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Biomedical subjects

Mark B Pepys

Publications and source records attributed to Mark B Pepys.

29 records · Page 2Linked to original sources
PubMed2003

Refinement of the association of serum C-reactive protein concentration and coronary heart disease risk by correction for within-subject variation over time: the MONICA Augsburg studies, 1984 and 1987.

The authors sought to assess the repeatability of measurements of C-reactive protein, an independent predictor of coronary heart disease, in a large cohort of apparently healthy men and to correct earlier estimates of the association of C-reactive protein and coronary heart disease for the measurement error in this protein. They measured C-reactive protein by a high-sensitivity assay in 936 men aged 45-64 years in the MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Augsburg cohort in 1984-1985 and remeasured it 3 years later. All men were subjected to an 8-year follow-up of their cardiovascular status. The analytical variation of the assay was small, with the analytical variance component at 1 percent of the within-subject variance component, a repeatability coefficient of 25 percent, and a reliability coefficient of 1.00. In contrast, the within-subject variation of C-reactive protein corresponded to a repeatability coefficient of 740 percent and a reliability coefficient of 0.54, indicating considerable within-subject variation. Based on the authors' estimates, three serial determinations of C-reactive protein should be done to achieve a reliability of 0.75, the value they found for total cholesterol. Correcting the hazard ratios in their original analysis of the association of coronary heart disease and high-sensitivity-assay C-reactive protein for the measurement error in C-reactive protein and covariables leads to a considerably larger estimate. The results suggest that the true association between C-reactive protein and cardiovascular risk is underestimated by a single C-reactive protein determination, and that several serial C-reactive protein measurements should be taken.

Biomarkers↗
PubMed2003

MHC typing in variant Creutzfeldt-Jakob disease.

Identification of factors that cause susceptibility to, and clinical expression of, variant Creutzfeldt-Jakob disease (vCJD) is essential for future management of the disease. We established MHC genotypes of 76 individuals with vCJD and 131 controls, and analysed MHC phenotypes in relation to age of onset of vCJD and its duration from presentation to death. There were no significant differences between vCJD and control populations in frequencies of any MHC types, nor were there associations between MHC type and age of onset or duration of vCJD disease. Our results do not support the idea of an association between MHC types and either susceptibility to, or expression of, vCJD.

Adolescent↗
PubMed2003

Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy.

Monoclonal immunoglobulin light chains are deposited as amyloid fibrils in systemic AL (primary) amyloidosis, but the underlying plasma cell dyscrasias are often difficult to detect or unquantifiable. The relationships between circulating monoclonal light chains, amyloid load and clinical outcome, and the relative efficacies of chemotherapy regimens aimed at suppressing monoclonal immunoglobulin production, have not been determined. Circulating free immunoglobulin light chain (FLC) concentration was measured with a sensitive nephelometric immunoassay in 262 patients with AL amyloidosis, and followed serially in 137 patients who received either high-dose chemotherapy or one of two intermediate-dose cytotoxic regimens. Amyloid load was quantified by serum amyloid P component scintigraphy. A monoclonal excess of FLC was identified at diagnosis in 98% of patients. Among 86 patients whose abnormal FLC concentration fell by more than 50% following chemotherapy, 5-year survival was 88% compared with only 39% among those whose FLC did not fall by half (P < 0.0001). Amyloid deposits regressed in 58 patients. The magnitude and duration of the FLC responses to intermediate- and high-dose chemotherapy regimens were similar. The FLC assay enabled the circulating fibril precursor protein in AL amyloidosis to be quantified and monitored in most patients. Reduction of the amyloidogenic FLC by more than 50% was associated with substantial survival benefit, regardless of the type of chemotherapy used. Clinical improvement following chemotherapy in AL amyloidosis is delayed, but treatment strategies can be guided by their early effect on serum FLC concentration.

Adult↗
PubMed2003

Markers of inflammation in women on different hormone replacement therapies.

BACKGROUND AND AIM: To measure inflammatory markers in postmenopausal women on different forms of hormone replacement therapy (HRT). METHOD: C-reactive protein (CRP), fibrinogen, plasma viscosity (PV), albumin and white blood cell (WBC) count were determined in 749 postmenopausal women. RESULTS: CRP concentration was significantly higher in women on estrogen monotherapy (difference of the median (d) 0.96 mg/l, P = 0.013), compared to those without HRT, but there was no difference in women on combined HRT. Fibrinogen concentration was significantly lower in women on estrogen monotherapy (d 0.25g/l, P = 0.004) and combined HRT (d 0.4 g/l, P < 0.001), compared to women without HRT. Similarly, PV was significantly lower in women on estrogen monotherapy (d 0.017 mPa x s, P = 0.007) and women on combined HRT (d 0.039mPa x s, P < 0.001), compared to those without HRT. No differences were found for WBC count and the negative acute phase marker albumin in the various treatment groups. In contrast to oral estrogen administration, levels of CRP, fibrinogen and PV in women on transdermal estrogen therapy did not differ from the no-HRT group. There was no association between these markers of inflammation and plasma estrogen levels. CONCLUSION: Oral estrogen monotherapy was associated with highest concentrations of CRP. In contrast, other markers of inflammation were either similar or lower in the oral HRT group, compared to the group of women without HRT, suggesting that higher CRP concentrations reflect estrogen effects on CRP expression rather than a systemic pro-inflammatory effect.

Acute-Phase Reaction↗
PubMed2002

Production of granulocyte colony-stimulating factor in the nonspecific acute phase response enhances host resistance to bacterial infection.

Mice mounting an acute phase response, induced by sterile inflammation after a single s.c. injection of casein 24 h beforehand, were remarkably protected against lethal infection with Gram-positive or Gram-negative bacteria. This was associated with enhanced early clearance of bacteremia, greater phagocytosis and oxidative burst responses by neutrophils, and enhanced recruitment of neutrophils into tissues compared with control, nonacute phase mice. Casein-induced inflammation was also associated with increased concentrations of G-CSF in serum, and administration of neutralizing Ab to this cytokine completely abrogated protection against Escherichia coli infection after casein pretreatment. Injection of recombinant murine G-CSF between 3 and 24 h before infection conferred the same protection as casein injection. In contrast, the casein-induced acute phase response affected neither serum values of TNF-alpha, IL-1 beta, or IL-6 after E. coli infection nor susceptibility to LPS toxicity. Furthermore, protection against infection was unaffected in IL-1R knockout mice, which have deficient acute phase plasma protein responses, or after nonspecific inhibition of acute phase protein synthesis by D-galactosamine or specific depletion of complement C3 by cobra venom factor. Increased production of G-CSF in the acute phase response is thus a key physiological component of host defense, and pretreatment with G-CSF to prevent bacterial infection in at-risk patients now merits further study, especially in view of increasing bacterial resistance to antibiotics.

Acute-Phase Proteins↗
PubMed2002

Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.

BACKGROUND: Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes encoding transthyretin, fibrinogen A alpha-chain, lysozyme, or apolipoprotein A-I, is thought to be extremely rare and is not routinely included in the differential diagnosis of systemic amyloidosis unless there is a family history. METHODS: We studied 350 patients with systemic amyloidosis, in whom a diagnosis of the light-chain (AL) type of the disorder had been suggested by clinical and laboratory findings and by the absence of a family history, to assess whether they had amyloidogenic mutations. RESULTS: Amyloidogenic mutations were present in 34 of the 350 patients (9.7 percent), most often in the genes encoding fibrinogen A alpha-chain (18 patients) and transthyretin (13 patients). In all 34 of these patients, the diagnosis of hereditary amyloidosis was confirmed by additional investigations. A low-grade monoclonal gammopathy was detected in 8 of the 34 patients (24 percent). CONCLUSIONS: A genetic cause should be sought in all patients with amyloidosis that is not the reactive systemic amyloid A type and in whom confirmation of the AL type cannot be obtained.

Adult↗
PubMed2002

Influenza virus infection is not affected by serum amyloid P component.

BACKGROUND: Binding of serum amyloid P component (SAP) to its ligands, including bacteria, chromatin and amyloid fibrils, protects them from degradation, is anti-opsonic and anti-immunogenic. SAP thereby enhances the virulence of pathogenic bacteria to which it binds. However SAP also contributes to host resistance against bacteria to which it does not bind. Human SAP has been reported to bind to the influenza virus and inhibit viral invasion of cells in tissue culture. We therefore investigated a possible role of SAP in either host resistance or viral virulence during influenza infection in vivo. MATERIALS AND METHODS: The clinical course of mouse adapted influenza virus infection, the host antibody response, and viral replication, were compared in wild type mice, mice with targeted deletion of the SAP gene, and mice transgenic for human SAP. The effects of reconstitution of SAP deficient mice with pure human SAP, and of a drug that specifically blocks SAP binding in vivo, were also studied. Binding of mouse and human SAP to immobilized influenza virus was compared. RESULTS: The presence, absence, or availability for binding of SAP in vivo had no significant or consistent effect on the course or outcome of influenza infection, or on either viral replication or the anti-viral antibody response. Mouse SAP bound much less avidly than human SAP to influenza virus. CONCLUSIONS: In marked contrast to the dramatic effects of SAP deficiency on host resistance to different bacterial infections, mouse SAP apparently plays no significant role during infection of mice with influenza virus. Human SAP binds much more avidly than mouse SAP to the virus, but also had no effect on any of the parameters measured and is therefore unlikely to be involved in human influenza infection.

Animals↗