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Impact of definition on the study of avoidable mortality: geographical trends in British deaths 1981-1998 using Charlton and Holland's definitions.

Avoidable mortality is defined as deaths that should not occur given current medical knowledge and technology. Numerous different lists of causes of death and the ages at which they should be considered avoidable have been used to measure avoidable mortality. In this analysis of the importance of definition we compare the two most commonly used approaches using a data set including all 11.8 million deaths that occurred in Britain in 1981-1998. These mortality data, disaggregated by age and sex, are analysed within a multilevel statistical framework, which allows analysis at a number of geographical scales simultaneously. A substantial difference in both the average trends and spatial patterns of the two definitions of avoidable mortality is found, indicating that the causes of death chosen have a considerable impact on the results found. Indeed, one particular cause of death was found to be largely responsible for the differences between the definitions. In addition, the spatial pattern of the two types of avoidable mortality is very different at the larger geographical scale while the pattern at the smaller scale is very similar. The findings illustrate the importance of considering the goals of any study before deciding on the definition of avoidable mortality to use.

Adolescent↗

Patterns of spatial genetic structuring in a hydropsychid caddisfly (Cheumatopsyche sp. AV1) from southeastern Australia.

We assessed levels of mitochondrial genetic spatial structuring in the hydropsychid caddisfly Cheumatopsyche sp. AV1 in southeastern New South Wales, Australia. No significant spatial structuring was detected within or between catchments using analysis of molecular variance, and nested clade contingency analysis suggested no strong relationship between haplotypes and geographical location, at any clade level. However, tests for association among haplotypes incorporating geographical distance in the nested clade analysis, revealed patterns of historical range expansion and recent restricted gene flow. Most likely, population fragmentation preceded range expansion, although subsequent recontact and gene flow among the previously sundered populations has apparently obscured the geographical signature of the former fragmentation. Taken together, our analyses suggest that a number of populations fragmented during the Pleistocene evolved in isolation for a time and subsequently expanded into secondary contact. Since expansion, there has apparently been substantial (albeit somewhat restricted) dispersal and gene flow of adult female Cheumatopsyche sp. AV1, throughout the study area.

Analysis of Variance↗

Persistent halogenated compounds in black guillemots (Cepphus grylle) from Greenland--levels, compound patterns and spatial trends.

Twenty-seven black guillemot eggs and 39 livers were analysed for polychlorinated biphenyls (PCBs), chlorinated pesticides including chlordane-related compounds and toxaphene, and polybrominated diphenylethers (PBDEs). The samples were collected at Qeqertarsuaq (Godhavn, West Greenland) and Ittoqqortoormiit (Scoresbysund, East Greenland). The concentrations of halogenated organic compounds in samples from East Greenland were somewhat higher than the corresponding concentrations from West Greenland. Differences in compound patterns were found between West and East Greenland, with higher percentages of the heavier PCB molecules, p,p(')-DDE and alpha-HCH in the samples from Ittoqqortoormiit. Similarly, different levels and different compositions were observed for eggs and livers. The eggs had generally higher concentrations of all compounds as well as higher percentages of CHB-50, CHB-62 and alpha-HCH than liver samples from the same area. Dividing the liver samples into age groups revealed increasing concentrations with age.

Animals↗

Immunohistological localization of insulin-like growth factor binding protein-1 in primary implantation sites and trauma-induced deciduomal tissues of the rhesus monkey.

We have earlier demonstrated that there is a close similarity in the temporo-spatial pattern in the onset of oedema, epithelial-plaque transformation, stromal decidualization and influx of granulated lymphocytes in artificially trauma-induced deciduomal endometrium with such events in maternal endometrium at the primary implantation site during early stages of pregnancy in the rhesus monkey. In the present study, we have immunohistochemically examined whether the pattern of insulin-like growth factor-binding protein 1 (IGFBP-1) protein expression in conceptus tissue and maternal endometrium during lacunae and villous placenta stages of gestation in the rhesus monkey is developmental stage-specific and whether a discernible difference exists in the temporo-spatial characteristics of IGFBP-1 protein expression between conceptus associated implantation-decidualization and trauma induced deciduoma in the rhesus monkey. Trophoblast cells failed to exhibit IGFBP-1 immunopositive staining at any stage of implantation-placentation studied. Epithelial cells in plaque acini, endothelial cells, and vascular smooth muscle also did not show any immunopositive staining for IGFBP-1 in samples of primary implantation sites and trauma-induced deciduoma. Maternal endometrial epithelial and stromal-decidual cells however exhibited a temporal and spatial pattern of IGFBP-1 expression in cell-type specific manner and clear distinctions were observed between conception and deciduoma samples. Our results suggest that IGFBP-1 expression is highly tissue and development-specific and that conceptus-derived signals are necessary to initiate the glandular expression of IGFBP-1 during the early stage of gestation.

Animals↗

Transcriptional integration of competence modulated by mutual repression generates cell-type specificity within the cardiogenic mesoderm.

The way in which spatially patterned cellular identities are generated is a central question of organogenesis. In the case of Drosophila heart formation, the cardiac progenitors are specified in precise mesodermal positions, giving rise to multiple cell types in a highly ordered arrangement. Here, we study the mechanisms by which positional information conveyed by signaling pathways and a combinatorial code of activating and repressing transcription factors work together to confine the expression of the homeobox gene even-skipped (eve) to a small region of the dorsal mesoderm. By manipulating both expression patterns and binding sites for transcription factors, we show that a complex combination of regulatory activities converge on a single enhancer of eve to generate precisely targeted gene expression within the cardiac mesoderm. In particular, ladybird early (lbe), a homeobox gene expressed adjacent to eve, restricts the positive actions of factors downstream of wingless, decapentaplegic, and ras to generate the eve pattern. Mutation of a Lbe binding site causes dramatic expansion of expression and abolishes the responsiveness to repression by lbe. Conversely, eliminating eve in the mesoderm expands lbe expression into the normal eve-expressing territory, suggesting that mutual repression between eve and lbe is essential for delineating the spatial patterns of gene expression that specify cell types within the cardiac mesoderm.

Animals↗

Modeling urban growth effects on surface runoff with the integration of remote sensing and GIS.

A methodology is developed to relate urban growth studies to distributed hydrological modeling using an integrated approach of remote sensing and GIS. This linkage is possible because both studies share land-use and land-cover data. Landsat Thematic Mapper data are utilized to detect urban land-cover changes. GIS analyses are then conducted to examine the changing spatial patterns of urban growth. The integration of remote sensing and GIS is applied to automate the estimation of surface runoff based on the Soil Conservation Service model. Impacts of urban growth on surface runoff and the rainfall-runoff relationship are examined by linking the two modeling results with spatial analysis techniques. This methodology is applied to the Zhujiang Delta of southern China, where dramatic urban growth has occurred over the past two decades, and the rampant urban growth has created severe problems in water resources management. The results revealed a notably uneven spatial pattern of urban growth and an increase of 8.10 mm in annual runoff depth during the 1989-1997 period. An area that experienced more urban growth had a greater potential for increasing annual surface runoff. Highly urbanized areas were more prone to flooding. Urbanization lowered potential maximum storage, and thus increased runoff coefficient values.

Automation↗

Forest gap dynamics and the Ising model.

The vegetation height in forest ecosystems is spatially heterogeneous. Canopy gaps (sites with low vegetation) are formed by treefalls, and they recover to canopy sites (with high vegetation) either by growth of small trees or by branch extension of surrounding trees. The dynamics of canopy gaps have been studied using a spatial Markov chain with nearest neighbor interaction. (1) If the canopy recovery rate is constant and if the gap formation rate for a site increases exponentially with the number of neighboring gap sites, the equilibrium distribution is the same as the one generated by the Ising model in statistical mechanics. Here, we extend the equivalence to the situation in which both the gap formation and canopy recovery depend on the neighborhood, as shown in recent forest data. (2) We develop a statistical test of whether a given spatial pattern is a random sample from the Ising model. The test is based on the conditional probability of configurations on a partial lattice. We apply the method to vegetation height data from the Ogawa forest reserve, Japan, measured on a 5x5 m grid in 1976, 1981, 1986, and 1991. The spatial pattern of the original forest data deviates significantly from the Ising model. We examine whether a larger sampling distance or the removal of the effects of the topography can reduce this deviation.

Ecosystem↗

Changes in the cortical map of the hand following postnatal median nerve injury in monkeys: modification of somatotopic aggregates.

Median nerves to the hands of 8-15-d-old marmoset monkeys were transected and precluded from regeneration by ligation. Following periods of 0.4-1.5 years, features of organization in the cortical area 3b hand map were assessed neurophysiologically, and compared to features in normally reared monkeys. Cortical features in monkeys with both histories were similar in certain respects. (1) Receptive field organization was similar in terms of tactile thresholds and receptive field size, continuity, and glabrous-hairy specificity. (2) Somatotopic organization was similar in terms of the continuity of the glabrous representation, and progressions of receptive field shifts across some parts of the hand map. (3) Finally, the overall size of the hand map did not change. In contrast, other cortical features clearly differed following these developmental histories. (1) Neurons at virtually all recording sites in normal hand maps responded to light mechanical stimulation, whereas, following injury, neurons at about 8% of the recording sites responded only to high-intensity stimuli. (2) Somatotopic organization differed in terms of the presence or absence of the representation of skin autonomously innervated by the median nerve, the number and continuity of representations of hairy skin, and the spatial interfacing of representations. (3) Finally, there were differences in the areas and widths of representations of parts of the hand. The overall impression is that there is a correspondence between the cortical features that changed most after injury, and the features that varied most in individual normal monkeys: in both circumstances the most variable features involved properties of spatial patterning across large aggregates of neurons as reflected by the size, shape, continuity, and interfacing of representations. A hypothesis is proposed that suggests that the cortical hand map normally consists of a number of representations that are capable of developing and surviving somewhat autonomously of each other. The features of spatial patterning in the mosaiclike map of these representations are influenced by postnatal availability of inputs from intact hand nerves.

Animals↗

Modeling dynamic PET-SPECT studies in the wavelet domain.

This work develops a theoretical framework and corresponding algorithms for the modeling of dynamic PET-SPECT studies both in time and space. The problem of estimating the spatial dimension is solved by applying the wavelet transform to each scan of the dynamic sequence and then performing the kinetic modeling and statistical analysis in the wavelet domain. On reconstruction through the inverse wavelet transform, one obtains parametric images that are consistent estimates of the spatial patterns of the kinetic parameter of interest. The theoretical setup allows the use of linear techniques currently used in PET-SPECT for kinetic analysis. The method is applied to artificial and real data sets. The application to dynamic PET-SPECT studies was performed both for validation purposes, when the spatial patterns are known, and for illustration of the advantages offered by the technique in case of tracers with an unknown pattern of distribution.

Benzamides↗

Mitochondrial reactive oxygen species regulate spatial profile of proinflammatory responses in lung venular capillaries.

Cytokine-induced lung expression of the endothelial cell (EC) leukocyte receptor P-selectin initiates leukocyte rolling. To understand the early EC signaling that induces the expression, we conducted real-time digital imaging studies in lung venular capillaries. To compare receptor- vs nonreceptor-mediated effects, we infused capillaries with respectively, TNF-alpha and arachidonate. At concentrations adjusted to give equipotent increases in the cytosolic Ca(2+), both agents increased reactive oxygen species (ROS) production and EC P-selectin expression. Blocking the cytosolic Ca(2+) increases abolished ROS production; blocking ROS production abrogated P-selectin expression. TNF-alpha, but not arachidonate, released Ca(2+) from endoplasmic stores and increased mitochondrial Ca(2+). Furthermore, Ca(2+) depletion abrogated TNF-alpha responses partially, but arachidonate responses completely. These differences in Ca(2+) mobilization by TNF-alpha and arachidonate were reflected in spatial patterning in the capillary in that the TNF-alpha effects were localized at branch points, while the arachidonate effects were nonlocalized and extensive. Furthermore, mitochondrial blockers inhibited the TNF-alpha- but not the arachidonate-induced responses. These findings indicate that the different modes of Ca(2+) mobilization determined the spatial patterning of the proinflammatory response in lung capillaries. Responses to TNF-alpha revealed that EC mitochondria regulate the proinflammatory process by generating ROS that activate P-selectin expression.

Aldehydes↗

Gradients of transgene expression directed by the human myoglobin promoter in the developing mouse heart.

Prior studies using transient transfection assays in cultured avian and murine skeletal myotubes indicate that the proximal 2-kb segment of the 5' flanking region of the human myoglobin gene contains transcriptional control elements sufficient to direct muscle-specific and developmentally regulated expression of reporter genes. To examine the function of the human myoglobin gene promoter during development of skeletal and cardiac myocytes in the intact animal, a 2.0-kb myoglobin gene upstream fragment was fused to an Escherichia coli lacZ reporter gene and injected into fertilized mouse oocytes. beta-Galactosidase (beta-gal) activity was detected selectively in cardiac and skeletal myocytes of fetal and adult transgenic mice. A distinctive spatial pattern of myoglobin promoter activity was observed in fetal hearts: beta-gal staining was more pronounced within the left ventricular subendocardium than within the subepicardium and was essentially undetectable in the ventricular trabeculae or atria. Expression of endogenous myoglobin mRNA and protein, assessed by in situ hybridization and immunohistochemistry, demonstrated a similar spatial pattern. In contrast, hearts from adult transgenic mice demonstrated essentially homogeneous expression of beta-gal and of endogenous myoglobin mRNA and protein throughout the myocardium, including the trabeculae and atria. These data indicate that the 2.0-kb upstream region of the human myoglobin gene includes cis-acting regulatory elements sufficient to direct transgene expression during murine cardiac development that is myocyte-specific and responsive to positional cues in a similar manner to the endogenous myoglobin gene.

Age Factors↗

Fronts, Waves, and Stationary Patterns in Electrochemical Systems In the appendix we list the minimal equations (prototype equations) that describe the phenomena of self-organization discussed in the individual sections.

Oscillatory behavior has been observed for almost all electrochemical reactions in a certain, although sometimes small, range of external parameters. Only in the past ten years has it been possible, however, to find a common explanation for the occurrence of these temporal self-organization phenomena of chemically completely different electrochemical reactions. The breakthrough was achieved because new methods and concepts, which had been developed in nonlinear dynamics to describe the spontaneous formation of order in various disciplines, could be applied. This development in turn was only possible because the underlying laws are universal at a certain abstract level. Oscillations are only one possible manifestation of nonlinear behavior. Examples of other features that are often closely associated with temporal instabilities are spatial structures and waves. Initiated by the theoretical progress and the development of new experimental techniques, spatial pattern formation in electrochemical systems has been targeted for investigations in the past few years. Based on these investigations, it can be predicted under which conditions temporal or spatial pattern formation can be expected. Furthermore, the possibility of predicting the occurrence of instabilities indicates that it might be feasible to exploit nonlinear effects to increase, for example, the yield of electrocatalytic reactions. Here we discuss physicochemical mechanisms that lead to pattern formation in electrochemical systems. At the same time, we stress the generic principles that are responsible for self-structuring processes in many chemical and biological systems.

Journal Article↗

Cell-cell adhesion in limb-formation, estimated from photographs of cell sorting experiments based on a spatial stochastic model.

We developed a new method to estimate the magnitude of differential cell-cell adhesion of two tissues based on the spatial patterns in cell-sorting experiments, and applied it to experimental data on progress-zone cells of avian limb bud at stages 20-26. The change in cell distribution in the experiment was recorded, and statistics qB/B for the degree of cell sorting was calculated from the photographs. Based on extensive computer simulations of spatial Markov processes on a 2-D lattice, we derived a formula for qB/B increasing with time. Using least square fitting, differential adhesion A and cell motility m are estimated from the time series data of qB/B obtained from the experiment. The estimated A was close to 0 (the spatial pattern remained random) if the mixed cells were from two tissues of the same stage. If the mixed cells were from different stages, and the estimated A was positive (cell sorting occurred). Estimated A increased with the difference in the stage number of the two tissues from which the cells were sampled. This result can be explained both by the stage-specific change in adhesion molecules and by a linear increase (or decrease) in the amount of adhesion molecules on cell surface.

Animals↗

Molecular analysis of smooth muscle development in the mouse.

Little is currently known regarding the ontogeny of smooth muscle tissues during normal mammalian development. The alpha-smooth muscle and gamma-smooth muscle isoactins have been shown to be excellent molecular markers of smooth muscle cell phenotype. This study characterizes both the temporal and spatial patterns of alpha-smooth muscle and gamma-smooth muscle isoactin expression in the developing mouse. In situ analysis was performed on serial sections of whole mouse embryos on embryonic day 9, 11, 13, 15, and 17 using alpha-smooth muscle and gamma-smooth muscle isoactin-specific riboprobes. Distinct temporal and spatial patterns of alpha-smooth muscle and gamma-smooth muscle isoactin gene expression were observed in the developing gastrointestinal tract, urogenital tract, respiratory tract, and vascular system. Independent expression of the alpha-smooth muscle isoactin was observed during the early stages of skeletal, cardiac, and smooth muscle myogenesis as well as in a novel subset of distinct organs including the postnatal component of the hindgut, allantois, and primitive placenta. The results of this study indicate that distinct cellular phenotypes are involved in smooth muscle myogenesis and suggest that organ-specific mechanisms might exist for the initiation of smooth muscle development in vivo. In addition, the pattern of independent alpha-smooth muscle isoactin expression observed in this study provides novel information regarding the early stages of hindgut and placental development, and suggests that a common functional phenotype may be associated with the early stages of skeletal, cardiac, and smooth muscle myogenesis.

Actins↗

Transgene integration into the same chromosome location can produce alleles that express at a predictable level, or alleles that are differentially silenced.

In an effort to control the variability of transgene expression in plants, we used Cre-lox mediated recombination to insert a gus reporter gene precisely and reproducibly into different target loci. Each integrant line chosen for analysis harbors a single copy of the transgene at the designated target site. At any given target site, nearly half of the insertions give a full spatial pattern of transgene expression. The absolute level of expression, however, showed target site dependency that varied up to 10-fold. This substantiates the view that the chromosome position can affect the level of gene expression. An unexpected finding was that nearly half of the insertions at any given target site failed to give a full spatial pattern of transgene expression. These partial patterns of expression appear to be attributable to gene silencing, as low gus expression correlates with DNA methylation and low transcription. The methylation is specific for the newly integrated DNA. Methylation changes are not found outside of the newly inserted DNA. Both the full and the partial expression states are meiotically heritable. The silencing of the introduced transgenes may be a stochastic event that occurs during transformation.

Alleles↗

The aftereffects of ventriloquism: patterns of spatial generalization.

We examined how visual recalibration of apparent sound location obtained at a particular location generalizes to untrained locations. Participants pointed toward the origin of tone bursts scattered along the azimuth, before and after repeated exposure to bursts in one particular location, synchronized with point flashes of light a constant distance to their left/right. Adapter tones were presented straight ahead in Experiment 1, and in the left or right periphery in Experiment 2. With both arrangements, different generalization patterns were obtained on the visual distractor's side of the auditory adapter and onthe opposite side. On the distractor side, recalibration generalized following a descending gradient; practically no generalization was observed on the other side. This dependence of generalization patterns on the direction of the discordance imposed during adaptation has not been reported before, perhaps because the experimental designs in use did not allow its observation.

Adolescent↗

Parallel somatic and synaptic processing in the induction of intermediate-term and long-term synaptic facilitation in Aplysia.

The induction of different phases of memory depends on the amount and patterning of training, raising the question of whether specific training patterns engage different cellular mechanisms and whether these mechanisms operate in series or in parallel. We examined these questions by using a cellular model of memory formation: facilitation of the tail sensory neuron-motor neuron synapses by serotonin (5-hydroxytryptamine, 5-HT) in the CNS of Aplysia. We studied facilitation in two temporal domains: intermediate-term facilitation (1.5-3 h) and long-term facilitation (LTF, >24 h). Both forms can be induced by using several different temporal and spatial patterns of 5-HT, including (i) repeated, temporally spaced pulses of 5-HT to both the sensory neuron soma and the sensory neuron-motor neuron synapse, and (ii) temporally asymmetric exposure of 5-HT to the soma and synapse under conditions in which neither exposure alone induces LTF. We first examined the protein and RNA synthesis requirements for LTF induced by these two patterns and found that asymmetric (but not repeated) 5-HT application induced LTF that required postsynaptic protein and RNA synthesis. We next focused on the patterning and protein synthesis requirements for intermediate-term facilitation. We found that intermediate-term facilitation (i) is induced locally at the synapse, (ii) requires multiple pulses of 5-HT, and (iii) requires synaptic protein synthesis. Our findings show that different temporal and spatial patterns of 5-HT induce specific temporal phases of long-lasting facilitation in parallel by engaging different cellular and molecular mechanisms.

Animals↗

Spatial analysis of childhood leukemia in a case/control study.

A simple and direct analysis of the spatial distribution of childhood leukemia was performed using geographic data from a large case/control study. The data consist of cases of childhood leukemia and their corresponding birth cohort controls located in seven San Francisco Bay Area counties. Both parametric and randomization analyses show no evidence of a non-random spatial pattern of childhood leukemia among six of these counties. The data from San Francisco County, however, produce a moderately small significance probability (0.08) arising from a distance analysis and a significant p-value (0.01) arising from a frequency analysis of concordant case pairs. Although these p-values accurately reflect the probability of the observed spatial pattern occurring by chance alone, these results are based on only four cases of leukemia.

Adolescent↗