Law, which states that the "critical" size for aneurysm rupture is related to the parent artery wall thickness. The larger size of unruptured aneurysms in older patients in this study may reflect referral bias or a biological model in which a subset of smaller "unstable" aneurysms are prone to rupture. Because distal aneurysms present at smaller sizes compared with aneurysms originating proximally on the Circle of Willis, prospective studies that focus on the rupture risk of this subset of intracranial aneurysms are appropriate for future investigation.

Age Factors↗
PubMed1997

Change of the microstructure of microcrystalline cellulose with grinding and compression.

The microstructure of microcrystalline cellulose was investigated by use of a radial distribution function (RDF) based on the intensity of X-ray scattering data. Changes in the microstructure of the cellulose as a result of grinding and compression were detected by use of the RDF. The RDF of intact microcrystalline cellulose had peak maxima corresponding to distances of approximately 1.5, 2.6, 5.0, 8.2, 13.3 and 17.0 A. The first two corresponded to the intramolecular atomic distances; other peaks were attributable to the intermolecular (inter-fibre) atomic distance. Changes in the RDF as a result of grinding indicated that the regular intermolecular atomic arrangement was gradually lost. Compression resulted in formation of long-range (> 20 A) ordering of the intermolecular (inter-fibre) atomic arrangement. These results show that RDF analysis is suitable for monitoring changes in the structure of microcrystalline cellulose which occur as a result of grinding and compression.

Cellulose↗
PubMed2006

Age of first faint in patients with vasovagal syncope.

INTRODUCTION: Understanding whether vasovagal syncope is a lifelong disorder might shed insight into its physiology and affect management strategies. Accordingly, we determined the age of the first syncopal spell in adult patients who sought care for syncope. METHODS AND RESULTS: Patients were 42 +/- 18 years old with 64% women. They had had a median 8 syncope spells (interquartile range [IQR]: 4, 20) with a median frequency of 1.0 syncopal spells per year. The range of syncopal spells was 1-3,375, and the range of duration of history of syncope was 0.003-70 years. The first syncopal spell occurred at ages 0-81 in a skewed distribution, with a marked mode age of 13 years, a median age of 18 years (IQR 12, 37), and a mean age of 26 +/- 20 years. The distributions were statistically indistinguishable across countries (P = 0.50), among Canadian regions (P = 0.69), and between the studies (P = 0.49). The same modal values were seen in males and females, and in patients <40 and > or =40 years old. However, patients > or =40 years had median ages of onset older than patients <40 years (36 +/- 23 vs 17 +/- 8 years). Patients had a recalled history of syncopal spells of median duration of 10 years (IQR: 2, 23), with a range of 0.003-70 years. An age of onset <44 years was 86% accurate for vasovagal syncope. CONCLUSION: The most common age at which vasovagal syncope first presents is 13 years, and patients remain at risk of syncope for many years. Lifelong coping strategies may be desirable.

Adolescent↗
PubMed2005

Conformation coupled enzyme catalysis: single-molecule and transient kinetics investigation of dihydrofolate reductase.

Ensemble kinetics and single-molecule fluorescence microscopy were used to study conformational transitions associated with enzyme catalysis by dihydrofolate reductase (DHFR). The active site loop of DHFR was labeled with a fluorescence quencher, QSY35, at amino acid position 17, and the fluorescent probe, Alexa555, at amino acid 37, by introducing cysteines at these sites with site-specific mutagenesis. The distance between the probes was such that approximately 50% fluorescence resonance energy transfer (FRET) occurred. The double-labeled enzyme retained essentially full catalytic activity, and stopped-flow studies of both the forward and reverse reactions revealed that the distance between probes increased prior to hydride transfer. A fluctuation in fluorescence intensity of single molecules of DHFR was observed in an equilibrium mixture of substrates but not in their absence. Ensemble rate constants were derived from the distributions of lifetimes observed and attributed to a reversible conformational change. Studies were carried out with both NADPH and NADPD as substrates, with no measurable isotope effect. Similar studies with a G121V mutant DHFR resulted in smaller rate constants. This mutant DHFR has reduced catalytic activity, so that the collective data for the conformational change suggest that the conformational change being observed is associated with catalysis and probably represents a conformational change prior to hydride transfer. If the change in fluorescence is attributed to a change in FRET, the distance change associated with the conformational change is approximately 1-2 A. These results are correlated with other measurements related to conformation coupled catalysis.

Algorithms↗
PubMed2005

Reference value for C-reactive protein and its distribution pattern in thai adults.

BACKGROUND: To set a reference value for high-sensitivity C-reactive protein (hs-CRP) in a healthy Thai population and study the effect of time, gender and age on that value. METHODS AND RESULTS: Three hundred and sixty-four subjects, aged between 18 and 74 years, comprising 185 men and 279 women, were studied. Another 10 healthy subjects, aged between 18 and 54 years, were recruited for the study of circadian variation in hs-CRP over the days of the week and the months of a year. The reference value for the Thai adults in the present study was 1.8 mg/L, range 0.2-7.9 mg/L. There was no significant difference in the hs-CRP concentration because of region, time, gender or age (p>0.05), nor was the value affected by time. CONCLUSION: The determination of hs-CRP can be performed at any time and the hs-CRP value determined by this study can be used as the reference for Thai adults.

Adolescent↗
PubMed2005

A gamma mixture model better accounts for among site rate heterogeneity.

MOTIVATION: Variation of substitution rates across nucleotide and amino acid sites has long been recognized as a characteristic of molecular sequence evolution. Evolutionary models that account for this rate heterogeneity usually use a gamma density function to model the rate distribution across sites. This density function, however, may not fit real datasets, especially when there is a multimodal distribution of rates. Here, we present a novel evolutionary model based on a mixture of gamma density functions. This model better describes the among-site rate variation characteristic of molecular sequence evolution. The use of this model may improve the accuracy of various phylogenetic methods, such as reconstructing phylogenetic trees, dating divergence events, inferring ancestral sequences and detecting conserved sites in proteins. RESULTS: Using diverse sets of protein sequences we show that the gamma mixture model better describes the stochastic process underlying protein evolution. We show that the proposed gamma mixture model fits protein datasets significantly better than the single-gamma model in 9 out of 10 datasets tested. We further show that using the gamma mixture model improves the accuracy of model-based prediction of conserved residues in proteins. AVAILABILITY: C++ source codes are available from the authors upon request.

Chromosome Mapping↗
PubMed2000

Durations and frequencies of free locomotion in wild type and GABAergic mutants of Caenorhabditis elegans.

We investigated how much time wild-type Caenorhabditis elegans (Bristol N2) nematodes and the GABA-deficient unc25 mutant and the vesicular GABA transporter-deficient unc47 mutant spent moving. The worms were allowed to move freely on the surface of agarose plates either with or without the food bacterium OP50. We identified forward movement, backward movement, resting and turns by watching images on video and computer displays. Forward movement lasted longer and rests were briefer without, than with, bacteria. Frequency distributions except for backward movement fitted a sum of two exponential functions. The duration of backward movement was not strongly influenced by exposure to bacteria, whereas the frequency of backward movements increased in their presence. The duration of forward movement of unc25 nematodes had no long component, thus differing from that of N2 and unc47 strain nematodes in treatments with and without bacteria. The durations of resting in these mutants were much longer than in the N2 strain, especially in the absence of bacteria. The turn frequency of unc47 nematodes had a higher short component than that of the wild type N2 and unc25 nematodes, in the absence of bacteria. A neural network model is discussed in conjunction with the features of mutants and current knowledge of GABAergic neural transmission.

Animals↗
PubMed2003

P300 (latency) event-related potential: an accurate predictor of memory impairment.

To determine if P300 latency changes precede and correlate with memory and mental status, patients (N=1506 aged 20-100 years) who received medical and psychiatric diagnoses (from 1997 to 2002), were assessed for P300 (N=1496), WMS-III (N=694), and MMSE (N=456). Patient and control groups included, a) normal WMS-III on all 4 subscales (N=36), b) normal WMS-III and MMSE (N=189) with subjective memory/mental status complaints, and c) medical patients with normal WMS-III and no memory complaints (N=205), and d) P300 control group without medical, psychiatric or memory problems for ROC. Patients with impaired/borderline memory had a prolonged P300 latency (P<0.02) compared to age matched non-impaired controls; in patients with normal WMS-III/MMSE, with subjective mild memory/mental status impairment, P300 latency was prolonged compared to controls (P=0.0004). The P300 latency increased by 0.72ms per year (P=7.9x10(-65)) and voltage decreased by 0.03dV per year (P=6.7x10(-10)), and both parameters were linearly correlated with the age of the subjects. Male subjects had an average voltage of 6.1dV and female 6.8dV (P=0.00009). Statistically, prolonged latency began at age range 41-50 (P=0.0002); reduced P300 voltage began at age range 51-60 (P=0.003). WMS-III memory decline for all measures began in females at age range 61-70 (P value at least=0.02) and for males at age range 61-80 (P=0.02). Prolonged P300 latency (P<0.0001) and memory impairment (at least <0.02) were greater for females than males. MMSE memory decline, male and female, began at age range 81-90 (P value of at least 0.00007). In our logistic regression model P300 latency was more predictive of WMS-III impairment than MMSE > 24. In patients whose WMS-III score is impaired < or = 69, or borderline < or = 79 (P at least=0.004), a P300 latency more prolonged than the norm (> or = 300 + 30 + Age) identifies these patients, whereas a MMSE > 24 failed. With the ROC curve, we confirmed that P300 latency could accurately identify borderline/impaired memory.

Adolescent↗
PubMed2000

Determination of the spatial distribution of major elements in the rat brain with X-ray fluorescence analysis.

An energy dispersive X-ray fluorescence analysis was applied for determining the spatial (two-dimensional) distribution of elemental concentrations in rat brain sections. Freeze-dried brain sections prepared from normal and ischemic rats with middle cerebral artery occlusion were scanned with a collimated X-ray beam (0.18 mm in diameter, 50-kV acceleration voltage). The fluorescent Kalpha X-rays of P, S, Cl, and K were detectable, so that the two-dimensional distribution of fluorescent X-ray intensities could be determined for these elements. Furthermore, quantitative determination was possible for P and K by using the fundamental parameter technique. However, the accurate determination of Na and Ca was difficult, because of the low energy of Kalpha X-ray of Na, and the interference of K-Kbeta with Ca-Kalpha. The change in elemental concentrations in ischemic tissue, including the decrease in K concentration and increase in Cl concentration, was demonstrated by this method as a two-dimensional contour map. Since it is possible to obtain a pictorial representation of the elemental concentration in tissue sections, this method may be useful to evaluate the ionic changes in injured brain tissue in relation to histological or autoradiographical observations.

Animals↗