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Challenges to understanding spatial patterns of disease: philosophical alternatives to logical positivism.

Most studies of disease distribution, in medical geography and other related disciplines, have been empirical in nature and rooted in the assumptions of logical positivism. However, some of the more newly articulated philosophies of the social sciences, and of social theory, have much to add in the understanding of the processes and mechanisms underlying disease distribution. This paper represents a plea for creative synthesis between logical positivism and realism or structuration, and uses specific examples to suggest how disease distribution, as a surface phenomenon, can be explained using deeper analysis.

Cross-Cultural Comparison

RAR beta isoforms: distinct transcriptional control by retinoic acid and specific spatial patterns of promoter activity during mouse embryonic development.

That both deficiency and excess of vitamin A lead to a wide spectrum of congenital abnormalities has strongly implicated the active metabolite, retinoic acid (RA), in normal embryonic development. There are 3 families of RA receptors (RARs), RAR alpha, RAR beta and RAR gamma, each having at least two isoforms derived from primary transcripts initiated at two promoters P1 and P2 (reviewed in Leid et al., 1992) Transcripts encoding all 4 isoforms of RAR beta (RAR beta 1 to RAR beta 4) accumulate in embryonal carcinoma (EC) cells in the presence of RA. It has been previously shown that the RA modulation of RAR beta 2/beta 4 transcripts is achieved at the level of transcriptional initiation via a RA response element (RARE) present in the P2 RAR beta 2/beta 4 promoter. In contrast, the mechanism by which RA up-regulates RAR beta 1/beta 3 transcripts has not yet been elucidated. We describe here the isolation of the P1 RAR beta 1/beta 3 promoter and characterization of its activity in transgenic animals. We find that RAR beta 1/beta 3 promoter activity, which is apparently confined to the embryonic CNS, is not modified by RA treatment, unlike that of the RAR beta 2/beta 4 promoter (Mendelsohn et al., 1991). Nuclear run-on transcription analysis in EC cells supports the conclusion that RAR beta 1/beta 3 transcript initiation is not modulated by RA, and that the RA-induced accumulation of RAR beta 1/beta 3 transcripts occur via a RA-dependent release of a block in RNA chain elongation.

Animals

Transcriptional regulation and spatial patterning in Drosophila.

Pattern formation in Drosophila is initiated by a small set of asymmetrically distributed maternal transcription factors that act as graded morphogens along the anterior-posterior and the dorsal-ventral axes of the embryo. Recent progress in the field provides first insight into the molecular mechanisms by which long-range positional information in the egg causes a series of localized zygotic transcription factors to position the developmental fate along the blastoderm.

Animals

A molecular dissection of spatial patterning in the olfactory system.

The identification and cloning of genes encoding odorant receptors has provided molecular probes with which to examine the molecular mechanisms and organizational strategies underlying olfactory information processing. Recent studies using odorant receptor genes have revealed unexpected patterns of expression that provide new insights into how information may be organized in the nose and in the axonal projection from the nose to the brain.

Amino Acid Sequence

Spatial patterns and travelling waves in population genetics.

We consider a reaction-diffusion equation to model a multi-allelic, single locus problem. The population can migrate in a homogeneous region and the diffusion rates depend upon the genotype. It is shown that if there is an equilibrium point with all alleles present and if this polymorphism is stable for the classical reaction system then it is also stable for the reaction-diffusion equation. Also a simplified model is used to investigate which allele will spread in the two-allele case. Alleles which are associated with large fitness and small dispersion do best.

Alleles

Development of the spatial pattern of 5-HT-induced locomotor rhythm in the lumbar spinal cord of rat fetuses in vitro.

Developmental changes in the 5-hydroxytryptamine (5-HT)-induced locomotor rhythm were examined in isolated spinal cord preparations taken from fetal rats at embryonic day (E) 16.5, E18.5 and E20.5. Motor activity was recorded from L2/L3 and L5 ventral roots. Bath application of 5-HT evoked rhythmic bursts that were synchronized in all ventral roots studied at E16.5. At E18.5, 5-HT evoked rhythmic bursts that alternated between the two sides, while the bursts in the L2/L3 ventral root were synchronous with those in the ipsilateral L5 ventral root. At E20.5, 5-HT evoked alternate rhythmic bursts in L2/L3 and L5 ventral roots, representing activity in flexors and extensors, respectively. In the presence of strychnine, 5-HT induced rhythmic bursts that were synchronized in all ventral roots studied at E18.5 and E20.5, suggesting that the change in the pattern of rhythmic motor activity that occurs with age is due to the development of glycine-mediated inhibition.

Animals

Using geographic information systems to assess spatial patterns of drug use, selection bias and attrition among a sample of injection drug users.

This study sought to assess whether frequency and type of drug use are geographically located within the city of Baltimore independent of neighborhood characteristics. The second goal was to assess geographic factors associated with sample selection and attrition. The sample consisted of 597 inner-city injection drug users who were enrolled in a HIV prevention study. The residential locations were plotted using Geographic Information Systems (GIS) software. Three patterns of drug use in the prior 6 months were examined: daily use of injection heroin, daily use of injection cocaine and any use of crack cocaine. Daily use of cocaine and any use of crack were found to be statistically associated with residing in the western portion of the city and distance from the western district sexually transmitted disease clinic. After adjusting for individual level characteristics and neighborhood level variables, as measured by 1990 census tract data, daily use of cocaine was found to be associated with residing in a more southern area of the city and distance from the western district sexually transmitted disease clinic, and any crack use was found to be associated with residing in a more western area of the city and distance from the western district sexually transmitted disease clinic. Men and younger participants were more likely to reside further away from the study clinic as were individuals who dropped out of the intervention condition. The results of this study suggest that type and frequency of drug use is associated with specific geographic areas, independent of neighborhood characteristics. These results have implications for the location of drug prevention, needle exchange and other HIV prevention activities.

Adult

The chicken caudal genes establish an anterior-posterior gradient by partially overlapping temporal and spatial patterns of expression.

The caudal genes in vertebrates as in invertebrates assume a posterior position along the anterior-posterior axis and they appear to regulate the expression of the Hox genes. The third chicken caudal gene, Cdx-C, was cloned. Extensive comparisons of the sequence of this protein to the other known members of this homeobox family has lead to the suggestion that vertebrate genomes contain three members of the caudal homeobox family. A comparative study of the chicken Cdx-A and Cdx-C genes during gastrulation and neurulation revealed the differences between the genes. The caudal genes exhibit sequential activation in the newly formed neural plate and sequential extinction in axial midline structures during the primitive streak regression along the anterior-posterior axis. This pattern of expression suggests that the number and identity of caudal genes expressed along the anterior-posterior axis changes dynamically.

Amino Acid Sequence

Temporal and spatial patterns of opsin gene expression in zebrafish (Danio rerio).

In zebrafish, the first class of cone photoreceptor to become morphologically distinct is the ultraviolet-sensitive short single cone, at 4 days postfertilization, whereas the last class, the red- and green-sensitive double cone, becomes distinct at 10 days postfertilization. We have examined the time course of visual pigment gene expression in zebrafish using whole-mount in situ hybridization. Within the retina, opsins may be detected as early as 40 h postfertilization with the ultraviolet and rod visual pigments being expressed before the blue- (48 h) and red- (60 h) sensitive pigments. In the pineal, red-sensitive opsin is expressed at 48 h postfertilization. Visual pigment expression provides a useful tool for investigations of early cell fate in zebrafish.

Animals

Odor-related bulbar EEG spatial pattern analysis during appetitive conditioning in rabbits.

Mildly thirsty rabbits were classically conditioned by reinforcement with water to give a discriminative licking response to the presentation of odors. The jaw movement component of the licking conditioned response (JM CR) was elicited only by the reinforced odor; an increase in the relative frequency of sniffing (RR CR) occurred to both reinforced (CS+) and nonreinforced (CS-) odors. Oscillatory electroencephalographic bursts of high-frequency (40-80 Hz) potentials were recorded epidurally from the lateral olfactory bulb with 64-electrode arrays (8 X 8, 3.5 X 3.5 mm) chronically implanted. Emphasis was on comparing bursts during odor presentation with bursts preceding odor arrival on each trial. A "detection" burst was characterized as occurring immediately after odor arrival and before the sniff response. "Discrimination" bursts occurred during the RR CR and before the JM CR onset. Significant air-odor burst differences (together with sniffing) occurred through up to six sessions for both CS+ and CS- odors for "discrimination" bursts but not for "detection" bursts.

Animals

Two-tiered regulation of spatially patterned engrailed gene expression during Drosophila embryogenesis.

A regulatory cascade, initiated during the syncytial stage of embryogenesis, culminates in the striped pattern of engrailed gene expression at the cellular blastoderm stage. The early regulatory genes, for example the pair-rule genes, are expressed transiently and as their products decay a distinct regulatory programme involving segment polarity genes takes over. This late programme maintains and perhaps modifies the striped pattern of engrailed expression through interactions that may involve cell communication.

Animals

Spatial patterns in electoral wards with high lymphoma incidence in Yorkshire health region.

The possibilities of clustering between those electoral wards which display higher than expected incidences of cases of the lymphomas occurring between 1978 and 1982 are examined. Clusters are defined as being those wards with cases in excess (at a probability of less than 10%) which are geographically adjacent to each other. A separate analysis extends the definition of cluster to include high incidence wards that are adjacent or separated by one other ward. The results indicate that many high incidence lymphoma wards do occur close together and when computer simulations are used to compute expected results, many of the observed results are shown to be highly improbable both in the overall number of clustering wards and in the largest number of wards comprising a 'cluster'.

Computer Simulation

Combinatorial interactions between positive and negative cis-acting elements control spatial patterns of 4CL-1 expression in transgenic tobacco.

The phenylpropanoid enzyme 4-coumarate:coenzyme A ligase (4CL) plays a key role in linking general phenylpropanoid metabolism to end-product specific biosynthetic pathways. During vascular system and floral organ differentiation, the parsley 4CL-1 gene is expressed in a restricted set of tissues and cell types where 4CL activity is required to supply precursors for the synthesis of diverse phenylpropanoid-derived products such as lignin and flavonoids. In order to localize cis-acting elements which specify complex patterns of 4CL-1 expression, we analyzed the expression of internally deleted promoter fragment-GUS fusions in tobacco plants and parsley protoplasts. Elements located between -244 and -78 were required for most aspects of developmentally regulated expression. Within this region, three separate promotor domains containing partially redundant cis-elements directed vascular-specific expression when combined with a TATA-proximal domain. A negative cis-acting element which represses phloem expression was revealed in one of the domains and appears to be responsible for restricting vascular expression to the xylem. Distinct but overlapping promoter domain combinations were required for expression in floral organs, suggesting that different combinations of cis-acting elements may direct expression in different organs. Gel retardation assays were used to demonstrate the formation of DNA-protein complexes between factors present in nuclear extracts of parsley tissue culture cells and various tobacco organs and a 4CL-1 promoter fragment. Competition experiments showed that complex formation required the presence of a 42 bp promoter domain shown to be critical for 4CL-1 expression in vascular and floral tissues. The results are discussed in light of the coordinate expression of 4CL and other phenylpropanoid genes.

Base Sequence

Spatial pattern of cdc2 expression in relation to meristem activity and cell proliferation during plant development.

The p34 protein kinase encoded by the cdc2 gene is a key component of the eukaryotic cell cycle required for the G1- to S-phase transition and entry into mitosis. To study the regulation of plant meristem activity and cell proliferation, we have examined the tissue-specific accumulation of cdc2 transcripts in Arabidopsis thaliana and the related crucifer radish (Raphanus sativus) by in situ hybridization using A. thaliana cdc2 cDNA sequences as a probe. cdc2 transcripts accumulated in leaf primordia and within the vegetative shoot apical meristem. During flower development, high levels of expression were observed in meristems, in the basal regions of developing organs, in the developing vasculature, and associated with rib meristems elaborated late in the development of some floral organs. In root tips, cdc2 transcripts accumulated in the meristematic region and adjacent daughter cells but were not detected in the quiescent center. There was strong hybridization throughout the pericycle, and a further localized accumulation of cdc2 transcripts was observed in the initial stages of the activation of a new meristem at sites of lateral root development. We conclude that cdc2 expression is a critical factor in the regulation of meristem activity and establishment of proliferative competence.

Base Sequence

Spatial pattern of receptor expression in the olfactory epithelium.

A PCR-based strategy for amplifying putative receptors involved in murine olfaction was employed to isolate a member (OR3) of the seven-transmembrane-domain receptor superfamily. During development, the first cells that express OR3 appear adjacent to the wall of the telencephalic vesicle at embryonic day 10. The OR3 receptor is uniquely expressed in a subset of olfactory cells that have a characteristic bilateral symmetry in the adult olfactory epithelium. This receptor and its specific pattern of expression may serve a functional role in odor coding or, alternatively, may play a role in the development of the olfactory system.

Amino Acid Sequence

Experimental specification of cell sorting, tissue spreading, and specific spatial patterning by quantitative differences in cadherin expression.

The sorting-out of embryonic cells from a cell mixture and the selective spreading of one cell population over the surface of another have been attributed to various causes. These include differentials in chemotaxis, in cellular adhesiveness, in cell surface contractility, in speed of cell movement, and in the timing of postulated changes in cellular adhesive and motile properties. One of us earlier predicted on mathematical grounds that two motile cell types differing only in the level of expression of a single cell adhesion system should not only segregate from one another but also arrange themselves with the less cohesive cells enveloping a core of the more cohesive ones. To test these predictions, we combined two populations of L cells transfected with P-cadherin cDNA and expressing this homophilic adhesion molecule in substantially differing amounts. When the two cell populations were intermixed, they segregated to approach a sphere-within-a-sphere configuration, the cell population expressing more P-cadherin forming islands which fused to become an internal "medulla." When the two cell populations were first formed into separate aggregates which were subsequently allowed to fuse, the cell population expressing more P-cadherin was enveloped by its partner, which formed an external "cortex." These observations confirm the early prediction and support the conclusion that both morphogenetic movements and the specific anatomical configurations to which they lead can be determined by particular sets of intercellular adhesive intensities, regardless of how these are generated and in the absence of differentials in other parameters.

Animals