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C H Jones

Publications and source records attributed to C H Jones.

At least 37 records · Page 2Linked to original sources
PubMed1997

Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination.

Virtually all uropathogenic strains of Escherichia coli, the primary cause of cystitis, assemble adhesive surface organelles called type 1 pili that contain the FimH adhesin. Sera from animals vaccinated with candidate FimH vaccines inhibited uropathogenic E. coli from binding to human bladder cells in vitro. Immunization with FimH reduced in vivo colonization of the bladder mucosa by more than 99 percent in a murine cystitis model, and immunoglobulin G to FimH was detected in urinary samples from protected mice. Furthermore, passive systemic administration of immune sera to FimH also resulted in reduced bladder colonization by uropathogenic E. coli. This approach may represent a means of preventing recurrent and acute infections of the urogenital mucosa.

Adhesins, Bacterial↗
PubMed1997

Serum albumin and survival in CAPD patients: the implications of concentration trends over time.

HYPOTHESIS: Trends in serum albumin concentration over time provide a better prediction of clinical outcome in CAPD patients than a single mean value. METHODS: This was a retrospective review of outcome at 36 months in 225 adult CAPD patients. Mean serum albumin was determined for the first (SA1) and second (SA2) 6 months of treatment and patients grouped according to SA1 (group I, > 37; group II, 34-37; group III, < 34 g/l) and according to the change in serum albumin (delta SA) between the first and second 6 months (increased/static or decreased). Patient (PS) and technique (TS) survival were determined by Kaplan-Meier survival analysis. The effect of SA1 and delta SA on survival were determined in a multivariate Cox regression analysis model that included age and presence or absence of a systemic disease. RESULTS: By SA1 group, PS and TS survival at 36 months were 94 and 76% (group I), 64 and 53% (group II) and 70 and 52% (group III). If delta SA increased/remained static, then SA1 did not predict PS (group I, 100%; group II, 96%; group III, 74%; P = n.s.) or TS (group I, 72%; group II, 63%; group III, 65%; P = n.s.). If delta SA decreased, PS was worse in groups II and III, both as compared to group I (PS group I, 88%; group II, 52%; group III, 34%; P = 0.02) and as compared to the groups II and III when delta SA increased (PS group II, 74 vs 52%, P = 0.05; group III, 82 vs 34%, P = 0.005) The same trend was seen for TS. In the multivariate Cox regression model, age, direction of change in serum albumin, and presence of a multisystem disease were significant predictors of survival, whereas SA1 was not. CONCLUSION: Early hypoalbuminaemia in CAPD only predicts a worse patient and technique survival if mean serum albumin decreases further from the first to second 6 months of dialysis therapy. Change in serum albumin between the first and second 6 months of CAPD and the mean serum albumin over the first 6 months together offer better discrimination of outcome than either alone.

Adult↗
PubMed1997

Assessment of nutritional status in CAPD patients: serum albumin is not a useful measure.

INTRODUCTION: In CAPD patients serum albumin is frequently used as an index of nutritional status, although it is recognized that hypoalbuminaemia may be caused by many factors. We have further examined the relationship between serum albumin and nutrition. METHODS: Nutritional status was assessed by biochemistry, anthropometry, mid-arm muscle circumference, muscle strength (hand grip and back), and lean body mass (from anthropometry, creatinine kinetics and bioimpedance) in a group of 76 stable CAPD patients. Correlations between biochemical and nutritional parameters were sought and data were compared between patient groups defined by serum albumin (> or = 37 vs < 37 g/l on two occasions 2 months apart) and separately according to subjective global assessment score (normal nutrition, A vs mild to moderate, B, and severe, C, malnutrition). RESULTS: In patients with a low SGA score, actual body weight, body mass index, mid-arm muscle circumference, lean body mass, subscapular skinfold thickness, hand grip strength (males and females) and iliac and triceps skinfold thicknesses and back strength (females only) were all significantly less than in patients with a normal SGA score. In contrast, none of these variables differed in either gender when patients were compared according to serum albumin. Serum albumin was correlated with serum creatinine (r = 0.45, P = 0.01), daily urine protein excretion (r = -0.42, P = 0.02) and uncorrected weekly creatinine clearance (r = -0.39) in females, but not with any index of body composition in either gender. CONCLUSION: Whilst SGA identified a patient group with significantly abnormal body mass, muscle mass and muscle strength, serum albumin did not. Serum albumin is not a useful marker of malnutrition in stable patients on CAPD.

Adolescent↗
PubMed1996

Development of pilus organelle subassemblies in vitro depends on chaperone uncapping of a beta zipper.

The major subassemblies of virulence-associated P pili, the pilus rod (comprised of PapA) and tip fibrillum (comprised of PapE), were reconstituted from purified chaperone-subunit complexes in vitro. Subunits are held in assembly-competent conformations in chaperone-subunit complexes prior to their assembly into mature pili. The PapD chaperone binds, in part, to a conserved motif present at the C terminus of the subunits via a beta zippering interaction. Amino acid residues in this conserved motif were also found to be essential for subunit-subunit interactions necessary for the formation of pili, thus revealing a molecular mechanism whereby the PapD chaperone may prevent premature subunit-subunit interactions in the periplasm. Uncapping of the chaperone-protected C terminus of PapA and PapE was mimicked in vitro by freeze-thaw techniques and resulted in the formation of pilus rods and tip fibrillae, respectively. A mutation in the leading edge of the beta zipper of PapA produces pilus rods with an altered helical symmetry and azimuthal disorder. This change in the number of subunits per turn of the helix most likely reflects involvement of the leading edge of the beta zipper in forming a right-handed helical cylinder. Organelle development is a fundamental process in all living cells, and these studies shed new light on how immunoglobulin-like chaperones govern the formation of virulence-associated organelles in pathogenic bacteria.

Bacterial Proteins↗
PubMed1996

Flosequinan in chronic heart failure: how is exercise capacity improved?

OBJECTIVE: Diuretics, angiotensin converting enzyme inhibitors and digoxin have become "standard" triple therapy for many patients with chronic cardiac failure. Flosequinan increases exercise duration and improves symptoms when added to standard triple therapy. Despite intensive study, the clinical pharmacology of flosequinan remains uncertain. SETTING: The University Hospital of Wales, a Regional Cardiac Centre. PATIENTS: Twenty four patients with chronic heart failure who remained symptomatic despite standard therapy including ACE inhibitors. METHODS: A double-blind placebo-controlled parallel group study of 100 mg daily of flosequinan. We measured changes in exercise duration using cardiorespiratory exercise testing and changes in large artery distensibility using Doppler ultrasound. RESULTS: Exercise duration after 8 weeks flosequinan treatment was significantly greater than following placebo treatment. The flosequinan-related increase in exercise duration (+14%) was associated with a significant reduction in VE/VCO2 slope (-16%). Brachial-radial pulse wave velocities were unaltered by flosequinan treatment. CONCLUSIONS: Our results confirm that flosequinan improves exercise duration in patients with chronic heart failure. They suggest that this observed beneficial effect is independent of any change in large artery distensibility and that in the presence of ACE inhibitors, this improvement may be independent of any vasodilating action of flosequinan. Although this study confirms the beneficial symptomatic effects of flosequinan in chronic cardiac failure, clinical trials have subsequently demonstrated an overall increase in mortality in patients treated with 100 mg flosequinan daily. This has resulted in the withdrawal of flosequinan from routine clinical use.

Adult↗
PubMed1995

FimH adhesin of type 1 pili is assembled into a fibrillar tip structure in the Enterobacteriaceae.

Type 1 pili are heteropolymeric mannosebinding fibers produced by all members of the Enterobacteriaceae family. The bulk of the fiber is composed of FimA. Two macromolecular complexes responsible for mediating an interaction with mannose-containing receptors were purified from fimA- Escherichia coli by mannose affinity chromatography and ion-exchange chromatography. One complex contained only the mannose-binding adhesin, FimH, associated with FimG, a minor component of the type 1 pilus. In the other complex the FimG-FimH moiety was loosely associated with a chaperone-minor subunit complex (FimC-FimF), possibly representing an intermediate in tip fibrilla assembly. The FimC chaperone has also been shown to form a preassembly complex with FimH that has been purified and characterized previously. Purified FimC did not bind to the FimG-FimH complex but did recognize FimH dissociated from the FimG-FimH complex. Quick-freeze deep-etch electron microscopy revealed that the FimG-FimH complex had a thin fibrillar architecture. High-resolution electron microscopy of type 1 pili revealed that a 16-nm fibrillar tip structure with an architecture identical to that of the FimG-FimH complex was joined end-to-end to the pilus rod. In a fimH- deletion mutant, the tip fibrillae joined to pilus rods were approximately 3 nm in length. The full-length tip fibrilla was restored by complementation with the fimH gene in trans. The bipartite nature of the type 1 pilus was also demonstrated on pili purified from clinical isolates of members of the Enterobacteriaceae family arguing that it is a conserved feature of the type 1 pilus.

Adhesins, Escherichia coli↗
PubMed1995

HDR microSelectron quality-assurance studies using a well-type ion chamber.

A modified Standard Imaging HDR 1000 re-entrant ion chamber has been used with an NE 2570/1 electrometer as part of a quality-assurance programme for checking 192Ir source strengths and for source localization studies. The chamber measurements correlate well with in-air calibration measurements made over a three-month source-decay period; the maximum discrepancy between the in-air measurement and the re-entrant chamber measurement was 0.9%. The source position may be determined with an uncertainty of lower than 0.5 mm. The reproducibility of measurements made with each of four electrometers used with the reentrant ion chamber was typically 0.1% (1 sigma).

Brachytherapy↗
PubMed1995

Molecular dissection of PapD interaction with PapG reveals two chaperone-binding sites.

P pili are composite adhesive fibres that allow uropathogenic Escherichia coli to gain a foothold in the host by binding to receptors present on the uroepithelium via the adhesin PapG. The assembly of P pili requires a periplasmic chaperone, PapD, that has an immunoglobulin-like three-dimensional structure. PapD-subunit complex formation involves a conserved anchoring mechanism in the chaperone cleft and a 'molecular zippering' to the extreme C-terminus of pilus subunits. A chaperone-binding assay was developed using fusions of the C-terminus of PapG to maltose-binding protein (MBP/G fusions) to investigate whether chaperone-subunit complex formation requires additional interactions. PapD bound strongly to an MBP/G fusion containing the C-terminal 140 amino acids of PapG (MBP/G175-314) but only weakly to the MBP/G234-314 fusion containing 81 C-terminal residues, arguing that the region between residues 175-234 contains additional information that is required for strong PapD-PapG interactions. PapD was shown to interact with a PapG C-terminal truncate containing residues 1-198 but not a truncate containing residues 1-145, suggesting the presence of a second, independent PapD interactive site. Four peptides overlapping the second site region were tested for binding to PapD in vitro to further delineate this motif. Only one of the peptides synthesized was recognized by PapD. The MBP/G fusion containing both binding sites formed a tight complex with PapD in vivo and inhibited pilus assembly by preventing chaperone-subunit complex formation.

ATP-Binding Cassette Transporters↗
PubMed1993

FimC is a periplasmic PapD-like chaperone that directs assembly of type 1 pili in bacteria.

Biogenesis of the type 1 pilus fiber in Escherichia coli requires the product of the fimC locus. We have demonstrated that FimC is a member of the periplasmic chaperone family. The deduced primary sequence of FimC shows a high degree of homology to PapD and fits well with the derived consensus sequence for periplasmic chaperones, predicting that it has an immunoglobulin-like topology. The chaperone activity of FimC was demonstrated by purifying a complex that FimC forms with the FimH adhesion. A fimC1 null allele could be complemented by the prototype member of the chaperone superfamily, PapD, resulting in the production of adhesive type 1 pili. The general mechanism of action of members of the chaperone superfamily was demonstrated by showing that the ability of PapD to assemble both P and type 1 pili was dependent on an invariant arginine residue (Arg-8), which forms part of a conserved subunit binding site in the cleft of PapD. We suggest that the conserved cleft is a subunit binding feature of all members of this protein family. These studies point out the general strategies used by Gram-negative bacteria to assemble adhesins into pilus fibers, allowing them to promote attachment to eukaryotic receptors.

Adhesins, Escherichia coli↗
PubMed1993

PapD and superfamily of periplasmic immunoglobulin-like pilus chaperones.

The formation of a P pilus requires a molecular chaperone in the periplasm and a molecular usher in the outer membrane. Each pilus is composed of six different types of proteins that are assembled into a composite fiber in a defined order. The correct folding of subunits into domains that can serve as assembly modules requires an association with the periplasmic chaperone. PapD is the prototype member of the family of bacterial pilus chaperones that have a three-dimensional structure consistent with an immunoglobulin fold. In general, proteins with an immunoglobulin fold structure have molecular recognition functions in eukaryotic cells that are often integrated with effector functions. PapD has also a recognition function, binding nascently translocated pilus subunits and maintaining them in assembly-competent conformations. The association of the chaperone with the subunit triggers the targeting of the latter to an outer membrane usher. The usher serves as a molecular gatekeeper, allowing the ordered incorporation of the pilus subunits into the pilus structure from the periplasmic chaperone complexes. The two immunoglobulin-like domains of PapD are oriented to form a cleft that contains the subunit binding site. This is a different binding paradigm from that used by either antibodies or the growth hormone receptor. The blend of genetics, biochemistry, X-ray crystallography, and carbohydrate chemistry in the study of pili biogenesis will continue to give insight into some of the most basic intellectual challenges in molecular biology concerning how proteins fold into domains that serve as modules for the formation of larger assemblies, and relating these processes to microbial pathogenesis.

Adhesins, Escherichia coli↗