Background. Coronary artery bypass grafting with hypothermic cardiac arrest and cardiopulmonary b... more Background. Coronary artery bypass grafting with hypothermic cardiac arrest and cardiopulmonary bypass (CPB) is associated with myocardial injury. Our study investigated whether an infusion of glucose, insulin and potassium (GIK) during elective coronary artery bypass surgery decreases myocardial cell death. Methods. We measured cardiac troponin I (cTnI), a myo®brillar structural protein, which is a sensitive and speci®c indicator of myocytic injury. With ethics committee approval, 42 patients were enrolled into a randomized, prospective, double-blinded study. In the GIK group, 500 ml of 50% dextrose solution containing 100 IU insulin and potassium 80 mmol was infused at the rate of 0.75 ml kg ±1 h ±1 . Patients in the non-GIK group received 5% dextrose solution at the same rate. Arterial blood samples were taken before induction of anaesthesia, after removal of the aortic clamp and 6 and 12 h after CPB. Results. In both groups there was an increase in cTnI concentration (P<0.05), which was greatest about 6 h after CPB. At no time did the cTnI concentration differ between the two groups. The results suggest that GIK does not decrease the irreversible myocardial damage associated with routine coronary artery bypass surgery.
enteritis and IBD. DNA was extracted using the QIAamp DNA Mini Kit. Libraries were prepared using... more enteritis and IBD. DNA was extracted using the QIAamp DNA Mini Kit. Libraries were prepared using Illumina Nextera XT DNA Library Prep Kit and Nextera XT Index Kit v2, multiplexed, and paired-end sequenced on the Illumina MiSeq. De novo read assembly used the A5-miseq pipeline with QUAST. Genome annotation was performed using the rapid prokaryotic genome annotation tool Prokka. Results Genome assembly of C. showae strains resulted in 8 to 59 contigs per strain (mean number = 21; average genome size 2,199,446 nucleotides); C. concisus isolates had an average contig number of 72 and average genome size of 1,982,586 nucleotides. C. ureolyticus strains average contig number was 134 and average genome size of 1,608,008 nucleotides. Through Prokka annotation, the average number of coding sequences was 2215 for C. showae isolates (range 2050-2368) with function predicted for~71.3%. For C. concisus the average number of coding sequences was 1985 (range 1833-2087) with function predicted for~71.9%. C. ureolyticus had a lower number of coding sequences (average 1613) with function predicted for~72.6%. We focused on the VirB4/D10 operon homologs, which are components of the Type IV secretion system. Contrary to previously published sequence data from oral strains, the majority of colonic C. showae isolated and 2 C. concisus strains possessed almost complete T4SS systems and additional virulence traits, including the exotoxin 9 gene. Conclusion The findings clearly demonstrate genetic differences among colonic Campylobacter isolates as compared to oral strains and sheds light on the pathogenic potential of these emerging colonic pathogens. The findings also further highlight the need for further sequencing studies to be undertaken.
The objective was to test the hypothesis that traditional and novel cardiometabolic risk factors ... more The objective was to test the hypothesis that traditional and novel cardiometabolic risk factors would be significantly different in groups of men of different fatness and fitness. Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, high-sensitivity C-reactive protein, alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, leptin, adiponectin, tumor necrosis factor-α, interleukin-6, interleukin-10, fibrinogen, and insulin resistance were assessed in 183 nonsmoking white men aged 35 to 53 years, including 62 who were slim and fit (waist girth ≤90 cm and maximal oxygen consumption [VO 2 max] above average), 24 who were slim and unfit (waist girth ≤90 cm and VO 2 max average or below), 39 who were fat and fit (waist girth ≥100 cm and VO 2 max above average), and 19 who were fat and unfit (waist girth ≥100 cm and VO 2 max average or below). Seventy-six percent gave blood on 2 occasions, and the average of 1 or 2 blood tests was used in statistical tests. Waist girth (centimeters) and fitness (milliliters of oxygen per kilogram of fat-free mass) were associated with high-density lipoprotein cholesterol, leptin, and insulin resistance after adjustment for age, saturated fat intake, and total energy intake. High-density lipoprotein cholesterol, triglycerides, alanine aminotransferase, and insulin resistance were significantly different in men who were fat and fit and those who were fat and unfit. These data suggest that differences in lipid and lipoprotein concentrations, liver function, and insulin resistance may explain why the risks of chronic disease are lower in men who are fat and fit than those who are fat and unfit.
Background: Optimal cytoreduction is a major prognostic factor in ovarian cancer; several clinica... more Background: Optimal cytoreduction is a major prognostic factor in ovarian cancer; several clinical, radiological and biochemical predictors have been studied. Tumour M2-PK (TU M2-PK) is over-expressed in tumour cells and can be detected in plasma samples but its role in ovarian cancer has not yet been evaluated. Objectives: To assess the potential clinical applications of TU M2-PK in ovarian cancer particularly in relation to surgical cytoreduction. Settings: The Gynaecological Cancer Centre at both King's College and St Thomas' Hospitals; London; UK. Methods: Patients with suspected ovarian cancer were recruited prospectively during the years 2004-2005. Blood samples were collected before surgery for plasma TU M2-PK assays. Data were analysed in relation to cancer diagnosis and outcome. Statistical analysis was performed using Analyse-It' and SPSS' V13. Results: 100 patients were recruited; 52 diagnosed with invasive ovarian cancer, 13 with borderline tumours and 35 patients had benign conditions. The mean M2-PK concentration in cancer patients was 52 U/ml vs 31 U/ml in patients with borderline tumours and 22 U/ml in those with benign conditions (p < 0.001); it was significantly raised in association with late stage disease and higher grade (p < 0.05). Taking 35 U/ml as a reference point, TU M2-PK predicted sub-optimal cytoreduction in advanced stage disease with a sensitivity of 69%, specificity of 60% and overall efficacy of 61% (95% CI: 44-75%). Conclusion: TU M2-PK was significantly raised in ovarian cancer patients, particularly those with higher stage disease. The potential clinical application as a predictor of surgical outcome in ovarian cancer needs further evaluation.
To assess and define the effects of heterocellular hereditary persistence of fetal haemoglobin (H... more To assess and define the effects of heterocellular hereditary persistence of fetal haemoglobin (HPFH) on the haematological phenotype of heterozygous b-thalassaemia, we have studied a large kindred that included a total of 204 subjects with 60 b-thalassaemia carriers, of whom 35 were also heterozygous, and five homozygous, for heterocellular HPFH. The study was possible because of the homogeneity of the b-thalassaemia mutation and the ability to genotype the heterocellular HPFH allele. Heterocellular HPFH had a significant effect on the mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV) and haemoglobin (Hb) A 2 values in the b-thalassaemia carriers and accounted for 29%, 30% and 24% of their respective variances. b-thalassaemia subjects with heterocellular HPFH had higher MCV and MCH values, concomitant with lower levels of Hb A 2 , and a reduced ineffective erythropoiesis. We conclude that co-inheritance of heterocellular HPFH leads to a primary increase in c-chain synthesis in b-thalassaemia trait and can be another confounding factor in the use of red cell indices and Hb A 2 levels in population screening for b-thalassaemia.
Background: Pyruvate kinase isoenzyme M2-PK is instrumental to tumour metabolism and hence over-e... more Background: Pyruvate kinase isoenzyme M2-PK is instrumental to tumour metabolism and hence over-expressed in tumour cells leading to detectable plasma concentrations. Objectives: To assess the degree of association between M2-PK plasma concentrations and ovarian cancer and to determine the cut-off values for its sensitivity and specificity for differentiating between benign and malignant ovarian disease. Settings: The Gynaecological Cancer Centre at both King's College and St. Thomas' Hospitals, London, UK. Methods: Patients with suspected ovarian cancer referred to the above centre were recruited prospectively during the years 2004-2005. Blood samples were collected before surgery for plasma M2-PK assays. Results were assessed with respect to cancer diagnosis, patient and tumour characteristics. Statistical analysis including the receiver operator characteristic (ROC) curve was performed using Analyse-It and SPSS V 13. Results: 100 patients with age range 14-88 years and a median of 57 years were recruited in the study. Of whom 52 were diagnosed with invasive ovarian cancer. Of these 35 (67%) were Stage III and above with two secondary tumours. M2-PK was not related to patient age (p = 0.43). There was a significant correlation between CA125 and M2-PK (p < 0.001). The mean M2-PK concentration in cancer patients was 52 U/ml versus 27 U/ml in patients with benign conditions (p < 0.001). At a cut-off value of 22 U/ml the sensitivity of M2-PK for detecting cancer was 70% with a specificity of 65%. Conclusion: M2-PK was significantly raised in ovarian cancer patients, however its role in clinical practice needs further evaluation.
The concentrations of amino acids in samples of coelomic fluid (n = 15), amniotic fluid (n = 9) a... more The concentrations of amino acids in samples of coelomic fluid (n = 15), amniotic fluid (n = 9) and maternal serum (n = 15) obtained from normal pregnancies between 7 and 12 weeks of gestation were measured using reversed-phase chromatography with pre-column derivatization. The total molar concentration of the 18 amino acids measured was 2.3 times higher in coelomic fluid than in maternal serum. All amino acids except serine and tryptophan were present in significantly higher concentrations in coelomic fluid than in maternal serum. Significant correlations between maternal serum and coelomic fluid were only found for proline, tyrosine, and tryptophan, suggesting that levels of the other amino acids are mainly influenced by placental synthesis and do not directly depend on maternal amino acid metabolism. Levels of all amino acids were significantly higher in coelomic fluid compared to amniotic fluid. Compared to maternal serum, the amniotic fluid contained significantly higher levels of arginine, lysine, alanine and tyrosine and lower levels of serine, glutamine and tryptophan. The total molar amino acid concentration decreased significantly with gestational age in both coelomic fluid and maternal serum. These results suggest that amino acids accumulate in coelomic fluid to support the metabolism of the secondary yolk sac, and that the exocoelomic cavity is the reservoir for most nutrients needed by the embryo and early fetus in the first trimester of human pregnancy.
A prospective study has been carried out, and 68 patients with hypercholesterolaemia have been in... more A prospective study has been carried out, and 68 patients with hypercholesterolaemia have been investigated to study the effects of central cooling on serum lipid levels. 2. Central cooling was obtained by the exposure of the whole body to cold water. All patients were trained to gradually reduce the water temperature from 22 to 14 mC and to increase the time of exposure from 5 to 20 min over a period of 90 days. The 33 male and 35 female patients were aged between 40 and 60 years at entry with total cholesterol of 6.0 mmol/l or greater and low-density lipoprotein (LDL)-cholesterol of 4.0 mmol/l or greater. Thyroid-stimulating hormone, free thyroxine (FT 4), total T 3 , total cholesterol, LDL-cholesterol, high-density lipoprotein (HDL)cholesterol, triacylglycerols and total fat mass (determined by dual-energy X-ray absorptiometry scan) were obtained at baseline and after 3 months treatment with hydrotherapy. 3. Central cooling obtained by hydrotherapy results in a median fall in tympanic temperature from 0.2 mC (P 0.001) to 0.8 mC (P 0.001). We have observed in these patients a significant reduction in total cholesterol (k0.2 mmol/l, P l 0.006) and LDL-cholesterol (k0.2 mmol/l, P l 0.004). Serum FT 4 level was higher than baseline results in 30 of these hypercholesterolaemic patients (15.5 pmol/l to 17.3 pmol/l) and there was no significant change in serum thyroidstimulating hormone and total T 3. 4. In conclusion, in our patients with hypercholesterolaemia we have observed a significant reduction of total cholesterol and LDL-cholesterol after body temperature regulation.
Inflammatory bowel disease (IBD) and irritable bowel syndrome share many symptoms. While irritabl... more Inflammatory bowel disease (IBD) and irritable bowel syndrome share many symptoms. While irritable bowel syndrome is a functional bowel disorder for which no specific treatment is available, the range of effective therapies for IBD is evolving rapidly. Accurate diagnosis of IBD is therefore essential. Clinical assessment, together with various imaging modalities and endoscopy, has been the mainstay of diagnosis for many years. Fecal biomarkers of gastrointestinal inflammation have appeared in the past decade, of which calprotectin, a neutrophil cytosolic protein, has been studied the most. Crohn's disease and ulcerative colitis are chronic remitting and relapsing diseases, and objective assessment of disease activity and response to treatment are important. This review focuses on the use of fecal calprotectin measurements in the diagnosis and monitoring of patients with IBD.
Background: Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation th... more Background: Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100β and its potential causal associations with Alzheimer's disease, we carried out genome-and epigenome-wide association studies (GWAS/EWAS) of serum S100β levels in older adults and performed Mendelian randomisation with Alzheimer's disease. Methods: GWAS (N=769, mean age 72.5 years, sd = 0.7) and EWAS (N=722, mean age 72.5 years, sd = 0.7) of S100β levels were performed in participants from the Lothian Birth Cohort 1936. Conditional and joint analysis (COJO) was used to identify independent loci. Expression quantitative trait locus (eQTL) analyses were performed for lead loci that had genome-wide significant associations with S100β. Bidirectional, two-sample Mendelian randomisation was used to test for causal associations between S100β and Alzheimer's disease. Colocalisation between S100β and Alzheimer's disease GWAS loci was also examined. Results: We identified 154 SNPs from chromosome 21 that associated (P<5x10-8) with S100β protein levels. The lead variant was located in the S100β gene (rs8128872, P=5.0x10-17). We found evidence that two independent causal variants existed for both transcription of S100β and S100β protein levels in our eQTL analyses. No CpG sites were Open Peer Review Reviewer Status AWAITING PEER REVIEW Any reports and responses or comments on the article can be found at the end of the article.
Protein S100 is a low molecular weight (10-12 kD) calcium-binding protein the beta subunit of whi... more Protein S100 is a low molecular weight (10-12 kD) calcium-binding protein the beta subunit of which is coded for at the 22.2-22.3 region of the long arm of chromosome 21. This region has also been shown to be responsible for the phenotypic expression of Down syndrome. Previous studies demonstrated increased immunoreactivity to protein S100 in brain tissue from adults with Down syndrome. We have previously observed a higher concentration of S100 protein in the fetal blood of trisomy 21 fetuses compared with normal subjects. The aim of this study was therefore to investigate the use of measuring S100 protein concentration in maternal blood for Down syndrome screening. Maternal blood was taken at the time of chorionic villus sampling or cordocentesis (11-38 weeks' gestation) for fetal karyotyping. Protein S100 was measured by a two-site immunoradiometric assay (S-100 IRMA, Sangtec). There was no significant difference in the concentration of maternal S100 protein between normal and trisomy 21 pregnancies (p<0.10). Moreover, there was no significant association between maternal serum S100 protein concentration and gestational age (r s =0.27, p=0.07), maternal age (r s = 0.17, p=0.7) or maternal weight (r s = 0.013, p=0.9). This study shows that measurement of maternal serum S100 protein concentration does not appear to have a value in Down syndrome screening.
The prevalence of depression and depressive symptoms is increased twofold in people with type 2 d... more The prevalence of depression and depressive symptoms is increased twofold in people with type 2 diabetes compared with the general population and is associated with worse biomedical outcomes and increased mortality. Type 2 diabetes, cardiovascular disease, and depression in nondiabetes subjects are independently associated with raised concentrations of circulating inflammatory markers, but it is not known if a similar association is observed in type 2 diabetes. We tested the hypothesis that higher depressive symptom scores in newly diagnosed type 2 diabetes patients were associated with higher concentrations of inflammatory markers. RESEARCH DESIGN AND METHODS Depressive symptoms in adults with newly diagnosed type 2 diabetes recruited from primary care were assessed using the Patient Health Questionnaire-9. Twelve markers of inflammation (C-reactive protein [hs-CRP], interleukin-4 [IL-4], IL-6, IL-10, vascular endothelial growth factor [VEGF], tumor necrosis factor-a [TNF-a], IL-1b, IL-1 receptor antagonist [IL-1RA], monocyte chemotactic protein-1 [MCP-1], white blood cell count [WBC], adiponectin, and triglyceride [TG]) were measured. Covariates included sociodemographic factors, adiposity, macrovascular disease, HbA 1c , and prescribed medication. The association between each inflammatory marker and depressive symptom score was estimated by multiple linear regression. RESULTS The baseline cohort consisted of 1,790 participants. After adjusting for covariates, CRP (B = 0.13, P < 0.001), IL-1b (B = 0.06, P = 0.047), IL-1RA (B = 0.13, P < 0.001), MCP-1 (B = 0.11, P = 0.001), WBC (B = 0.13, P < 0.001), and TG (B = 0.10, P < 0.001) were associated with depressive symptoms. CONCLUSIONS Increased inflammation may be involved in the pathogenesis of depressive symptoms in type 2 diabetes and contribute to the increased risk of complications and mortality in this group.
Background. Coronary artery bypass grafting with hypothermic cardiac arrest and cardiopulmonary b... more Background. Coronary artery bypass grafting with hypothermic cardiac arrest and cardiopulmonary bypass (CPB) is associated with myocardial injury. Our study investigated whether an infusion of glucose, insulin and potassium (GIK) during elective coronary artery bypass surgery decreases myocardial cell death. Methods. We measured cardiac troponin I (cTnI), a myo®brillar structural protein, which is a sensitive and speci®c indicator of myocytic injury. With ethics committee approval, 42 patients were enrolled into a randomized, prospective, double-blinded study. In the GIK group, 500 ml of 50% dextrose solution containing 100 IU insulin and potassium 80 mmol was infused at the rate of 0.75 ml kg ±1 h ±1 . Patients in the non-GIK group received 5% dextrose solution at the same rate. Arterial blood samples were taken before induction of anaesthesia, after removal of the aortic clamp and 6 and 12 h after CPB. Results. In both groups there was an increase in cTnI concentration (P<0.05), which was greatest about 6 h after CPB. At no time did the cTnI concentration differ between the two groups. The results suggest that GIK does not decrease the irreversible myocardial damage associated with routine coronary artery bypass surgery.
enteritis and IBD. DNA was extracted using the QIAamp DNA Mini Kit. Libraries were prepared using... more enteritis and IBD. DNA was extracted using the QIAamp DNA Mini Kit. Libraries were prepared using Illumina Nextera XT DNA Library Prep Kit and Nextera XT Index Kit v2, multiplexed, and paired-end sequenced on the Illumina MiSeq. De novo read assembly used the A5-miseq pipeline with QUAST. Genome annotation was performed using the rapid prokaryotic genome annotation tool Prokka. Results Genome assembly of C. showae strains resulted in 8 to 59 contigs per strain (mean number = 21; average genome size 2,199,446 nucleotides); C. concisus isolates had an average contig number of 72 and average genome size of 1,982,586 nucleotides. C. ureolyticus strains average contig number was 134 and average genome size of 1,608,008 nucleotides. Through Prokka annotation, the average number of coding sequences was 2215 for C. showae isolates (range 2050-2368) with function predicted for~71.3%. For C. concisus the average number of coding sequences was 1985 (range 1833-2087) with function predicted for~71.9%. C. ureolyticus had a lower number of coding sequences (average 1613) with function predicted for~72.6%. We focused on the VirB4/D10 operon homologs, which are components of the Type IV secretion system. Contrary to previously published sequence data from oral strains, the majority of colonic C. showae isolated and 2 C. concisus strains possessed almost complete T4SS systems and additional virulence traits, including the exotoxin 9 gene. Conclusion The findings clearly demonstrate genetic differences among colonic Campylobacter isolates as compared to oral strains and sheds light on the pathogenic potential of these emerging colonic pathogens. The findings also further highlight the need for further sequencing studies to be undertaken.
The objective was to test the hypothesis that traditional and novel cardiometabolic risk factors ... more The objective was to test the hypothesis that traditional and novel cardiometabolic risk factors would be significantly different in groups of men of different fatness and fitness. Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, high-sensitivity C-reactive protein, alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, leptin, adiponectin, tumor necrosis factor-α, interleukin-6, interleukin-10, fibrinogen, and insulin resistance were assessed in 183 nonsmoking white men aged 35 to 53 years, including 62 who were slim and fit (waist girth ≤90 cm and maximal oxygen consumption [VO 2 max] above average), 24 who were slim and unfit (waist girth ≤90 cm and VO 2 max average or below), 39 who were fat and fit (waist girth ≥100 cm and VO 2 max above average), and 19 who were fat and unfit (waist girth ≥100 cm and VO 2 max average or below). Seventy-six percent gave blood on 2 occasions, and the average of 1 or 2 blood tests was used in statistical tests. Waist girth (centimeters) and fitness (milliliters of oxygen per kilogram of fat-free mass) were associated with high-density lipoprotein cholesterol, leptin, and insulin resistance after adjustment for age, saturated fat intake, and total energy intake. High-density lipoprotein cholesterol, triglycerides, alanine aminotransferase, and insulin resistance were significantly different in men who were fat and fit and those who were fat and unfit. These data suggest that differences in lipid and lipoprotein concentrations, liver function, and insulin resistance may explain why the risks of chronic disease are lower in men who are fat and fit than those who are fat and unfit.
Background: Optimal cytoreduction is a major prognostic factor in ovarian cancer; several clinica... more Background: Optimal cytoreduction is a major prognostic factor in ovarian cancer; several clinical, radiological and biochemical predictors have been studied. Tumour M2-PK (TU M2-PK) is over-expressed in tumour cells and can be detected in plasma samples but its role in ovarian cancer has not yet been evaluated. Objectives: To assess the potential clinical applications of TU M2-PK in ovarian cancer particularly in relation to surgical cytoreduction. Settings: The Gynaecological Cancer Centre at both King's College and St Thomas' Hospitals; London; UK. Methods: Patients with suspected ovarian cancer were recruited prospectively during the years 2004-2005. Blood samples were collected before surgery for plasma TU M2-PK assays. Data were analysed in relation to cancer diagnosis and outcome. Statistical analysis was performed using Analyse-It' and SPSS' V13. Results: 100 patients were recruited; 52 diagnosed with invasive ovarian cancer, 13 with borderline tumours and 35 patients had benign conditions. The mean M2-PK concentration in cancer patients was 52 U/ml vs 31 U/ml in patients with borderline tumours and 22 U/ml in those with benign conditions (p < 0.001); it was significantly raised in association with late stage disease and higher grade (p < 0.05). Taking 35 U/ml as a reference point, TU M2-PK predicted sub-optimal cytoreduction in advanced stage disease with a sensitivity of 69%, specificity of 60% and overall efficacy of 61% (95% CI: 44-75%). Conclusion: TU M2-PK was significantly raised in ovarian cancer patients, particularly those with higher stage disease. The potential clinical application as a predictor of surgical outcome in ovarian cancer needs further evaluation.
To assess and define the effects of heterocellular hereditary persistence of fetal haemoglobin (H... more To assess and define the effects of heterocellular hereditary persistence of fetal haemoglobin (HPFH) on the haematological phenotype of heterozygous b-thalassaemia, we have studied a large kindred that included a total of 204 subjects with 60 b-thalassaemia carriers, of whom 35 were also heterozygous, and five homozygous, for heterocellular HPFH. The study was possible because of the homogeneity of the b-thalassaemia mutation and the ability to genotype the heterocellular HPFH allele. Heterocellular HPFH had a significant effect on the mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV) and haemoglobin (Hb) A 2 values in the b-thalassaemia carriers and accounted for 29%, 30% and 24% of their respective variances. b-thalassaemia subjects with heterocellular HPFH had higher MCV and MCH values, concomitant with lower levels of Hb A 2 , and a reduced ineffective erythropoiesis. We conclude that co-inheritance of heterocellular HPFH leads to a primary increase in c-chain synthesis in b-thalassaemia trait and can be another confounding factor in the use of red cell indices and Hb A 2 levels in population screening for b-thalassaemia.
Background: Pyruvate kinase isoenzyme M2-PK is instrumental to tumour metabolism and hence over-e... more Background: Pyruvate kinase isoenzyme M2-PK is instrumental to tumour metabolism and hence over-expressed in tumour cells leading to detectable plasma concentrations. Objectives: To assess the degree of association between M2-PK plasma concentrations and ovarian cancer and to determine the cut-off values for its sensitivity and specificity for differentiating between benign and malignant ovarian disease. Settings: The Gynaecological Cancer Centre at both King's College and St. Thomas' Hospitals, London, UK. Methods: Patients with suspected ovarian cancer referred to the above centre were recruited prospectively during the years 2004-2005. Blood samples were collected before surgery for plasma M2-PK assays. Results were assessed with respect to cancer diagnosis, patient and tumour characteristics. Statistical analysis including the receiver operator characteristic (ROC) curve was performed using Analyse-It and SPSS V 13. Results: 100 patients with age range 14-88 years and a median of 57 years were recruited in the study. Of whom 52 were diagnosed with invasive ovarian cancer. Of these 35 (67%) were Stage III and above with two secondary tumours. M2-PK was not related to patient age (p = 0.43). There was a significant correlation between CA125 and M2-PK (p < 0.001). The mean M2-PK concentration in cancer patients was 52 U/ml versus 27 U/ml in patients with benign conditions (p < 0.001). At a cut-off value of 22 U/ml the sensitivity of M2-PK for detecting cancer was 70% with a specificity of 65%. Conclusion: M2-PK was significantly raised in ovarian cancer patients, however its role in clinical practice needs further evaluation.
The concentrations of amino acids in samples of coelomic fluid (n = 15), amniotic fluid (n = 9) a... more The concentrations of amino acids in samples of coelomic fluid (n = 15), amniotic fluid (n = 9) and maternal serum (n = 15) obtained from normal pregnancies between 7 and 12 weeks of gestation were measured using reversed-phase chromatography with pre-column derivatization. The total molar concentration of the 18 amino acids measured was 2.3 times higher in coelomic fluid than in maternal serum. All amino acids except serine and tryptophan were present in significantly higher concentrations in coelomic fluid than in maternal serum. Significant correlations between maternal serum and coelomic fluid were only found for proline, tyrosine, and tryptophan, suggesting that levels of the other amino acids are mainly influenced by placental synthesis and do not directly depend on maternal amino acid metabolism. Levels of all amino acids were significantly higher in coelomic fluid compared to amniotic fluid. Compared to maternal serum, the amniotic fluid contained significantly higher levels of arginine, lysine, alanine and tyrosine and lower levels of serine, glutamine and tryptophan. The total molar amino acid concentration decreased significantly with gestational age in both coelomic fluid and maternal serum. These results suggest that amino acids accumulate in coelomic fluid to support the metabolism of the secondary yolk sac, and that the exocoelomic cavity is the reservoir for most nutrients needed by the embryo and early fetus in the first trimester of human pregnancy.
A prospective study has been carried out, and 68 patients with hypercholesterolaemia have been in... more A prospective study has been carried out, and 68 patients with hypercholesterolaemia have been investigated to study the effects of central cooling on serum lipid levels. 2. Central cooling was obtained by the exposure of the whole body to cold water. All patients were trained to gradually reduce the water temperature from 22 to 14 mC and to increase the time of exposure from 5 to 20 min over a period of 90 days. The 33 male and 35 female patients were aged between 40 and 60 years at entry with total cholesterol of 6.0 mmol/l or greater and low-density lipoprotein (LDL)-cholesterol of 4.0 mmol/l or greater. Thyroid-stimulating hormone, free thyroxine (FT 4), total T 3 , total cholesterol, LDL-cholesterol, high-density lipoprotein (HDL)cholesterol, triacylglycerols and total fat mass (determined by dual-energy X-ray absorptiometry scan) were obtained at baseline and after 3 months treatment with hydrotherapy. 3. Central cooling obtained by hydrotherapy results in a median fall in tympanic temperature from 0.2 mC (P 0.001) to 0.8 mC (P 0.001). We have observed in these patients a significant reduction in total cholesterol (k0.2 mmol/l, P l 0.006) and LDL-cholesterol (k0.2 mmol/l, P l 0.004). Serum FT 4 level was higher than baseline results in 30 of these hypercholesterolaemic patients (15.5 pmol/l to 17.3 pmol/l) and there was no significant change in serum thyroidstimulating hormone and total T 3. 4. In conclusion, in our patients with hypercholesterolaemia we have observed a significant reduction of total cholesterol and LDL-cholesterol after body temperature regulation.
Inflammatory bowel disease (IBD) and irritable bowel syndrome share many symptoms. While irritabl... more Inflammatory bowel disease (IBD) and irritable bowel syndrome share many symptoms. While irritable bowel syndrome is a functional bowel disorder for which no specific treatment is available, the range of effective therapies for IBD is evolving rapidly. Accurate diagnosis of IBD is therefore essential. Clinical assessment, together with various imaging modalities and endoscopy, has been the mainstay of diagnosis for many years. Fecal biomarkers of gastrointestinal inflammation have appeared in the past decade, of which calprotectin, a neutrophil cytosolic protein, has been studied the most. Crohn's disease and ulcerative colitis are chronic remitting and relapsing diseases, and objective assessment of disease activity and response to treatment are important. This review focuses on the use of fecal calprotectin measurements in the diagnosis and monitoring of patients with IBD.
Background: Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation th... more Background: Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100β and its potential causal associations with Alzheimer's disease, we carried out genome-and epigenome-wide association studies (GWAS/EWAS) of serum S100β levels in older adults and performed Mendelian randomisation with Alzheimer's disease. Methods: GWAS (N=769, mean age 72.5 years, sd = 0.7) and EWAS (N=722, mean age 72.5 years, sd = 0.7) of S100β levels were performed in participants from the Lothian Birth Cohort 1936. Conditional and joint analysis (COJO) was used to identify independent loci. Expression quantitative trait locus (eQTL) analyses were performed for lead loci that had genome-wide significant associations with S100β. Bidirectional, two-sample Mendelian randomisation was used to test for causal associations between S100β and Alzheimer's disease. Colocalisation between S100β and Alzheimer's disease GWAS loci was also examined. Results: We identified 154 SNPs from chromosome 21 that associated (P<5x10-8) with S100β protein levels. The lead variant was located in the S100β gene (rs8128872, P=5.0x10-17). We found evidence that two independent causal variants existed for both transcription of S100β and S100β protein levels in our eQTL analyses. No CpG sites were Open Peer Review Reviewer Status AWAITING PEER REVIEW Any reports and responses or comments on the article can be found at the end of the article.
Protein S100 is a low molecular weight (10-12 kD) calcium-binding protein the beta subunit of whi... more Protein S100 is a low molecular weight (10-12 kD) calcium-binding protein the beta subunit of which is coded for at the 22.2-22.3 region of the long arm of chromosome 21. This region has also been shown to be responsible for the phenotypic expression of Down syndrome. Previous studies demonstrated increased immunoreactivity to protein S100 in brain tissue from adults with Down syndrome. We have previously observed a higher concentration of S100 protein in the fetal blood of trisomy 21 fetuses compared with normal subjects. The aim of this study was therefore to investigate the use of measuring S100 protein concentration in maternal blood for Down syndrome screening. Maternal blood was taken at the time of chorionic villus sampling or cordocentesis (11-38 weeks' gestation) for fetal karyotyping. Protein S100 was measured by a two-site immunoradiometric assay (S-100 IRMA, Sangtec). There was no significant difference in the concentration of maternal S100 protein between normal and trisomy 21 pregnancies (p<0.10). Moreover, there was no significant association between maternal serum S100 protein concentration and gestational age (r s =0.27, p=0.07), maternal age (r s = 0.17, p=0.7) or maternal weight (r s = 0.013, p=0.9). This study shows that measurement of maternal serum S100 protein concentration does not appear to have a value in Down syndrome screening.
The prevalence of depression and depressive symptoms is increased twofold in people with type 2 d... more The prevalence of depression and depressive symptoms is increased twofold in people with type 2 diabetes compared with the general population and is associated with worse biomedical outcomes and increased mortality. Type 2 diabetes, cardiovascular disease, and depression in nondiabetes subjects are independently associated with raised concentrations of circulating inflammatory markers, but it is not known if a similar association is observed in type 2 diabetes. We tested the hypothesis that higher depressive symptom scores in newly diagnosed type 2 diabetes patients were associated with higher concentrations of inflammatory markers. RESEARCH DESIGN AND METHODS Depressive symptoms in adults with newly diagnosed type 2 diabetes recruited from primary care were assessed using the Patient Health Questionnaire-9. Twelve markers of inflammation (C-reactive protein [hs-CRP], interleukin-4 [IL-4], IL-6, IL-10, vascular endothelial growth factor [VEGF], tumor necrosis factor-a [TNF-a], IL-1b, IL-1 receptor antagonist [IL-1RA], monocyte chemotactic protein-1 [MCP-1], white blood cell count [WBC], adiponectin, and triglyceride [TG]) were measured. Covariates included sociodemographic factors, adiposity, macrovascular disease, HbA 1c , and prescribed medication. The association between each inflammatory marker and depressive symptom score was estimated by multiple linear regression. RESULTS The baseline cohort consisted of 1,790 participants. After adjusting for covariates, CRP (B = 0.13, P < 0.001), IL-1b (B = 0.06, P = 0.047), IL-1RA (B = 0.13, P < 0.001), MCP-1 (B = 0.11, P = 0.001), WBC (B = 0.13, P < 0.001), and TG (B = 0.10, P < 0.001) were associated with depressive symptoms. CONCLUSIONS Increased inflammation may be involved in the pathogenesis of depressive symptoms in type 2 diabetes and contribute to the increased risk of complications and mortality in this group.
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Papers by Roy Sherwood