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Biomedical subjects

R J Hill

Publications and source records attributed to R J Hill.

At least 19 recordsLinked to original sources
PubMed2007

Interleukin-1beta induced activation of nuclear factor-kappab can be inhibited by novel pharmacological agents in osteoarthritis.

OBJECTIVES: To investigate the importance of activation of the transcription factor, nuclear factor-kappaB (NF-kappaB) by interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) in the pathogenesis of osteoarthritis (OA) and assess its suitability as a target for therapy by determining its role in the induction of the cytokine IL-6 and the degenerative enzymes, matrix metalloproteinase (MMP)-1 and MMP-3 in vitro. METHODS: Three distinct cellular models, derived from primary OA tissue, were employed, namely, fibroblast-like synoviocytes (OA-SF); co-cultures containing phenotypic macrophage-like and fibroblast-like cells (OA-COCUL); and primary OA synovial tissue explants (OA-EXP). These were treated with specific inhibitors of IL-1beta, TNF-alpha and NF-kappaB to assess their differential role in the production of pathologically relevant mediators, specifically IL-6, MMP-1, MMP-3 and the tissue inhibitor of metalloproteinases-1 (TIMP-1), which were quantified by enzyme-linked immunosorbent assay. RESULTS: Inhibition of NF-kappaB by a novel agent, RO100 at a dose of 0.1 microM, exerted significant (P < 0.05) repression of IL-6, MMP-1 and MMP-3 production in OA-SF. Notably, neither TIMP-1 production nor cell viability was significantly affected at the dose tested. These data were reproduced in OA-EXP, which might be considered as having greater physiological relevance. Interestingly, comparable efficacy was noted using IL-1beta and TNF-alpha neutralizing antibodies in OA-COCUL. CONCLUSIONS: We have demonstrated that a novel pharmacological inhibitor of NF-kappaB, RO100 inhibits pathological mediators of OA progression with equivalent efficacy as established IL-1beta and TNF-alpha neutralizing strategies. Our findings highlight a potential for developing NF-kappaB targeted therapeutics for positively regulating disease activity and improving clinical outcome in OA.

Antirheumatic Agents↗
PubMed2005

An analphoid marker chromosome inv dup(15)(q26.1qter), detected during prenatal diagnosis and characterized via chromosome microdissection.

A small, mosaic, C-band negative marker chromosome was detected in amniocyte cultures during prenatal diagnosis due to advanced maternal age. Following spontaneous premature labor at 29 weeks gestation, a dysmorphic infant was delivered, with flat nasal bridge, short palpebral fissures, micrognathia, high forehead, low-set ears, telecanthus and corneal dystrophy. Additional folds of skin were present behind the neck, and feet, fingers and toes were abnormally long. The child died at age five days, after two days of renal failure. The origin of the marker chromosome was subsequently identified from a cord blood sample, via chromosome microdissection. Through reverse FISH, we found the marker to be an inverted duplication of the region 15q26.1-->qter. FISH with alphoid satellite probe was negative, while whole chromosome 15 paint was positive. Both ends of the marker chromosome were positive for the telomeric TTAGGG probe. These data, plus the G-banding pattern, identified the marker as an analphoid, inverted duplicated chromosome, lacking any conventional centromere. We discuss the etiology and clinical effects of this marker chromosome, comparing it to the few reported cases of "tetrasomy 15q" syndrome. We also discuss the possible mechanisms that are likely responsible for this neocentromere formation.

Abnormalities, Multiple↗
PubMed2001

LcUSP, an ultraspiracle gene from the sheep blowfly, Lucilia cuprina: cDNA cloning, developmental expression of RNA and confirmation of function.

A DNA sequence corresponding to most of the DNA-binding domain of a Lucilia cuprina ultraspiracle protein (LcUSP) was amplified by PCR from genomic DNA and cloned. This cloned fragment was used to screen a L. cuprina cDNA library and to isolate a full-length LcUSP encoding sequence within a 3800-bp cDNA clone. The conceptually translated amino acid sequence of this open reading frame (467 amino acids) was used in alignment comparisons and phylogenetic analyses to reveal that LcUSP most closely resembles DmUSP relative to other known insect nuclear hormone receptors. An antisense RNA probe specific for the 5' end of Lcusp was used in ribonuclease protection assays to detect significant levels of Lcusp RNA throughout L. cuprina development. Highest levels were detected in embryos, late third instar larvae, pupae and adult females. This pattern parallels the pattern of expression observed for Dmusp RNAs during Drosophila melanogaster development. Finally, the LcUSP sequence was engineered for expression in mammalian cells and we now report that the cloned LcUSP is functional in vivo and can act as a partner for a chimeric L. cuprina ecdysone receptor to form an ecdysteroid-dependent transcription factor in mammalian cells.

Amino Acid Sequence↗
PubMed2001

New value of m(mu)/m(e) from muonium hyperfine splitting.

The complete contribution to the muonium hyperfine splitting of relative order alpha(3)(m(e)/m(mu))lnalpha is calculated. The result is much smaller than suggested by a previous estimate and leads to a 2sigma upward shift of the most precise value for the muon-electron mass ratio. Analogous contributions are calculated for the positronium hyperfine splitting, where a discrepancy with experiment remains.

Journal Article↗
PubMed2001

Discovery of zoniporide: a potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility.

Zoniporide (CP-597,396) is a potent and selective inhibitor of NHE-1, which exhibits high aqueous solubility and acceptable pharmacokinetics for intravenous administration. The discovery, synthesis, activities, and rat and dog pharmacokinetics of this compound are presented. The potency and selectivity of zoniporide may be due to the conformation that the molecule adopts due to the presence of a cyclopropyl and a 5-quinolinyl substituent on the central pyrazole ring of the molecule.

Animals↗
PubMed2001

Performance of constructed evaporation ponds for disposal of smelter waste water: a case study at Portland Aluminum, Victoria, Australia.

The construction of evaporative ponds and wetlands for the disposal of waste water high in ionic concentrations is a waste disposal strategy currently considered by many industries. However, the design, construction and management of these ponds and wetlands are not straightforward as complex chemical interactions result in both spatial and temporal changes in water quality. The effects of evaporation and drainage on the water quality in two constructed ponds, an adjacent man-made wetland and local groundwater at Portland Aluminium were investigated. The minimum volume of water entering the ponds during the study period was 0.96 +/- 0.16 ML per month. The predicted theoretical evaporative capacity of the two ponds was calculated to be 0.30 +/- 0.07 ML per month. More water enters the ponds than it is theoretically possible to evaporate under the ambient weather conditions at Portland, yet the ponds do not overflow, suggesting percolation through the pond lining. No spatial differences in solute concentrations (fluoride, sulphate, bicarbonate, carbonate, sodium, potassium, calcium, and magnesium ions) were found within the waters of either pond, although temporal differences were apparent. The results support the conclusion that the ponds are not impermeable, and that much of the waste water entering the ponds is being lost through seepage. The impacts on local groundwater chemistry of this seepage are addressed. Significant correlations exist between solute presence within and between the ponds. wetland and groundwater. Fluoride and sulphate concentrations were significantly higher in pond waters throughout the duration of the experiment. Pond sediments revealed a high degree of spatial and temporal heterogeneity in the concentration of all monitored ions resulting from the chemical heterogeneity of the material making up the pond linings. Adsorption isotherms for fluoride indicate that the adsorption capacity of the pond linings remains high for this ion. Implications for the management of waste water by this strategy are discussed.

Aluminum↗
PubMed2001

The validity of self-reported energy intake as determined using the doubly labelled water technique.

In the 1980s the development of the doubly labelled water (DLW) technique made it possible to determine the validity of dietary assessment methods using external, independent markers of intake in free-living populations. Since then, the accuracy of self-reported energy intake (EI) has been questioned on a number of occasions as under-reporting has been found to be prevalent in many different populations. This paper is a review of investigations using the DLW technique in conjunction with self-reported EI measures in groups including adults, children and adolescents, obese persons, athletes, military personnel and trekking explorers. In studies where a person other than the subject is responsible for recording dietary intake, such as parents of young children, EI generally corresponds to DLW determined energy expenditure. However, in instances where the subjects themselves report their intake, EI is generally under-reported when compared with energy expenditure. It was originally believed that this phenomenon of under-reporting was linked to increased adiposity and body size, however, it is now apparent that other factors, such as dietary restraint and socio-economic status, are also involved. This paper therefore aims to present a more comprehensive picture of under-reporting by tying in the findings of many DLW studies with other studies focusing particularly on the characteristics and mechanisms for under-reporting. Awareness of these characteristics and mechanisms will enable researchers to obtain more accurate self-reports of EI using all dietary recording techniques.

Adolescent↗
PubMed2001

Energy expenditure during 2 wk of an ultra-endurance run around Australia.

PURPOSE: For ultra-endurance athletes, whose energy expenditure is likely to be at the extremes of human tolerance for sustained periods of time, there is increased concern regarding meeting energy needs. Due to the lack of data outlining the energy requirements of such athletes, it is possible that those participating in ultra-endurance exercise are compromising performance, as well as health, as a result of inadequate nutrition and energy intake. To provide insight into this dilemma, we have presented a case study of a 37-yr-old ultra-marathon runner as he runs around the coast of Australia. METHODS: Total energy expenditure was measured over a 2-wk period using the doubly labeled water technique. RESULTS: The average total energy expenditure of the case subject was 6321 kcal x d(-1). Based on the expected accuracy and precision of the doubly labeled water technique the subject's total energy expenditure might range between 6095 and 6550 kcal x d(-1). The subject's average daily water turnover was 6.083 L over the 14-d period and might range between 5.9 L and 6.3 L x d(-1). CONCLUSIONS: This information will provide a guide to the energy requirements of ultra-endurance running and enable athletes, nutritionists, and coaches to optimize performance without compromising the health of the participant.

Adult↗
PubMed2001

A novel sodium-hydrogen exchanger isoform-1 inhibitor, zoniporide, reduces ischemic myocardial injury in vitro and in vivo.

The cardioprotective efficacy of zoniporide (CP-597,396), a novel, potent, and selective inhibitor of the sodium-hydrogen exchanger isoform 1 (NHE-1), was evaluated both in vitro and in vivo using rabbit models of myocardial ischemia-reperfusion injury. In these models, myocardial injury was elicited with 30 min of regional ischemia and 120 min of reperfusion. Zoniporide elicited a concentration-dependent reduction in infarct size (EC(50) of 0.25 nM) in the isolated heart (Langendorff) and reduced infarct size by 83% (50 nM). This compound was 2.5- to 20-fold more potent than either eniporide or cariporide (EC(50) of 0.69 and 5.11 nM, respectively), and reduced infarct size to a greater extent than eniporide (58% reduction in infarct size). In open-chest, anesthetized rabbits, zoniporide also elicited a dose-dependent reduction in infarct size (ED(50) of 0.45 mg/kg/h) and inhibited NHE-1-mediated platelet swelling (maximum inhibition 93%). Furthermore, zoniporide did not cause any in vivo hemodynamic (mean arterial pressure, heart rate, rate pressure product) changes. Zoniporide represents a novel class of potent NHE-1 inhibitors with potential utility for providing clinical cardioprotection.

Animals↗
PubMed2000

Landau-level spectroscopy of a two-dimensional electron system by tunneling through a quantum dot.

A single InAs self-assembled quantum dot is incorporated in the barrier of a tunnel diode and used as a spectroscopic probe of an adjacent two-dimensional electron system from the Fermi energy to the subband edge. We obtain quantitative information about the energy dependence of the quasiparticle lifetime. For magnetic field B, applied parallel to the current, we observe peaks in the current-voltage characteristics I(V) corresponding to the formation of Landau levels. Close to filling factor nu=1 we observe directly the exchange enhancement of the Lande g factor.

Journal Article↗
PubMed1999

Pristionchus pacificus, a nematode with only three juvenile stages, displays major heterochronic changes relative to Caenorhabditis elegans.

The nematode Pristionchus pacificus (Diplogastridae) has been described as a satellite organism for a functional comparative approach to the model organism Caenorhabditis elegans because genetic, molecular, and cell-biological tools can be used in a similar way in both species. Here we show that P. pacificus has three juvenile stages, instead of the usual four found in other nematodes. Embryogenesis is lengthened and many developmental events that take place during the first juvenile stage in C. elegans occur during late embryogenesis in P. pacificus. Video imaging and transmission electron microscopy revealed no embryonic moult. The timing of later developmental events relative to the moults differs between P. pacificus and C. elegans. In addition, the post-embryonic blast-cell divisions display a specific change in timing between the two species, resulting in heterochrony between different cell lineages, such as vulval and gonadal lineages. Developmental events appear to come into register during the last larval stage. Thus, differences in developmental timing between P. pacificus and C. elegans represent a deep heterochronic change. We designate the three juvenile stages of P. pacificus as J1 to J3. Comparison with other species of the family Diplogastridae indicates that this pattern represents an apomorphic character for the monophylum Diplogastridae.

Animals↗
PubMed1999

Extracting parity and magnitude from Arabic numerals: developmental changes in number processing and mental representation.

Children from Grades 2, 3, 4, 6, and 8 (7.8, 9.2, 9.8, 11.7, and 13. 6 years old, respectively) made speeded, bimanual parity (odd/even) judgments of the Arabic numerals 0-9. Analysis of response times indicated that from fourth grade on, parity information is retrieved directly from memory rather than being extracted by means of a mental calculation strategy. As early as Grade 3, children exhibited the SNARC (Spatial-Numerical Association of Response Codes) effect, where small numbers were responded to faster with the left hand than with the right hand, while the converse held true for large numbers. This finding, previously demonstrated only in adults, confirms that (a) children represent magnitude information in the form of a left-to-right oriented mental number line, and (b) this information is accessed obligatorily even when irrelevant. Finally, although the SNARC effect remained strong at Grade 4, it was attenuated at Grades 6 and 8 by a linguistic effect based on associations between the unmarked adjectives "even" and "right" and between the marked adjectives "odd" and "left."

Adolescent↗
PubMed1999

Mapping signal transduction pathways by phage display.

Rapid identification of proteins that interact with a novel gene product is an important element of functional genomics. Here we describe a phage display-based technique for interaction screening of complex cDNA libraries using proteins or synthetic peptides as baits. Starting with the epidermal growth factor receptor (EGFR) cytoplasmic tail, we identified known protein interactions that link EGFR to the Ras/MAP kinase signal transduction cascade and several novel interactions. This approach can be used as a rapid and efficient tool for elucidating protein networks and mapping intracellular signal transduction pathways.

3T3 Cells↗
PubMed1999

The validity of a four day weighed food record for measuring energy intake in female classical ballet dancers.

OBJECTIVES: To assess the validity of a four day weighed food record in the measurement of energy intake in female classical ballet dancers. DESIGN: Twelve classical ballet dancers volunteered to take part in this study. SETTING: Queensland University of Technology. SUBJECTS: Twelve classical ballet dancers. Data collected from one subject was not used due to poor compliance with the requirements of the study. INTERVENTIONS: Measurements of energy intake via a four day weighed record and total energy expenditure via the doubly labelled water technique. RESULTS: There was a mean bias to under-reporting energy intake of 667 kcal/day or 21% of real intake. CONCLUSIONS: Results of dietary data obtained via a four day weighed intake should be viewed with caution in the light of the evidence of major under-reporting in this cohort.

Dancing↗
PubMed1999

Structural requirements for the tissue-specific and tissue-general functions of the Caenorhabditis elegans epidermal growth factor LIN-3.

Caenorhabditis elegans lin-3 encodes a homolog of the epidermal growth factor (EGF) family of growth factors. LIN-3 is the inductive signal for hermaphrodite vulval differentiation, and it is required for animal viability, hermaphrodite fertility, and the specification of anterior cell fates in the male B cell lineage. We describe the cloning of a lin-3 homolog from C. briggsae, sequence comparison of C. elegans lin-3 with C. briggsae lin-3, and the determination of molecular lesions in alleles of C. elegans lin-3, including three new alleles. We also analyzed the severity of phenotypes caused by the new and existing alleles of lin-3. Correlation of mutant phenotypes and their molecular lesions, as well as sequence comparison between two species, reveal that the EGF motif and the N-terminal portion of the cytoplasmic domain are important for the functions of LIN-3 in all tissues, while the C-terminal portion of the cytoplasmic domain is involved in the tissue-specific functions of lin-3. We discuss how the structure of lin-3 contributes to its functions in multiple developmental processes.

Alleles↗
PubMed1999

pos-1 encodes a cytoplasmic zinc-finger protein essential for germline specification in C. elegans.

Germ cells arise during early C. elegans embryogenesis from an invariant sequence of asymmetric divisions that separate germ cell precursors from somatic precursors. We show that maternal-effect lethal mutations in the gene pos-1 cause germ cell precursors to inappropriately adopt somatic cell fates. During early embryogenesis, pos-1 mRNA and POS-1 protein are present predominantly in the germ precursors. POS-1 is a novel protein with two copies of a CCCH finger motif previously described in the germline proteins PIE-1 and MEX-1 in C. elegans, and in the mammalian TIS11/Nup475/TTP protein. However, mutations in pos-1 cause several defects in the development of the germline blastomeres that are distinct from those caused by mutations in pie-1 or mex-1. The earliest defect detected in pos-1 mutants is the failure to express APX-1 protein from maternally provided apx-1 mRNA, suggesting that POS-1 may have an important role in regulating the expression of maternal mRNAs in germline blastomeres.

Amino Acid Sequence↗
PubMed1998

Relative sedimentation of hematopoietic progenitors in human cord blood, peripheral blood, and bone marrow as determined by counterflow centrifugal elutriation.

BACKGROUND: The current use of cord blood (CB) and peripheral blood (PB) stem cells as alternatives or adjunctives to bone marrow (BM) for hematopoietic reconstitution in the treatment of various diseases prompted an examination of the progenitors of these tissues by counterflow centrifugal elutriation (CCE). METHODS: The cells, obtained from normal donors not primed with colony-stimulating factors, were centrifuged at 3000 rpm in a Beckman Sanderson Chamber. Fractions (Frs.) were collected at (1) 18 ml/min, (2) 25 ml/min, (3) 32 ml/min, (4) 40 ml/min, and (5) the rotor-off fraction. RESULTS: Clonogenic assays revealed differences in the fraction localizations for CB and PB when compared to BM, i.e., recovery of the colony-forming units for CB and PB was greater in the small-medium cell size CCE fractions, and those from BM were found primarily among the medium-large cell size fractions. Thus, although colony-forming unit granulocyte/macrophage colonies were distributed throughout Frs. 2-5 of BM, CB and PB showed 80% of the total to be in Frs. 2 and 3. Further, although burst-forming unit erythroid colonies of BM were distributed equally in Frs. 2 and 3, greater than 70% of the total burst-forming unit erythroid colonies in CB and PB were found in Fr. 2. Distribution of the CD34 cells in the fractions correlated with the colony-forming units in that these were found primarily in Frs. 2 and 3 of CB and PB, whereas they were present in significant numbers throughout Frs. 1-5 of BM. CONCLUSIONS: We interpret these findings to indicate CB and PB to be qualitatively similar in their hematopoietic lineage development and to contain a greater proportion of early versus late progenitors relative to those found in BM.

Blood Cells↗