Search PubMed⌕ Search

Biomedical subjects

I Hunter

Publications and source records attributed to I Hunter.

At least 19 recordsLinked to original sources
PubMed2001

Stimulation of stress-activated but not mitogen-activated protein kinases by tumour necrosis factor receptor subtypes in airway smooth muscle.

The multifunctional cytokine tumour necrosis factor-alpha (TNF) displays many physiological effects in a variety of tissues, especially proliferative and cytotoxic actions in immunological cells. Recently, we uncovered an important new mechanism by which TNF can sensitise airway smooth muscle (ASM) to a fixed intracellular Ca2+ concentration which in vivo would produce a marked hypercontractility of the airways. Here, we report that both 50-60 kDa type I TNFR (TNFR1) and 70-80 kDa type II TNFR (TNFR2) receptor subtypes were expressed in ASM cells and selectively activated the stress kinases, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase (p38 MAPK). However, TNF caused no activation of p42/p44 MAPK or cytosolic phospholipase A(2) activity. In contrast, TNF stimulation of the TNFR1, but not the TNFR2, elicited nuclear factor-kappaB transcription factor function, a species known to be important in mediation of certain inflammatory cellular responses. This is the first report of TNF receptor subtypes in ASM cells causing selective kinase activation, which may prove important in therapeutic strategies for treating immune airway disorders such as chronic obstructive pulmonary disease and asthma.

Animals↗
PubMed2001

Caspase-dependent cleavage of cadherins and catenins during osteoblast apoptosis.

As transmembrane, Ca2+-dependent cell-cell adhesion molecules, cadherins play a central role in tissue morphogenesis and homeostasis. Stable adhesion is dependent on interactions of the cytoplasmic domain of the cadherins with a group of intracellular proteins, the catenins. In the present study, we have detected the expression of alpha-, beta-, and gamma-catenins in human osteoblasts, which assemble with cadherins to form two distinct complexes containing cadherin and alpha-catenin, with either beta- or gamma-catenin. In osteoblasts undergoing apoptosis, proteolytic cleavage of N-cadherin and beta- and gamma- catenins but not alpha-catenin was associated with the activation of caspase-3 and prevented by the caspase inhibitor Z-VAD-fmk. The pattern of cadherin/catenin cleavage detected in apoptotic osteoblasts was reproduced in vitro by recombinant caspase-3. The presence of a 90-kDa extracellular domain fragment of N-cadherin in conditioned medium from apoptotic cells indicates that additional extracellular or membrane-associated proteases also are activated. Disruption of N-cadherin-mediated cell-cell adhesion with function-blocking antibodies induced osteoblast apoptosis, activation of caspases, and cleavage of beta-catenin. These findings provide compelling evidence that N-cadherin-mediated cell-cell adhesion promotes osteoblast survival and suggest that the underlying mechanism may involve activation of beta-catenin signaling.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Fat absorption in cystic fibrosis after correction of hypokalaemia.

Extracellular potassium up-regulates exocrine pancreatic function in tissue preparations of mammalian pancreatic lobules. We report on a child with cystic fibrosis in whom clinical evidence suggested that this laboratory observation may be of relevance to clinical practice.

Administration, Oral↗
PubMed2000

Prevalence and aetiology of hypothyroidism in the young.

AIMS: To define the prevalence of hypothyroid disease in children and young people, and describe its aetiology. METHODS: We identified all patients on the Medicines Monitoring Unit (MEMO) database in the Tayside region of Scotland who had received two or more prescriptions for thyroxine during the study period (January 1993 to December 1995). Using this as a surrogate marker of hypothyroidism, we calculated the prevalence of hypothyroidism in those aged less than 22 years. Main outcome measures were prevalence of thyroxine prescription, estimated prevalence of hypothyroidism, and aetiology of the hypothyroidism (determined from case records, and biochemistry and immunology databases). RESULTS: Of 103,500 residents aged less than 22 years, 140 were identified as receiving thyroxine on prescription, giving a population prevalence of 0.135%. The ratio of male to female was 1:2.8. Acquired hypothyroidism was the commonest aetiology found in 73%, 66% of which had an autoimmune basis. The prevalence of congenital hypothyroidism was 0.027%. Seven had received treatment for malignancy (two primary thyroid). Fifteen per cent of patients had no record of secondary care follow up in Tayside. CONCLUSIONS: The overall prevalence of hypothyroidism in young people less than 22 years of age is 0.135%, and in the group aged 11-18 years it is 0.113%; these values are at least twice those of previous estimates. This suggests an increase in autoimmune thyroid disease, similar to the rising prevalence of type 1 diabetes, possibly indicating a rising incidence of autoimmunity in young people.

Adolescent↗
PubMed2000

A waterborne outbreak of Salmonella Saintpaul.

Contamination of a tank water supply system led to an outbreak of Salmonella Saintpaul with 28 cases of gastroenteritis amongst over 200 workers at a large construction site. The outbreak was identified following notification of two salmonellosis cases by general practitioners from different towns during March 1999. The source of infection, contaminated drinking water, was identified through environmental sampling and confirmed by epidemiological investigations. Frogs and/or mice may have been the original source of the contamination. This report details control measures, the results of investigations and recommendations for future research.

Animals↗
PubMed2000

The use of molecular biology to reprogram Streptomyces to make polyketide antibiotics more efficiently, and create novel secondary metabolites.

Recent advances in the molecular genetics of Streptomyces have increased our understanding of polyketide antibiotic biosynthesis, to the point where recombinant DNA approaches to generate novel structures are possible. Our understanding of how antibiotic pathways are regulated and integrated into central metabolism also provides the opportunity for strain manipulation to enhance productivity.

Anti-Bacterial Agents↗
PubMed1999

Macrophage-inflammatory protein-1alpha regulates preosteoclast differentiation in vitro.

A validated in vitro system was used to investigate the nature of osteoclast-inducing growth factors (OGF) present in fetal rat calvarial conditioned medium (RCCM). Evidence is presented here that macrophage inflammatory protein-1alpha (MIP-1alpha), a member of the C-C chemokine family, is an essential factor for the induction of osteoclast differentiation in this system. Specific polyclonal antibodies against MIP-1alpha significantly inhibited development of TRAP-positive osteoclast precursors and multinucleated osteoclasts induced by RCCM. Anti-MIP-1alpha antibody treatment was accompanied by an increase in the number of macrophage-like cells, suggesting that bone-derived MIP-1alpha is involved in the direction of preosteoclast formation with an inhibitory action on progenitor cell proliferation. Reverse-phase HPLC of RCCM resolved multiple fractions with OGF activity. OGF fractions separated at low acetonitrile (AcN) concentrations (</=15%) did not bind heparin and were not blocked in their bioactivity by the anti-MIP-1alpha antibody. However, OGF fractions eluted at higher AcN concentrations (30-70%) showed heparin-binding activity and were inhibited in their bioactivity by the anti-MIP-1alpha antibody. Western blotting of RCCM with the anti-MIP-1alpha antibody revealed a distinct band with a molecular mass of around 8-14 kDa corresponding to MIP-1alpha. Recombinant rat MIP-1alpha dose dependently stimulated formation of mononuclear osteoclast precursors with maximum stimulation at 50 ng/ml, though it could not fully mimic RCCM activity. These results identify MIP-1alpha as a candidate responsible for bone-derived OGF bioactivity and confirm that chemokines play an important role in the process of osteoclast recruitment and differentiation.

Animals↗
PubMed1998

The cell adhesion molecule C-CAM is a substrate for tissue transglutaminase.

C-CAM, a ubiquitously expressed cell adhesion molecule belonging to the carcinoembryonic antigen family, appears as two co-expressed isoforms, C-CAM-L and C-CAM-S, with different cytoplasmic domains, that can form homodimers in epithelial cells. In addition, C-CAM-L has been found in large molecular weight forms suggesting posttranslational, covalent modification. Here we have investigated the possibility that the cytoplasmic domain of C-CAM-L can act as a transglutaminase substrate. Glutathione S-transferase fusion proteins of the cytoplasmic domains of rat and mouse C-CAM-L as well as free cytoplasmic domains, released by thrombin cleavage from the fusion proteins, were converted into covalent dimers by tissue transglutaminase. These results demonstrate that the cytoplasmic domains of rat and mouse C-CAM-L are substrates for tissue transglutaminase, and lend support to the notion that higher molecular weight forms of C-CAM-L are formed by transglutaminase modification.

Adenosine Triphosphatases↗
PubMed1997

Viscosity discrimination: a comparison of an adaptive two-alternative forced-choice and an adjustment procedure.

Differential thresholds for viscosity were measured in ten subjects with the use of an adaptive two-alternative forced-choice procedure. An electromagnetic linear motor was connected to each wrist and the viscosity of the motors was under computer servo control. For each block of 50 trials the viscosity of one motor was fixed at a reference value which ranged from 4 to 512 N s m-1, and the viscosity of the other motor varied according to the subject's responses. On each trial subjects were required to indicate which motor had the greater viscosity and were given feedback of the correct response. By this procedure the Weber fraction for viscosity was calculated to be 19%, which is lower than the Weber fraction of 34% estimated by using the method of adjustment. The criterion used for determining the threshold differs in the two procedures (71% and 84% correct, respectively), and the results from the two studies were found to be consistent. They suggest that the Weber fraction for viscosity remains remarkably stable despite differences in the methods of measurement.

Adult↗
PubMed1996

Evidence for regulated dimerization of cell-cell adhesion molecule (C-CAM) in epithelial cells.

C-CAM is a Ca(2+)-independent cell adhesion molecule (CAM) belonging to the immunoglobulin superfamily. Addition of chemical cross-linkers to isolated rat liver plasma membranes, intact epithelial cells and purified preparations of C-CAM stabilized one major C-CAM-containing product whose apparent molecular mass was approximately twice that of the C-CAM monomer. The failure to detect additional proteins after cleavage of the cross-linked species demonstrated that C-CAM exists as non-covalently linked dimers both in solution and on the cell surface. Dimerization occurred to the same extent in adherent monolayers and in single cell populations, indicating that dimer formation was the result of cis-interactions within the membranes of individual cells. Using isoform-specific anti-peptide antibodies, both C-CAM1 and C-CAM2 were found to be involved in dimerization, forming predominantly homo-dimeric species. Both calmodulin and Ca2+ ionophore modulated the level of dimer formation, suggesting a role for regulated self-association in the functional activity of C-CAM.

Adenosine Triphosphatases↗
PubMed1996

The papers of Cicely Williams (1893-1992) in the Contemporary Medical Archives Centre at the Wellcome Institute.

The papers of Cicely Williams were given to the Contemporary Medical Archives Centre in 1993, and subsequently catalogued. They cover most aspects of her work in the field of maternal and child health, as practitioner, teacher and consultant, 1929-1989, especially in the developing world. The collection includes correspondence, reports, lectures, publications, photographs and sound recordings, and is of relevance to a wide range of issues related to maternal and child health and the development of appropriate local health care systems. In particular, it is of interest in relation to Williams' pioneering work on the identification of the childhood malnutrition disease kwashiorkor. The Cicely Williams papers complement many other collections held by the Contemporary Medical Archives Centre. This article focuses on two pre-war reports of her work in the Gold Coast and Singapore, which show the early development of ideas which are echoed throughout the rest of her papers.

Adolescent↗
PubMed1994

Differential regulation of C-CAM isoforms in epithelial cells.

C-CAM is a Ca(2+)-independent cell adhesion molecule (CAM) that mediates intercellular adhesion of isolated rat hepatocytes. It is widely distributed in epithelia, where its presence both at lateral cell borders and on apical cell surfaces suggests that it may have diverse biological functions. Two major isoforms, C-CAM1 and C-CAM2, which differ in the lengths of their cytoplasmic domains, have been identified. The lack of suitable in vitro systems has so far prevented a detailed study of the physiological role of C-CAM in epithelia. We now report on the identification, biochemical characterization and functional analysis of C-CAM isoforms in the established epithelial cell line NBT II, derived from a chemically induced carcinoma of rat bladder. C-CAM in NBT II cells is a 110-115 kDa cell surface glycoprotein located predominantly at sites of cell-cell contact but also present on the apical cell surface. Northern blotting analysis revealed the presence of both C-CAM1 and C-CAM2, with the major transcripts for both isoforms present within the 4.0 kb size range. The dissociation of NBT II cell colonies by anti-C-CAM antibodies indicated that at least one function of C-CAM in these cells is to mediate intercellular adhesion. The maintenance of extensive cell-cell contacts and the expression of C-CAM at the contact sites in cells grown in low Ca2+ medium suggested that, like its counterpart in hepatocytes, C-CAM in NBT II cells may be a Ca(2+)-independent cell-cell adhesion molecule. The co-localization and coordinate reorganization of both C-CAM and actin by anti-C-CAM antibodies indicated that these two proteins were associated and suggested that interactions with the cytoskeleton may be important for the regulation of C-CAM function. The specific upregulation of C-CAM1 in cells induced to undergo epithelial to mesenchymal-like transitions (EMT) by the serum substitute Ultroser G suggested that C-CAM isoforms are important modulators of the adhesive properties of these cells.

Actins↗
PubMed1992

Laminin chain assembly by triple and double stranded coiled-coil structures.

We have previously provided evidence that laminin assembly occurs by the specific interaction of the alpha-helical domains of the A, B1, and B2 chains, located within the long arm of the molecule (Hunter, I., Schulthess, T., Bruch, M., Beck, K., and Engel, J. (1990) Eur. J. Biochem. 188, 205-211). Recent evidence for noncoordinate synthesis of the laminin chains, and in particular, the absence of the 400-kDa A chain from laminins produced by a number of cell types, has led us to examine the molecular mechanism of laminin assembly using the isolated A and B1-B2 chains of laminin fragment E8. E8A shows little tendency to self-associate, and when renatured from urea forms globular structures with little detectable alpha-helix. In contrast, E8B1-B2 renatures to form rod-like molecules, 30 nm in length. The rod-like structure, high alpha-helix content, and sharp thermal transition indicate that they are double stranded coiled coils. When mixed in equimolar amounts, E8A and E8B1-B2 renature to form molecules which are biochemically and ultrastructurally indistinguishable from native E8. If E8A and E8B1-B2 are renatured separately and mixed at a 1:1 molar ratio, they also form E8 molecules. These results suggest a mechanism of laminin assembly which involves the formation of a double coiled-coil B1-B2 intermediate with which the A chain subsequently interacts to form a triple coiled-coil laminin molecule. In addition, our results indicate that isoforms consisting of the B1 and B2 chains only would form stable "laminin-like" structures.

Circular Dichroism↗