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D Syndercombe-Court

Publications and source records attributed to D Syndercombe-Court.

16 recordsLinked to original sources
PubMed2005

Analysis of artificially degraded DNA using STRs and SNPs--results of a collaborative European (EDNAP) exercise.

Recently, there has been much debate about what kinds of genetic markers should be implemented as new core loci that constitute national DNA databases. The choices lie between conventional STRs, ranging in size from 100 to 450 bp; mini-STRs, with amplicon sizes less than 200 bp; and single nucleotide polymorphisms (SNPs). There is general agreement by the European DNA Profiling Group (EDNAP) and the European Network of Forensic Science Institutes (ENFSI) that the reason to implement new markers is to increase the chance of amplifying highly degraded DNA rather than to increase the discriminating power of the current techniques. A collaborative study between nine European and US laboratories was organised under the auspices of EDNAP. Each laboratory was supplied with a SNP multiplex kit (Foren-SNPs) provided by the Forensic Science Service, two mini-STR kits provided by the National Institute of Standards and Technology (NIST) and a set of degraded DNA stains (blood and saliva). Laboratories tested all three multiplex kits, along with their own existing DNA profiling technique, on the same sets of degraded samples. Results were collated and analysed and, in general, mini-STR systems were shown to be the most effective. Accordingly, the EDNAP and ENFSI working groups have recommended that existing STR loci are reengineered to provide smaller amplicons, and the adoption of three new European core loci has been agreed.

Analysis of Variance↗
PubMed2003

Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting.

PURPOSE: To evaluate the use of reduced-intensity (RI) conditioning with allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical family donors in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). PATIENTS AND METHODS: Sixteen patients (median age, 54 years; range, 37 to 66 years) underwent RI-HSCT using a conditioning regimen of fludarabine 25 mg/m2 daily for 5 days and either cyclophosphamide 1 g/m2 daily for 2 days (14 patients) or melphalan 140 mg/m2 for 1 day (two patients). The median number of CD34+ cells and CD3+ cells infused per kilogram of recipient weight was 4.5 x 106 (range, 1.8 to 7.3 x 106 cells) and 2.9 x 108 (range, 0.1 to 9.6 x 108 cells), respectively. RESULTS: There was no transplant-related mortality (TRM) within 100 days of HSCT. Grade 1 to 2 acute graft-versus-host disease (GVHD) occurred in three patients, but neither grade 3 nor grade 4 disease was observed. Chronic GVHD occurred in 10 patients. One patient had cytomegalovirus (CMV) reactivation but did not develop CMV disease. With a median follow-up of 26 months (range, 15 to 45 months), 11 patients are alive (nine in continuous complete remission and one in complete remission after a second transplantation), and five have died (four from disease progression and one from bone-marrow aplasia induced by cyclosporine withdrawal). The 2-year actuarial overall and event-free survival rates were 69% (95% confidence interval [CI], 40% to 86%) and 56% (95% CI, 30% to 68%), respectively. CONCLUSION: This strategy of RI-HSCT resulted in reliable engraftment with low incidence of acute GVHD and TRM. Durable remissions were observed in patients with MDS and AML consistent with a graft-versus-leukemia effect.

Acute Disease↗
PubMed2002

Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?

BACKGROUND: Vitamin-D deficiency and vitamin-D receptor genotype (VDR) are risk factors for several disorders with inflammatory components, including coronary heart disease (CHD) and diabetes, though the mechanisms involved are unclear. AIM: To examine the hypothesis that vitamin D status modulates the matrix metalloproteinase (MMP) system in a population with a high prevalence of vitamin D deficiency, a situation affecting susceptibility to CHD and diabetes. DESIGN: Prospective cross-sectional, interventional and embedded studies. METHODS: Circulating MMP2,9, the inhibitor TIMP-1 and C-reactive protein (CRP) were measured during studies of vitamin-D deficiency as a risk factor for type 2 diabetes and CHD in 171 healthy British Bangladeshi adults, free of known diabetes or major illness. Vitamin D status, VDR genotype, body-build, blood pressure, lipid and insulin profiles, glucose tolerance, fibrinogen, PAI-1, folate and homocysteine were measured. Vitamin-D-deficient subjects were re-assessed after 1 years' supplementation. MMP, TIMP-1 and CRP levels were measured in 41 subjects halfway through 5-year follow-up. Independent determinants of circulating concentrations of MMP9, TIMP-1 and CRP were assessed by multiple regression analysis. RESULTS: Vitamin D status was the sole determinant of circulating MMP9 (inversely) and an independent determinant of CRP (inversely). Determinants of TIMP-1 were MMP9, systolic blood-pressure (directly) and VDR genotype (TaqI). Significant reductions in MMP9 (-68%), TIMP-1 (-38%) and CRP (-23%) concentrations followed vitamin-D supplementation. DISCUSSION: Vitamin-D insufficiency is associated with increased circulating MMP2,9 and CRP, correctable by supplementation. This finding provides a possible mechanism for tissue damage in chronic inflammatory conditions, including CHD and diabetes.

Adult↗
PubMed2001

Role for CCG-trinucleotide repeats in the pathogenesis of chronic lymphocytic leukemia.

Chromosome 11q deletions are frequently observed in chronic lymphocytic leukemia (CLL) in association with progressive disease and a poor prognosis. A minimal region of deletion has been assigned to 11q22-q23. Trinucleotide repeats have been associated with anticipation in disease, and evidence of anticipation has been observed in various malignancies including CLL. Loss of heterozygosity at 11q22-23 is common in a wide range of cancers, suggesting this is an unstable area prone to chromosome breakage. The location of 8 CCG-trinucleotide repeats on 11q was determined by Southern blot analysis of a 40-Mb YAC and PAC contig spanning 11q22-qter. Deletion breakpoints in CLL are found to co-localize at specific sites on 11q where CCG repeats are located. In addition, a CCG repeat has been identified within the minimal region of deletion. Specific alleles of this repeat are associated with worse prognosis. Folate-sensitive fragile sites are regions of late replication and are characterized by CCG repeats. The mechanism for chromosome deletion at 11q could be explained by a delay in replication. Described here is an association between CCG repeats and chromosome loss suggesting that in vivo "fragile sites" exist on 11q and that the instability of CCG repeats may play an important role in the pathogenesis of CLL.

B-Lymphocytes↗
PubMed1999

Results of collaborative study regarding the standardization of the Y-linked STR system DYS385 by the European DNA Profiling (EDNAP) group.

Y-chromosome linked short tandem repeat (STR) loci are inherited as a closely linked haplotype, which appears to remain stable in a given paternal lineage over many generations. In forensic cases, Y-linked STRs are particularly useful for the identification of human remains as well as in rape cases with mixed male/female stain samples. DYS385 is derived from tandemly duplicated segments of the Y chromosome thus giving rise to two fragments of variable length which do not behave like alleles but genotypes. The European DNA Profiling (EDNAP) group has carried out a collaborative exercise among 14 participating laboratories using DYS385 for typing of five unknown bloodstains and a control sample. Furthermore, population data from eight different European countries with samples sizes between 91 and 150 male individuals were collected. The results confirm previous observations that DYS385 is one of the most informative Y-linked STR loci. It could also be demonstrated that reproducible results can be obtained independently from the electrophoretic separation and detection methods used. Thus DYS385 may serve as a useful complementation to the routinely used autosomal STR systems in special cases.

Blood Protein Electrophoresis↗
PubMed1998

Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease: effects of beta-adrenoreceptor blockers and angiotensin-converting enzyme inhibitors.

OBJECTIVES: To examine circadian changes in the sympathovagal balance, the activity of the renin-angiotensin system and hemostatic variables in patients with stable coronary artery disease, and the effects of beta-adrenoceptor blockade and angiotensin-converting enzyme inhibition. BACKGROUND: Sympathovagal balance and key components of the fibrinolytic system show circadian variability. The effects of beta-adrenergic blocking agents and angiotensin-converting enzyme inhibitors on these autonomic and hemostatic rhythms are not well defined. METHODS: Twenty patients with coronary artery disease underwent 24-h Holter monitoring for heart rate variability and blood sampling (6 hourly for 24 hours) after three consecutive treatment phases, (firstly with placebo, then bisoprolol, and finally quinapril). The effects on sympathovagal balance, hemostatic variables and the renin-angiotensin system activity were measured. RESULTS: The fibrinolytic capacity showed marked circadian variation at the end of the placebo phase (p = 0.002), plasminogen activator inhibitor-1 (PAI-1) activity peaking at 06.00 AM when tissue plasminogen activator (tPA) activity was at its nadir. Sympathovagal balance showed a sharp increase at approximately the same time but plasma renin activity did not rise until later in the day. Inspection of the 24-h profiles suggested that bisoprolol reduced sympathovagal balance and the morning peak of PAI-1 activity and antigen, with a small increase in tPA activity, although these changes were not significant. Quinapril produced a substantial rise in renin (p = 0.01) but did not significantly affect either PAI-1 or tPA. Sympathovagal balance was unaffected by quinapril. CONCLUSIONS: In patients with stable coronary artery disease, angiotensin-converting enzyme inhibition with quinapril does not affect either sympathovagal balance or the endogenous fibrinolytic system. Our data suggest that the sympathoadrenal system may modify fibrinolytic activity, judged by the response to beta-adrenoreceptor blockade with bisoprolol.

Adrenergic beta-Antagonists↗
PubMed1995

Administration of recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy regulates the expression and secretion of monocyte tumor necrosis factor (TNF) and TNF receptors p55 and p75.

Monocyte expression and secretion of tumor necrosis factor (TNF) and TNF receptors (TNF-R) p55 and p75 was studied in patients receiving granulocyte-macrophage colony-stimulating factor (GM-CSF) after intensive chemotherapy. TNF expression and secretion of biologically active TNF was increased at regeneration compared with that of patients who had received chemotherapy alone. This effect persisted for several weeks after cessation of growth factor therapy. GM-CSF restored the responsiveness of monocytes to bacterial lipopolysaccharide (LPS), which appeared to be diminished after chemotherapy alone. Expression and secretion of TNF-R p55 and p75 by monocytes was augmented by GM-CSF therapy in association with the increase in TNF protein. We propose that GM-CSF administration after chemotherapy restores the normal responsiveness of monocytes to a secondary stimulus such as LPS and primes monocytes to respond to LPS with increased expression and secretion of TNF and TNF-R.

Adult↗
PubMed1994

Neopterin release by myeloid leukaemic cells can be synergistically augmented by 1,25-dihydroxyvitamin D3 in combination with gamma interferon or granulocyte-macrophage colony stimulating factor.

Neopterin is a pteridine molecule released by immune activated monocytes. Monocytic maturation may be induced in acute myeloid leukaemia (AML) blasts and the U937 leukaemic cell line by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], an effect which is augmented by both gamma interferon (IFN) or granulocyte-macrophage colony stimulating factor (GM-CSF). We have demonstrated that, while 1,25(OH)2D3 and GM-CSF alone have little effect, both IFN and GM-CSF act synergistically with 1,25(OH)2D3 to increase neopterin secretion in the U937 cell line. Neopterin secretion was associated with, but not necessarily dependent on, the degree of phenotypic differentiation achieved by cells. Neopterin secretion was also synergistically enhanced in AML blasts by the action of 1,25(OH)2D3 in combination with IFN but not GM-CSF; secretion was enhanced in AML blasts without concomitant evidence of phenotypic maturation. We have shown that the monocytoid cell line U937, under appropriate conditions, may secrete neopterin in response to stimulatory agents other than IFN. In addition, the distinct difference in the pattern of response to the combination of 1,25(OH)2D3 with GM-CSF compared with that of 1,25(OH)2D3 plus IFN suggests that the augmentation of 1,25(OH)2D3 effect by IFN and GM-CSF is mediated by separate mechanisms.

Biopterins↗
PubMed1994

Cold-induced increases in erythrocyte count, plasma cholesterol and plasma fibrinogen of elderly people without a comparable rise in protein C or factor X.

1. Six elderly (66-71 years) and six young (20-23 years) subjects (half of each group women) were cooled for 2 h in moving air at 18 degrees C to investigate possible causes of increased mortality from arterial thrombosis among elderly people in cold weather. Compared with thermoneutral control experiments, skin temperature (trunk) fell from 35.5 to 29.5 degrees C, with little change in core temperature. 2. Erythrocyte count rose in the cold from 4.29 to 4.69 x 10(12)/l, without a change in mean corpuscular volume, indicating a 14% or 438 ml decline in plasma volume; increased excretion of water, Na+ and K+ accounted for loss of only 179 ml of extracellular water. 3. Plasma cholesterol and fibrinogen concentrations rose in the elderly subjects from 4.90 mmol/l and 2.97 g/l (control) to 5.45 mmol/l and 3.39 g/l in the cold, and in the young subjects from 3.33 mmol/l and 1.84 g/l (control) to 3.77 mmol/l and 2.07 g/l in the cold. Increases were significant for the elderly subjects, the young subjects and the group as a whole, except for cholesterol in the young subjects, and all were close to those expected from the fall in plasma volume. 4. Plasma levels of Protein C and factor X did not increase significantly in the cold in the elderly subjects, young subjects, or the group as a whole. 5. The results suggest that loss of plasma fluid in the cold concentrates major risk factors for arterial thrombosis, while small molecules, including protective Protein C, redistribute to interstitial fluid.

Adult↗
PubMed1993

Angiographic restenosis after angioplasty: comparison of definitions and correlation with clinical outcome.

BACKGROUND: The aim of this study was to assess which of the currently used definitions of restenosis most closely indicates degree of recurrence and clinical status by 1) correlating percentage luminal renarrowing with restenosis defined according to each of four definitions, and 2) evaluating which definition was best predicted by clinical recurrence. METHODS: Quantitative angiography in 125 patients was undertaken either at time of early clinical presentation or at 6-month follow-up after percutaneous transluminal coronary angioplasty (PTCA). Absolute luminal diameters measured before and after PTCA and at follow-up were plotted as the percentage return from post-PTCA toward pre-PTCA value. All patients were also defined as restenosed or not restenosed according to each of the four definitions. RESULTS: The angiographic restenosis rate varied from 31% to 47%. Other than for "loss of 50% absolute gain," all definitions defined restenosis in some patients, despite the degree of return from post-PTCA to pre-PTCA value being less than 50%. Early recurrent symptoms predicted angiographic restenosis best, irrespective of angiographic definition, whereas history of recurrent angina or positive exercise testing alone at follow-up were poor predictors (range, 0.46 to 0.54). The predictive value increased (0.75 to 0.87) when exercise testing was positive in patients complaining of angina. The definition "loss of 2 standard deviations" gave the lowest values for positive or negative predictive values irrespective of clinical parameter. CONCLUSIONS: "Loss of 50% absolute gain" may be the best compromise definition. Patients admitted early with angina should undergo recatheterization, whereas exercise tests should be reserved for patients who complain of angina at routine follow-up.

Angioplasty, Balloon, Coronary↗
PubMed1992

Streptokinase induced defibrination assessed by thrombin time: effects on residual coronary stenosis and left ventricular ejection fraction.

OBJECTIVE: To evaluate laboratory markers of defibrination early after thrombolytic therapy and to determine their relation to residual stenosis and left ventricular ejection fraction measured angiographically before discharge from hospital. DESIGN: Prospective analysis of defibrination after streptokinase measured by fibrinogen assay and thrombin time to provide a comparison of these coagulation variables for predicting angiographic responses to treatment in patients with acute myocardial infarction. SETTING: The coronary care unit of a district general hospital. PATIENTS: 44 patients with acute myocardial infarction treated by streptokinase infusion, all of whom underwent paired blood sampling before and one hour after streptokinase and cardiac catheterisation at a median of six (interquartile range 3-9) days later. MAIN OUTCOME MEASURES: Assay of thrombin time and plasma fibrinogen concentrations one hour after streptokinase infusion. Relations between these coagulation variables and residual stenosis in the infarct related coronary artery and left ventricular ejection fraction. Separate analyses are presented for all patients (n = 44) and those with patency of the infarct related artery (n = 35). RESULTS: Streptokinase infusion produced profound defibrination in every patient as shown by changes in thrombin time and circulating fibrinogen. Thrombin time after streptokinase infusion correlated significantly with both residual stenosis (r = -0.43, p < 0.005) and left ventricular ejection fraction (r = 0.38, p < 0.02). The importance of these correlations was emphasised by the interquartile group comparison which showed that a thrombin time > or = 49 seconds predicted a residual stenosis of 74% and an ejection fraction of 65%, compared with 90% and 49% for a thrombin time < or = 31 seconds (p < 0.01). When the analysis was restricted to patients with patency of the infarct related artery, the correlation between thrombin time and residual stenosis remained significant and group comparisons continued to show that patients in the highest quartile range had more widely patent arteries and better preservation of ejection fraction. Analysis of the fibrinogen data, on the other hand, showed insignificant or only marginally significant correlations with these angiographic variables. CONCLUSIONS: Early after streptokinase infusion for acute myocardial infarction, the level of defibrination measured by thrombin time has an important influence on residual coronary stenosis and left ventricular ejection fraction at discharge from hospital, values above 49 seconds being associated with the best angiographic result.

Aged↗
PubMed1992

Recombinant alpha 2B interferon in combination with oral chemotherapy in late chronic phase chronic myeloid leukaemia.

The place of alpha interferon (IFN) therapy in the treatment of chronic myeloid leukaemia (CML) is under intensive investigation at present. It is now established that as a single agent it can provide good disease control in the chronic phase and that cytogenetic responses will occur in a minority of patients. However its impact on long term survival has been less certain. Optimal haematological and cytogenetic results have to date been seen when IFN is used in the early phase of the disease, i.e. within one year of diagnosis. We have performed a prospective single arm study on the effect on survival of the addition of low dose IFN (9 mU/week) to conventional oral chemotherapy in patients who were at a median of 19 months from the initial diagnosis at the time of study entry. Comparison of this cohort with a control group of CML patients treated with oral chemotherapy only at the same participating institutions gave an estimated 72% reduction in the risk of death as a result of IFN therapy. Median survival for the IFN group has not been reached at 43 months compared with a median survival of 33 months for the chemotherapy alone group. These results suggest that the introduction of low dose IFN at any stage in the chronic phase may produce a worthwhile improvement in survival.

Antineoplastic Agents↗
PubMed1991

Thrombolytic treatment in acute myocardial infarction: neutrophil activation, peripheral leucocyte responses, and myocardial injury.

OBJECTIVE: To examine early leucocyte responses and neutrophil activation in acute myocardial infarction treated by streptokinase and to relate the findings to coronary recanalisation and indices of myocardial damage in order to provide further information about the role of neutrophils in the evolution of injury. DESIGN: Group analysis of paired blood samples, obtained before streptokinase treatment and one hour after it, and of three indirect measures of myocardial injury: left ventricular ejection fraction, QRS score, and peak creatine kinase. SETTING: The coronary care unit of a district general hospital. PATIENTS: 39 patients with acute myocardial infarction who underwent paired blood sampling (before streptokinase and one hour after streptokinase) and cardiac catheterisation 5 (3-8) days later. END POINTS: Changes in peripheral white cell and neutrophil counts and plasma elastase one hour after streptokinase infusion. Comparison of these variables in patients with and without patency of the infarct related coronary artery. Correlations between these variables and indirect measures of myocardial injury. RESULTS: Neutrophil activation, as reflected by plasma elastase, increased sharply one hour after streptokinase. Total white cell and neutrophil counts also increased. Changes tended to be more pronounced in patients with patency of the infarct related artery, though the trend was not statistically significant. Neutrophil activation before streptokinase was unrelated to indirect indices of myocardial injury but only one hour after streptokinase a weak negative correlation with left ventricular ejection fraction had developed. Peripheral neutrophil responses showed a similar relation to ejection fraction and also correlated with peak creatine kinase and QRS score. CONCLUSIONS: Thrombolytic treatment in acute myocardial infarction is associated with an abrupt reactive neutrophil response which provides an early measure of injury. It is also associated with neutrophil activation, probably in response to coronary recanalisation and myocardial reperfusion. Activated neutrophils are recognised as mediators of reperfusion injury in experimental infarction and the data in the present study provide preliminary evidence of a similar pathogenic role in the clinical setting.

Aged↗
PubMed1991

Increased platelet aggregate formation in patients with chronic airflow obstruction and hypoxaemia.

Platelet aggregate formation in vivo was assessed by means of the platelet aggregate ratio and from platelet release products (beta thromboglobulin, platelet factor 4, thromboxane B2) in 23 patients with chronic airflow obstruction with and without hypoxaemia and in 10 control subjects without respiratory disease. Eight of the 11 hypoxaemic patients were having long term oxygen therapy. The platelet aggregate ratio was lower in the hypoxaemic patients (0.88 (SE 0.03] than in the non-hypoxaemic (0.97 (0.01] and control groups (1.00 (0.02], and there was a trend to lower aggregate ratios in the more hypoxaemic patients. Platelet release products in the peripheral venous blood were not increased in the patients or control subjects. Platelet behaviour is altered in chronic hypoxaemia and this enhanced platelet activity could contribute to the pulmonary vascular damage found in these patients through direct effects or mediator release.

Aged↗