PubMed Health⌕ Search

Biomedical subjects

R P Harvey

Publications and source records attributed to R P Harvey.

At least 19 recordsLinked to original sources
PubMed2006

Uncertainty of the thyroid dose conversion factor for inhalation intakes of 131I and its parametric uncertainty.

Inhalation exposures of 131I may occur in the physical form of a gas as well as a particulate. The physical characteristics pertaining to these different types of releases influence the intake and subsequent dose to an exposed individual. The thyroid dose received is influenced by the route through which 131I enters the body and its subsequent clearance, absorption and movement throughout the body. The radioactive iodine taken up in the gas-exchange tissues is cleared to other tissues or absorbed into the bloodstream of the individual and transferred to other organs. Iodine in the circulatory system is then taken up by the thyroid gland with resulting dose to that tissue. The magnitude of and uncertainty in the thyroid dose is important to the assessment of individuals exposed to airborne releases of radioiodine. Age- and gender-specific modelling parameters have resulted in significant differences between gas uptake, particulate deposition and inhalation dose conversion factors for each age and gender group. Inhalation dose conversion factors and their inherent uncertainty are markedly affected by the type of iodine intake. These differences are expected due to the modelling of particulate deposition versus uptake of gas in the respiratory tract. Inhalation dose estimates via iodine gases are very similar and separate classifications may not be necessarily based on this assessment.

Administration, Inhalation↗
PubMed2004

A modified ICRP 66 iodine gas uptake model and its parametric uncertainty.

Intakes via inhalation may occur from radionuclides released in the form of a gas. The chemical characteristics pertaining to the release influence the intake and subsequent dose to an exposed individual. Gases are taken up or absorbed in the entire respiratory tract and the associated uptake mechanisms are quite different from deposition of particulates. Gaseous iodine can exist in various chemical forms, e.g., elemental iodine, inorganic, and organic iodine compounds. These different chemical species play an integral role in the gaseous uptake o f iodine in t he respiratory tract. Gas uptake in the various regions of the respiratory tract results in the intake of iodinated material into the body. The radioactive iodine taken up in the gas-exchange tissues is absorbed into the bloodstream of an individual and subsequently transferred to other organs. Iodine in the circulatory system can then be taken up by the thyroid gland, with resulting dose to the thyroid. The magnitude and uncertainty in regional gas uptake is important in the assessment of individuals exposed to airborne releases of radioiodine. The current ICRP 66 model is rudimentary and estimates regional gas uptake based on solubility and reactivity of the different radionuclides entering the respiratory tract. The modified model proposed here employs methodology and a mathematical structure to determine estimates of fractional gas uptake rather than defaulting to literature values, as in the current ICRP model. Model parameters have been assigned input distributions and estimates of uncertainty have been determined. A sensitivity analysis of these parameters has been performed to demonstrate the importance of each of these parameters. The sensitivity analysis ranks the model-input parameters by their importance to estimates of regional gas uptake. The model developed herein may be used for improved estimation of gas uptake in the respiratory tract and subsequent dose estimates from the different chemical forms of radioiodine.

Adult↗
PubMed2003

Age-specific uncertainty of the 131I ingestion dose conversion factor.

The production of weapons-grade nuclear materials and their by-products has resulted in a number of releases from United States Department of Energy facilities. 131I, a fission by-product, is one of the most common radionuclides generated and released to the environment. It is known that there are differences in various physiological parameters over all age groups when considering biokinetic modeling of iodine. The establishment of age-specific dose conversion factor uncertainty is necessary for accurate internal dose assessment. The 131I dose conversion factor determined herein is log-normally distributed with varying age-specific distribution characteristics. The two most important parameters for determination of the dose conversion factor, in all age groups, are thyroid mass and iodine uptake fraction. These parameters are assumed to be highly correlated with a relationship that is quite important to dose conversion factor uncertainty. Dose estimates to individuals exposed to radioiodine can be determined more accurately with an increased understanding of the correlation between thyroid mass and uptake fraction. Improved dose estimates following oral intakes of 131I can be made from the consideration of age-specific dose conversion factors and their input parameters.

Administration, Oral↗
PubMed2002

Age-specific uncertainty in particulate deposition for 1 microm AMAD particles using the ICRP 66 lung model.

The ICRP 66 lung model may be used to determine age-specific dose estimates for members of the public via the inhalation pathway. A significant source of uncertainty in internal dosimetric modeling is due to particulate deposition in regions of the respiratory tract. Uncertainties in estimates of particulate deposition are present because of the inherent variability in the deposition model and its various input parameters. An improved understanding of the uncertainty in particulate deposition will further guide research efforts and improve our ability to quantify internal dose estimates. The ICRP 66 lung deposition model is most sensitive to breathing rate when 1 microm AMAD particles are inhaled by members of the public. Uncertainties in deposition fractions are shown to span an order of magnitude with their distributions varying by age and sex for a particular lung region. Age-specific uncertainties of deposition fraction demonstrate increased estimates of extrathoracic deposition in younger age groups due to the decreased size of the respiratory tract airways. This age-specific trend becomes more pronounced for very young children and infants. The largest fractional deposition occurs in the alveolar and extrathoracic regions, regardless of age and sex.

Adolescent↗
PubMed2001

The combinatorial activities of Nkx2.5 and dHAND are essential for cardiac ventricle formation.

Nkx2.5/Csx and dHAND/Hand2 are conserved transcription factors that are coexpressed in the precardiac mesoderm and early heart tube and control distinct developmental events during cardiogenesis. To understand whether Nkx2.5 and dHAND may function in overlapping genetic pathways, we generated mouse embryos lacking both Nkx2.5 and dHAND. Mice heterozygous for mutant alleles of Nkx2.5 and dHAND were viable. Although single Nkx2.5 or dHAND mutants have a morphological atrial and single ventricular chamber, Nkx2.5(-/-)dHAND(-/-) mutants had only a single cardiac chamber which was molecularly defined as the atrium. Complete ventricular dysgenesis was observed in Nkx2.5(-/-)dHAND(-/-) mutants; however, a precursor pool of ventricular cardiomyocytes was identified on the ventral surface of the heart tube. Because Nkx2.5 mutants failed to activate eHAND expression even in the early precardiac mesoderm, the Nkx2.5(-/-)dHAND(-/-) phenotype appears to reflect an effectively null state of dHAND and eHAND. Cell fate analysis in dHAND mutants suggests a role of HAND genes in survival and expansion of the ventricular segment, but not in specification of ventricular cardiomyocytes. Our molecular analyses also revealed the cooperative regulation of the homeodomain protein, Irx4, by Nkx2.5 and dHAND. These studies provide the first demonstration of gene mutations that result in ablation of the entire ventricular segment of the mammalian heart, and reveal essential transcriptional pathways for ventricular formation.

Alleles↗
PubMed2001

Differential binding of an SRF/NK-2/MEF2 transcription factor complex in normal versus neoplastic smooth muscle tissues.

The malignant potential of smooth muscle tumors correlates strongly with the disappearance of gamma-smooth muscle isoactin, a lineage-specific marker of smooth muscle development. In this paper, we identify a 36-base pair regulatory motif containing an AT-rich domain, CArG box, and a non-canonical NK-2 homeodomain-binding site that has the capacity to regulate smooth muscle-specific gene expression in cultured intestinal smooth muscle cells. Serum-response factor associates with an NK-2 transcription factor via protein-protein interactions and binds to the core CArG box element. Our studies suggest that the NK-2 transcription factor that associates with serum-response factor during smooth muscle differentiation is Nkx2-3. Myocyte-specific enhancer factor 2 binding to this regulatory complex was also observed but limited to uterine smooth muscle tissues. Smooth muscle neoplasms displayed altered transcription factor binding when compared with normal myometrium. Differential nuclear accessibility of serum-response factor protein during smooth muscle differentiation and neoplastic transformation was also observed. Thus, we have identified a unique regulatory complex whose differential binding properties and nuclear accessibility are associated with modulating gamma-smooth muscle isoactin-specific gene expression in both normal and neoplastic tissues.

3T3 Cells↗
PubMed2001

Two CCAAT boxes in a novel inverted repeat motif are required for Hlx homeobox gene expression.

Hlx is a homeobox transcription factor gene required for normal intestinal and hepatic growth in development. We previously found high sequence identity and 17 conserved consensus cis-regulatory/transcription factor binding elements in the mouse and human Hlx 5' regions. A 594 bp sequence in the Hlx 5' region possessing the same activity in driving luciferase expression as larger Hlx 5' sequences had three segments each necessary but not sufficient for luciferase expression in NIH 3T3 cells (which express Hlx). Nine of the conserved putative regulatory elements are positioned within these segments, including two CCAAT boxes on opposite strands within a conserved 44 bp inverted repeat sequence. To test the hypothesis that these elements are required for promoter activity, we compared the reporter expression activity of segments containing mutations of these elements with activity of the parent Hlx promoter sequence. We found that mutation of either CCAAT box or a conserved AP-2 site resulted in a significant decrease in promoter activity. Restoration of the inverted repeat with complementary mutations of both CCAAT boxes did not restore activity. Further, mutation of other portions of the inverted repeat did not affect promoter activity. Mutation of other elements had no effect on promoter activity.

Animals↗
PubMed2001

The small muscle-specific protein Csl modifies cell shape and promotes myocyte fusion in an insulin-like growth factor 1-dependent manner.

We have isolated a murine cDNA encoding a 9-kD protein, Chisel (Csl), in a screen for transcriptional targets of the cardiac homeodomain factor Nkx2-5. Csl transcripts were detected in atria and ventricles of the heart and in all skeletal muscles and smooth muscles of the stomach and pulmonary veins. Csl protein was distributed throughout the cytoplasm in fetal muscles, although costameric and M-line localization to the muscle cytoskeleton became obvious after further maturation. Targeted disruption of Csl showed no overt muscle phenotype. However, ectopic expression in C2C12 myoblasts induced formation of lamellipodia in which Csl protein became tethered to membrane ruffles. Migration of these cells was retarded in a monolayer wound repair assay. Csl-expressing myoblasts differentiated and fused normally, although in the presence of insulin-like growth factor (IGF)-1 they showed dramatically enhanced fusion, leading to formation of large dysmorphogenic "myosacs." The activities of transcription factors nuclear factor of activated T cells (NFAT) and myocyte enhancer-binding factor (MEF)2, were also enhanced in an IGF-1 signaling-dependent manner. The dynamic cytoskeletal localization of Csl and its dominant effects on cell shape and behavior and transcription factor activity suggest that Csl plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.

Aging↗
PubMed2001

Uncertainty in particulate deposition for 1 microm AMAD particles in an adult lung model.

The ICRP 66 lung model may be used to determine dose estimates for members of the public via the inhalation pathway. A significant source of uncertainty in internal dosimetric modelling is due to particulate deposition in regions of the respiratory tract. Uncertainties in estimates of particulate deposition are present because model input parameters have their own inherent variability. These sources of uncertainty need to be examined in an effort to understand better model processes and to estimate better the doses received by individuals exposed through the inhalation pathway. An improved understanding of the uncertainty in particulate deposition will further guide research efforts and improve our ability to quantify internal dose estimates. The ICRP 66 lung deposition model is most sensitive to breathing rate when 1 microm AMAD particles are inhaled by members of the public. Uncertainties in deposition fractions are shown to span an order of magnitude with their distributions varying by gender for a particular lung region. The largest fractional deposition occurs in the deep lung alveolar and extrathoracic regions.

Administration, Inhalation↗
PubMed2000

Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5.

Heterozygous mutations in the cardiac homeobox gene, NKX2-5, underlie familial cases of atrial septal defect (ASD) with severe atrioventricular conduction block. In this study, mice heterozygous for Nkx2-5-null alleles were assessed for analogous defects. Although ASD occurred only rarely, atrial septal dysmorphogenesis was evident as increased frequencies of patent foramen ovale and septal aneurysm, and decreased length of the septum primum flap valve. These parameters were compounded by genetic background effects, and in the 129/Sv strain, septal dysmorphogenesis bordered on ASD in 17% of Nkx2-5 heterozygotes. In a proportion of neonatal heterozygotes, as well as in adults with ASD, we found that the size of the foramen ovale was significantly enlarged and altered in shape, potentially exposing the normally thin septum primum to excessive hemodynamic forces. Therefore, defective morphogenesis of the septum secundum may be one contributing factor in the generation of patent foramen ovale, septal aneurysm, and certain ASDs. Mild prolongation of P-R interval in females and an increased frequency of stenotic bicuspid aortic valves were also features of the Nkx2-5 heterozygous phenotype. Our data demonstrate that the complex effects of Nkx2-5 haploinsufficiency in mice are weaker but convergent with those in humans. As in the mouse, the phenotype of human NKX2-5 mutations may be modulated by interacting alleles.

Alleles↗
PubMed2000

Homeodomain factor Nkx2-3 controls regional expression of leukocyte homing coreceptor MAdCAM-1 in specialized endothelial cells of the viscera.

Regulated emigration of blood-borne leukocytes plays a defining role in lymphoid organ development, immune surveillance, and inflammatory responses. We report here that mice deficient in the homeobox gene Nkx2-3, expressed in developing visceral mesoderm, show a complex intestinal malabsorption phenotype and striking abnormalities of gut-associated lymphoid tissue and spleen suggestive of deranged leukocyte homing. Mutant Peyer's patches were reduced in number and size, intestinal villi contained few IgA(+) plasma cells, and mutant spleens were small and often atrophic, showing fused periarterial lymphoid sheaths, partially merged T and B cell zones, an absent marginal zone, and a dearth of macrophages in red pulp. Semiquantitative RT-PCR analysis and immunohistochemistry revealed down-regulation of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in endothelial cells in which Nkx2-3 is normally expressed. MAdCAM-1 is a member of the immunoglobulin superfamily, acting as an endothelial cell ligand for leukocyte homing receptors L-selectin and alpha4beta7 integrin. Our data suggest a role for a homeodomain factor in establishing the developmental and positional cues in endothelia that regulate leukocyte homing through local control of cellular adhesion and identify MAdCAM-1 as a candidate target gene of Nkx2-3.

Animals↗
PubMed2000

Chamber formation and morphogenesis in the developing mammalian heart.

In this study we challenge the generally accepted view that cardiac chambers form from an array of segmental primordia arranged along the anteroposterior axis of the linear and looping heart tube. We traced the spatial pattern of expression of genes encoding atrial natriuretic factor, sarcoplasmic reticulum calcium ATPase, Chisel, Irx5, Irx4, myosin light chain 2v, and beta-myosin heavy chain and related these to morphogenesis. Based on the patterns we propose a two-step model for chamber formation in the embryonic heart. First, a linear heart forms, which is composed of "primary" myocardium that nonetheless shows polarity in phenotype and gene expression along its anteroposterior and dorsoventral axes. Second, specialized ventricular chamber myocardium is specified at the ventral surface of the linear heart tube, while distinct left and right atrial myocardium forms more caudally on laterodorsal surfaces. The process of looping aligns these primordial chambers such that they face the outer curvature. Myocardium of the inner curvature, as well as that of inflow tract, atrioventricular canal, and outflow tract, retains the molecular signature originally found in linear heart tube myocardium. Evidence for distinct transcriptional programs which govern compartmentalization in the forming heart is seen in the patterns of expression of Hand1 for the dorsoventral axis, Irx4 and Tbx5 for the anteroposterior axis, and Irx5 for the distinction between primary and chamber myocardium.

Animals↗
PubMed2000

Targeted insertion of a lacZ reporter gene into the mouse Cer1 locus reveals complex and dynamic expression during embryogenesis.

The mouse Cer1 (mCer1, Cer-l, Cerr1) gene encodes one member of a family of cytokines structurally and functionally related to the Xenopus head-inducing factor, Cerberus (xCer). We generated a mouse line in which the Cer1 gene was inactivated by replacing the first coding exon with a lacZ reporter gene. Mice homozygous for this allele (Cer1(lacZ)) showed no apparent perturbation of embryogenesis or later development. However, the lacZ reporter revealed a number of hitherto uncharacterised sites of Cer1 expression in late fetal and adult tissues. Preliminary analysis suggests that Cer1 is not essential for their morphogenesis, differentiation, or homeostasis.

Animals↗
PubMed2000

Structural and functional characterization of the mouse Hlx homeobox gene.

Hlx is a mesenchymally expressed homeobox transcription factor gene that is essential for normal intestinal and hepatic development in the mouse. Here we report further characterization of the mouse Hlx gene, including an additional 3.7 kb of 5' sequence as well as the sequence of the three introns. Comparison of the sequence of the mouse Hlx gene 5' to the coding region with that of the human gene revealed multiple regions of high conservation. Neither the mouse nor the human gene contained a TATA box, and ribonuclease protection studies defined heterogeneous transcription start sites for the mouse gene. A number of consensus transcription factor binding sites were conserved between the mouse and human Hlx genes both within and outside of the highly conserved regions. Reporter constructs containing 4.2 or 1.4 kb of mouse 5' sequence showed active expression in cell lines that express Hlx. Further characterization of the mouse Hlx gene will provide insight into the developmental regulation of the mouse digestive system.

3T3 Cells↗
PubMed1999

Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway.

Skeletal muscle hypertrophy and regeneration are important adaptive responses to both physical activity and pathological stimuli. Failure to maintain these processes underlies the loss of skeletal muscle mass and strength that occurs with ageing and in myopathies. Here we show that stable expression of a gene encoding insulin-like growth factor 1 (IGF-1) in C2C12 skeletal muscle cells, or treatment of these cells with recombinant IGF-1 or with insulin and dexamethasone, results in hypertrophy of differentiated myotubes and a switch to glycolytic metabolism. Treatment with IGF-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the Ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor NF-ATc1. Hypertrophy is suppressed by the calcineurin inhibitors cyclosporin A or FK506, but not by inhibitors of the MAP-kinase or phosphatidylinositol-3-OH kinase pathways. Injecting rat latissimus dorsi muscle with a plasmid encoding IGF-1 also activates calcineurin, mobilizes satellite cells and causes a switch to glycolytic metabolism. We propose that growth-factor-induced skeletal-muscle hypertrophy and changes in myofibre phenotype are mediated by calcium mobilization and are critically regulated by the calcineurin/NF-ATc1 signalling pathway.

3T3 Cells↗