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Biomedical subjects

J Davies

Publications and source records attributed to J Davies.

At least 217 records · Page 12Linked to original sources
PubMed1996

Endogenous modulators of TNF and IL-1 response are under partial control of TNF in baboon bacteremia.

Tumor necrosis factor (TNF) and interleukin (IL)-1 are two cytokines for which naturally occurring inhibitors have been identified. The present study was undertaken to evaluate the extent to which scavenging of TNF in bacteremia attenuates the plasma levels of IL-1 receptor antagonist (IL-1ra) and soluble TNF receptors (sTNFR). Ten male baboons received 2 x 10(9) colony-forming units/kg live Escherichia coli over 2 h and were subjected to either placebo or anti-TNF antibody (anti-TNF Ab) treatment (1 mg/kg CDP571, Celltech, UK) 2 h before E. coli infusion (observation time: 72h). IL-1ra (range: 50-100 ng/ml) and sTNFR (range: 55kDa, 20-25 ng/ml; 75 kDa, 30-35 ng/ml) release was more sustained than that of IL-1 and TNF and was significantly attenuated by anti-TNF treatment, as were the circulating levels of IL-1, IL-8, and monocyte chemotactic peptide-1 (MCP-1) in the anti-TNF Ab group. We conclude that the increase in circulating natural cytokine modulators observed in nonhuman primate bacteremia is under the partial control of endogenous TNF because it was influenced by anti-TNF pretreatment. This attenuation is comparable to the anti-TNF effect on the chemokine MCP-1.

Animals↗
PubMed1996

Aspects on the interaction of Streptococcus pneumoniae and Haemophilus influenzae with human respiratory tract mucosa.

Haemophilus influenzae and Streptococcus pneumoniae are common causes of respiratory tract infections. H. influenzae attach to receptor epitopes in mucins and in epithelial cell membranes. Attachment is followed by an epithelial cell cytokine response. Secreted cytokines then initiate inflammation, upset the integrity of the mucosal barrier, and lead to disease. S. pneumoniae do not bind to mucins but attach to respiratory tract epithelial cells. Attachment is increased by viral infection of the epithelial cells. Unlike H. Influenzae, S. pneumoniae induce apoptosis in epithelial cells, thus disrupting the mucosal barrier. Attachment and persistence is counterbalanced by antiadhesive as well as bactericidal molecules in secretions such as human milk. These examples illustrate the balance between host defenses and microbial virulence as it has coevolved to maintain the health of the respiratory mucosa.

Adenovirus Infections, Human↗
PubMed1996

Severe small airways disease resistant to medical treatment in a child with cystic fibrosis.

At the age of 12, a child with cystic fibrosis developed severe small airways obstruction of unknown aetiology, in the absence of significant bronchiectasis. He remained resistant to medical treatment until, following an exacerbation of allergic bronchopulmonary aspergillosis 18 months later, he responded to high dose oral steroids. He now remains steroid-dependent, and suffering from multiple side-effects. Possible aetiology and further therapeutic strategies are discussed.

Aspergillosis, Allergic Bronchopulmonary↗
PubMed1996

Origins and evolution of antibiotic resistance.

The massive prescription of antibiotics and their non-regulated and extensive usage has resulted in the development of extensive antibiotic resistance in microorganisms; this has been of great clinical significance. Antibiotic resistance occurs not only by mutation of microbial genes which code for antibiotic uptake into cells or the binding sites for antibiotics, but mostly by the acquisition of heterologous resistance genes from external sources. The physical characteristics of the microbial community play a major role in gene exchange, but antimicrobial agents provide the selective pressure for the development of resistance and promote the transfer of resistance genes among bacteria. The control of antibiotic usage is essential to prevent the development of resistance to new antibiotics.

Bacteria↗
PubMed1996

Community health workers' response to violence against women.

This paper reports on a qualitative study of community health workers from a predominantly rural based region in Queensland. The purpose of this study was to determine the community health worker barriers to identification, assessment and intervention on the issue of violence against women. The qualitative research method comprised five structured focus group interviews with 28 community health workers using open-ended questions to explore their perceptions. Analysis of the focus group data revealed that community health workers expressed reluctance to become involved in cases of violence against women. The reasons they provided are grouped under three main themes: barriers to identification; barriers to assessment; and barriers to intervention. Training programs offered to rural community health workers need to be aware of the barriers to identifying, assessing and intervening in cases of violence against women that are highlighted by this study. Further studies are needed to assess the wider relevance of these findings to other groups of community health workers in rural and non-rural settings.

Attitude of Health Personnel↗
PubMed1995

An antibody VH domain with a lox-Cre site integrated into its coding region: bacterial recombination within a single polypeptide chain.

Bacterial lox-Cre recombination within a single antibody VH domain was achieved through integration of a loxP site into its coding sequence. The 5' half of the VH gene, in which the H2 loop was replaced by a mutant loxP site, was fused to geneIII in an 'acceptor' fd-phage vector containing also a wild type loxP site. With a 'donor' plasmid vector harbouring the 3' half of the VH gene flanked by the same, differing loxP sites it recombined into a full-length VH with the loxP site-H2 loop. This VH was purified from bacterial periplasm, where it folded into a typical immunoglobulin domain. The system allows the generation of large VH repertoires using lox-Cre recombination.

Amino Acid Sequence↗
PubMed1995

Euthanasia.

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Euthanasia↗
PubMed1995

Scanning tunnelling microscopy and dynamic contact angle studies of the effects of partial denaturation on immunoassay solid phase antibody.

A range of partial denaturation antibody pre-treatments that affect immunoassay performance have been evaluated. Monoclonal anti-ferritin antibody was either partially denatured by heat, urea or pH pre-treatment or left untreated and then passively adsorbed to polystyrene microtiter wells. The adsorption characteristics and functionality of the different surfaces produced have been evaluated by dynamic contact angle (DCA) analysis and scanning tunnelling microscopy (STM) imaging respectively. The DCA data show that the effect of partial denaturation is to change the wetting characteristics of the antibody surfaces, while, in addition, STM imaging reveals marked effects seen in the aggregation properties of the denatured antibodies.

Adsorption↗
PubMed1995

The structure of U17 isolated from Streptomyces clavuligerus and its properties as an antioxidant thiol.

The predominant low-molecular-mass thiol produced by streptomycetes is a cysteine derivative previously designated as U17 [Newton, G. L., Fahey, R. C., Cohen, G. & Aharonowitz, Y. (1993) J. Bacteriol. 175, 2734-2742]. In this study we report the elucidation of the structure of the monobromobimane derivative of U17, which establishes the structure of U17 as 2-(N-acetylcysteinyl)amido-2-deoxy-alpha-D-glucopyranosyl-myo-inositol. The presence of the N-acetylcysteine moiety was indicated by formation of N-acetylcysteine-monobromobimane during acid hydrolysis of the monobromobimane derivative of U17. Complete hydrolysis released 1 mol glucosamine/mol cysteine as determined by carbohydrate and amino acid analysis. High-resolution mass spectral analysis gave a precise mass consistent with the molecular formula C27H40N4O14S. Analysis of 13C-NMR, one-dimensional 1H-NMR and two-dimensional NMR experiments identified the remaining C6H12O6 moiety as myo-inositol, confirmed the presence of N-acetylcysteine and glucosamine, and established the connectivity of the components. Two chemical properties of this novel thiol make it suitable as an intracellular storage form of cysteine and as an antioxidant thiol. First, it undergoes heavy-metal-ion catalyzed autoxidation at a rate dramatically lower than that for cysteine and markedly lower than that for glutathione or N-acetylcysteine. Secondly, the alpha-(1-->1) glycosidic link between glucosamine and myo-inositol is resistant to acid hydrolysis, hydrolysing at a rate comparable to that of the two amide bonds in the molecule.

Antioxidants↗
PubMed1995

Expression of the zinc-finger gene PLZF at rhombomere boundaries in the vertebrate hindbrain.

To investigate the potential biological role(s) of the PLZF gene, discovered as a fusion with the RARA locus in a patient with acute promyelocytic leukemia harboring a t(11;17) chromosomal translocation, we have isolated its murine homologue (mPLZF) and studied its patterns of developmental expression. The levels of mPLZF mRNAs increased perinatally in the liver, heart, and kidney, but with the exception of the heart, they were either absent or very low in the adult tissues. In situ analysis of mPLZF expression in mouse embryos between 7.0 and 10.5 days of development revealed that mPLZF mRNAs and proteins were coexpressed in spatially restricted and temporally dynamic patterns in the central nervous system. In the hindbrain region, a segmental pattern of expression correlated with the development of the rhombomeres. From 9.0 days of development, starting first in rhombomeres 3 and 5, there was an ordered down-regulation of expression in the center of each rhombomere, so that 1 day later elevated levels of mPLZF mRNAs and proteins were restricted to cells surrounding the rhombomeric boundaries. The chicken homologue of the PLZF gene, which we have also cloned, demonstrated a similar segmental pattern of expression in the hindbrain. To date, PLZF represents the only example of a transcription factor with elevated expression at rhombomeric boundaries. The high degree of evolutionary conservation between the patterns of PLZF expression during mammalian and avian central nervous system development suggests that it has an important functional role in the regionalization of the vertebrate hindbrain, potentially regulating boundary cell interactions.

Amino Acid Sequence↗
PubMed1995

Biochemical diagnosis of myocardial infarction within the thrombolytic time window.

A demonstrated temporal change in the total activity of creatine kinase or mass measurement of the cardio-specific isoenzyme creatine kinase MB is currently used as the biochemical diagnosis of myocardial infarction. The isoforms of creatine kinase MB may provide an earlier diagnostic marker of myocardial infarction than the currently available biochemical markers. We compare the sensitivity and specificity of total creatine kinase activity, creatine kinase MB mass measurement and the muscle and heart specific isoforms of creatine kinase in the early diagnosis of myocardial infarction. Using current methodologies, neither CK isoform offered any advantage over CK mass measurement as an early marker of ischaemic myocardial damage.

Clinical Enzyme Tests↗
PubMed1995

Essential and neural transcripts from the Drosophila shaking-B locus are differentially expressed in the embryonic mesoderm and pupal nervous system.

The shaking-B gene of Drosophila encodes two functions: one specifically neural and the other required for viability. Flies carrying neural mutations show a range of defects, the best characterized of which is a disruption of some synapses in the giant fibre system, while mutations in the essential function cause animals to die as first instar larvae. We have characterised an essential transcript from this locus and show that mutant lesions underlying two lethal shaking-B alleles map to its coding sequence. We also propose a new model for the topologies of Shaking-B proteins and their relatives. Essential shaking-B transcripts are found in embryonic mesodermal derivatives, while during metamorphosis both essential and neural transcripts are dynamically expressed in the pupal nervous system. Although the expression patterns of these transcripts overlap in many cells, only the neural form is expressed in the giant fibre cell bodies and the lamina and medulla of the optic lobes. This observation correlates with the phenotypes of mutations which disrupt the coding region of this neural transcript. On the basis of the expression patterns of shaking-B transcripts and the phenotypes conferred by mutations of shaking-B and homologous genes, we suggest that Shaking-B proteins and their homologues may be involved in the organisation of cellular membranes.

Alleles↗
PubMed1995

Backbone assignment, secondary structure and protein A binding of an isolated, human antibody VH domain.

Antibody heavy chain variable domains (VH) lacking their light chain (VL) partner are prime candidates for the design of minimum-size immunoreagents. To obtain structural information about isolated VH domains, a human VH was labelled with 15N or doubly labelled with both 15N and 13C and was studied by heteronuclear nuclear magnetic resonance spectroscopy. Most (90%) of the 1H and 15N main-chain signals were assigned through two-dimensional TOCSY and NOESY experiments on the unlabelled VH and three-dimensional heteronuclear multiple quantum correlation TOCSY and NOESY experiments on the 15N-labelled VH. Four short stretches of the polypeptide chain could only be assigned on the basis of three-dimensional HNCA and HN(CO)CA experiments on the 13C-/15N-labelled protein. Long-range interstrand backbone NOEs suggest the presence of two adjacent beta-sheets formed by altogether nine antiparallel beta-strands. 3JNHC alpha H coupling constants and the location of slowly exchanging backbone amides support this interpretation. The secondary structure of the isolated VH is identical to that of heavy chain variable domains in intact antibodies, where VH domains are packed against a VL domain. The backbone assignments of the VH made it possible to locate its Protein A binding site. Chemical shift movements after complexing with the IgG binding fragment of Protein A indicate binding through one of the two beta-sheets of the VH. This beta-sheet is solvent exposed in intact antibodies. The Protein A binding site obviously differs from that on the Fc portion of immunoglobulins and is unique to members of the human VHIII gene subgroup.

Amino Acid Sequence↗
PubMed1995

Antibody VH domains as small recognition units.

To develop immunoglobulin based recognition units of minimum size, a human heavy chain variable domain (VH) was designed for selection of phage displayed VH. Non-specific binding of the VH through its interface for the light chain variable domain (VL) was prevented through three mutations (G44E, L45R and W47G) in this interface. These mutations were introduced to mimic camelid antibody heavy chains naturally devoid of light chain partners. The third hypervariable loop of the modified VH was then randomised to yield a repertoire of 2 x 10(8) independent clones, which was displayed on phage and selected through antigen binding. VH clones specific for hapten and protein antigens were isolated. Soluble VH was expressed with an isoleucine residue at position 47 to improve expression and stability compared to VH containing a glycine residue at this position, which however was preferable for phage selection. Affinities of soluble VH for hapten were between 100 nM and 400 nM. The VH domains were highly specific, stable and well expressed in Escherichia coli. These positive biophysical properties and their small size make them attractive for biotechnological applications.

Amino Acid Sequence↗
PubMed1995

A placental clock controlling the length of human pregnancy.

We report the existence of a 'placental clock', which is active from an early stage in human pregnancy and determines the length of gestation and the timing of parturition and delivery. Using a prospective, longitudinal cohort study of 485 pregnant women we have demonstrated that placental secretion of corticotropin-releasing hormone (CRH) is a marker of this process and that measurement of the maternal plasma CRH concentration as early as 16-20 weeks of gestation identifies groups of women who are destined to experience normal term, preterm or post-term delivery. Further, we report that the exponential rise in maternal plasma CRH concentrations with advancing pregnancy is associated with a concomitant fall in concentrations of the specific CRH binding protein in late pregnancy, leading to a rapid increase in circulating levels of bioavailable CRH at a time that coincides with the onset of parturition, suggesting that CRH may act directly as a trigger for parturition in humans.

Biological Clocks↗