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M Barton

Publications and source records attributed to M Barton.

At least 73 records · Page 4Linked to original sources
PubMed1997

Angiotensin II increases tissue endothelin and induces vascular hypertrophy: reversal by ET(A)-receptor antagonist.

BACKGROUND: In vitro studies on vascular smooth muscle cells suggest that endothelin has a stimulating effect on cellular proliferation. This study was designed to determine the endogenous effect of endothelin on angiotensin II-induced hypertrophy of small arteries in vivo. METHODS AND RESULTS: Two weeks of angiotensin II administration (200 ng x kg[-1] x min[-1]) increased media thickness, media/lumen ratio, and cross-sectional area of basilar and small mesenteric arteries, confirming the proliferative properties of angiotensin II. The tissue levels of endothelin-1 were elevated in mesenteric arteries after angiotensin II administration. The administration of the selective and specific ET(A)-receptor antagonist LU135252 (50 mg x kg[-1] x d[-1]) in combination with angiotensin II prevented the changes of vascular geometry and partially reduced the increase in blood pressure induced by angiotensin II. Indeed, part of the effect on the vascular structure of the endothelin-receptor antagonist seemed pressure-independent. CONCLUSIONS: Our results therefore demonstrate that angiotensin II increases the production of endothelin in the blood vessel wall that, via ET(A) receptors, mediates changes in vascular structure of the cerebral and mesenteric circulation. Endothelin antagonists may therefore be of value to reduce blood pressure and to prevent vascular structural changes in conditions of increased activity of the renin-angiotensin system.

Angiotensin II↗
PubMed1997

Uncoupling of S-phase and mitosis by recombinant cytotoxic necrotizing factor 2 (CNF2).

Cytotoxic necrotizing factor 2 (CNF2) is an exotoxin identified from virulent clinical isolates of Escherichia coli. It has been characterized in adherent cell lines as an inducer of cellular death, hyperploidy (multinucleation), and cytoskeletal reorganization. The molecular mechanism of these actions is unclear. Two cellular mechanisms can be hypothesized to explain the DNA content increase (hyperploidy) induced by the toxin. The first is that the toxin interferes with cytoplasmic division without interfering with normal nuclear cycling, such that DNA is replicated in the absence of cell division. The second is that the toxin drives the nuclear machinery to replicate the DNA multiple times within one cell cycle, without interfering with cytoplasmic division. In order to investigate these phenomena, we have constructed a recombinant CNF2 gene that expresses a toxin with both an epitope tag and a polyhistidine tag. Extracts made from E. coli that express this gene have a high multinucleating activity that colocalizes with the recombinant 115-kDa protein. To distinguish between these hypotheses, we used recombinant CNF2 and several growth conditions (time, partial differentiation, and stage of growth) to establish a relationship between cellular divisions and generation of hyperploidy. It was also determined that the toxin had no effect upon in vitro DNA replication using a Xenopus egg extract system. In aggregate, these data are consistent with the hypothesis that CNF2 is affecting cytoplasmic division and thereby removing the requirement for a completed mitosis before the initiation of another S-phase. These data are discussed in relation to the generation of polyploid cells during megakaryopoeisis and the generation of aneuploid cells during tumorigenesis.

3T3 Cells↗
PubMed1997

Endothelial-derived superoxide anions in pig coronary arteries: evidence from lucigenin chemiluminescence and histochemical techniques.

1. The generation of superoxide anions (O2-) by intact pig coronary artery rings was measured using a lucigenin-enhanced chemiluminescence technique and a histochemical technique with Nitroblue Tetrazolium (NBT) staining. 2. Isolated arteries with intact endothelium generated O2- at a rate of 9.0 +/- 0.8 pmol min-1 (mg dry weight)-1; this rate was diminished by about 24% when the endothelium was removed. The NBT staining of arterial ring preparations showed formazan precipitation mainly in the intima. Arterial rings were pretreated with diethylthiocarbamate in order to inhibit Cu-Zn superoxide dismutase (SOD) activity which increased the O2- generation by 184 +/- 55% (n = 10; P < 0.01). Stimulation of protein kinase C with phorbol 12-myristate 13-acetate (5 microM) enhanced endothelium-dependent O2- generation by 136 +/- 20% (n = 19; P < 0.01). Neither stimulation with bradykinin or substance P, nor inhibition with NG-nitro-L-arginine methyl ester of endothelial nitric oxide synthase had a significant effect on O2- generation. In contrast, the inhibition of flavoproteins with diphenyliodonium decreased concentration-dependent O2- generation (IC50, 1.85 +/- 5.33 microM). Inhibition of tetrahydrobiopterin synthesis with 2,4-diamino-6-hydroxy-pyrimidine resulted in a reduced generation of O2- by about 55%. 3. The addition of 100 microM NADH and 100 microM NADPH resulted in an excessive generation of O2- at a rate of 0.68 +/- 0.03 and 0.26 +/- 0.01 nmol O2- min-1 (mg protein)-1, respectively, in the membrane fraction, but not in the cytosolic fraction, of homogenates obtained from arteries. 4. The results suggest that intact coronary arteries do generate O2- under basal conditions and that the endothelial layer significantly contributes to this phenomenon. This generation of O2- is greatly influenced by intrinsic SOD activity. It is suggested that basal vascular O2- generation is mainly due to membrane-bound NAD(P)H oxidase activity and/or tetrahydrobiopterin-dependent processes.

Acridines↗
PubMed1997

[Vascular protection with estrogen. In-vitro and in-vivo effects--mechanisms and clinical implication].

Myocardial infarction is the major cause of death in the western world. Men are more prone to develop coronary artery disease than women of the same age, in whom coronary disease is rare before menopause. Epidemiological data have shown that estrogens are vasoprotective--especially in the coronary circulation--but the underlying mechanisms have been investigated more thoroughly only in recent years. Only up to half of the protective effect of estrogen replacement therapy an be attributed to its positive effects of the lipid profile. However, a large part of this protection is caused by mechanisms distinct from lipid metabolism. It is now known that estrogens also exert effects on vascular function and structure of the vessel wall involving numerous cellular and molecular mechanisms. Actions of natural estrogens on human vascular cells and arteries will be discussed. Estrogens modulate vascular function by increasing nitric oxide production via stimulation of endothelial nitric oxide synthase (eNOS) and decreasing endothelin-1 levels in vivo. Furthermore, 17-beta estradiol is a potent inhibitor of vascular smooth muscle cell proliferation and migration, which play a major role in atherosclerotic vascular disease and in the remodeling process. 17-beta estradiol also acutely affects vascular tone in human arteries and attenuates constriction induced by contractile agonists. Finally, clinical studies showed that 17-beta estradiol can acutely and chronically ameliorate vascular function in women with and without vascular disease. In conclusion, results from clinical and in vitro studies showed positive effects of natural estrogens on vascular function which could explain in part their protective actions against coronary heart disease. Thus, primary prevention of coronary heart disease by estrogen replacement therapy after menopause appears to be a new approach to reduce cardiovascular mortality in women.

Adult↗
PubMed1997

Sucralfate cream in the management of moist desquamation during radiotherapy.

Randomized trials have shown that sucralfate is effective in the management of acute radiation reactions such as oesophagitis, mucositis and proctitis. However, at the time of commencement of the present trial, it had never been used in the management of moist desquamation of the skin. The purpose of the present study was to assess the value of sucralfate cream in the management of moist desquamation during radiotherapy. Patients who developed moist desquamation during radiation were eligible. Patients were stratified by site of radiotherapy into three groups: (i) the head and neck; (ii) the breast; and (iii) other sites. Patients were randomized to receive 10% sucralfate in sorbolene cream or sorbolene alone. Patients' pain and skin healing were assessed by using linear analogue self-assessment (LASA) scales and by serial measurement of the desquamated area. Due to poor patient accrual, the trial was terminated after 2 years and 39 patients. No statistically significant difference was found between the two arms in either time from randomization to healing or improvement in pain score. Twenty patients in the sucralfate arm took a geometric mean of 14.8 days to heal whereas 19 patients receiving sorbolene alone took a geometric mean of 14.2 days. The ratio of mean times of healing, 1.043, is not statistically different from 1 (P = 0.86; 95% CI = 0.65, 1.67). A total of 75% of the patients reported pain relief on application of either cream. Mean LASA scores for pain for each day after randomization were compared by treatment arm and there was no statistically significant difference (P = 0.32). The present trial was unable to show a difference in terms of time to healing or pain relief in the treatment of moist desquamation. The small number of patients in the trial gave a wide confidence interval for treatment difference, implying that an important effect of sucralfate has not been excluded. Given the poor accrual in the present, single-institution study, future studies may need to be multi-institutional and we encourage other centres to perform randomized trials in the management of moist desquamation.

Administration, Topical↗
PubMed1997

Contractile responses to histamine, serotonin, and angiotensin II are impaired by 17 beta-estradiol in human internal mammary arteries in vitro.

There is accumulating evidence that estrogen replacement therapy protects against the development of coronary atherosclerosis and myocardial infarction in postmenopausal women. The mechanism of this protective effect is uncertain. The purpose of the present study was to determine whether 17 beta-estradiol acutely modifies vascular smooth muscle contractile responses to various agonists in human arteries in vitro. Human mammary artery rings were obtained during aortocoronary bypass operations. Rings were suspended in organ baths for isometric tension measurements. Concentration response curves induced by serotonin (0.01-30 mumol/l), histamine (0.01-300 mumol/l), and angiotensin II (0.1-100 nmol/l) were generated after pre-incubation for 30 min with either 17 beta-estradiol (3 mumol/l) or solvent (0.2% ethanol). The presence of 17 beta-estradiol significantly reduced the maximal contractile effects induced by histamine, serotonin, and angiotensin II, but not by 80 mmol/l potassium chloride. It is concluded that short-term incubation with 17 beta-estradiol reduces the maximal contractile responses to serotonin, histamine, and angiotensin II. These modulating effects of estrogen on vascular tone may contribute to the proposed beneficial role of estrogen replacement therapy on the incidence of myocardial infarction in postmenopausal women.

Aged↗
PubMed1997

Effects of chronic ETA-receptor blockade in angiotensin II-induced hypertension.

Angiotensin II, a constrictor and mitogen of vascular smooth muscle cells, affects the release of endothelium-derived factors such as nitric oxide or endothelin-1. This study investigated the influence of endothelin-1, using the selective endothelin A receptor antagonist LU135252, on blood pressure and endothelial function in angiotensin II-induced hypertension in the rat. Two weeks of angiotensin II administration (200 ng/kg per minute) increased systolic blood pressure (+35 +/- 5 mm Hg; tail-cuff method) compared with placebo (P < .05). LU135252 alone did not affect systolic pressure but lowered the angiotensin II-induced pressure increase (P < .05). In isolated aortic rings, endothelium-dependent relaxations to acetylcholine were reduced in the angiotensin II group (P < .05 versus placebo) and improved by concomitant chronic LU135252 treatment (P < .05 versus angiotensin II). Blood pressure elevation strongly correlated with impaired endothelium-dependent relaxations to acetylcholine (r = -.967). LU135252 did not affect endothelium-independent relaxations to sodium nitroprusside, which were diminished after angiotensin II treatment (P < .05). In quiescent rings, chronic angiotensin II administration enhanced endothelium-dependent contractions to acetylcholine, which were reduced by LU135252 (P < .05). Impaired contractions to endothelin-1 and norepinephrine in the angiotensin II group were normalized after treatment with LU135252 (P < .05). Thus, chronic therapy with LU135252 partially prevents angiotensin II-induced hypertension and the alternations of the endothelial function observed in this experimental model.

Acetylcholine↗
PubMed1997

Anatomic heterogeneity of vascular aging: role of nitric oxide and endothelin.

We investigated the effects of aging, a cardiovascular risk factor, on vascular function with regard to endothelial nitric oxide synthase (eNOS), superoxide dismutase (SOD), and endothelin (ET-1) in aorta and femoral artery of the rat. Concentration-response curves to acetylcholine, calcium ionophore A23187, norepinephrine, ET-1, big endothelin, sodium nitroprusside, and exogenous SOD were obtained. Expression of eNOS mRNA was analyzed by reverse-transcription polymerase chain reaction, SOD activity was assessed using a chemiluminescence-based cytochrome c assay, and ET-1 plasma concentrations were measured by radioimmunoassay. In aorta of old rats, relaxations to acetylcholine and calcium ionophore A23187, basal NO release, and expression of eNOS mRNA in aortic endothelial cells were reduced (P<.05). In femoral arteries, relaxations to acetylcholine were preserved, whereas basal release of NO was attenuated (P<.05). Aging selectively increased contractions to norepinephrine and functional endothelin converting enzyme activity and attenuated contractions to ET-1 in aortas but not femoral arteries. Vascular SOD activity was higher in the femoral artery (P<.05) and unaffected by aging. Plasma ET-1 levels increased and plasma SOD activity decreased with age (P<.05). Aging was associated with an anatomic heterogeneity of endothelial dysfunction, functional endothelin converting enzyme activity, and vascular SOD activity. Vascular function was impaired in the aorta but not the femoral artery, which may be related to lower eNOS mRNA expression and SOD activity. These data suggest differential regulation of the vascular aging process that may contribute to the anatomic heterogeneity of atherosclerosis.

Aging↗
PubMed1997

Structure and function of small arteries in salt-induced hypertension: effects of chronic endothelin-subtype-A-receptor blockade.

The involvement of endothelin in salt-induced hypertension is unclear. In the Dahl rat model, we studied the effects of a selective endothelin-subtype A (ET[A]) receptor antagonist, LU135252, on blood pressure, vascular structure, and function. Dahl salt-sensitive and salt-resistant rats were treated for 8 weeks with 4% NaCl alone or in combination with LU135252 taken orally (60 mg/kg per day). The geometry and reactivity of basilar and mesenteric arteries were studied in vitro under perfused and pressurized conditions using a video dimension analyzer. Chronic salt administration increased systolic blood pressure by 37 +/- 3 mm Hg and media-lumen ratio of the basilar and mesenteric arteries in salt-sensitive rats (P<.05). These structural changes were caused by eutrophic remodeling in basilar and hypertrophic remodeling in mesenteric arteries. Endothelium-dependent relaxations to acetylcholine and contractions to endothelin-1 were impaired in mesenteric arteries of salt-sensitive rats on a high NaCl diet. LU135252 prevented part of the increase in systolic blood pressure and structural and functional alterations but increased plasma endothelin 1 levels (P<.05 versus salt-treated, saltsensitive rats). LU135252 had no effect on these parameters in salt-resistant rats. These findings suggest that the long-term pressor effect of salt administration is mediated in part by the action of endogenous endothelin acting via ET(A) receptors. Thus, chronic ET(A) receptor blockade may be useful therapeutically to lower arterial pressure and prevent endothelial dysfunction and hypertrophic remodeling of resistance arteries in salt-sensitive forms of hypertension.

Animals↗
PubMed1997

New computer-based tools for empiric antibiotic decision support.

Since 1995 we have been developing a decision-support model, called Q-ID, which uses a series of infectious disease knowledge bases to make recommendations for empirical treatment or to check the appropriateness of current antibiotic therapy. From disease manifestations and risk factors, a differential diagnosis for the patient is generated by a diagnostic medical expert system. The resulting probability of each: disease is multiplied by the expected benefit in improved mortality and morbidity from optimal antibiotic treatment of each disease. To generate empirical treatment recommendations, site-specific data on sensitivity to antibiotics of each organism is used as an estimate of the likelihood of achieving maximum benefit for each disease on the patient's differential. Combining this data with drug and patient specific factors, the model recommends the antibiotic(s) most likely to produce the optimal benefit in this patient with the least risk and expense. In this paper the model is described, excerpts from each of the knowledge bases are presented, and performance of the model in a real case is shown for illustration.

Aged↗
PubMed1997

Biology of the endothelium.

The endothelium releases factors that control vascular relaxation and contraction, thrombogenesis and fibrinolysis, and platelet activation and inhibition. Maintaining the functional integrity of the endothelium, therefore, is critical for the preservation of blood flow and the prevention of thrombosis. This article reviews the primary endothelium-dependent substances that promote either relaxation (e.g., nitric oxide, prostacyclin) or contraction (e.g., endothelin) of blood vessels, including their physiology, mechanism of effect, and role in endothelial dysfunction. Risk factors for cardiovascular disease, such as hypertension, hypercholesterolemia, diabetes, vascular aging, and estrogen deficiency, are discussed in terms of their contributions to endothelial dysfunction, which may be the initial step in atherogenesis.

Animals↗
PubMed1996

[Action of natural estrogens on the vessel wall: molecular mechanisms and clinical implications].

Myocardial infarction is the major cause of death in the Western world. Men are more prone to develop coronary artery disease than women, who rarely develop coronary disease before menopause. Although epidemiological data has long been available showing a protective effect of estrogen on the vascular system, the underlying mechanisms have been investigated more thoroughly only in recent years. Meta-analysis studies have revealed that only half of the protective effect on estrogen replacement therapy is due to its positive effects on the lipid profile and that a large part of this protection is caused by mechanisms distinct from lipid metabolism. It is now known that estrogens also exert effects on vascular function and structure of the vessel wall involving numerous cellular and molecular mechanisms. Here we review actions of natural estrogens on human vascular cells and arteries. Estrogens can modulate vascular function by increasing nitric oxide production via stimulation of endothelial nitric oxide synthase (eNOS) and decreasing endothelin-1 levels in vivo. Furthermore, 17 beta-estradiol is an inhibitor of vascular smooth muscle cell proliferation and migration, phenomena that play a major role in atherosclerotic vascular disease and in the remodelling process. 17 beta-estradiol can also acutely affect vascular tone in human arteries and attenuates constriction induced by contractile agonists. Finally, clinical studies have shown that 17 beta-estradiol can acutely and chronically ameliorate vascular function in women with and without vascular disease. In conclusion, results from clinical and in vitro studies confirm the positive effects of natural estrogens on vascular function and protection from coronary heart disease. Thus, primary prevention of coronary heart disease by estrogen replacement therapy after the menopause appears to be a new and straightforward approach by which cardiovascular mortality in women can be reduced.

Adult↗
PubMed1996

Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery.

Aging is an important determinant of vascular disease. Endothelium-derived nitric oxide (NO) is protective as a vasodilator and inhibitor of platelet function. This study was designed to directly measure effects of prolonged aging on endotheliai NO release in isolated blood vessels and to delineate differences between the systemic and pulmonary circulation. Aortas and pulmonary arteries from 5-6-mo-old (young), 18-19-mo-old (middle-aged), and 32-33-mo-old (old) normotensive female rats were used. Blood pressure and plasma estradiol-17beta (E2) remained unchanged. In isolated blood vessels, NO release was induced by the receptor-independent agonist calcium ionophore A23187 (10 micromol/liter) and measured in situ on the endothelial surface of vessels using a porphyrinic microsensor. In vessels suspended in organ chambers isometric tension was recorded. In the aorta, the initial rate of NO release and peak NO concentration were reduced in middle-aged and old rats (P < 0.0006 vs. young rats, n = 6). Furthermore, endothelium-dependent relaxations to calcium ionophore and acetylcholine (both 10(-10) - 10(-5) mol/liter) were also reduced in aortas from old as compared with young rats (n = 6, P < 0.05). The initial rate of NO release and peak NO concentration significantly correlated with maximal relaxation to calcium ionophore A23187 (correlation coefficients r - 0.916, P < 0.0018 and r = 0.961, P < 0.0001, respectively, n = 7). In pulmonary arteries, however, the initial rate of NO release as well as peak NO concentration did not decrease with age (n = 6 for each age group, NS). In both blood vessels, the NO release was unaffected by superoxide dismutase in all age groups (n = 6, NS). Thus, aging specifically reduces initial rate and peak concentrations of endothelial NO release from aorta but not pulmonary artery indicating reduced NO production. As arterial pressure did not change with aging, the chronic exposure of the aorta to higher pressure and/or pulsatility than in the pulmonary artery may be the cause. This appears important as NO plays a protective role by preventing vasoconstriction, thrombosis and atherosclerosis.

Aging↗
PubMed1996

Radiotherapy for early infradiaphragmatic Hodgkin's disease: the Australasian experience.

PURPOSE: To review the Australasian results of Stage I and IIA Infradiaphragmatic Hodgkin's Disease (IHD) treated solely by irradiation. METHODS AND MATERIALS: Eligible patients had IHD only and were treated by irradiation with curative intent over the period of 1969 to 1988. Ten radiation oncology centres from within Australia and New Zealand were surveyed for patient, tumour and treatment variables. Disease free rates, survival and complications were analysed. RESULTS: 106 patients with IHD were studied. The average potential follow up was 9.4 years. The male to female ratio was 3.3:1. The median age was 37.5 years. Histological subgroups were as follows; lymphocyte predominant 43%, mixed cellularity 21%, lymphocyte depleted 5%, nodular sclerosing 27% and unclassifiable 4%. Fifty nine patients had laparotomy of which 22 (37%) were positive for tumour. Nine laparotomies were performed for diagnosis and the remainder for staging. One patient was up-staged by laparotomy and three were down-staged. Sixty-eight patients presented with inguinal disease alone, five with abdominal disease alone, 19 with two sites of involvement and 12 with inguinal, pelvic and abdominal disease. In two patients the site was unknown. There was no correlation between site of involvement, age, sex or histological subtype. Forty seven cases were clinically staged (CS) as follows: CS IA-23, CS IIA-24. The other 59 were pathologically staged (PS) as follows: PS IA-37, PS IB-1, PS IIA-21. Treatment consisted of involved field alone (16), inverted Y (68), inverted Y and spleen (13), para-aortic irradiation only (3), or total nodal irradiation (6). Mean dose was 37 Gy. There were 30 recurrences to give an acturial 10-year disease-free rate of 70%. In multivariate analysis lower number of tumour sites, lymphocyte predominant histology and higher dose were all significantly correlated with higher disease free rates. Eight patients died of Hodgkin's disease and 19 of other causes. The 10-year overall survival rate was 71%. Older age and higher number of disease sites were significantly correlated with shorter survival. Fourteen of 30 relapses may have been avoidable by the use of total nodal irradiation. In particular ten of 21 patients with abdominal disease relapsed in nodal sites which would have been covered by total nodal irradiation. CONCLUSIONS: The rate of control in IHD could perhaps be improved by avoiding involved field irradiation or by aggressive therapy with total nodal irradiation or combined modality chemo-irradiation in Stage II disease. Staging laparotomy does not appear to be indicated.

Abdominal Neoplasms↗
PubMed1996

Multicentre dosimetry study of mantle treatment in Australia and New Zealand.

PURPOSE: To determine the difference between expected and measured dose for patients prescribed a mantle treatment for Hodgkin's disease and estimate the range of dose at critical sites and between different treatment centres. METHODS AND MATERIALS: Twenty three radiotherapy centres were surveyed with regard to the accuracy of dose delivery to a custom-built upper-torso phantom. Thermoluminescent dosimeters were used to monitor the delivered dose at sites such as mid-plane, spinal cord, neck, axilla and lung. RESULTS: The intended dose to the phantom at each centre was 1 Gy to central axis mid-plane. Of the centres surveyed, the median measured dose to this region was 0.96 Gy with a minimum of 0.92 and a maximum of 1.00 Gy. Median dose to the axilla region was low (0.90 Gy) whereas median dose to the blocked lung and neck region were higher than expected, 0.18 Gy and 1.25 Gy, respectively. The 95% confidence interval on the reported relative dose using the 4000 thermoluminescence dosimetry readings in this study was +/- 1.5% CONCLUSION: In this controlled experiment, using conventional methods to calculate dose, there was a surprising variability in the dose delivered at the central axis mid-plane position. This was traced to lack of uniformity in the use of equivalent squares to calculate the output factor. The measured doses to axilla and lung are explained by photon and electron scattering effects. Centres, where dose compensation was included, had a superior dose homogeneity in the neck. The off-axis dose calculations depend on computer planning software but the magnitude of these differences is secondary to that of central axis mid-point dose differences. Improved consistency of dose calculation techniques between centres would enable more reliable dose response evaluation from multicentre clinical studies of Hodgkin's disease.

Australia↗
PubMed1996

Treatment principles in advanced colorectal cancer.

BACKGROUND: Colorectal cancer is an important disease in the Australian community. Whilst there has been much discussion about the appropriate management of local disease, particularly with respect to the issue of adjuvant therapy, there has been relatively little local discussion of treatment options in metastatic colorectal cancer. METHODS: The critical principles underlying treatment in this setting are briefly outlined in the present article, indicating wherever possible what options could be considered standard, and based on the available literature, which approaches must still be considered experimental at this time. RESULTS: Overall, the results of treatment in this group of patients remain poor. CONCLUSION: Further clinical trials are required to address the issues affecting patients with metastatic colorectal cancer.

Colorectal Neoplasms↗