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Biomedical subjects

J Davies

Publications and source records attributed to J Davies.

At least 19 recordsLinked to original sources
PubMed1992

Cortically evoked excitatory synaptic transmission in the cat red nucleus is antagonised by D-AP5 but not by D-AP7.

Extracellular recordings were made from magnocellular red nucleus neurons (mRN) in alpha-chloralose (50 mg/kg, iv.) anaesthetised cats. Iontophoretically applied N-methyl-D-aspartate (NMDA) excited the neuronal firing which was antagonised by 4 selective NMDA receptor antagonists: 2-amino-5-phosphonopentanoate (AP5), 2-amino-7-phosphonoheptanoate (AP7), RS-4-(phosphonomethyl) piperazine-2-carboxylic acid (PMPC) and R-4-(3-phosphonopropyl) piperazine-2-carboxylic acid (CPP), whereas AMPA responses were uneffected. Monosynaptic excitatory responses were produced by stimulation of the sensorimotor cortex. These responses were reduced and often abolished by AP5 and PMPC but not by AP7 or CPP. It is postulated that two NMDA receptor subtypes exist on mRN neurones.

2-Amino-5-phosphonovalerate↗
PubMed1992

Non-competitive inhibition of group I intron RNA self-splicing by aminoglycoside antibiotics.

Aminoglycoside antibiotics inhibit self-splicing of group I intron RNA in vitro at concentrations as low as 10(-6) M. The sites of interaction and the mechanism of inhibition have yet to be determined. A comparative study of inhibition by different 2-deoxystreptamine analogues reveals structural features of the aminoglycoside antibiotics required for their interaction and effect on group I introns. Complete antibiotic inhibition of the two steps of splicing was not reversed at high concentrations of guanosine, indicating a non-competitive inhibition. A mutant group I intron in which the conserved guanosine nucleotide of the G-binding site had been replaced by an adenosine, was sensitive to the antibiotics providing direct evidence that the antibiotics do not interact with the G-binding site in the same way as the guanine base. In addition kinetic analyses of the self-splicing process in the presence of antibiotic inhibitors supported a non-competitive mechanism of the mixed type for inhibition of the ribozyme.

Aminoglycosides↗
PubMed1992

Use of antibody fragments in immunoaffinity chromatography. Comparison of FV fragments, VH fragments and paralog peptides.

Some new antibody fragments have recently been described: FV fragments (Mr 25,000), VH fragments or "dAbs" (12,500) and paralog peptides (1000-2000). FV fragments, VH fragments and a paralog peptide that had been derived from a parent antibody with a specificity for hen lysozyme were produced. All three reagents were immobilized on Sepharose and evaluated for their ability to recover hen lysozyme from "spiked" serum and to separate hen lysozyme from turkey lysozyme. The FV column had excellent specificity for hen lysozyme, the VH column had significantly reduced specificity and the paralog peptide column did not bind lysozyme at all.

Animals↗
PubMed1992

Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy.

Myotonic dystrophy (DM) is the most common form of adult muscular dystrophy, with a prevalence of 2-14 per 100,000 individuals. The disease is characterized by progressive muscle weakness and sustained muscle contraction, often with a wide range of accompanying symptoms. The age at onset and severity of the disease show extreme variation, both within and between families. Despite its clinical variability, this dominant condition segregates as a single locus at chromosome 19q13.3 in every population studied. It is flanked by the tightly linked genetic markers ERCC1 proximally and D19S51 distally; these define the DM critical region. We report the isolation of an expressed sequence from this region which detects a DNA fragment that is larger in affected individuals than in normal siblings or unaffected controls. The size of this fragment varies between affected siblings, and increases in size through generations in parallel with increasing severity of the disease. We postulate that this unstable DNA sequence is the molecular feature that underlies DM.

Chromosomes, Human, Pair 19↗
PubMed1992

Evolution of secondary metabolite production: potential roles for antibiotics as prebiotic effectors of catalytic RNA reactions.

It has been proposed that organic molecules related to known secondary metabolites have existed since the beginning of biochemical evolution and were present in primordial soups. Under primitive earth conditions certain of these molecules may have played roles as effectors in prebiotic reactions, especially those involving catalytic RNA (ribozymes). We demonstrate that a number of antibiotic-related secondary metabolites bind to group I introns and either inhibit splicing reactions or promote the formation of intron oligomers. This is consistent with the functional co-evolution of catalytic RNA and secondary metabolites as antibiotic inhibitors of translation, and supports the notion of an evolutionary relationship between group I introns and ribosomal RNA.

Anti-Bacterial Agents↗
PubMed1992

A fractographic investigation of PMMA bone cement focusing on the relationship between porosity reduction and increased fatigue life.

Fracture surfaces of both monotonic and fatigue loaded bone cement samples were examined to investigate the fractographic characteristics of PMMA. Classic cleavage step river patterns were observed on all monotonically loaded samples, running downstream in the direction of crack propagation. All fatigue cracks initiated at internal pores and the direction of crack propagation of many cracks was discernible. Porosity, pore size, and pore size distribution were found to affect the crack initiation and fatigue behavior of bone cement. Statistical analysis revealed a strong negative correlation between two-dimensional porosity present on the fracture surfaces and the cycles to failure. The fractographic observations of these fatigue samples elucidate one reason why porosity reduction by centrifugation or vacuum mixing increases the fatigue life of PMMA bone cement.

Biocompatible Materials↗
PubMed1992

In vivo model for evaluation of species-specific virus vaccines.

It is difficult to evaluate the protective efficacy of species-specific viruses of humans and expensive companion animals where there is no non-human animal model. This study describes an in vivo model system which allows simultaneous operation of humoral, cell-mediated, interferon-like or other unidentified immunological defence mechanisms. There was evidence of in vivo inactivation of both enveloped and unenveloped DNA and RNA viruses including retrovirus mouse sarcoma virus/mouse leukaemia virus as evaluated by assay of the enzyme reverse transcriptase. This model will allow examination of vaccine efficacy in immunocompetent host animals while avoiding morbidity and/or mortality from virus infection in these animals.

Animals↗
PubMed1992

Characterization of a YAC and cosmid contig containing markers tightly linked to the myotonic dystrophy locus on chromosome 19.

Myotonic dystrophy (DM) is caused by a defect in an unknown gene that maps to 19q13.3, flanked by the tightly linked markers ERCC1 on the proximal side and D19S51 on the distal side. We report the isolation and characterization of overlapping YAC and cosmid clones around D19S51 for the construction of a physical map around this locus. The resulting contig contains the markers D19S51 and D19S62 (another new marker tightly linked to the DM locus) and the distal breakpoint of a radiation hybrid cell line used in the physical mapping of the DM region. We have compared the restriction maps of the YACs and cosmids with that of the genome to investigate the fidelity of these clones.

Base Sequence↗
PubMed1992

Transcriptional mapping of the promoter of the aminoglycoside acetyltransferase gene (aacC9) of neomycin-producing Micromonospora chalcea.

We have studied the promoter of the gene encoding aminoglycoside acetyltransferase (aacC9) in neomycin-producing Micromonospora chalcea. S1 nuclease mapping showed that the transcription initiation point of this gene is at the translation start point, with no evidence of a conventional ribosome-binding site. The aac of paromycin-producing Streptomyces rimosus forma paromomycinus shows the same characteristic; there is no homology in the promoter regions of the two genes, whereas the coding sequences are very similar.

Acetyltransferases↗
PubMed1992

The pulmonary autograft--a permanent aortic valve.

Between 1969 and 1991, 339 patients had an aortic valve replacement with their own living pulmonary valve at the National Heart Hospital, Guy's Hospital and the Harley Street Clinic, London. The longest follow-up is 24 years and cumulative follow-up is 3774 patient-years. No form of anticoagulation was used and there were no emboli. There were 25 hospital deaths (7.4%) but only 1 death since 1976. Late deaths occurred in 38 patients mainly from technical mal-insertion. Bacterial endocarditis occurred in 11 patients. Thirty-eight patients were re-operated upon and account for 15 of the late deaths. Freedom from re-operation was 85% and the actuarial patient survival was 80% at 20 years. There has been no evidence of primary tissue degeneration and explanted valves showed normal cusp cellularity. Accumulating evidence suggests that the cusps not only survive permanently but can grow with the patient making the operation ideal for children.

Adolescent↗
PubMed1992

Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype.

Myotonic dystrophy (DM) is associated with the expansion and instability of a trinucleotide (CTG) repeat in a sequence encoding a cAMP-dependent protein kinase. The normal copy number of 5-35 repeats is exceeded in DM patients, with the size of the expansion broadly correlating with the severity of symptoms experienced. In most families reported, the unstable DNA sequence has increased in size on transmission to affected offspring, thereby providing a molecular explanation for the phenomenon of anticipation in DM, i.e. an increase in the severity of symptoms associated with an earlier age at onset of the disease in successive generations of a family. Here we present the first reported case of a family where the transmission of the affected chromosome from father to son is accompanied by a reduction in the size of the triplet expansion, such that it falls within the normal range. As the son remains asymptomatic, this type of molecular event may provide an explanation for the incomplete penetrance of the disease phenotype reported for this disorder. The implications for genetic counselling of DM families and the mechanistic considerations of the trinucleotide instability are discussed.

Adult↗
PubMed1992

Isolation and analysis of IS6120, a new insertion sequence from Mycobacterium smegmatis.

Insertion sequence IS6120 from Mycobacterium smegmatis was identified by its ability to transpose into different sites in the lambda repressor gene, cl857, carried on an Escherichia coli/mycobacteria shuttle plasmid. IS6120 is a novel 1.5 kb insertion sequence, which has 24-bp imperfect terminal inverted repeats and generates 9-bp duplications of the target DNA following insertion. IS6120 is present in at least three copies in M. smegmatis but was not found in other species, including Mycobacterium tuberculosis. Nucleotide sequence analysis revealed that IS6120 contains two open reading frames, one of which encodes a putative transposase with similarities to those found in IS256 from Staphylococcus aureus, IST2 from Thiobacillus ferrooxidans, and ISRm3 from Rhizobium meliloti. The fact that IS6120 does not recognize a consensus target sequence for insertion and has no homologous sequences in the other strains studied makes IS6120 useful for transposon mutagenesis in mycobacteria.

Amino Acid Sequence↗
PubMed1992

Comparison of the myotonic dystrophy associated CTG repeat in European and Japanese populations.

Gene amplification using polymerase chain reaction (PCR) was carried out on DNA samples from a total of 92 normal subjects and 52 subjects with myotonic dystrophy (DM) from European and Japanese populations, to determine the copy number of the CTG repeat associated with DM for each group. In the two populations, the number of repeats on normal chromosomes only were compared, as CTG copy number on DM chromosomes was difficult to determine by PCR alone. In this study, normal chromosomes were found which had as many as 35 copies of the repeat, which is larger than the normal range reported previously but still does not overlap with the repeat number associated with DM pathology, which is at least 50 copies. Using data from normal chromosomes from unrelated subjects, the frequencies of five, 11, and 13 copies of the CTG repeat were found to be significantly different between the two populations, with five and 11 copies more commonly seen in the European population and 13 copies in the Japanese population. This difference may be the result of natural divergence of the normal chromosomes between the population groups.

Alleles↗
PubMed1992

Creatine kinase isoforms: investigation of inhibitors of in vitro degradation and establishment of a reference range.

The in vitro stability of creatine kinase isoforms was examined by separation with high voltage electrophoresis. The effect of inhibitors of carboxypeptidase was evaluated. Preservation of samples is essential to inhibit in vitro changes in isoform pattern. EDTA at a final concentration of 15 mmol/L is recommended. Using appropriately preserved samples, normal reference intervals for the MM isoforms have been established.

Carboxypeptidases↗
PubMed1992

Hyperdynamic sepsis in baboons: II. Relation of organ damage to severity of sepsis evaluated by a newly developed morphological scoring system.

The purpose of our study was to set up a baboon hyperdynamic sepsis model with live bacteria administration, which produces within 8 hr an organ failure comparable to human pathological conditions. Twelve adult male baboons were instrumented and studied for 8 hr under pentobarbital (2-3 mg/kg BW/hr) anesthesia breathing spontaneously. The animals were divided into two groups: 1) Live Escherichia coli were infused intravenously at a dose of 1.0-2.0 x 10(10) CFU/kg BW over 8 hr; 2) Live E. coli were infused i.v. at a dose of 5 x 10(8) CFU/kg BW over 2 hr. Organ damage was monitored by a newly developed scoring system. Organ damage was clearly dependent on the concentration of the bacterial challenge. Bacterial challenge at a dosage of 5.0 x 10(8) produces insignificant hemodynamic effects, while the 1.0-2.0 x 10(10) animals demonstrated massive hemodynamic alterations and needed much higher fluid support. The higher E. coli dosage was associated with an overwhelming organ damage seen, e.g., from the lung weight (12 g/kg BW vs. 9.6 g/kg BW with the lower dosage) or from the organ failure score, which is based on macroscopic pathology, histological data and organ weight. The percentage of animals with one, two, or three organ failures (organ failure score > or = 2) was higher in baboons with the higher dosage/kg BW. Therefore, we believe that the less severe organ damage in the acute phase after 8 hr with live bacteria 5 x 10(8) CFU/kg BW infusion over 2 hr is better to monitor the efficacy of newly developed therapeutic regimens, since in another set of experiments this model still produces lethal organ damage (80%) in a subchronic setting over 72 hr.

Adrenal Glands↗