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Geostatistical analysis of disease data: accounting for spatial support and population density in the isopleth mapping of cancer mortality risk using area-to-point Poisson kriging.

BACKGROUND: Geostatistical techniques that account for spatially varying population sizes and spatial patterns in the filtering of choropleth maps of cancer mortality were recently developed. Their implementation was facilitated by the initial assumption that all geographical units are the same size and shape, which allowed the use of geographic centroids in semivariogram estimation and kriging. Another implicit assumption was that the population at risk is uniformly distributed within each unit. This paper presents a generalization of Poisson kriging whereby the size and shape of administrative units, as well as the population density, is incorporated into the filtering of noisy mortality rates and the creation of isopleth risk maps. An innovative procedure to infer the point-support semivariogram of the risk from aggregated rates (i.e. areal data) is also proposed. RESULTS: The novel methodology is applied to age-adjusted lung and cervix cancer mortality rates recorded for white females in two contrasted county geographies: 1) state of Indiana that consists of 92 counties of fairly similar size and shape, and 2) four states in the Western US (Arizona, California, Nevada and Utah) forming a set of 118 counties that are vastly different geographical units. Area-to-point (ATP) Poisson kriging produces risk surfaces that are less smooth than the maps created by a naïve point kriging of empirical Bayesian smoothed rates. The coherence constraint of ATP kriging also ensures that the population-weighted average of risk estimates within each geographical unit equals the areal data for this unit. Simulation studies showed that the new approach yields more accurate predictions and confidence intervals than point kriging of areal data where all counties are simply collapsed into their respective polygon centroids. Its benefit over point kriging increases as the county geography becomes more heterogeneous. CONCLUSION: A major limitation of choropleth maps is the common biased visual perception that larger rural and sparsely populated areas are of greater importance. The approach presented in this paper allows the continuous mapping of mortality risk, while accounting locally for population density and areal data through the coherence constraint. This form of Poisson kriging will facilitate the analysis of relationships between health data and putative covariates that are typically measured over different spatial supports.

Cluster Analysis↗

A 60-kDa plant microtubule-associated protein promotes the growth and stabilization of neurotubules in vitro.

The search for microtubule-associated proteins (MAPs) in plants is relatively recent. In particular, the "classical MAPs," which stimulate the polymerization and stabilization of microtubules, have only been examined in heterogeneous fractions. As a first step in dissecting the role of individual MAPs, we have chromatographically purified a single 60-kDa protein from a carrot MAP fraction and analyzed its effects on tubulin assembly. MAP60 promoted the formation of long, morphologically regular brain microtubules in vitro, an effect inhibited by preincubation of the MAP with affinity-purified antibodies against this protein. MAP60 also increased the stability of microtubules to dilution and significantly enhanced cold stability to the normally cold-sensitive neurotubules. These in vitro properties are consistent with a role for MAP60 in regulating the turnover/assembly of dynamic plant microtubules in vivo.

Animals↗

Denaturation mapping of the ribosomal DNA of Saccharomyces cerevisiae.

The thermal melting profile of purified Saccharomyces cerevisiae ribosomal DNA (rDNA) is biphasic indicating considerable intramolecular heterogeneity in base composition. The first phase of the transition, about 20% of the total hyperchromic shift, has a Tm of 80.6 degrees C and the second phase has a Tm of 87.3 degrees C, corresponding to GC contents of 28 and 44%, respectively. The Tm of the nonribosomal nuclear DNA, called alpha DNA, is 85.7 degrees C. This heterogeneity in GC distribution in the rDNA is also reflected in its denaturation map. A denaturation map of the 5.6 X 10(6) dalton rDNA SmaI restruction fragment, which represents monomer units of the rDNA, shows that specific regions of the repeating unit denature more readily than the remainder and apparently have a significantly higher AT content. By aligning the rDNA denaturation map with the restriction endonuclease map, we have been able to determine that the AT-rich segments are localized in the transcribed and nontranscribed spacer regions of the rDNA repeating unit. Buoyant density determinations of individual rDNA restriction fragments corroborate the locations of AT-rich regions. A denaturation map of the tandem repeating units in higher molecular weight rDNA has also been constructed and compared with the map of the SmaI fragment. The results show that the repeating units are uniform in size, that they are not separated by large heterogeneous regions, and that they are arranged in head-to-tail array.

Base Composition↗

Regional heterogeneity of the astroglial immunoreactive phenotype: effect of lipopolysaccharide.

In order to find out whether the concept of regional heterogeneity in astrocytes also applies to the immunoreactive phenotype, we studied cultured primary rat astrocytes originating from five different brain regions (cortex, hippocampus, striatum, septum, and brainstem).We investigated this heterogeneity through the ability of lipopolysaccharide (LPS) to differentially induce several parameters that are known to characterize activated astroglia: major histocompatibility complex (MHC) class II and intercellular adhesion molecule (ICAM)-1 expression, nitric oxide (NO) production, synthesis of interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). Under basal conditions, some of these parameters are already heterogeneic. The presence of LPS enhances these differences: expression of MHC class II increases after a 48-hour incubation with LPS, with brainstem and hippocampus astrocytes reaching the highest levels; NO production is induced by an LPS incubation, with the brainstem showing low NO production levels; septum and striatum instead show higher cytokine (TNF-alpha, IL-6) productions. The baseline expression of ICAM-1 also shows major regional differences, with the brainstem displaying the highest ICAM-1 expression. Our results demonstrate that the immunoreactive abilities of astrocytes show regional heterogeneities. This specialization may be implicated in the pathophysiological pathways of several neurodegenerative disorders.

Animals↗

Mode of inheritance and evidence for cistron heterogeneity of chloroplast 16S ribosomal RNA genes in Nicotiana.

Oligonucleotide maps (fingerprints) of T1 RNase digests of 125I-labeled 16 S chloroplast rRNA of Nicotiana tabacum and N. gossei revealed the presence of T1 oligonucleotide fragment 100 in the 16 S rRNA of N. gossei while N. tabacum 16 S rRNA had a unique T1 oligonucleotide (fragment 101) as well as some fragment 100. From the positions in the fingerprints and from fingerprints of secondary enzymatic digestion of the fragments, we conclude that fragments 100 and 101 are similar in sequence and size, but fragment 100 probably contains an extra uracil residue. This difference is shown to be maternally inherited, thus confirming the location of 16 S chloroplast rRNA genes on chloroplast DNA and ruling out the possibility of genetically active chloroplast rRNA genes in the nucleus. The presence of both fragments 100 and 101 in N. tabacum may indicate sequence heterogeneity between the two cistrons for 16 S chloroplast rRNA. These results demonstrate the feasibility of determining the inheritance of organelle genes by genetic analysis of their primary transcripts.

Chloroplasts↗

A gene for Meckel syndrome maps to chromosome 11q13.

Meckel syndrome (MKS) is a rare autosomal recessive lethal condition of unknown origin, characterized by (i) an occipital meningo-encephalocele with (ii) enlarged kidneys, with multicystic dysplasia and fibrotic changes in the portal area of the liver and with ductal proliferation, and (iii) postaxial polydactyly. A gene responsible for MKS in Finland has been mapped to chromosome 17q21-q24. Studying a subset of Middle Eastern and northern African MKS families, we have recently excluded the chromosome 17 region and have suggested a genetic heterogeneity. In the present study, we report on the mapping of a second MKS locus (MKS2) to chromosome 11q13, by homozygosity mapping in seven families that do not show linkage to chromosome 17q21-q24 (maximum LOD score 4.41 at recombination fraction .01). Most interestingly, the affected fetuses of southern Tunisian ancestry shared a particular haplotype at loci D11S911 and D11S906, suggesting that a founder effect is involved. Our observation gives support to the clinical and genetic heterogeneity of MKS.

Abnormalities, Multiple↗

Concepts in the treatment of bipolar disorder.

OBJECTIVE: Concepts in the treatment of bipolar disorder are discussed considering clinical practice. METHOD: Results of the Multicenter Study of Long-term Treatment of Affective and Schizoaffective Psychoses (MAP) study, a controlled maintenance trial, are interpreted with respect to treatment concepts. RESULTS: The spectrum of patients diagnosed as bipolar has become more heterogeneous. It now comprises subtypes requiring differentiated treatment. The MAP study confirms that prophylactic efficacy of lithium seems to be specific to classic manic-depressive illness, whereas carbamazepine might be more efficacious in non-classic bipolar patients. With respect to clinical practice, treatment evaluation should also consider anti suicidal effects, inter-episodic morbidity and compliance. In these respects, results are in favour of lithium. Furthermore, data indicate that adherence to lithium clearly depends on illness concepts. This encourages efforts to supplement pharmacotherapy by psychoeducation and psychotherapy. CONCLUSION: With the broadening of diagnostic criteria, the treatment of bipolar disorder has become more complex. Patients need an integrated approach, including differentiated mood-stabilizing pharmacotherapy and psychotherapeutic measures.

Affect↗

Microarray analysis of evolution of RNA viruses: evidence of circulation of virulent highly divergent vaccine-derived polioviruses.

Two approaches based on hybridization of viral probes with oligonucleotide microarrays were developed for rapid analysis of genetic variations during microevolution of RNA viruses. Microarray analysis of viral recombination and microarray for resequencing and heterogeneity analysis were able to generate instant genetic maps of vaccine-derived polioviruses (VDPVs) and reveal the degree of their evolutionary divergence. Unlike conventional methods based on cDNA sequencing and restriction fragment length polymorphism, the microarray approaches are better suited for analysis of heterogeneous populations and mixtures of different strains. The microarray hybridization profile is very sensitive to the cumulative presence of small quantities of different mutations, including those that cannot be revealed by sequencing, making this approach useful for characterization of profiles of nucleotide sequence diversity in viral populations. By using these methods, we identified a type-3 VDPV isolated from a healthy person and missed by conventional methods of screening. The mutational profile of the polio strain was consistent with >1 yr of circulation in human population and was highly virulent in transgenic mice, confirming the ability of VDPV to persist in communities despite high levels of immunity. The proposed methods for fine genotyping of heterogeneous viral populations can also have utility for a variety of other applications in studies of genetic changes in viruses, bacteria, and genes of higher organisms.

Animals↗

Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3.

The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive spasticity in the lower limbs. Twenty-nine different loci (SPG) have been mapped so far, and 11 responsible genes have been identified. Clinically, one distinguishes between pure and complex HSP forms which are variably associated with numerous combinations of neurological and extra-neurological signs. Less is known about autosomal recessive forms (ARHSP) since the mapped loci have been identified often in single families and account for only a small percentage of patients. We report a new ARHSP locus (SPG30) on chromosome 2q37.3 in a consanguineous family with seven unaffected and four affected members of Algerian origin living in Eastern France with a significant multipoint lod score of 3.8. Ten other families from France (n = 4), Tunisia (n = 2), Algeria (n = 3) and the Czech Republic (n = 1) were not linked to the newly identified locus thus demonstrating further genetic heterogeneity. The phenotype of the linked family consists of spastic paraparesis and peripheral neuropathy associated with slight cerebellar signs confirmed by cerebellar atrophy on one CT scan.

Adult↗

Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable variable to improve drug delivery.

Maturation of tumor vasculature involves the recruitment of pericytes that protect the endothelial tubes from a variety of stresses, including antiangiogenic drugs. Mural cells also provide mature tumor blood vessels with the ability to either relax or contract in response to substances present in the tumor microenvironment. The observed cyclic alterations in tumor blood flow and the associated deficit in chemotherapeutic drug delivery could in part arise from this vasomodulatory influence. To test this hypothesis, we focused on endothelin-1 (ET-1), which, besides its autocrine effects on tumor cell growth, is a powerful vasoconstrictor. We first document that an ET(A) receptor antagonist induced relaxation of microdissected tumor arterioles and selectively and quantitatively increased tumor blood flow in experimental tumor models. We then combined dye staining of functional vessels, fluorescent microsphere-based mapping, and magnetic resonance imaging to identify heterogeneities in tumor blood flow and to examine the reversibility of such phenomena. Data from all these techniques concurred to show that administration of an ET(A) receptor antagonist could reduce the extent of underperfused tumor areas, proving the key role of vessel tone variations in tumor blood flow heterogeneity. We also provide evidence that ET(A) antagonist administration could, despite an increase in tumor interstitial fluid pressure, improve access of cyclophosphamide to the tumor compartment and significantly influence tumor growth. In conclusion, tumor endogenous ET-1 production participates largely in the temporal and spatial variations in tumor blood flow. ET(A) antagonist administration may wipe out such heterogeneities, thus representing an adjuvant strategy that could improve the delivery of conventional chemotherapy to tumors.

Animals↗

An evolutionarily conserved germ cell-specific hnRNP is encoded by a retrotransposed gene.

The gene encoding heterogeneous ribonucleoprotein (hnRNP) G recently has been mapped to the X chromosome. All mammals have a Y chromosome-encoded homologue of HNRNP G called RBMY, which is implicated with a role in male fertility and is a candidate for the azoospermia factor gene. We have identified a new member of this gene family, HNRNP G-T, and have mapped it as a single-copy gene on chromosome 11. This gene contains an uninterrupted open reading frame and no introns, consistent with derivation from a retroposon. However, unlike many retroposon-derived genes, HNRNP G-T is not a pseudogene. An antiserum raised to the conceptual reading frame of HNRNP G-T showed that it encodes a protein that is highly expressed in germ cells and in particular in the nuclei of meiotic spermatocytes. Surprisingly, although this antiserum was raised against human hnRNP G-T protein, it can also detect a similar protein in the testis of several mammals. This suggests that the protein is highly conserved and that the retrotransposition event generating the HNRNP G-T gene pre-dated at least the common ancestor of mouse and man. The existence of an additional testis-specific hnRNP G family member provides evidence for the importance of these proteins in normal germ cell development.

Amino Acid Sequence↗

Physical and genetic mapping at the ATA/ATC locus on chromosome 11q22-23.

Genetic heterogeneity in ataxia-telangiectasia (A-T) points to four different genes responsible for this disease. The two major A-T genes, ATA and ATC, were localized by genetic analysis close to each other on chromosome 11q22-23, prompting efforts of positional cloning. Essential steps in positional cloning are long-range cloning of the genomic region of interest, and derivation of highly polymorphic markers that would allow further reduction of the interval carrying the A-T gene. We constructed genomic contigs across the D11S611-D1S424 region harbouring the ATA and ATC genes in yeast artificial chromosome (YAC) vectors. These contigs were used as a fine mapping tool and enabled us to localize along the A-T region, eight microsatellite markers generated randomly by genome mapping centres. In addition, we used specific YAC clones to generate five new microsatellite markers based on polymorphic CA repeats. Recombination mapping based on Israeli A-T families indicates that the ATC gene is distal to the locus D11S1817. Further linkage analysis using these markers is expected to reduce the major A-T locus considerably to a size appropriate for cosmid cloning and identification of transcribed sequences.

Ataxia Telangiectasia↗

[Molecular genetics and familial ataxia].

Linkage studies with DNA polymorphic markers allowed to map the loci of three inherited ataxia and to explore genetic heterogeneity in inherited ataxia in general. The locus of Friedreich ataxia, the most frequent of all recessive ataxias, has been mapped in 9q13-q21. In addition, Friedreich ataxia is an homogeneous genetic entity since all families from all populations tested (mainly European, North-American and from the Mediterranean basin) show linkage with this locus. But the severity of the disease varied in a few families. A form of recessive ataxia associated with a selective and severe serum vitamin E deficiency, which frequently presents clinically like typical Friedreich ataxia, is not linked to 9q13-q21 markers. The autosomal recessive spastic ataxia from Charlevoix-Saguenay (a region of Quebec) is also not linked to these markers. Both entities are therefore distinct genetically from Friedreich ataxia. Among dominant ataxias, the most important group is olivo-ponto-cerebellar ataxia which is heterogeneous and for which any classification is hindered by important intra-familial variability. This group corresponds to at least three distinct loci, two of which have been mapped, one in 6p23-p24, and the other, more recently, on chromosome 12. Prenatal and presymptomatic diagnosis based on linked markers can be made for the three mapped ataxias, but only in families with an affected individual for whom the diagnosis has been ascertained by through clinical investigation or by linkage analysis if the family is large enough (mainly for the dominant diseases). Linked markers are also the first tools for the search of the defective genes by positional cloning.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebellar Ataxia↗

Assessment of nonallelic genetic heterogeneity of chronic (type II and III) spinal muscular atrophy.

We have previously reported the mapping of the chronic (type II/intermediate and type III/mild/Kugelberg-Welander) form of the childhood-onset spinal muscular atrophies (SMA) to chromosome 5q11.2-13.3, with evidence for nonallelic genetic heterogeneity within a small sample of seven families [Brzustowicz et al., Nature 1990;344:540-541]. We now report the results of linkage analysis and heterogeneity testing on a set of 38 families with chronic SMA. Significant evidence for nonallelic heterogeneity was detected among these families, with the predominant locus for chronic SMA mapping to a 0.51-cM region on 5q, between the loci D5S6 and MAP1B. The estimated proportion of linked families, alpha, was 0.91, with a 2.3-unit support interval of 0.75 to 0.98. The indication that some families diagnosed with chronic SMA are not linked to chromosome 5q must be considered in strategies to map the SMA locus. The relevance of these findings to acute SMA (SMA type I, severe, Werdnig-Hoffmann disease) is still unknown.

Adolescent↗

Alzheimer's neurofibrillary tangles contain unique epitopes and epitopes in common with the heat-stable microtubule associated proteins tau and MAP2.

Ten monoclonal antibodies raised against Alzheimer's neurofibrillary tangles (ANTs) were characterized for reactivity with heat-stable microtubule fractions from bovine and human brain. Five of the antibodies showed very little reaction, but the other five reacted strongly with heat-stable microtubule associated proteins (MAPs). The proteins recognized by these antibodies have estimated molecular weights similar to those of known heat-stable MAPs, tau (52-68 kd) and MAP2 (200-250 kd). That the proteins are indeed tau and MAP2 is demonstrated by reaction of electroblotted proteins with antibodies raised in mouse and guinea pig against bovine brain tau and MAP2. One anti-ANT antibody reacts only with tau, two bind strongly to tau and weakly to MAP2, one recognizes both tau and MAP2 equally well, and one primarily stains MAP2. Extraction of ANT with 2% SDS does not remove tau or MAP2 epitopes from ANT, indicating that epitopes shared with heat-stable MAPs are integral components of ANT. The existence of tau epitopes in ANT is also demonstrated by immunoblotting of ANT-enriched fractions with anti-tau antibodies. Most of the material recognized by anti-tau antibodies in ANT-enriched fractions is present in large molecules excluded by 3% polyacrylamide gel upon electrophoresis. Anti-tau antibodies immunostain ANT in immunofluorescence and immunoperoxidase studies. The immunostaining can be blocked by absorption of anti-tau antibodies with purified tau proteins from bovine brain. Not all ANTs in any given tissue section or isolated Alzheimer perikarial preparations, however, are stained by anti-tau antibodies. These results are consistent with previous studies that have demonstrated heterogeneity of ANTs. Whether this heterogeneity is due to biochemical modification of MAPs or absence of MAPs in some ANTs is unknown. The significance of what appear to be shared epitopes recognized by monoclonal antibodies in tau and MAP2, and the implications this may have on the pathogenesis of ANT formation, requires further investigation.

Alzheimer Disease↗

A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3.

Hereditary spastic paraplegia is a genetically and phenotypically heterogeneous disorder. Both pure and complicated forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Various loci (SPG1-SPG6) associated with this disorder have been mapped. Here, we report linkage analysis of a large consanguineous family affected with autosomal recessive spastic paraplegia with age at onset of 25-42 years. Linkage analysis of this family excluded all previously described spastic paraplegia loci. A genomewide linkage analysis showed evidence of linkage to chromosome 16q24.3, with markers D16S413 (maximum LOD score 3.37 at recombination fraction [theta] of .00) and D16S303 (maximum LOD score 3.74 at straight theta=.00). Multipoint analysis localized the disease gene in the most telomeric region, with a LOD score of 4.2. These data indicate the presence of a new locus linked to pure recessive spastic paraplegia, on chromosome 16q24.3, within a candidate region of 6 cM.

Adult↗

Multiple molecular forms of endothelial cell factor VIII related antigen.

Heterogeneous factor VIII related antigen isolated from endothelial cell postculture medium was characterized. On crossed immunoelectrophoresis, slow moving less anodal populations of factor VIII related antigen molecules were more prominent in endothelial cell postculture medium than in plasma. The protein synthesized by endothelial cells appeared as two discrete protein bands of different molecular weight in sodium dodecyl sulfate polyacrylamide gels. In contrast the factor VIII related antigen isolated from plasma moved as a single protein band in an identical gel system. The factor VIII related antigen from endothelial cell postculture medium was immunoisolated using monospecific rabbit antibody to normal human plasma factor VIII related antigen, electrophoresed on sodium dodecyl sulfate polyacrylamide gels, radiolabeled with 125I, trypsinized and subjected to peptide mapping using two-dimensional high voltage electrophoresis and thin-layer chromatography. The two forms of endothelial cell factor VIII antigen had virtually identical peptide maps. These studies suggest that the molecular heterogeneity of the factor VIII related antigen system reflects polymeric associations of identical subunits. Circulation in vivo may alter the ratio of polymer subsets.

Animals↗