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Biomedical subjects

J W Stephens

Publications and source records attributed to J W Stephens.

At least 19 recordsLinked to original sources
PubMed2006

Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus.

Lipoprotein associated phospholipase A2 (Lp-PLA2) modulates low-density lipoprotein (LDL) oxidation by hydrolysing oxidised phospholipids present on particle surfaces. We investigated whether Lp-PLA2 activity and PLA2G7 A379V genotype were related to mediators of atherosclerosis in a diabetic study. Plasma Lp-PLA2 activity (taken in men only) and A379V genotype were investigated with regards to metabolic syndrome (MS), UKPDS risk score, and oxidised LDL (oxLDL/LDL), in a cohort of Caucasian men and women (n=783, age 62.5+/-13.7 years). After adjustment for type of diabetes, CHD status, and statin use, those individuals with features defining the MS (WHO guidelines) had higher Lp-PLA2 activity (35.6+/-11.9 nmol/min/ml) compared to those without (33.0+/-10.8 nmol/min/ml) (p=0.02). Quartiles of UKPDS coronary heart disease (CHD) risk score were also positively associated with Lp-PLA2 activity (p=0.006, p=0.004 linear trend). Those men in the highest quartile of oxLDL/LDL level had the lowest Lp-PLA2 activity (31.3+/-10.5 nmol/min/ml) when compared to the middle two (32.3+/-9.8 and 35.9+/-10.9 nmol/min/ml, respectively) and lowest quartile (35.6 +/-12.5 nmol/min/ml; p=0.03, p=0.004 linear trend). There was no significant association between A379V genotype and Lp-PLA2 enzyme activity (p=0.34) or oxLDL/LDL (p=0.32). Lp-PLA2 activity is an independent predictor of CHD risk and MS in a sample of subjects with diabetes mellitus. The association of Lp-PLA2 activity with oxLDL/LDL suggests that Lp-PLA2 may be a modulating factor in the process of atherosclerosis.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2006

Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes.

AIMS: To compare blood glucose control using insulin glargine + insulin lispro with that on NPH insulin + unmodified human insulin in adults with Type 1 diabetes managed with a multiple injection regimen. METHODS: In this 32-week, five-centre, two-way cross-over study, people with Type 1 diabetes (n = 56, baseline HbA1c 8.0 +/- 0.8%) were randomized to evening insulin glargine + mealtime insulin lispro or to NPH insulin (once- or twice-daily) + mealtime unmodified human insulin. Each 16-week period concluded with a 24-h inpatient plasma glucose profile. RESULTS: HbA1c was lower with glargine + lispro than with NPH + human insulin [7.5 vs. 8.0%, difference -0.5 (95% CI -0.7, -0.3) %, P < 0.001]. This was confirmed by an 8% lower 24-h plasma glucose area under the curve (AUC) (187 vs. 203 mmol l(-1) h(-1), P = 0.037), a 24% reduction in plasma glucose AUC > 7.0 mmol/l1 (47 vs. 62 mmol l(-1) h(-1), P = 0.017) and a 15% lower post-prandial plasma glucose AUC (75 vs. 88 mmol l(-1) h(-1), P = 0.002). There was no reduction in night-time plasma glucose AUC or increase in plasma glucose area < 3.5 mmol/l. Monthly rate of nocturnal hypoglycaemia was reduced by 44% with glargine + lispro (0.66 vs. 1.18 episodes/month, P < 0.001). CONCLUSIONS: Compared with NPH insulin + unmodified human insulin, the combination of insulin glargine with a rapid-acting insulin analogue as multiple-injection therapy for Type 1 diabetes improves overall glycaemic control as assessed by HbA1c and 24-h plasma glucose monitoring to a clinically significant degree, together with a reduction in nocturnal hypoglycaemia.

Adult↗
PubMed2005

The significant increase in cardiovascular disease risk in APOEepsilon4 carriers is evident only in men who smoke: potential relationship between reduced antioxidant status and ApoE4.

Data from 1668 men (316 cardiovascular disease events) from the Framingham Offspring Study was reanalysed, specifically examining APOE:smoking interactions. Overall hazard ratio (HR) for smoking was 1.95 (1.52, 2.50) compared to non-smokers. Using epsilon3/3 as a referent group, in non-smokers HRs for epsilon2 carriers (epsilon2+; 1.04 (0.61, 1.76) and epsilon4 carriers (epsilon4+; 1.04 (0.70, 1.54) showed no major risk increase. In smokers, HRs were 1.96 (1.26, 2.78) in epsilon3epsilon3 men, 3.46 (2.14, 5.60; p = 0.09 for interaction) in epsilon2+ and 3.81 (2.49, 5.84; p = 0.01 for interaction), with a significant interaction between daily cigarette consumption and APOE genotype on risk (p = 0.03). The potential mechanism for this APOEepsilon4:smoking interaction was examined in a second study of 728 Caucasian patients with diabetes, where markers of reactive oxygen species were available. APOE genotype was not associated with plasma OX-LDL or total antioxidant status (TAOS) in non-smokers. However, in smokers epsilon4+ had 26.7% higher plasma OX-LDL than other genotypes (APOE:smoking interaction p = 0.04), while epsilon2+ had 28.4% higher plasma TAOS than epsilon3epsilon3 and epsilon4+ combined (APOE:smoking interaction p = 0.026). Although direct extrapolation needs to be considered with caution, these results identify that the cardiovascular disease risk-raising effect of epsilon4+ is confined to smokers, and a feasible mechanism is presented by the reduced antioxidant capacity/increased OX-LDL of apoE4.

Adult↗
PubMed2004

Mechanical probes can predict tenderness of cooked beef longissimus using uncooked measurements.

Two experiments were conducted to determine the effectiveness of using mechanical probes and objective color measurement on beef LM to predict cooked tenderness. In Exp. 1, sharp needle (SN), sharp blade (SB), blunt needle (BN), blunt blade (BB), and plumb bob (PB) probes were used to measure uncooked LM (n = 29) at 2 d postmortem in both a perpendicular and parallel orientation to the long axis of the strip loin. Additionally, instrumental color measurements were measured on uncooked muscle at 2 d postmortem. Steaks for trained sensory panel (TSP) and Warner-Bratzler shear force (WBSF) measurements were aged 14 d postmortem before cooking. Probe measurements taken perpendicular to the long axis of the LM were not correlated (P = 0.22 to 0.82) to TSP tenderness. Probe measurements (BB, BN, SN, SB, and PB) taken parallel to the long axis were correlated to TSP tenderness (r = -0.57, -0.40, -0.77, -0.52, and -0.53, respectively). A regression equation using the SN probe to predict TSP tenderness had a R2 value of 0.74. The SB probe combined with L* accounted for 45% of the variation in TSP tenderness, whereas the PB probe combined with L* accounted for 56% of the variation in TSP tenderness. A second experiment (n = 24) was conducted using the SN, SB, and PB probes on uncooked sections at 2 d and on cooked steaks at 14 d postmortem. Probe measurements on cooked steaks were not correlated to TSP tenderness. New regression equations were calculated using the probe measurements on uncooked steaks from both experiments. Prediction equations formulated with L* values and either SN, SB, or PB probes accounted for 49, 50, and 47% of the variability in TSP tenderness scores, respectively. An equation using WBSF of cooked steaks to predict TSP tenderness had an R2 of 0.58. Of the steaks predicted to be tender (predicted tenderness > 5.0) by the equations using the SN, SB, and PB probes on uncooked steaks and WBSF on cooked steaks, 85, 88, 80, and 84%, respectively, were actually tender (TSP tenderness > 5.0). Mechanical probe measurements of uncooked steaks at 2 d postmortem can potentially classify strip loins into groups based on tenderness, as well as WBSF measurements, which are more costly and time consuming.

Aging↗
PubMed2003

The molecular genetics of cardiovascular disease: clinical implications.

Coronary heart disease (CHD) is one of the main leading causes of death worldwide. CHD is a complex condition resulting from numerous gene-gene and gene-environment interactions. A large number of candidate genes exist. We review the evidence for the role of apolipoprotein E, lipoprotein lipase and interleukin-6 in CHD and their interaction with smoking (an environmental risk). The main objective of genetic research into CHD is to provide a complete risk assessment, complementing the well-studied traditional clinical and biochemical risk factors. Unravelling the role that functional gene polymorphisms play in determining risk, and in determining the levels of intermediate phenotypes is crucial to our understanding of the key metabolic pathways and physiology not only in the diseased, but also in the disease-free state. The identification of new molecules (implicated in the relevant metabolic pathways) may subsequently lead to potential targets for therapeutic intervention. Improving our molecular understanding may also lead to the development of improved diagnostics. Sequencing of the entire genome is now a reality. Advances in technology, such as the development of "gene chips" may allow us to study 100 000 genes at a time on a single chip. Such advances will amplify the power available to us in the realms of research into genetic physiology and interaction with environmental stimuli. The insights that these novel approaches may yield are eagerly awaited.

Apolipoproteins E↗
PubMed2002

Insulin reduces serum glycosylphosphatidylinositol phospholipase D levels in human type I diabetic patients and streptozotocin diabetic rats.

The enzyme glycosylphosphatidylinositol phospholipase D has a postulated role in the insulin-mimetic signaling pathway of glycosylphosphatidylinositol compounds. We have investigated enzyme activity in the serum of human type I diabetic patients and plasma and tissues of streptozotocin-induced diabetic rats following insulin administration. In the human diabetic patients serum enzyme activity fell by an average of 10.6% (SEM = 2.7; P = 0.008; n = 20) following administration of insulin. In addition serum enzyme activity appeared to be depleted by 27% (SEM = 8.8; P = 0.011; n = 10) compared to nondiabetic controls. In untreated diabetic rats plasma enzyme activity gradually increased 0.3-fold over a 6-week period (P < 0.001; n = 8), this increase was reversed and activity normalized when these animals were treated with insulin. Cloning of the rat glycosylphosphatidylinositol phospholipase D cDNA enabled confirmation of the liver as the principal organ of synthesis. Analysis of mRNA levels in the livers of the diabetic rats showed that gene expression was reduced in the insulin-treated animals compared to the noninsulin-treated controls by 0.7-fold (P = 0.004; n = 4). Tissue enzyme activity was also reduced in the insulin-treated rats; in skeletal muscle enzyme activity was 0.3-fold lower (P = 0.001; n = 4). Insulin therefore decreases glycosylphosphatidylinositol phospholipase D synthesis in diabetic animals resulting in decreased serum enzyme levels, suggesting a relationship between this enzyme and the function of insulin.

Animals↗
PubMed2002

An unusual steroid-producing ovarian tumour: case report.

The rapid onset of virilization in a post-menopausal woman is usually the result of androgen secretion from a tumour of adrenal or ovarian origin. Androgen secreting neoplasms of the ovary are rare and usually show autonomous secretion. Rarely, these may be driven by the high levels of gonadotrophins seen in the post-menopausal state. We describe the case of a 67-year-old woman with high serum testosterone and estradiol in association with the high gonadotrophin levels usually associated with the post-menopausal state. All hormonal parameters showed a significant suppression over 12 h with administration of the GnRH antagonist, cetrorelix. This observation implies that excess hormone synthesis was of ovarian origin and was gonadotrophin driven. Localization of the tumour was not possible by conventional ultrasound or computerized tomography scanning, but was achieved by venous sampling. Complete cure was achieved by total abdominal hysterectomy and bilateral salpingo-oophorectomy, with restoration of the endocrine profile to that expected for a post-menopausal woman. Rapidly acting GnRH antagonists, such as cetrorelix, offer a safe and useful diagnostic and therapeutic option in the management of ovarian steroid-secreting tumours, which show gonadotrophin dependency.

Aged↗
PubMed2002

Safety and efficacy of quinupristin/dalfopristin for treatment of invasive Gram-positive infections in pediatric patients.

BACKGROUND: Antibiotic-resistant Gram-positive pathogens are an increasingly common cause of serious pediatric infections. Although quinupristin/dalfopristin demonstrates favorable activity against resistant Gram-positive pathogens (including many vancomycin-resistant and methicillin-resistant staphylococci), published experience in the pediatric patient population is limited. METHODS: We retrospectively analyzed data from the global quinupristin/dalfopristin Emergency-Use Program, which enrolled patients with serious Gram-positive infections who had no further therapy options because of resistance to, failure on or intolerance to standard antibiotic treatments. Our subset included safety and efficacy data from pediatric patients (age <18 years). There were no restrictions on underlying diseases, severity of illness or prior/concomitant antimicrobial use. RESULTS: Between May 1995 and October 1999, 127 pediatric patients with 131 infections were enrolled. Microbiologic confirmation of etiology was available in 124 patients. All patients had 1 or more concomitant conditions, including malignancy and solid organ or bone marrow transplantation. The most frequent causative pathogens were vancomycin-resistant (80%), spp. (7%), methicillin-resistant (6%) and (4%). All but 21 patients received intravenous quinupristin/dalfopristin 7.5 mg/kg every 8 h. The favorable clinical response rate of quinupristin/dalfopristin was 86 of 124 (69%); the favorable microbiologic response rate was 97 of 124 (78%). Eleven patients (8%) had nonvenous adverse events classified as possibly or probably related to quinupristin/dalfopristin. CONCLUSIONS: Quinupristin/dalfopristin demonstrated favorable response rates and was reasonably well-tolerated in pediatric patients with serious Gram-positive infections unable to receive alternative therapy. In our opinion quinupristin/dalfopristin is a therapeutic option for the management of such infections.

Adolescent↗
PubMed1999

A study of the effect of chrysotile fiber surface composition on genotoxicity in vitro.

Chrysotile fibers (NIEHS intermediate length) were treated with ultrapure HCl to alter the fiber surface chemistry without substantially changing fiber morphology or dimensions. The objective of the study was to determine whether fiber surface chemistry is an important variable in fiber genotoxicity in vitro. The modified fibers, along with native chrysotile fibers, were used to challenge Chinese hamster lung fibroblasts (V79) in vitro using the micronucleus induction genotoxicity assay. Fiber dimensions were assessed using scanning electron microscopy by measuring the distribution of fiber lengths in 3 length ranges: less than 3 microm, 3-10 microm, and greater than 10 microm. For both treated and native fiber samples, 500 fibers were examined. Results indicate that acid-treated fibers were about 20% shorter than untreated chrysotile. Surface chemistry alterations were verified by zeta-potential reversal, x-ray photoelectron spectroscopy (XPS), and scanning electron microscopy/energy-dispersive x-ray spectroscopy (SEM-EDS) elemental analysis. Scanning Auger spectrometry indicated the presence of Mg, O, and Si in both treated and native chrysotile samples, which confirmed the surface purity of both fiber samples. Both XPS and SEM-EDS analysis demonstrated substantial depletion of Mg from fiber surfaces. Results of the micronucleus assay showed a positive concentration-related response for both samples, with toxicity evident only at the highest concentration. No significant difference was found for the treated and untreated chrysotile samples. These results indicate that the surface chemistry is not an important variable in the in vitro genotoxicity of chrysotile asbestos in V79 cells as detected by the micronucleus assay under the conditions used in this study, and support a model of chemically nonspecific chromosomal and spindle damage effects.

Animals↗
PubMed1999

The role of fructose-1,6-diphosphate in cell migration and proliferation in an in vitro xenograft blood vessel model of vascular wound healing.

Both smooth muscle cells and endothelial cells play an important role in vascular wound healing. To elucidate the role of fructose-1,6-diphosphate, cell proliferation and cell migration studies were performed with human endothelial cells and rat smooth muscle cells. To mimic blood vessels, endothelial and smooth muscle cells were used in 1:10, 1:5, and 1:1 concentrations, respectively, mimicking large-, mid-, and capillary-sized blood vessels. Cell migration was studied with fetal bovine serum-starved cells. For cell proliferation assay, cells were plated at 30-50% confluency and then starved. The cells were incubated for 48 h with fructose-1,6-diphosphate at (per ml) 10 mg, 1 mg, 500 microg, 250 microg, 100 microg, and 10 microg, pulsed with tritiated-thymidine and incubated with 1 N NaOH for 30 min at room temperature, harvested, and counted. For migration assay, confluent cells were starved, wounded, and incubated for 24 h with same concentrations of fructose-1,6-diphosphate as in proliferation assay. The cells were fixed and counted. Smooth muscle cell proliferation was inhibited by fructose-1,6-diphosphate at 10 mg/ml. In the xenograft models of 1:10, 1:5, and 1:1 fructose-1,6-diphosphate inhibited proliferation at 10 mg/ml. In migration studies 10 mg fructose-1,6-diphosphate per ml was inhibitory to both cell types. In large-, mid-, and capillary-sized blood vessels, fructose-1,6-diphosphate inhibited proliferation of both cell types at 10 mg/ml. At the individual cell level, fructose-1,6-diphosphate is nonstimulatory to proliferation of endothelial cells while inhibiting migration, and it acts on smooth muscle cells by inhibiting both proliferation and migration.

Animals↗
PubMed1995

Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep venous thrombosis after elective knee arthroplasty. Enoxaparin Clinical Trial Group.

This study was a randomized, parallel-group, open-label clinical trial comparing the efficacy and safety of Enoxaparin, a low-molecular-weight heparin, and unfractionated heparin to prevent deep venous thrombosis after elective total knee arthroplasty. Four hundred fifty-three patients were randomized and received study medications. The primary efficacy evaluation was unilateral contrast venography done at the end of study or earlier if clinically indicated. The primary safety outcome was the incidence of bleeding episodes. Patients were assigned to 1 of 2 postoperative treatment groups: Enoxaparin 30 mg subcutaneous every 12 hours (228 patients), or unfractionated heparin 5000 units subcutaneous every 8 hours (225 patients). The incidence of proximal and distal deep venous thrombosis in the Enoxaparin group was 24.6% (56/228), and in the heparin group 34.2% (77/225). Three major hemorrhagic episodes were observed in each treatment group. Two cases of pulmonary embolism occurred in patients receiving heparin (1 fatal); no cases occurred in patients receiving Enoxaparin. This study showed that Enoxaparin administered postoperatively 30 mg every 12 hours is more effective and as safe as unfractionated heparin prophylaxis to prevent deep venous thrombosis in patients having elective total knee arthroplasty.

Aged↗
PubMed1988

The effect of glucose priming solutions in diabetic patients undergoing coronary artery bypass grafting.

To assess the impact of glucose-containing priming solutions on plasma glucose level in diabetic patients during and after coronary artery bypass graft surgery, we studied 50 diabetic patients and 10 nondiabetic patients who underwent bypass graft surgery. Glucose-containing priming solutions profoundly elevated plasma glucose levels during and after bypass graft surgery. In diabetic patients who received glucose primes, intraoperative peak plasma glucose levels averaged 696 +/- 48 mg/dl as compared with 341 +/- 17 mg/dl in diabetic patients who received nonglucose primes (p less than 0.001). Despite an insulin infusion, diabetic patients underwent a much slower decline in plasma glucose levels postoperatively over a 2-hour period than did nondiabetics (who did not receive an insulin infusion). We conclude that during and immediately after coronary artery bypass surgery in diabetic patients, it is desirable to avoid administration of glucose-containing priming solutions, since such solutions profoundly elevate plasma glucose levels.

Aged↗