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Biomedical subjects

H Marshall

Publications and source records attributed to H Marshall.

18 recordsLinked to original sources
PubMed1992

Neuroblastoma. Effect of genetic factors on prognosis and treatment.

BACKGROUND AND METHODS. Genetic analysis of tumor tissue has provided considerable insight into mechanisms of malignant transformation and progression. Neuroblastomas have been studied by cytogenetics, flow cytometry, and molecular genetic techniques, and these studies have identified several specific abnormalities that allow subclassification of these tumors into genetic/clinical subtypes. RESULTS AND DISCUSSION. Four genetic abnormalities have been identified that are characteristic of certain neuroblastomas. These include: (1) loss of heterozygosity (LOH) for the short arm of chromosome 1, including band 1p36; (2) amplification of the N-myc protooncogene; (3) hyperdiploidy, or near triploidy; and (4) defects in expression or function of the nerve growth factor receptor (NGFR). Abnormalities of the NGFR are found in virtually all neuroblastoma cell lines, and some primary tumors. The latter have not been studied extensively. Hyperdiploidy is associated with lower stages of disease and with a favorable outcome in infants. LOH for chromomors. The latter have not been studied extensively. Hyperdiploidy is associated with lower stages of disease and with a favorable outcome in infants. LOH for chromosome 1, band p36, and N-myc amplification are more common in patients older than 1 year of age with advanced stages of disease. The latter two genetic abnormalities may be related, and LOH for 1p36 may precede the development of amplification. When these abnormalities are combined with assessment of DNA content, three distinct genetic subsets of neuroblastomas can be identified. The first is characterized by a hyperdiploid or near-triploid modal karyotype, with few if any cytogenetic rearrangements. These patients generally are younger than 1 year of age with localized disease and a good prognosis. The second has a near-diploid karyotype, with no consistent abnormality identified currently. These patients generally are older with more advanced stages of disease that progress slowly and are often fatal. The third group has a near-diploid or tetraploid karyotype, with deletions or LOH for 1p36, amplification of N-myc, or both. These patients generally are older with advanced stages of disease that rapidly are progressive. Thus, genetic analysis of neuroblastoma cells provides information that has prognostic significance and can direct a more appropriate choice of treatment.

Cell Line↗
PubMed1992

Arctic terrestrial ecosystem contamination.

Limited data have been collected on the presence of contaminants in the Arctic terrestrial ecosystem, with the exception of radioactive fallout from atmospheric weapons testing. Although southern and temperate biological systems have largely cleansed themselves of radioactive fallout deposited during the 1950s and 1960s, Arctic environments have not. Lichens accumulate radioactivity more than many other plants because of their large surface area and long life span; the presence and persistence of radioisotopes in the Arctic is of concern because of the lichen----reindeer----human ecosystem. Effective biological half-life of cesium 137 is reckoned to be substantially less than its physical half-life. The database on organochlorines in Canadian Arctic terrestrial mammals and birds is very limited, but indications are that the air/plant/animal contaminant pathway is the major route of these compounds into the terrestrial food chain. For terrestrial herbivores, the most abundant organochlorine is usually hexachlorobenzene followed by hexachlorocyclohexane isomers. PCB accumulation favours the hexachlorobiphenyl, pentachlorobiphenyl and heptachlorobiphenyl homologous series. The concentrations of the various classes of organochlorine compounds are substantially lower in terrestrial herbivore tissues than in marine mammal tissues. PCBs and DDT are the most abundant residues in peregrine falcons (a terrestrial carnivore) reaching average levels of 9.2 and 10.4 micrograms.g-1, respectively, more than 10 times higher than other organochlorines and higher than in marine mammals, including the polar bear. Contaminants from local sources include metals from mining activities, hydrocarbons and waste drilling fluids from oil and gas exploration and production, wastes from DEW line sites, naturally occurring radionuclides associated with uranium mineralization, and smoke containing SO2 and H2SO4 aerosol from the Smoking Hills at Cape Bathurst, N.W.T.

Animals↗
PubMed1992

Elevated stromelysin-1 and reduced collagenase-IV expression in invasive rat embryo fibroblasts expressing E1A deletion mutants + T24-H-ras.

We have studied the in vitro invasive properties of 3 cell lines derived from the co-transfection of rat embryo fibroblasts (REF) with EIA genes deficient in exon 2 and T24-ras. All 3 cell lines showed invasive properties at passage 10 after isolation. Invasive cells expressed elevated levels of stromelysin-1 and reduced levels of 68-kDa type-IV collagenase compared with untransfected REF. In 2 cell lines the invasive capacity increased during in vitro propagation. The expression of stromelysin-1 increased during this process, whereas 68-kDa type-IV collagenase was persistently expressed at reduced levels. In the third clone analyzed, the invasive capacity decreased during culture, in parallel with decreased expression of stromelysin-1. The low level of stromelysin-1 expression observed in this cell line did not result from loss of AP-1-transcription-factor activity, and was not reversed by phorbol-ester treatment.

Adenovirus Early Proteins↗
PubMed1992

Neuroectodermal autonomy of Hox-2.9 expression revealed by rhombomere transpositions.

Involvement of the Hox genes in regional specifications of the vertebrate body axis is suggested by sequence similarity with the homeotic selector genes of Drosophila, the conservation of a collinear relationship between genomic organization and site of expression, and mutational analysis. Subdivision of vertebrate embryo hindbrain neuroepithelium into lineage compartments (rhombomeres) underlies segmental patterning of neuronal differentiation. The rhombomere boundaries delimit domains of expression of Hox genes, presumed to be determinants of rhombomere phenotype, suggesting that Hox genes confer positional value; the formation of rhombomere 4 (r4) is followed by strong expression of Hox-2.9 within its confines. If the Hox genes are determinants, their expression should be autonomous from the developmental stage at which regional commitment becomes fixed and irreversible. We have transplanted the future r4 region (from state-9-chick embryos) into the more anterior position of r2 and probed for Hox-2.9 transcripts. We report here that Hox-2.9 was expressed in the ectopic r4 as strongly as in the normal r4, whereas reciprocal grafts of future r2 to r4 position did not express Hox-2.9. The phenotype of ectopic rhombomeres developed according to their original position, as demonstrated by retrograde tracing of efferent cranial nerve nuclei. As early as stage-9-(six somites), both Hox-2.9 expression and segment identity are autonomous in the chick embryo hindbrain, independent both of position in the neuroepithelium and of signals from the underlying mesoderm.

Animals↗
PubMed1992

Thrombolysis-related early patency reduces ECG late potentials after acute myocardial infarction.

To assess the effects of thrombolysis and reperfusion on late potentials after myocardial infarction, 101 patients (79 men, age 63.2 +/- 10.5 years) underwent signal-averaged ECG studies at 10.7 +/- 9.2 days, with the use of a 40 to 250 Hz band-pass filter. Patients were divided into four groups: (1) 54 patients treated with thrombolytic agents at 2.8 +/- 1.1 hours, with 81% "early" patency/reperfusion (TIMI grades 2 and 3); (2) 47 patients treated conventionally with 45% "late" patency/reperfusion; (3) 56 patients with patency (TIMI grades 2 and 3); and (4) 26 patients without patency (TIMI grades 0 and 1). A late potential was present when greater than or equal to 2 of 3 defined criteria were present. There was a significant difference in the incidence of late potentials between groups 1 and 2 (22% vs 43%, respectively; p = 0.048) and between groups 3 and 4 (18% vs 50%, respectively; p = 0.006). Late potentials also tended to occur less often after "early" than after "late" patency/reperfusion (12.5% vs 25%). The odds ratio for developing a late potential was 0.39 for thrombolysis versus no thrombolysis (p less than 0.05) and 0.22 for patency/reperfusion (TIMI grades 2 and 3) versus no patency/reperfusion (TIMI grades 0 and 1) (p less than 0.05). By analysis of covariance the effects of thrombolysis on late potentials were entirely explained by reperfusion. Thus the risk of late potentials after myocardial infarction is high but is reduced by thrombolysis and reperfusion. In addition, the effectiveness of "early" reperfusion appears to be greater than that of "late" but requires further clarification.

Adult↗
PubMed1992

Enhanced invasive properties of rat embryo fibroblasts transformed by adenovirus E1A mutants with deletions in the carboxy-terminal exon.

E1A genes deficient in the carboxy-terminal exon can cooperate with activated ras oncogenes to induce transformation of rat embryo fibroblasts. However, the resulting transformed foci show a distinct appearance characterized by a decreased adhesion of the cells to the substrate. Here, we demonstrate that cell lines derived from foci showing the variant morphology are defective in down-regulation of stromelysin 1 metalloprotease expression and show an increased invasive propensity compared with cells transformed by wild-type E1A. The altered focus morphology, the high invasive propensity and the elevated stromelysin 1 expression were abrogated by glucocorticoid treatment. Our results show that E1A functions necessary for transformation and inhibition of invasive properties may be separated, and indicate that a 23 amino acid serine/threonine-rich region within the E1A carboxy-terminal exon is required for efficient repression of metalloprotease expression in transformed cells.

Adenovirus Early Proteins↗
PubMed1991

Pulse oximetry during apparent tonic-clonic seizures.

A pulse oximeter was used to monitor arterial oxygen saturations in 11 patients during apparent tonic-clonic seizures. 8 had a clinical diagnosis of genuine fits, 6 of whom showed striking falls in oxygen saturation during the seizures. 3 had a clinical diagnosis of pseudoseizures, none of whom had hypoxia during these episodes. Pulse oximetry during apparent tonic-clonic seizures may help to identify patients with low arterial oxygen tension who need immediate intervention.

Adolescent↗
PubMed1991

Glucocorticoid hormones may partially substitute for adenovirus E1A in cooperation with ras.

The effects of hormonal promotion of T24-ras oncogene-transfected rat embryo fibroblasts (REF) were compared to cotransformation of these cells with adenovirus E1A and ras. Cotransfection of E1A + ras resulted in the appearance of morphologically transformed cells which were very efficiently established into cell lines. Addition of glucocorticoid hormones to T24-ras-transfected REF cells resulted in cells with a transformed morphology and a capacity to form foci. These foci were, however, inefficiently established into stable cell lines. Removal of hormone from growing cells resulted in retarded growth, suggesting that the hormone acted as a growth factor on these cells. Both E1A-transformed cells and hormone-treated ras-transformed cells showed a reduction in synthesis of high molecular weight tropomyosin isoforms and a decreased expression of surface fibronectin. Control experiments demonstrated that the effects of hormone were mediated through the glucocorticoid receptor. Our findings suggest that glucocorticoid hormones may promote the in vitro growth of ras-initiated REF cells into stably transformed cell lines, but that this ability is limited compared to that of adenovirus E1A.

Adenoviridae↗
PubMed1991

Multiple spatially specific enhancers are required to reconstruct the pattern of Hox-2.6 gene expression.

Murine Hox genes are organized into four clusters that share many features with the homeotic clusters of Drosophila. This evolutionary conservation and the clear relationships between the position of a gene within a cluster and its expression pattern have led to the suggestion that the structure of the cluster is essential for proper regulation. Using a Hox-2.6-lacZ reporter gene in transgenic mice we have shown that the overall expression pattern of the endogenous Hox-2.6 gene can be reconstructed when it is isolated from the complex. The transgene was expressed in the proper tissues, with the correct spatial distribution and temporal pattern. Furthermore, direct comparison by in situ hybridization revealed that the levels of transgene expression are similar to those of the endogenous gene. This has allowed us to define three elements that regulate particular aspects of the Hox-2.6 pattern, two of which act as spatially specific enhancers. One enhancer, region A, directed expression only in the neural tube, whereas the other, region C, specified the majority of the Hox-2.6 pattern. Both were also capable of imposing the correct boundaries of expression on heterologous promoters. The definition of such elements will allow the characterization of the trans-acting factors that mediate spatial regulation in the mammalian embryo.

Animals↗
PubMed1991

Homeobox genes and models for patterning the hindbrain and branchial arches.

Antennapedia class homeobox genes, which in insects are involved in regional specification of the segmented central regions of the body, have been implicated in a similar role in the vertebrate hindbrain. The development of the hindbrain involves the establishment of compartments which are subsequently made distinct from each other by Hox gene expression, implying that the lineage of neural cells may be an important factor in their development. The hindbrain produces the neural crest that gives rise to the cartilages of the branchial skeleton. Lineage also seems to be important in the neural crest, as experiments have shown that the crest will form cartilages appropriate to its level of origin when grafted to a heterotopic location. We show how the Hox genes could also be involved in patterning the mesenchymal structures of the branchial skeleton. Recently it has been proposed that the rhombomere-restricted expression pattern of Hox 2 genes is the result of a tight spatially localised induction from underlying head mesoderm, in which a prepattern of Hox expression is visible. We find no evidence for this model, our data being consistent with the idea that the spatially localised expression pattern is a result of segmentation processes whose final stages are intrinsic to the neural plate. We suggest the following model for patterning in the branchial region. At first a segment-restricted code of Hox gene expression becomes established in the neuro-epithelium and adjacent presumptive neural crest. This expression is then maintained in the neural crest during migration, resulting in a Hox code in the cranial ganglia and branchial mesenchyme that reflects the crest's rhombomere of origin. The final stage is the establishment of Hox 2 expression in the surface ectoderm which is brought into contact with neural crest-derived branchial mesenchyme. The Hox code of the branchial ectoderm is established later in development than that of the neural plate and crest, and involves the same combination of genes as the underlying crest. Experimental observations suggest the idea of an instructive interaction between branchial crest and its overlying ectoderm, which would be consistent with our observations. The distribution of clusters of Antennapedia class genes within the animal kingdom suggests that the primitive chordates ancestral to vertebrates had at least one Hox cluster. The origin of the vertebrates is thought to have been intimately linked to the appearance of the neural crest, initially in the branchial region.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

The branchial Hox code and its implications for gene regulation, patterning of the nervous system and head evolution.

In this study we have examined the expression of murine Hox homeobox containing genes by in situ hybridisation in the branchial region of the head. Genes from the Hox complexes display segmentally restricted domains of expression in the developing hindbrain, which are correlated with similar restricted domains in the neural crest and surface ectoderm of the branchial arches. Comparison of related genes from the different clusters shows that subfamily members are expressed in identical rhombomeres and branchial arches. These patterns suggest a combinatorial system for specifying regional variation in the head, which we refer to as a Hox code. The Hox genes also display dynamic dorso-ventral (D-V) restrictions in the developing neural tube which mirror the timing and spatial distributions of the birth of major classes of neurons in the CNS. Genes in the Hox-2 cluster all have a similar D-V distribution that differs from that of genes from the other Hox clusters, and suggests that members of a subfamily may be used to specify positional values to different subsets of cells at the same axial level. These results are discussed in terms of a system for patterning the branchial regions of the vertebrate head, and evolution of head structures. We have also examined aspects of the transcriptional regulation of Hox-2 genes in transgenic mice using a lacZ reporter gene. We have been able to reconstruct the major pattern of the Hox-2.6 gene on the basis of identical expression of the transgene and the endogenous gene with respect to timing, spatial restrictions and tissue-specific distributions. Deletion analysis has enabled us to identify three regions involved in generating this pattern. Two of these regions have the properties of enhancers which are capable of imposing spatially-restricted domains of expression on heterologous promoters. We have generated similar Hox-lacZ fusions that reconstruct the highly restricted patterns of the Hox-2.1 and Hox-2.8 genes in the developing nervous system, supporting our in situ analysis and the idea of a Hox code. These transgenic experiments are a useful step in examining regulation in the Hox cascade.

Amino Acid Sequence↗
PubMed1990

Immortalization of primary cells by DNA tumor viruses.

Cellular senescence is characterized by a decline in sensitivity to growth factors resulting in cessation of cellular growth. The expression of cellular or viral oncogenes may result in the establishment of cell lines with unlimited proliferative potential ("immortalization"). A variety of viral and cellular oncogenes have been reported to immortalize cells, suggesting that multiple mechanisms may lead to an escape from senescence. Immortalization has been reported to occur as a result of an interaction of viral proteins with cellular suppressor gene products or may result from the elevated expression of "transforming" oncoproteins (such as the polyomavirus middle-t antigen). Here we speculate that a selection for cells with a further decreased probability of cell cycle withdrawal can occur during the growth of cells expressing viral early genes, resulting in a process of tumor progression. Explaining immortalization in terms of mitogenic stimulation due to the expression of viral oncogenes followed by genetic/epigenetic changes may help to explain why lytic DNA viruses have a biological activity which may not be necessary for their life cycle.

Animals↗
PubMed1989

Triplanar closing base wedge osteotomy for tailor's bunion.

The authors discuss mathematical evaluations when considering base wedge osteotomies to correct a tailor's bunion. A review of the literature is presented in order to use clinical results when algebraic and trigonometric functions are discussed.

Hallux Valgus↗
PubMed1986

Lymphadenopathy and lymph node infarction in the course of gold therapy.

Lymphadenopathy, as a complication of gold therapy, appears to be an uncommon occurrence. Lymph node infarction has not been previously documented in this setting. The unique pathologic features in this case may reflect: a phenomenon specific to gold; early examination of the infarcted node; or underlying leukocytoclastic angiitis secondary to gold toxicity. Polymorphonuclear leukocytic infiltration of an infarcted lymph node has apparently not been previously reported.

Adult↗
PubMed1977

The use of public transportation in urban areas: toward a causal model.

In this study, using the statistical models recently introduced by Goodman, we analyze the reasons why individuals choose the car or public transportation for the journey to work and draw out some of the implications of our analysis for public policy. Building on the work of Schnore, we develop a model in which both structural and individual variables are interrelated and show that the structural contexts within which individuals make decisions about their choice are crucial. We also show that, while status differentials are largely accounted for by income differences, male preferences for the automobile tend not to be due either to the structural variables or to income differences. Our findings suggest that present policies designed to induce people to shift to public transportation for the journey to work are not likely to be effective, since they do nothing to alter present cost differentials between the two modes.

Automobiles↗
PubMedDate not supplied

Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity.

It has been suggested that Hox genes play an important part in the patterning of limbs, vertebrae and craniofacial structures by providing an ordered molecular system of positional values, termed the Hox code. Little is known about the nature of the signals that govern the establishment and regulation of Hox genes, but retinoic acid can affect the expression of these genes in cell lines and in embryonic tissues. On the basis of experimental and clinical evidence, the hindbrain and branchial region of the head are particularly sensitive to the effects of retinoic acid but the phenotypes are complex and hard to interpret, and how and if they relate to Hox expression has not been clear. Here we follow the changes induced by retinoic acid to hindbrain segmentation and the branchial arches using transgenic mice which contain lacZ reporter genes that reveal the endogenous segment-restricted expression of the Hox-B1 (Hox-2.9), Hox-B2(Hox-2.8) and Krox-20 genes. Our results show that these genes rapidly respond to exposure to retinoic acid at preheadfold stages and undergo a progressive series of changes in segmental expression that are associated with specific phenotypes in hindbrain of first branchial arch. Together the molecular and anatomical alterations indicate that retinoic acid has induced changes in the hindbrain Hox code which result in the homeotic transformation of rhombomeres (r) 2/3 to an r4/5 identity. A main feature of this rhombomeric phenotype is that the trigeminal motor nerve is transformed to a facial identity. Furthermore, in support of this change in rhombomeric identity, neural crest cells derived from r2/3 also express posterior Hox markers suggesting that the retinoic acid-induced transformation extends to multiple components of the first branchial arch.

Animals↗