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Biomedical subjects

J F Arthur

Publications and source records attributed to J F Arthur.

At least 19 recordsLinked to original sources
PubMed2001

Targeted alpha(1A)-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy.

Activation of the alpha(1A)-adrenergic receptor (alpha(1A)-AR)/Gq pathway has been implicated as a critical trigger for the development of cardiac hypertrophy. However, direct evidence from in vivo studies is still lacking. To address this issue, transgenic mice with cardiac-targeted overexpression of the alpha(1A)-AR (4- to 170-fold) were generated, using the rodent alpha-myosin heavy chain promoter. Heterozygous animals displayed marked enhancement of cardiac contractility, evident from increases in dP/dt(max) (80%, P<0.0001), dP/dt(max)/LVP(inst) (76%, P<0.001), dP/dt(max):dP/dt(min) (104%, P<0.0001), and fractional shortening (33%, P<0.05). Moreover, changes in the dP/dt(max)-end-diastolic volume relationship provided load-independent evidence of a primary increase in contractility. Blood pressure and heart rate were largely unchanged, and there was a small increase in (-)norepinephrine-stimulated, but not basal, phospholipase C activity. Increased contractility was directly related to the level of receptor overexpression and could be completely reversed by acute alpha(1A)- but not beta-AR blockade. Despite the robust changes in contractility, transgenic animals displayed no morphological, histological, or echocardiographic evidence of left ventricular hypertrophy. In addition, apart from an increase in atrial natriuretic factor mRNA, expression of other hypertrophy-associated genes was unchanged. To our knowledge, these data provide the first in vivo evidence for an inotropic action of the alpha(1A)-AR.

Adenylyl Cyclases↗
PubMed2001

Evidence for selective coupling of alpha 1-adrenergic receptors to phospholipase C-beta 1 in rat neonatal cardiomyocytes.

Activation of phospholipase C (PLC) in neonatal rat cardiomyocytes (NCM) generates primarily inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) in response to rises in intracellular Ca(2+), or inositol 1,4-bisphosphate (Ins(1,4)P(2)) in response to norepinephrine (NE) (Matkovich, S. J. and Woodcock, E. A. (2000) J. Biol. Chem. 275, 10845-10850). To examine the PLC subtype mediating the alpha(1)-adrenergic receptor response, PLC-beta(1) and PLC-beta(3) were overexpressed in NCM using adenoviral infection (Ad-PLC-beta(1) NCM and Ad-PLC-beta(3) NCM, respectively) and PLC responses assessed from [(3)H]inositol phosphate (InsP) generation in the presence of 10 mm LiCl. The [(3)H]InsP response to NE (100 microm) was enhanced in Ad-PLC-beta(1) NCM relative to cells infected with blank virus (Ad-MX NCM), but was reduced in Ad-PLC-beta(3) NCM. In contrast, the [(3)H]InsP response to ATP (100 microm) was not elevated in Ad-PLC-beta(1) NCM, and was enhanced rather than diminished in Ad-PLC-beta(3) NCM, showing that effects of the two PLC-beta isoforms were specific for particular receptor types. PLC-delta(1) overexpression selectively reduced NE-induced [(3)H]InsP responses, without affecting the ATP stimulation. The reduced NE response was associated with a selective loss of PLC-beta(1) expression in Ad-PLC-delta(1) NCM. alpha(1)-Adrenergic receptor activation caused phosphorylation of PLC-beta(1) but not PLC-beta(3), whereas stimulation by ATP induced phosphorylation of PLC-beta(3) but not PLC-beta(1.) Taken together, these studies provide evidence that NE-stimulated InsP generation in NCM is primarily mediated by PLC-beta(1), despite the presence of both PLC-beta(1) and PLC-beta(3) isoforms.

Animals↗
PubMed2001

Reperfusion-induced Ins(1,4,5)P(3) generation and arrhythmogenesis require activation of the Na(+)/Ca(2+) exchanger.

Reperfusion of globally ischemic rat hearts causes rapid generation of inositol(1,4,5) trisphosphate [Ins(1,4,5)P(3)] and the development of arrhythmias, following stimulation of alpha(1)-adrenergic receptors by norepinephrine released from the cardiac sympathetic nerves. The heightened inositol phosphate response in reperfusion depends on the activation of the Na(+)/H(+) exchanger, which might reflect a central role for increased Ca(2+)following reverse mode activation of the Na(+)/Ca(2+) exchanger (NCX). Isolated, perfused rat hearts were subjected to 20 min ischemia followed by 2 min reperfusion and the content of Ins(1,4,5)P(3) measured by mass analysis or by anion-exchange high performance liquid chromatography (HPLC) following [(3)H]inositol labeling. Reperfusion caused generation of Ins(1,4,5)P(3) (1266+/-401 to 3387+/-256 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01) and the development of arrhythmias. Inhibition of NCX either by reperfusion at low Ca(2+) (1133+/-173 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01 relative to reperfusion control) or by adding 10 microm KB-R7943, an inhibitor of reverse mode Na(+)/Ca(2+) exchange, prevented the Ins(1,4,5)P(3) response (1151+/-243 cpm/g tissue, mean+/-s.e.m., n=6, P<0.01 relative to reperfusion control) and the development of ventricular fibrillation. Lower concentrations of KB-R7943 were less effective. Reverse mode activation of NCX is therefore required for the enhanced Ins(1,4,5)P(3) response in early reperfusion, and inhibitors of this transporter may be useful in the prevention of arrhythmias under such conditions.

Animals↗
PubMed2000

Activation of the Na(+)/H(+) exchanger is required for reperfusion-induced Ins(1,4,5)P(3) generation.

Post-ischemic reperfusion causes a change in inositol phosphate responses to norepinephrine from primary generation of inositol(1,4) bis phosphate (Ins(1,4)P(2)) to generation of inositol(1,4,5) tris phosphate (Ins(1,4,5)P(3)) that is required for the initiation of reperfusion arrhythmias. The current study was undertaken to investigate the role of Na(+)/H(+)exchange in facilitating this transient change in inositol phosphate response. Rat hearts were subjected to 20 min ischemia followed by 2 min reperfusion and Ins(1, 4,5)P(3)content was measured by mass analysis or by anion-exchange HPLC following [(3)H]inositol labeling. Reperfusion caused generation of [(3)H]Ins(1,4,5)P(3)(1732+/-398 to 3103+/-214, cpm/g tissue, mean+/-S.E.M., n=5, P<0.01) and the development of arrhythmias. Inhibition of Na(+)/H(+)exchange, by reperfusing at pH 6.3 or by pretreating with HOE-694 (10 n M-3 microM) or HOE-642 (3 microM) prevented the [(3)H]Ins(1,4,5)P(3)generation, without causing any suppression of norepinephrine release. Increases in Ins(1,4,5)P(3)mass were similarly reduced by inhibition of Na(+)/H(+)exchange. Thus, activation of Na(+)/H(+)exchange is required for the enhanced Ins(1,4,5)P(3)response observed under reperfusion conditions, and prevention of Ins(1,4,5)P(3)generation may be an important contributor to the anti-arrhythmic actions of inhibitors of Na(+)/H(+)exchange.

Animals↗
PubMed2000

Inositol 1,4,5-trisphosphate and reperfusion arrhythmias.

1. The present review focuses on the role of the Ca2+-releasing second messenger inositol 1,4,5-trisphosphate (IP3) in initiating arrhythmias during early reperfusion following a period of myocardial ischaemia. 2. Evidence for an arrhythmogenic action of IP3 was provided by studies showing a correlation between the extent of the increase in IP3 and the incidence of arrhythmias in early reperfusion. In addition, phospholipase C inhibitors selective for thrombin receptor stimulation were anti-arrhythmic only when arrhythmias were thrombin initiated. 3. Mechanisms by which IP3 could initiate arrhythmias are discussed, with particular emphasis on the role of slow and unscheduled Ca2+ release. 4. The reperfusion-induced IP3 and arrhythmogenic responses can be initiated through either alpha1-adrenoceptors or thrombin receptors, but endothelin receptor stimulation was ineffective. Further studies have provided evidence that the noradrenaline-mediated response was mediated by alpha1A-receptors, while the alpha1B-adrenoceptor subtype appeared to be protective. 5. Reperfusion-induced IP3 responses could be inhibited by procedures known to reduce the incidence of arrhythmias under these conditions, including preconditioning, inhibiting Na+/H+ exchange or by dietary supplementation with n-3 polyunsaturated fatty acids. 6. Inositol 1,4,5-trisphosphate generation in cardiomyocytes can be facilitated by raising intracellular Ca2+ and it seems likely that the rise in Ca2+ in ischaemia and reperfusion is responsible for the generation of IP3, which will, in turn, further exacerbate Ca2+ overload.

Animals↗
PubMed1997

Induction of nitric oxide synthase in the neointima induced by a periarterial collar in rabbits.

A Silastic collar placed around the common carotid artery of rabbits causes the formation, within 7 days, of an atheroma-like neointima containing cells with the appearance of synthetic-phenotype smooth muscle cells. Using immunohisto-chemistry, we detected the appearance of the cytokine-inducible form of nitric oxide synthase (iNOS, or isoform II) in the neointima of rabbits that had the collar in place for 7 or 14 days. This iNOS immunofluorescence collocalized with anti-smooth muscle myosin in the intima, indicating that it is expressed in smooth muscle cells, and iNOS was also present in a few endothelial cells in collared sections. There was no evidence of iNOS expression in the arterial wall before the neointima was apparent, that is, after only 2 days with the collar. The expression of endothelial NOS (eNOS, or isoform III) immunofluorescence was confined to the endothelial cells in control sections, as it was in collared sections with neointima at 7 and 14 days. Specific immunofluorescence for neuronal NOS (nNOS, or isoform I) was not observed in any sections. Our results suggest that nitric oxide is produced by the inducible isoform of NOS in modified smooth muscle cells of the developing neointima. Activity of iNOS might deprive the endothelium of substrate for nitric oxide production and might explain the compromised endothelium-dependent vasodilatation observed both in this model of atherosclerosis and in human coronary artery disease.

Animals↗
PubMed1992

Incidence and clinical features of breast cancer in the Auckland region.

Data on all new breast cancer cases in the Auckland area during the nine years September 1976 to September 1985 were used to obtain epidemiological information on breast cancer in the Auckland region. Breast tumours were found in 2706 women (300 per year), yielding a lifetime risk of breast cancer of one in 15. No significant difference in breast cancer incidence was detected between European, Maori and Pacific Island Polynesian women. Confidence limits for incidence were wide in the later groups. Fifty-one percent of women presented with intermediate sized (2-5 cm) tumours, and most (66%) were node negative. Eleven percent had evidence of metastatic disease at presentation. When the relationships between race, tumour size, nodal status and metastases were examined, Pacific Island women more frequently presented with large tumours and metastases, whereas Maori women were more frequently node positive. Eighty-five percent of tumours were invasive ductal carcinomas, 55% grade II, 35% grade III, and 10% grade I. Sixty-seven percent of tumours were oestrogen receptor positive (ER+ve) and ER status was significantly related to age; the proportion of ER+ve tumours was greater in older women. Fifty-seven percent of tumours were progesterone receptor positive (PR+ve), and PR distribution was bimodal with age. These data from the Auckland region are similar to breast cancer figures from other western countries, with some ethnic differences in tumour size and frequency of metastatic disease at presentation.

Adolescent↗
PubMed1991

Intestinal pseudoobstruction secondary to amyloidosis responsive to cisapride.

A case of chronic intestinal pseudoobstruction secondary to systemic amyloidosis in a patient with multiple myeloma is described. Gastrointestinal symptoms and indices of nutrition improved markedly after commencing treatment with cisapride, which may have been responsible for relatively prolonged survival compared with similar reported cases.

Amyloidosis↗
PubMed1983

Levamisole in primary breast cancer. A controlled study in conjunction with l-phenylalanine mustard.

Between September 1976 and May 1980, 135 patients with operable breast cancer and positive axillary nodes received l-phenylalanine mustard, adjunct to surgery, 0.15 mg/kg for five days, six weekly, and were randomised prospectively to levamisole 150 mg for three days, two weekly, or a placebo. Treatment was continued for two years or until evidence of treatment failure, whichever was the sooner. At 4 1/2 years, for all patients, there was no significant difference between the two groups (P = 0.09), but in a subgroup of women less than or equal to 50 with 1-3 positive nodes, levamisole had a negative effect (P = 0.05). Although an analysis of the same age group, independent of the nodal status, did not reach significance, there was a trend in favor of placebo (P = 0.08) which was also apparent in premenopausal women (P = 0.15). In postmenopausal patients, however, and in those with more advanced disease with four or more positive nodes, although the results also failed to reach significance the trend in these subgroups favored levamisole. The results of this study suggest that levamisole has no place in the primary therapy of breast cancer in younger women and those with more favorable disease. The value of this agent in older patients and those with more advanced primary disease, remains unproven, but the favorable trends are in accord with a number of other studies with levamisole in metastatic breast and resectable lung cancer. Retrospective analysis confined to those women who received 75% or more of the total dose of l-phenylalanine mustard showed no evidence for a dose-responsive effect of adjuvant chemotherapy on the described pattern of results.

Age Factors↗
PubMed1983

Giant cell tumour of bone: its aggressiveness and potential for malignant change.

Thirty cases of giant cell tumour of bone are reviewed. The average follow-up for 22 cases was 7.5 years. The recurrence rate in 19 appendicular tumours treated by curettage, with or without bone grafting, was 52%. Treatment of recurrences, however, resulted in cure of an additional 10 tumours, for an overall success rate of primary and secondary treatment of 89%. Pulmonary metastases occurred in two patients (6.7%) and there was one death attributable to the tumour (3.3%). The authors conclude that the conservative primary treatment is justified even with a 52% recurrence rate, since normal function and appearance are preserved and, further, more aggressive treatment of the recurrent tumour can be performed. They prefer limb-saving resection and occasionally amputation for this more aggressive secondary treatment rather than cryosurgery with its complications, allograft replacement with its uncertainties or supervoltage radiation with its risk of later development of malignant tumours.

Adolescent↗
PubMed1980

Metaplastic polyps and polyposis of the colorectum.

Five hundred and fifty-four colorectal metaplastic polyps have been studied histologically. Whilst most lesions were small and sessile, 16.1% measured greater than 0.5 cm in diameter and 0.9% were greater than 1 cm. The larger polyps were frequently pedunculated and occasionally showed a tubulo-villous or villous pattern. A structural similarity between the larger metaplastic polyps and colorectal adenomas is illustrated and the importance of the distinction of metaplastic from dysplastic epithelium in the differentiation of these lesions is stressed. Other unusual features of metaplastic polyps are described. Evidence is given to suggest that males have a greater propensity to develop metaplastic polyps than females. A search for men adenomas, but relatively frequent (20.8%) in juvenile polyps. Finally, seven patients with multiple metaplastic polyps of the colorectum are described, in whom a diagnosis of adenomatous polyposis had been made at some stage in their management. Six of the seven patients were males and the mean age at presentation was 37.4 years. Larger metaplastic polyps were frequent in these cases. The necessity for histological confirmation in all cases of intestinal polyposis is stressed, and the possibility that 'metaplastic polyposis' is a pathological entity is discussed.

Adenoma↗
PubMed1979

Histological staining of hepatitis B antigen in paraffin embedded liver tissue.

Two hundred and six unselected liver biopsies were stained with Gomori's aldehyde fuschin, aldehyde thionine, and a modified orcein stain, according to Shikata and others (1974). Six cases showed positive cytoplasmatic staining indicative of hepatitis B antigen. It is suggested that one of these methods should be used in the study of liver biopsies, as an additional tool in the detection of hepatitis B carriers.

Hepatitis B Antigens↗
PubMed1968

Structure and significance of metaplastic nodules in the rectal mucosa.

Small nodules are commonly seen in the rectal mucosa during sigmoidoscopy of patients over 40 years of age and are often noted in rectums excised for carcinoma. There is little information in the literature on the pathology of these small nodules. There is evidence that there are various histological types which are possibly of different clinical significance. This problem has been studied using a series of rectums removed surgically for carcinoma and a comparable series of rectums obtained at necropsy from subjects with no evidence of large bowel disease. The incidence, distribution, and histological structure of nodules more than 1 mm in diameter has been studied. The commonest histological types of lesion are found to be adenomas and metaplastic nodules. The histological structure, mode of formation, natural history, and clinical significance of metaplastic nodules is considered in detail. It is concluded that metaplastic nodules are a normal finding in the rectal mucosa of subjects over 40 years old. It is suggested that they represent an aging change in the mucosa. They are easily distinguished histologically from adenomas and evidence is presented that they have no relation to them and are not liable to undergo malignant change.

Adenoma↗