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J Webber

Publications and source records attributed to J Webber.

At least 37 records · Page 2Linked to original sources
PubMed1996

Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM.

Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.

Adult↗
PubMed1996

An apoptotic response to photodynamic therapy with endogenous protoporphyrin in vivo.

CDF1 mice bearing the colon-26 tumor were treated with aminolevulinic acid (200 mg kg-1) by tail-vein injection, with tumor sites irradiated 4 h later at 633 nm (75-120 J cm-2). 10 h after irradiation, samples of tumors were removed for histology studies and analysis of DNA fragmentation by static gel electrophoresis. The resulting patterns indicate an apoptotic response to photodynamic therapy with endogenously formed protoporphyrin.

Animals↗
PubMed1995

Detection of p53 mutations in benign and dysplastic nevi.

We have examined melanocytic cells derived directly from fresh biopsy tissue for the presence of p53 mutations. Using selective media that permits growth of melanocytes and inhibits growth of fibroblasts and keratinocytes, we established short-term, primary cultures of melanocytes from skin biopsies of common acquired nevi, dysplastic nevi, and from metastatic melanoma. Using PCR-single-stranded conformational polymorphism analysis, we have detected p53 mutations in 2 of 11 benign compound nevi and 2 of 5 dysplastic nevi. All nevi positive for p53 mutations were derived from patients who previously had cutaneous moles and three of the four had a family and/or personal history of melanoma.

Base Sequence↗
PubMed1995

Relationship between clinical manifestations of footrot and specific DNA products of Dichelobacter nodosus amplified through PCR.

A total of 141 Dichelobacter nodosus isolates from 46 merino sheep farms with various clinical forms of footrot was examined by the gelatin gel test and the polymerase chain reaction (PCR) using virulent (Vf2 and Vr2) and benign (Bf and Br) specific primers. Isolates from sheep with virulent and high intermediate footrot usually produced relatively thermostable proteases, but a decreasing proportion of the isolates from sheep with medium and low intermediate or benign footrot had thermostable proteases, as determined by the gelatin gel test. The amplification by PCR of a major band of 857 bp by Vf2 and Vr2 was often associated with isolates from the more virulent forms of footrot whereas the presence of a major band of 1300 bp by Vf2 and Vr2 and/or a band of 609 bp by Bf and Br was associated with isolates from less virulent forms of footrot. Nevertheless, the virulent and benign gene regions represented by Vf2 and Vr2 and Bf and Br are only two of the many factors involved in determining the virulence of D nodosus. As a result the relationship observed between the clinical manifestations of footrot and specific DNA products amplified by PCR was not complete.

Animals↗
PubMed1995

A polymerase chain reaction assay for improved determination of virulence of Dichelobacter nodosus, the specific causative pathogen for ovine footrot.

Three sets of oligonucleotide primers (Vf1 and Vr1, Vf2 and Vr2, Bf and Br) were derived from a D. nodosus virulent-specific clone pV470-13 (2146 bp) and a benign-specific clone pB645-335 (737 bp), respectively. Using the virulent-specific primers Vf1 and Vr1 in a polymerase chain reaction (PCR) enabled amplification of a DNA fragment of 460 bp in 25/27 virulent, 9/25 high intermediate, 9/24 low intermediate and 2/20 benign isolates of D. nodosus. On the other hand, using the second set of the virulent-specific primers Vf2 and Vr2 resulted in the production of either a fragment of 857 bp or 1300 bp in virulent, intermediate and 3/20 benign isolates. There appeared to be some correlation between the amplification of the smaller fragment (857 bp) and higher elastase activity and between the amplification of the larger fragment (1300 bp) and lower elastase activity of D. nodosus. The use of the benign-specific primers Bf and Br in PCR enabled amplification of a fragment of 609 bp in all 20 benign, 23/24 low intermediate, 20/25 high intermediate and 0/27 virulent isolates. The combination of the virulent-specific primers Vf2 and Vr2 and benign-specific primers Bf and Br in PCR would provide a rapid, specific and sensitive differentiation of strains of D. nodosus causing virulent, intermediate or benign footrot.

Animals↗
PubMed1995

Novel cytotoxic DNA sequence and minor groove targeted photosensitizers: conjugates of pyrene and netropsin analogues.

The design, syntheses, photochemical and biological properties of conjugates of pyrene with pyrrole- (1) and imidazole-containing (2) analogues of netropsin are reported. The results of an ethidium displacement assay and circular dichroism (CD) titration studies show both compounds bind with a higher affinity to poly(dA-dT) than to poly(dG-dC). In addition they bind as strongly to T4 coliphage DNA as to calf thymus DNA suggesting the binding occurs in the minor groove. The quenching rate constants of the singlet excited states of agents 1 and 2 by molecular oxygen were found to be 8.5 x 10(9) M-1S-1 and 7.7 x 10(9) M-1S-1, suggesting the involvement of singlet oxygen. Both compounds showed some cytotoxicity to human chronic myeloid leukemia K562 cells in the dark. Upon irradiation the activities were significantly enhanced resulting in photoinduced dose modifications of 8 and 14 for 1 and 2, respectively under the conditions employed. Both agents were markedly more phototoxic than 1-pyrenebutyric acid 8. To address the mechanism of action of compounds 1 and 2 their photoactivated abilities to produce DNA strand breaks were measured. Both agents caused increased single strand breakage with increasing UV exposure. The concentrations (EC50) of 1 and 2 needed to cause 50% single-strand cleavage of pBR322 DNA upon UV-A activation were found to be 40 microM and 45 microM, respectively. In contrast, no DNA strand breaks were observed in the dark with either conjugate or with 8 following irradiation. DNA strand breaks were measured in drug treated K562 cells using alkaline elution.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1995

The effects of fasting on the thermogenic, metabolic and cardiovascular responses to infused adrenaline.

The effects of fasting on the thermogenic, lipolytic and cardiovascular responses to adrenaline were examined in nine normal, young, non-obese subjects. Each subject attended for study after 12, 36 and 72 h fasting. After basal measurements adrenaline was infused at 25 ng/min per kg ideal body weight for 90 min. Fasting increased the thermogenic effect of the adrenaline (mean 14.6 (SE 1.7), 16.6 (SE 1.8), 22.6 (SE 1.6) J/min per kg fat-free mass after 12, 36 and 72 h fasting respectively; P < 0.001, ANOVA). Basal plasma palmitate turnover increased with duration of fasting (1.48 (SE 0.22), 1.95 (SE 0.34) and 2.26 (SE 0.33) mumol/min per kg body weight; P < 0.001, ANOVA), but the response to adrenaline was unaffected by fasting. The percentage values for basal plasma palmitate turnover oxidized were 44 (SE 2; 12 h), 46 (SE 5; 36 h) and 42 (SE 4)% (72 h). In response to adrenaline this percentage fell, suggesting that adrenaline infusion may favour intra-tissue lipid oxidation.

Adult↗
PubMed1995

Cardiovascular and metabolic responses to adrenaline infusion in patients with short-term hypothyroidism.

OBJECTIVE: The relation between the clinical manifestations of thyroid disease (both hypo and hyper-thyroidism) and tissue sensitivity to catecholamines remains uncertain. It has been suggested that tissue adrenergic responsiveness is decreased in hypothyroidism, but the reports have been conflicting and have invariably focused on a single physiological response. Therefore the aim of the present study was to determine in patients with moderate, short-term, symptomatic hypothyroidism the responses of heart rate, systolic and diastolic blood pressure, forearm blood flow and metabolic rate to adrenaline infused at a rate known to achieve plasma concentrations in the middle of the physiological range. PATIENTS: Ten subjects (5M, age 43 +/- 3 years, mean +/- SEM) were studied. All were on thyroxine replacement for hypothyroidism following either thyroidectomy or radioactive iodine and had been biochemically euthyroid for at least 6 months. DESIGN: Studies were performed in random order. One study was undertaken on full replacement therapy and the other after 50 micrograms thyroxine daily for 2 weeks. After basal, supine measurements adrenaline was infused at 25 ng/kg/min for 30 minutes. MEASUREMENTS: Heart rate, blood pressure, blood glucose, metabolic rate and forearm blood flow were measured at rest and at 10-minute intervals throughout the adrenaline infusion. RESULTS: Free T4 (10.6 +/- 1.3 vs 17.6 +/- 2.0 pmol/l, P < 0.001) and free T3 (3.6 +/- 0.2 vs 4.6 +/- 0.3 pmol/l, P < 0.01) concentrations were significantly lower on 50 micrograms thyroxine than full replacement therapy. Fasting blood glucose concentrations (4.7 +/- 0.2 vs 4.7 +/- 0.1 mmol/l) were similar. The resting adrenaline concentrations were comparable, 0.29 +/- 0.18 and 0.24 +/- 0.14 nmol/l on 50 micrograms thyroxine and full replacement therapy respectively, and increased to a similar level (2.36 +/- 0.39 and 2.36 +/- 0.35 nmol/l) throughout the adrenaline infusion. The resting heart rate and metabolic rate were significantly lower on 50 micrograms thyroxine than full replacement therapy (68 +/- 2 vs 72 +/- 3 beats/min, P < 0.01; and 4.48 +/- 0.35 vs 4.88 +/- 0.39 kJ/min, P < 0.01) respectively, but the increase in heart rate (7 +/- 2 vs 8 +/- 2 beats/min) and metabolic rate (0.43 +/- 0.09 vs 0.43 +/- 0.06 kJ/min) did not differ on the two study days. Resting systolic blood pressure, diastolic blood pressure and forearm blood flow were comparable on 50 micrograms thyroxine and full replacement therapy as were the changes in systolic blood pressure (1 +/- 1 vs 1 +/- 1 mmHg), diastolic blood pressure (-7 +/- 2 vs -7 +/- 1 mmHg), forearm blood flow (1.4 +/- 0.1 vs 1.7 +/- 0.2 ml/min/100ml forearm) and blood glucose concentration (0.7 +/- 0.1 vs 0.7 +/- 0.1 mmol/l). CONCLUSIONS: Patients with short-term hypothyroidism appear to have a normal response to adrenaline infusion despite reduced baseline heart rate and metabolic rate. Thus, under physiological and mild pathophysiological conditions there appears to be no evidence of any synergy between thyroid status and sensitivity to catecholamines.

Adult↗
PubMed1995

Enhancement of liposome-mediated gene transfer into vascular tissue by replication deficient adenovirus.

For both in vitro and in vivo experiments, especially in vascular cells, an efficient and easy method of gene transfer into this tissue would be extremely useful. Previous methods have either yielded low levels of expression or require complicated manipulation of viral vectors. The goal of this study was to develop an easy, efficient method to introduce unmodified plasmid DNA into vascular tissue. In this report it is demonstrated that complexing unmodified plasmid DNA with replication-deficient adenovirus (Ad5 dl312) via cationic lipids enhances gene transfer up to 1000-fold in cultured bovine aortic endothelial cells (BAECs). Further, utilizing a balloon-injured rabbit femoral artery model, intense nuclear staining in both the neointimal smooth muscle cell layer and the adventitia was seen following transfection with a plasmid containing the lacZ gene and the SV40 nuclear localization signal. Control arteries demonstrated no detectable staining. Our studies suggest that complexing plasmid DNA with adenovirus via lipids greatly enhances gene transfer both in vivo and in vitro. This method could have a wide range of applications for experiments in vascular tissue.

Adenoviruses, Human↗
PubMed1994

New directions in palliative care education.

In the past, palliative care education in the United Kingdom has tended to be patchy and ad hoc, rather that systematic and comprehensive. Recently the picture has begun to change, and this paper identifies and discusses three areas where developments are occurring. Firstly, educational provision has become more comprehensive and systematic, so that the needs of staff in all care settings and at all levels of practice and experience are now being addressed. Secondly, palliative nursing curricula that draw on research into the problems of nurses working with dying patients and the dimensions of the supportive role are now being developed. Thirdly, a number of initiatives are underway to assure the quality of palliative care education. Two of those initiatives concern the preparation, support and evaluation of educational roles and the development of educational research programmes.

Clinical Competence↗
PubMed1994

A comparison of skinfold thickness, body mass index, bioelectrical impedance analysis and dual-energy X-ray absorptiometry in assessing body composition in obese subjects before and after weight loss.

The assessment of body composition in obese subjects by anthropometric means (skinfolds), presents many difficulties. This study compares the estimates provided of fat free mass in 21 obese subjects (mean body mass index 36.6 +/- 1.2 kg/m(2)) using body mass index and skinfold thickness, with those obtained using the more recently developed techniques of bioelectrical impedance analysis and dual-energy X-ray absorptiometry. Despite highly significant correlations between some of the methods (r(2) = 0.94 for dual-energy X-ray absorptiometry versus bioelectrical impedance analysis), there was a considerable lack of agreement in the measurements, particularly when skinfold thickness was compared with dual-energy X-ray absorptiometry (limits of agreement -21.9 to -1.5 kg for fat free mass estimated from dual-energy X-ray absorptiometry and skinfold thickness) and even for dual-energy X-ray absorptiometry and bioelectrical impedance analysis (limits of agreement -10.7 to 0.4 kg). After weight loss the intermethod differences were reduced.

Journal Article↗
PubMed1994

A retrospective study of clinical and laboratory characteristics of ovine footrot.

The infection of the feet of sheep by the anaerobic bacterium Dichelobacter nodosus results in a spectrum of diseases ranging from virulent through intermediate to benign footrot. By examining the clinical characteristics of various forms of footrot from 22 properties in Victoria, Australia in association with the results of several laboratory tests including the gene probe-based dot blot hybridisation, it was shown that virulent footrot could not be differentiated from intermediate footrot using the clinical characteristics alone. In addition, D. nodosus isolates from sheep with benign footrot as diagnosed by the clinical manifestations might in fact show characteristics associated with those causing virulent, intermediate or benign footrot as determined by the laboratory tests. Although the elastase test, gelatin gel test and dot blot were in agreement with isolates from 9 of the 22 properties under investigation, they displayed differences from one another in many other cases, especially those with clinical benign footrot. The results of the elastase test appeared to be slightly closer to those of the dot blot compared with the gelatin gel test. Like any other tests based on the measurements of phenotypic characteristics of D. nodosus bacteria, the elastase test and gelatin gel test are subject to changes with factors that affect bacterial growth and metabolism. The use of DNA based detection methods would eliminate many of the problems associated with the conventional tests for differentiating strains causing virulent, intermediate and benign footrot.

Animals↗
PubMed1994

Metabolic effects of acute hyperketonaemia in man before and during an hyperinsulinaemic euglycaemic clamp.

1. The effects of acutely raising blood ketone body levels to those seen after 72 h of starvation were examined in 10 subjects after an overnight fast. Metabolic rate and respiratory exchange ratio were measured with indirect calorimetry before and during an insulin-glucose clamp. Arteriovenous differences were measured across forearm and subcutaneous abdominal adipose tissue. 2. In response to the clamp the respiratory exchange ratio rose from 0.82 to 0.83 during 3-hydroxybutyrate infusion and from 0.83 to 0.94 during control (saline) infusion (P < 0.001). 3. Forearm glucose uptake at the end of the clamp was 4.02 +/- 0.95 (3-hydroxybutyrate infusion) and 7.09 +/- 1.24 mmol min-1 100 ml-1 forearm (saline infusion). Whole body glucose uptake at the end of the clamp was 72.8 +/- 7.9 (3-hydroxybutyrate infusion) and 51.0 +/- 3.0 (saline infusion) mmol min-1 kg-1 body weight-1. 4. 3-Hydroxybutyrate infusion reduced the baseline abdominal venous-arterialized venous glycerol difference from 84 +/- 28 to 25 +/- 12 mmol/l and the non-esterified fatty acid difference from 0.60 +/- 0.17 to 0.02 +/- 0.09 mmol/l (P < 0.05 versus saline infusion). 5. Hyperketonaemia reduces adipose tissue lipolysis and decreases insulin-mediated forearm glucose uptake. Hyperketonaemia appears to prevent insulin-stimulated glucose oxidation, but does not reduce insulin-mediated glucose storage.

3-Hydroxybutyric Acid↗
PubMed1994

Effects of fasting on fatty acid kinetics and on the cardiovascular, thermogenic and metabolic responses to the glucose clamp.

1. The effects of fasting for 12, 36 and 72 h were examined in 19 normal subjects. Each subject was studied before and during a euglycaemic (4 mmol/l) hyperinsulinaemic (100 m-units min-1 m-2) clamp. Measurements were made of palmitate turnover and oxidation, glucose disposal, thermogenesis, intermediary metabolites and cardiovascular variables. 2. Basal respiratory exchange ratio fell from 0.78 +/- 0.01 to 0.75 +/- 0.01 to 0.72 +/- 0.01 with fasting (P < 0.001). In response to the clamp it rose to 0.91 +/- 0.02, 0.83 +/- 0.01 and 0.77 +/- 0.01 after 12, 36 and 72h respectively. Metabolic rate rose during the clamp by 0.41 +/- 0.06, 0.11 +/- 0.03 and 0.14 +/- 0.04 kJ/min respectively (P < 0.001 for 36- and 72-h values versus that at 12h). 3. Fasting reduced total insulin-mediated glucose disposal rates from 42.6 +/- 2.5, to 31.0 +/- 1.8 to 21.3 +/- 1.5 mumol min-1 kg-1 body weight after 12, 36 and 72h respectively (P < 0.001). Glucose oxidation fell from 16.9 +/- 1.1 to 8.7 +/- 1.7 to 0.2 +/- 1.3 mumol min-1 kg-1 body weight over the same period (P < 0.001). Non-oxidative glucose disposal rates did not change significantly. 4. Basal plasma palmitate turnover increased with duration of fasting, being 1.16 +/- 0.08, 1.72 +/- 0.17 and 2.30 +/- 0.35 mumol min-1 kg-1 body weight. In response to the clamp, palmitate turnover fell to 0.42 +/- 0.05, 0.69 +/- 0.08 and 1.28 +/- 0.45 mumol min-1 kg-1 body weight. Plasma palmitate oxidation was 0.58 +/- 0.04, 0.75 +/- 0.06 and 1.13 +/- 0.11 mumol min-1 kg-1 body weight basally, and fell to 0.16 +/- 0.02, 0.28 +/- 0.04 and 0.43 +/- 0.13 mumol min-1 kg-1 body weight by the end of the clamp. The proportion of total lipid oxidation represented by plasma non-essential fatty acid oxidation was not affected by fasting, but fell in response to the clamp. 5. Fasting caused a progressive resistance to the effects of insulin and glucose on oxidative glucose disposal and on forearm glucose uptake. Insulin-mediated glucose storage was unaffected by fasting, but the apparent cost of this storage was reduced by fasting.

Adult↗
PubMed1994

The cardiovascular, metabolic and hormonal changes accompanying acute starvation in men and women.

The effect of fasting for 12, 36 and 72 h was studied in twenty-nine healthy subjects (seventeen women and twelve men). Measurements were made of cardiovascular variables, metabolic rate, respiratory exchange ratio, plasma metabolites, insulin, thyroid hormones and catecholamines. During starvation there were no significant changes in blood pressure, whilst heart rate (beats/min) increased at 36 h and remained elevated after 72 h (12 h 62.5 (SE 1.8), 36 h 68.0 (SE 1.9), 72 h 69.2 (SE 1.8); P < 0.001). Forearm blood flow (FBF) increased progressively from 3.32 (SE 0.20) to 6.21 (SE 0.46) ml/100 ml per min (P < 0.001). Resting metabolic rate (kJ/min) was significantly increased after 36 h of starvation (12 h 4.60 (SE 0.14), 36 h 4.88 (SE 0.13), P < 0.001), but was not significantly different from the 12 h value after 72 h (72 h 4.72 (SE 0.15) P = 0.06). The respiratory exchange ratio fell progressively from 0.80 to 0.76 to 0.72 (P < 0.001). Blood glucose fell, whilst plasma glycerol and beta-hydroxybutyrate rose and plasma lactate did not change. Plasma insulin and free triiodothyronine fell during starvation. Plasma adrenaline and noradrenaline were unchanged at 36 h, but were significantly increased after 72 h. Both sexes showed a similar pattern of response to starvation, although absolute values of blood pressure, forearm blood flow, metabolic rate and plasma catecholamines were higher in men than women. Acute starvation produces profound cardiovascular and metabolic changes which are not explained by the accompanying hormonal changes.

Adult↗
PubMed1994

A comparison of the thermogenic, metabolic and haemodynamic responses to infused adrenaline in lean and obese subjects.

The objective of this work was to study adrenoceptor sensitivity in vivo in a number of tissues in lean and obese humans. The thermogenic, metabolic and cardiovascular responses to a 90 min infusion of adrenaline were measured. The subjects were eleven obese subjects (Body Mass Index 36.0 +/- 1.2 kg/m2) and 10 non-obese subjects (Body Mass Index 21.9 +/- 0.7 kg/m2). Metabolic rate, heart rate, blood pressure, forearm blood flow, plasma palmitate turnover and oxidation were measured. Thermogenic responses to adrenaline were similar in the lean and obese groups (14.4 +/- 1.6 and 15.1 +/- 1.6 J/min/kg fat free mass respectively). Of the cardiovascular variables measured, only the increase in forearm blood flow during adrenaline infusion differed between lean and obese, being 3.9 +/- 0.5 and 1.9 +/- 0.3 ml/min/100 ml forearm respectively. Basal plasma palmitate turnover rates were lower in the obese when expressed per unit fat mass (2.32 +/- 0.17 and 7.61 +/- 1.20 mumol/min/kg fat mass respectively). Basal plasma palmitate oxidation rates were higher in the obese when expressed per unit fat free mass (1.53 +/- 0.19 and 0.82 +/- 0.12 mumol/min/kg fat free mass respectively). In response to adrenaline palmitate turnover increased similarly in both groups, but plasma palmitate oxidation rates fell in the obese whilst they were unchanged in the lean. In the basal state the obese do not appear to have a defect in fat oxidation, but their response to infused adrenaline may favour fat storage over oxidation. No thermogenic defect was shown in the obese.

Adult↗
PubMed1994

The effects of weight loss in obese subjects on the thermogenic, metabolic and haemodynamic responses to the glucose clamp.

The aim of this work was to examine the effects of weight loss in obese subjects on the thermogenic, metabolic and cardiovascular responses to a glucose clamp. Resting measurements were made, followed by a hyperinsulinaemic (100 mU/m2/min) euglycaemic clamp (4.5 mmol/l). The subjects were six healthy, obese subjects (mean body mass index before weight loss 37.0 +/- 1.7 kg/m2 and after weight loss 31.4 +/- 2.3 kg/m2). The following measurements were made: indirect calorimetry, blood pressure, heart rate, forearm blood flow, plasma catecholamines, plasma deuterated glucose turnover before and during a glucose clamp. Glucose disposal during the clamp increased from 2.53 +/- 0.40 to 3.31 +/- 0.42 mmol/min after weight loss (P < 0.01). Glucose-induced thermogenesis rose from 0.15 +/- 0.09 to 0.50 +/- 0.12 kJ/min (P < 0.05). The apparent cost of glucose storage was not significantly different from zero prior to weight loss, but increased to 11.0 +/- 2.2% after weight loss. In response to the clamp endogenous glucose production was suppressed by 66 +/- 7% initially and this was not affected by weight loss. Weight loss was accompanied by increased peripheral insulin sensitivity and glucose-induced thermogenesis, but it did not affect hepatic insulin sensitivity.

Adult↗