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Precision and sensitivity of aminobiphenyl hemoglobin adduct assays in a long-term population study.

Exploratory statistical analysis of aminobiphenyl hemoglobin adduct data obtained in a large-scale population study was performed to assess precision and sensitivity over the 7 years required to conduct the analyses. A time-dependent trend toward higher values was observed that may be attributable to aging of the internal standard used throughout the study. A several-fold improvement in sensitivity from the beginning to end of the study was also noted. Repeated analysis of duplicate blood specimens provided a worst-case estimate of the coefficient of variation to be 0.31, attributable almost entirely to sample preparation rather than instrumental analysis. Substantial variability in calibration curves for the deuterated internal standard (standard deviation was +/-15% of the mean) was observed. The results obtained here will be used in support of further analyses of the data with respect to factors of epidemiological interest.

Aminobiphenyl Compounds↗

Sources of variability in genetic association studies: insights from the analysis of hepatic lipase (LIPC).

Genetic association studies have been widely used to identify loci that influence plasma lipoprotein concentrations, but few of the associations reported have proved consistently reproducible across different study populations. This lack of consistency is a widely recognized limitation of association studies, and is often ascribed to inadequate statistical power, population substructure, and population-specific linkage disequilibrium. However, few studies have assessed the causes of variability underlying a given genotype-phenotype association. We have examined two possible sources of variability in the association between the -514 polymorphism in hepatic lipase (LIPC) and plasma HDL-C concentrations. First, we compared the association between this polymorphism and hepatic lipase activity in four populations. A single copy of the -514C allele was associated with a 10 mmol.hr(-1).l(-1) increase in hepatic lipase activity in white American and Turkish men but only approximately 5 mmol.hr(-1).l(-1) in Chinese and African-American men. Second, we tested the effects of a stanozolol-induced increase in hepatic lipase activity on plasma HDL-C concentrations in men with normal (< 150mg/dl) or elevated (150-300mg/dl) levels of plasma triglyceride. The increase in hepatic lipase activity was similar in the two groups, but the resulting decline in HDL-C levels was significantly greater in normolipidemic men. These data suggest that the effect of a polymorphism on gene expression can vary among individuals, and that the resulting phenotype may be further modified by interactions with other factors. Three novel LIPC polymorphisms were identified in the study (-1596insC, -2740A>G, and -2880G>C).

Adult↗

[Markers of hepatitis virus A and B infection in subjects undergoing a hiring examination in a large business].

The prevalence of some hepatitis-A and hepatitis-B markers has been studied in 495 individuals (male 291, female 204) attending a preemployment medical examination at a great factory in Northern Italy between November 1978 and April 1979. A 2.0% and 13.7% incidence has been respectively found for HBsAg and anti-HBs in the whole population. A statistically significative difference has been recognized between people coming from Southern and Northern Italy, as well as between first-employment subjects and workmen or countrymen. A higher incidence of anti-HBc has been detected in men, in older age groups, and Southern immigrants, without any statistically significative difference related to their previous activities. Anti-HAV antibody has been found in 57.9% of whole population, with a greater incidence in younger people and in southern immigrants. First-employment group showed a lower incidence of anti-HAV, notwithstanding the great number of southern immigrants in this group.

Adolescent↗

The use of Markovian metapopulation models: a comparison of three methods reducing the dimensionality of transition matrices.

The use of Markovian models is an established way for deriving the complete distribution of the size of a population and the probability of extinction. However, computationally impractical transition matrices frequently result if this mathematical approach is applied to natural populations. Binning, or aggregating population sizes, has been used to permit a reduction in the dimensionality of matrices. Here, we present three deterministic binning methods and study the errors due to binning for a metapopulation model. Our results indicate that estimation errors of the investigated methods are not consistent and one cannot make generalizations about the quality of a method. For some compared output variables of populations studied, binning methods that caused a strong reduction in dimensionality of matrices resulted in better estimations than methods that produced a weaker reduction. The main problem with deterministic binning methods is that they do not properly take into account the stochastic population process itself. Straightforward usage of binning methods may lead to substantial errors in population-dynamical predictions.

Markov Chains↗

Effect of changes in population size on genetic microdifferentiation.

Changes in local population size are expected to have an effect on the degree of genetic microdifferentiation. A decrease in population size is expected to lead to an increase in microdifferentiation, and an increase in population size to a decrease in microdifferentiation. These expectations are routinely used with historical and/or demographic data to evaluate changes in estimates of microdifferentiation obtained over time for human populations. Here I look more closely at these expectations by using simple mathematical models that relate a change in average effective population size to the degree of microdifferentiation. The direction of change in microdifferentiation is influenced by the migration structure of the populations and the proximity of the region to an equilibrium state. A change in population size always leads to a new equilibrium, but the speed at which this new equilibrium is reached depends on migration and time depth. A decline in population size in one generation always leads to an immediate increase in the degree of microdifferentiation. An increase in population size in one generation could lead to an initial decrease or increase in the degree of microdifferentiation or to no change at all. Consideration of the parameters of the models shows under what conditions such changes occur. The relevance of these models is explored using summary data from a number of human populations.

Emigration and Immigration↗

A geometric morphometric study of regional differences in the ontogeny of the modern human facial skeleton.

This study examines interpopulation variations in the facial skeleton of 10 modern human populations and places these in an ontogenetic perspective. It aims to establish the extent to which the distinctive features of adult representatives of these populations are present in the early post natal period and to what extent population differences in ontogenetic scaling and allometric trajectories contribute to distinct facial forms. The analyses utilize configurations of facial landmarks and are carried out using geometric morphometric methods. The results of this study show that modern human populations can be distinguished based on facial shape alone, irrespective of age or sex, indicating the early presence of differences. Additionally, some populations have statistically distinct facial ontogenetic trajectories that lead to the development of further differences later in ontogeny. We conclude that population-specific facial morphologies develop principally through distinctions in facial shape probably already present at birth and further accentuated and modified to variable degrees during growth. These findings raise interesting questions regarding the plasticity of facial growth patterns in modern humans. Further, they have important implications in relation to the study of growth in the face of fossil hominins and in relation to the possibility of developing effective discriminant functions for the identification of population affinities of immature facial skeletal material. Such tools would be of value in archaeological, forensic and anthropological applications. The findings of this study underline the need to examine more deeply, and in more detail, the ontogenetic basis of other causes of craniometric variation, such as sexual dimorphism and hominin species differentiation.

Adolescent↗

Phylogeography and genetic structure of Hibiscus tiliaceus--speciation of a pantropical plant with sea-drifted seeds.

Phylogenetic relationships and the spatial genetic structure of a pantropical plant with sea-drifted seeds, Hibiscus tiliaceus L., and its allied species were investigated. The combined distribution range of these species is over almost the entire littoral area of the tropics worldwide, which might result from the dispersal of their sea-drifted seeds and from recurrent speciation in local populations. A phylogenetic tree constructed using the nucleotide sequences of a c. 7500-bp portion of chloroplast DNA suggested the possibility that recurrent speciation from H. tiliaceus has given rise to all of its allied species. Three major sequence haplotypes of H. tiliaceus had wide and overlapping distributions throughout the Pacific, Atlantic and Indian Ocean regions. This distribution pattern was also confirmed by PCR-SSCP (polymerase chain reaction amplification with single-strand conformation polymorphism) and PCR-SSP (PCR amplification with sequence specific primers) analyses performed on more than 1100 samples from 65 populations worldwide. Statistical analysis using F(ST) and analysis of molecular variance did not show significant genetic differentiation among the H. tiliaceus populations in the three oceanic regions. The results reported here suggested substantial gene flow occurred between populations in the different oceanic regions due to sea-drifted seeds. A strong genetic difference between the Pacific and Atlantic populations of Hibiscus pernambucensis Arruda was observed, which indicates that gene flow in this species between the two regions has been prevented. The wide and dominant distribution of a haplotype shared by H. pernambucensis and H. tiliaceus in the Atlantic region suggests significant introgression between the two species in this region.

DNA, Chloroplast↗

MTBE and gasoline hydrocarbons in ground water of the United States.

The occurrence of methyl tert-butyl ether (MTBE) and gasoline hydrocarbons was examined in three types of studies of ground water conducted by the U.S. Geological Survey: major aquifer surveys, urban land-use studies, and agricultural land-use studies. The detection frequency of MTBE was dependent on the study type, with the highest detection frequency in urban land-use studies. Only 13 ground water samples from all study types, or 0.3%, had concentrations of MTBE that exceeded the lower limit of the U.S. EPA's Drinking-Water Advisory. The detection frequency of MTBE was highest in monitoring wells located in urban areas and in public supply wells. The detection frequency of any gasoline hydrocarbon also was dependent on study type and generally was less than the detection frequency of MTBE. The probability of detecting MTBE in ground water was strongly associated with population density, use of MTBE in gasoline, and recharge. Ground water in areas with high population density, in areas where MTBE is used as a gasoline oxygenate, and in areas with high recharge rates had a greater probability of MTBE occurrence. Also, ground water from public supply wells and shallow ground water underlying urban land-use areas had a greater probability of MTBE occurrence compared to ground water from domestic wells and ground water underlying rural land-use areas. The probability of detecting MTBE in ground water was weakly associated with the density of leaking underground storage tanks, soil permeability, and aquifer consolidation, and only concentrations of MTBE >0.5 microg/L were associated with dissolved oxygen.

Fresh Water↗

The impact of pituitary adenoma on morbidity. Increased sick leave and disability retirement in a cross-sectional analysis of Swedish national data.

OBJECTIVE: To quantify sick leave and medical retirement for the year 1989 in adults with a history of nonsecreting pituitary adenoma. DESIGN AND SETTING: A cross-sectional analysis of official Swedish data from 1989 was performed. Sick leave and disability pension data for these patients were obtained from the Swedish National Social Insurance Board, which also supplied information on sick leave taken by an age- and gender-matched control population of 5121 individuals. Uptake of disability pensions and the reasons for drawing these pensions in the study group were compared with national statistics. STUDY POPULATION: A group of 809 eligible adults with nonsecreting pituitary adenoma was identified from the national cancer registry. MAIN OUTCOME MEASURES AND RESULTS: Almost a quarter of the patients with a history of pituitary adenoma had retired due to ill health (23.8%); this was twice the figure expected from national statistics (11.5%). Similar results were obtained when men and women were considered separately. Some patients (17%) had received disability pensions before the diagnosis of pituitary adenoma, but the majority (75%) retired on medical grounds at least 1 year after their diagnosis. The reasons for early retirement in the study group were largely related to the diagnosis of pituitary adenoma (e.g. neoplasm, endocrine disorders), but there was some evidence of an increase in the number of disability pensions awarded because of diseases of the nervous system and sensory organs. Patients with a history of pituitary adenoma took significantly more sick leave in 1989 than those in the control group (mean 40.2 vs 24.0 days), and this significant difference applied to both sexes. CONCLUSIONS: A cross-sectional analysis of Swedish national data from 1989 showed excess morbidity, relative to reference data, in patients with a history of nonsecreting pituitary adenoma. Suboptimal conventional hormone replacement therapy and untreated growth hormone deficiency might to some extent explain the increased morbidity found in the present study.

Adenoma↗

Proposed Sheffield quantitative criteria in cervical cytology to assist the grading of squamous cell dyskaryosis, as the British Society for Clinical Cytology definitions require amendment.

OBJECTIVE: In 1986, the British Society for Clinical Cytology (BSCC) published quantitative criteria to assist diagnosis in a three-tier grading system of squamous cell dyskaryosis. In dyskaryotic cells, area nuclear to cytoplasmic (NC) ratios below 50%, between 50% and 66% and over 66% were defined as equating with mild, moderate and severe grades respectively. Following the Terminology Conference in 2002, however, the BSCC recommended on their website that the three-tier model should be replaced by a new two-tier system of low- and high-grade squamous abnormalities. The latter broadly equate with the two-grade Bethesda System (TBS) for reporting squamous intraepithelial lesions. The purpose of this study was to assess the accuracy and reproducibility of the BSCC three-tier quantitative definitions, to investigate if they were applicable to liquid-based cytology (LBC) and to see how they related to the proposed new two-tier BSCC system. METHODS: Quantitative image analysis was undertaken on illustrations from the 1986 BSCC terminology publication and on microscope slides from external quality assessment and Cytology Training Centre teaching sets. RESULTS: Analysis of mean NC ratios showed that mild, moderate and severe dyskaryosis exist as statistically different populations. Overlap of NC ratio ranges, however, limits their practical application in the three-tier model, although interestingly no overlap was noted between mild and severe dyskaryosis. No grade of dyskaryosis had a mean area NC ratio over 50%, indicating that the BSCC quantitative definitions are incorrect. The mean diameter NC ratios for mild, moderate and severe dyskaryosis were found to be 40%, 49% and 66% respectively. Accordingly it is possible that those reporting cervical cytology could be interpreting the BSCC NC ratios as meaning diameter rather than area. Amalgamation of the three-tier results into the proposed two-tier model shows that the resulting mean NC area and diameter ratios identify statistically different low- and high-grade populations. The reduced degree of overlap, however, of NC ratio ranges in the two-tier model implies that NC ratios could have a useful practical role in the separation of the low- and high-grade categories. The two categories were reasonably well separated by mean area and diameter NC ratios of 25% and 50% respectively. A two-tier model combining mild with moderate rather than severe dyskaryosis was found to be a statistically valid alternative but gave rise to NC ratios that would be difficult to use in practice. Except for moderate dyskaryosis, no significant differences were identified between the mean NC ratios of either conventional and LBC preparations or LBC preparations using two different commercial methodologies (SurePath and ThinPrep). Differences, however, were noted in area measurements between SurePath and ThinPrep and this has potential implications for classifications (such as TBS) using area comparisons as their basis. In addition, it was found that the increased NC ratio, associated with higher grades of dyskaryosis is more a consequence of progressive cytoplasmic area reduction rather than nuclear area increase. The similar NC ratios of borderline nuclear changes associated with human papilloma virus and mild dyskaryosis support the BSCC proposal that these can be combined to constitute a low-grade category. This study shows that the BSCC area NC ratio criteria of grading squamous cell dyskaryosis require amendment. In addition, this study supports the new BSCC recommendation of low- and high-grade squamous cell categories. CONCLUSIONS: The study proposes Sheffield quantitative criteria to assist the grading of squamous cell abnormalities. Quantitative diameter NC ratio measurements, however, must always be accompanied by detailed assessment of qualitative morphological features and in particular those relating to nuclear chromatin. This is equally relevant to both two- and three-tier models.

Carcinoma, Squamous Cell↗

The hyperexponential growth of the human population on a macrohistorical scale.

A qualitative comparison of human population dynamics with some other biological populations growth in free regime is given in this paper along with a quantitative description of human population growth in the last 2000 years. It is shown that human population growth law is very different from the growth laws of other populations: all biological populations grow according to exponential law, whereas the human population grows according to hyperexponential law which essentially moves ahead of the exponential one. It is found that unlike cell populations, the differential equation of rate of human population growth is of second order. This phenomenon can be described due to accelerating function which grows simultaneously with human population number. An analytical hyperexponential equation, which allows to describe dynamics of human population, was obtained.

Animals↗

Prognostic factors and the curability of breast cancer.

Over the years three different concepts regarding the cure of treated breast cancer have emerged. These are clinical cure, personal cure and statistical cure. The latter is the most accurate estimate of the curability of a disease which is presumed to be fatal unless treated. Statistical cure is the elimination of the hazard of death in a treated group compared with an age-matched control population. When statistical cure is studied in patients treated for early breast cancer, it is clear that breast cancer is an incurable disease. The expected gains from the relatively recent introduction of adjuvant therapy are too small to alter this concept. The significance of prognostic factors in a disease deemed to be incurable therefore requires re-examination. The conventional prognostic factors of tumour size, nodal status and a combination of those two in staging systems significantly discriminates in terms of survival in the short term. However, when the characteristics of long-term survivors are examined, neither tumour size nor nodal status discriminates effectively. If this is the case, then we need to reconsider novel treatment strategies which have been introduced in the hope of increasing the curability of the disease and the selection for those treatment strategies of patients using the conventional prognostic factors of tumour size or nodal involvement.

Age Distribution↗

Linkage disequilibrium between the M470V variant and the IVS8 polyT alleles of the CFTR gene in CBAVD.

Congenital bilateral absence of the vas deferens (CBAVD) is a cause of male sterility mostly resulting from mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The most common defect is the 5T variant at the branch/acceptor site of intron 8, which induces high levels of exon 9 skipping leading to non-functional protein. However, this 5T variant has incomplete penetrance and variable expressivity, suggesting that some other regulatory factors may modulate the splicing of exon 9. To identify such factors, we report here the genetic analysis of a polymorphic locus, M470V, located in exon 10 of the CFTR gene in 60 patients with CBAVD, compared to a normal control population. The statistical analysis showed strong linkage disequilibrium between the 5T allele and the V allele of the M470V polymorphism in the CBAVD population, but not in the normal population. The V allele in a gene carrying 5T could, however, contribute to lowering the level of normal transcripts, as already suggested by in vitro transcriptional studies. These genetic findings, together with previous studies, suggest involvement of the M470V variant in the modulation of the splicing of exon 9 of the CFTR gene.

Alleles↗