Nature's randomised trials.
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C-Reactive Protein↗
Biomedical subjects
Steve Humphries
Publications and source records attributed to Steve Humphries.
Inflammatory response to coronary artery bypass surgery: does the heme-oxygenase-1 gene microsatellite polymorphism play a role?
BACKGROUND: Heme-oxygenase 1 (HO-1) is a rate-limiting enzyme in the degradation of heme to bilirubin, ferritin and carbon monoxide (CO) and may have significant anti-inflammatory function. The HO-1 gene promoter region shows microsatellite polymorphism with different (GT)n repeats, reported to differently induce gene expression, with the short allele associated with higher gene expression. We measured the acute inflammatory response using coronary artery bypass surgery (CABG) as a well-characterized and uniform stimulus and examined the correlation between levels of IL-6, C-reactive protein (CRP) and fibrinogen and their relationship to HO-1 genotype. METHODS: Two hundred and seventy-five consecutive patients undergoing CABG were genotyped for the HO-1 promoter polymorphism using PCR and automated DNA capillary sequencer. IL-6, CRP and fibrinogen were measured at baseline and 6, 24, 48, 72, 96 and 120 hours after CABG. RESULTS: Complete IL-6, CRP and fibrinogen measures were available in 220 patients. Before surgery IL-6 levels showed a strong correlation with CRP and fibrinogen (r = 0.48, P < 0.0001; r = 0.41, P < 0.0001 respectively), with a significant correlation between CRP and fibrinogen (r = 0.61, P < 0.0001). All three acute phase reactants showed a significant increase after CABG. After surgery, peak IL-6 was strongly correlated with peak CRP (r = 0.34, P = 0.0009) but not with peak fibrinogen (r = 0.15, P = 0.13), while peak CRP and peak fibrinogen were significantly correlated (r = 0.415, P < 0.0001). HO-1 allelic repeats ranged from 22-42, with (GT)25 and (GT)32 being the two most common alleles, and subsequently divided into three groups according to previous published work: <30 (GT)n were designated as S (short), 30-37 (GT)n as M (middle) and long repeats with >37 (GT)n as L (long); allele frequency 0.35, 0.58 and 0.07 respectively. Baseline CRP differed by genotype: those carrying at least one long allele having higher CRP than those with no long allele (3.76 +/- 0.79 vs. 2.07 +/- 0.17, P = 0.013). Conversely, those carrying at least one short allele had higher fibrinogen levels than those with no short allele (3.83 +/- 0.79 vs. 3.51 +/- 0.88, P = 0.006). CONCLUSIONS: There is a strong correlation between the measured acute phase reactants both at baseline and after the inflammatory response to CABG in patients with coronary disease. There was an association between the HO-1 microsatellite polymorphism and CRP and fibrinogen levels at baseline but there was no similar association following CABG. This may indicate that HO-1 is associated with chronic atherosclerotic inflammatory processes rather than acute.
Adult↗
The ACE gene insertion/deletion polymorphism and elite endurance swimming.
Human physical performance is influenced by genetic factors. A variation in the human angiotensin I-converting enzyme (ACE) gene has been identified, in which the insertion (I) variant may be associated with elite endurance performance, and the deletion (D) variant seems overrepresented amongst elite sprinters and short-distance swimmer status. We might thus anticipate I-allele frequency to be elevated amongst swimmers competing over very much greater distances, and have examined this hypothesis. Thirty-five truly elite very-long-distance swimmers were classified as better at 1- to 10-km distances (n=19, SLD group) or those best at 25-km races (n=16, LLD group). Genotype frequencies (II versus ID versus DD) differed between the two groups: 6% versus 47% versus 47% for SLD, and 18.8% versus 75% versus 6.2% for LLD (P=0.01). I-allele frequency was 0.29 for the shorter distance swimmers, and 0.59 for the 25 km group. These data are consistent with an association of ACE I allele with longer distance swimming, and the ACE D allele with swimming shorter distances.
Adult↗
Plasma fibrinogen concentration predicts the risk of myocardial infarction differently in various parts of Europe: effects of beta-fibrinogen genotype and environmental factors. The HIFMECH Study.
The propensity to atherothrombotic disease differs in Europe, with high-risk regions located in the North of Europe and lowrisk regions in the South of Europe. The HIFMECH study (Hypercoagulability and Impaired Fibrinolytic function MECHanisms predisposing to myocardial infarction (MI) study) was undertaken to elucidate genetic and environmental mechanisms underlying MI based on investigations of postinfarction patients and healthy individuals recruited from Stockholm, Sweden, London, England (North of Europe), Marseille, France and San Giovanni Rotondo, Italy (South of Europe). In the present report, emphasis was placed on fibrinogen, a multifunctional protein, widely recognized as an independent predictor of atherothrombotic disease. The adjusted plasma fibrinogen concentration was an independent discriminator between cases and controls in London (SOR 3.58; 95% CI 1.31; 9.83), but not in the other centres. Genotyping for six beta-fibrinogen promoter single nucleotide polymorphisms was performed of which -249C/T, -455G/A and -854G/A were used in analysis as a consequence of the linkage disequilibrium pattern. Four haplotypes, with similar distribution across Europe, were detected: CGG (46.7%), CAG (20.3%), TGG (18.2%) and CGA (14.8%). A significant haplotype effect on plasma fibrinogen concentration was observed in patients (p < 0.001) but not in controls (p = 0.08). The -455G/A genotype related to plasma fibrinogen concentration amongst patients along with centre and IL-6 concentration (together explaining 11.5% of the variation), whereas predictors amongst controls included centre, body mass index, IL-6 and smoking habit (explaining 15.7%). Thus, plasma fibrinogen concentration contributes differently to MI across Europe, and a disease-related stimulus is required to evoke allele-specific regulation of fibrinogen synthesis.
Aged↗
Cognitive change 5 years after coronary artery bypass surgery.
A longitudinal study of cognitive function after coronary artery bypass surgery examined 107 participants using 11 tests, preoperatively and at 6 days, 8 weeks, and 5 years after surgery. The overall neuropsychological (NP) change score declined at 6 days, showed some recovery at 8 weeks, and declined again at 5 years. The number of microemboli recorded during surgery, postoperative short-term cognitive change, and degree of recovery at 8 weeks were identified as predictors of change in NP score to 5 years. This suggests that even over a 5-year period, operative damage is detectable. Patients' vulnerability to short-term deterioration and resilience or ability to recover over a few weeks from operative cerebral insult are important processes of unknown mechanisms.
Acetamides↗
Angiotensin-converting enzyme DD genotype is associated with worse perinatal cardiorespiratory adaptation in preterm infants.
OBJECTIVES: The angiotensin-converting enzyme (ACE) deletion (D) variant is associated with greater ACE activity and perhaps with deleterious cardiorespiratory pathophysiological responses. We determined whether the early health status of the preterm infant was adversely influenced by homozygosity for the D allele (DD genotype) compared with ID or II genotype. Study design Angiotensin-converting enzyme genotype was determined in a cohort of 148 preterm infants born in Bristol, United Kingdom (median gestational age, 31 weeks; range, 28-32). Intensive care data were prospectively obtained. Primary analysis was by Mann-Whitney U and chi(2) tests. RESULTS: Higher oxygen, circulatory support requirements, and base deficit in the first 12 hours after birth were found in infants with DD genotype (minimum inspired oxygen concentration in first 12 hours, median [interquartile range], DD 0.26 [0.21-0.40], ID/II 0.21 [0.21-0.30], P=.028; blood pressure support in first 12 hours, DD 12 [30%], ID/II 15 [14%], P=.039; worse base deficit in first 12 hours, DD 4.8 [7.7 to 0], ID/II 0 [5.3 to 0], P=.020). CONCLUSIONS: Angiotensin-converting enzyme polymorphism has a role in the development of preterm cardiorespiratory disease. The DD genotype, encoding higher angiotensin-converting enzyme activity, may adversely influence the early health status of preterm infants.
Cardiovascular Diseases↗
Making image guidance work: understanding control of accuracy.
Use of image-guided surgery is becoming increasingly common in both sinus surgery and neuro-otologic applications. The purpose of this study was to determine the effect of fiducial distribution and mean fiducial error on point accuracy. Using a plastic model, we determined that optimal navigation accuracy was achieved by surrounding the operative target with a widespread field of fiducials. True accuracy was always highest when we targeted a surface point. Accuracy was decreased at points removed from the center of the registration target zone created by the fiducials. Inaccurate registration resulted in increased mean fiducial error and lower accuracy at the target point. Understanding the registration process will enhance the utility of image-guided surgery in otolaryngology and skull base surgery.
Cranial Fossa, Middle↗
Is interleukin-6 -174 genotype associated with the development of septicemia in preterm infants?
OBJECTIVE: Systemic infection affects one quarter of preterm infants. Defense from infection is in part mediated by the cytokine interleukin-6 (IL-6). We tested the hypothesis that the IL-6 -174 GG genotype, associated with lower IL-6 response to inflammation, is also associated with the development of septicemia in preterm infants. METHODS: The study group comprised 157 infants who were born at < or =32 weeks. Genotype distribution (34% [54] GG, 46% [72] GC, 20% [31] CC) and C allele frequency (0.43; 95% confidence interval [CI]: 0.37-0.48) were similar to the UK adult population. Among the patients who developed bacterially confirmed septicemia (n = 51 [33%]), there was a significantly higher prevalence of the IL-6 -174 GG genotype than that observed in those who did not develop infection (47% vs 28% for GG: odds ratio [OR]: 2.3; 95% CI: 1.1-4.5). This association remained statistically significant (OR: 2.7; 95% CI: 1.2-6.3) after multiple binary logistic regression adjustment for other significant predictors of the development of septicemia. Late infection alone was similarly associated with GG genotype (septicemia 47% vs no septicemia 29% for GG: OR: 2.2; 95% CI: 1.1-4.3). CONCLUSIONS: Variation in the IL-6 gene seems to influence the defense against bacterial pathogens in the very preterm infant.
Alleles↗