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Biomedical subjects

M J Robinson

Publications and source records attributed to M J Robinson.

At least 73 records · Page 4Linked to original sources
PubMed1991

Effects of quinolone derivatives on eukaryotic topoisomerase II. A novel mechanism for enhancement of enzyme-mediated DNA cleavage.

The effects of two novel quinolone derivatives, CP-67,804 and CP-115,953 (the 1-ethyl and 1-cyclopropyl derivatives of 6,8-difluoro-7-(4-hydroxyphenyl)-4-quinolone-3-carboxylic acid, respectively), on the enzymatic activities of Drosophila melanogaster topoisomerase II were examined. Both drugs enhanced the enzyme's pre- and post-strand passage DNA cleavage activities. CP-67,804 was nearly as potent an enhancer as etoposide, while CP-115,953 was approximately 2 times more potent than this topoisomerase II-targeted antineoplastic drug. In contrast to etoposide, which stabilizes enzyme-DNA cleavage complexes primarily by inhibiting topoisomerase II-mediated DNA religation, neither quinolone impaired the enzyme's ability to religate cleaved DNA. To further assess the characteristics of these unusual quinolone derivatives, the cytotoxic effects of CP-67,804 and CP-115,953 toward wild-type Chinese hamster ovary cells and VpmR-5 cells (an epipodophyllotoxin-resistant Chinese hamster ovary line) were examined. Both quinolones were cytotoxic to the wild-type cells. CP-115,953 was the more potent agent and displayed a level of cytotoxicity similar to that of etoposide. Finally, the VpmR-5 line showed cross-resistance to CP-67,804 (approximately 3.7-fold) and CP-115,953 (approximately 1.3-fold). Although quinolone cross-resistance was less pronounced than observed for etoposide (approximately 12-fold), it indicates that topoisomerase II is a physiological target for CP-67,804 and CP-115,953 in mammalian cells. These findings strongly suggest that these quinolone derivatives represent a novel class of topoisomerase II-targeted drugs which have potential as antineoplastic agents.

Animals↗
PubMed1991

Effects of antineoplastic drugs on the post-strand-passage DNA cleavage/religation equilibrium of topoisomerase II.

The post-strand-passage DNA cleavage/religation equilibrium of Drosophila melanogaster topoisomerase II was examined. This was accomplished by including adenyl-5'-yl imidodiphosphate, a nonhydrolyzable ATP analogue which supports strand passage but not enzyme turnover, in assays. Levels of post-strand-passage enzyme-mediated DNA breakage were 3-5 times higher than those generated by topoisomerase II prior to the strand-passage event. This finding correlated with a decrease in the apparent first-order rate of topoisomerase II mediated DNA religation in the post-strand-passage cleavage complex. Since previous studies demonstrated that antineoplastic drugs stabilize the pre-strand-passage cleavage complex of topoisomerase II by impairing the enzyme's ability to religate cleaved DNA [Osheroff, N. (1989) Biochemistry 28, 6157-6160; Robinson, M.J., & Osheroff, N. (1990) Biochemistry 29, 2511-2515], the effects of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and etoposide on the enzyme's post-strand-passage DNA cleavage complex were characterized. Both drugs stimulated the ability of topoisomerase II to break double-stranded DNA after strand passage. As determined by two independent assay systems, m-AMSA and etoposide stabilized the enzyme's post-strand-passage DNA cleavage complex primarily by inhibiting DNA religation. These results strongly suggest that both the pre- and post-strand-passage DNA cleavage complexes of topoisomerase II serve as physiological targets for these structurally disparate antineoplastic drugs.

Adenylyl Imidodiphosphate↗
PubMed1991

Reduction in local cerebral blood flow induced by endothelin-1 applied topically to the middle cerebral artery in the rat.

The role of endothelin-1 (ET-1) in cerebral ischemic injury remains the subject of much debate. Vasoconstriction in large conduit vessels may not be associated with reductions in flow at the tissue level. We present two studies examining the effects on local cerebral blood flow of topical application of ET-1 to the surgically exposed middle cerebral artery (MCA) in adult male Sprague-Dawley rats. In the first series using 14C-iodoantipyrine autoradiography, 10 min following application of ET-1 (1 nmol) to the MCA, up to 80% reduction in blood flow in the territory of distribution of the MCA is seen (e.g., dorsolateral caudate nucleus--flow reduced from 131 +/- 3 ml/100 g/min to 29 +/- 25 ml/100 g/min). These levels of flow are comparable with those seen with permanent bipolar diathermy occlusion and division of the proximal MCA--a standard rat model of focal cerebral ischemia. In a second series using hydrogen clearance technique for measurement of local cerebral blood flow in the caudate nucleus, we have shown that flow ipsilateral to application of ET-1 (0.25 nmol) is significantly reduced compared with saline controls for 80 min. Such reduction of flow, at the tissue level, sustained over this duration is consistent with the induction of ischemic cell damage by ET-1.

Administration, Topical↗
PubMed1991

Endothelin-1-induced hypertension: a consequence of medullary ischemia?

The central hemodynamic effects of the peptide endothelin-1 (ET-1) have been investigated in the conscious, normotensive rat. Intracisternal administration of ET-1 (0.01-0.03 nmol) gave rise to an increase in mean arterial pressure with minimal effects on heart rate and was accompanied in some cases by barrel rolling activity. Intracisternal administration of 0.03 nmol ET-1 gave rise to a significant elevation in plasma noradrenaline and adrenaline levels. This elevation in plasma catecholamines was present only in those animals that also exhibited marked behavioral changes. Autoradiographic measurement of cerebral blood flow carried out during the maximum response to 0.03 nmol of intracisternal ET-1 revealed a widespread and profound ischemia throughout the caudal brainstem. Cerebral ischemia is known to activate compensatory circulatory reflexes in the medulla oblongata that result in increased sympathetic and vagal outflow. This is the most likely cause of intracisternal ET-1-induced hypertension. ET-1 is unique in its ability to override the brain's autoregulatory mechanisms and induce ischemia of pathological magnitude.

Animals↗
PubMed1990

Reduction of local cerebral blood flow to pathological levels by endothelin-1 applied to the middle cerebral artery in the rat.

Endothelin-1 (1 nmol) was applied to the exposed left middle cerebral artery (MCA) in anaesthetised adult male Sprague-Dawley rats. Local cerebral blood flow (1CBF), using [14C]iodoantipyrine and quantitative autoradiography, was measured in 27 anatomically defined structures, 10 min after topical application of endothelin-1. In those areas supplied by the MCA, 1CBF was markedly reduced beyond the threshold for ischaemic damage (e.g. dorsolateral caudate nucleus reduced from 131 +/- 3 to 29 +/- 25 ml.100 g-1.min-1, sensorimotor cortex from 109 +/- 5 to 31 +/- 21 ml.100 g-1.min-1). Distant areas were not affected.

Animals↗
PubMed1990

Stabilization of the topoisomerase II-DNA cleavage complex by antineoplastic drugs: inhibition of enzyme-mediated DNA religation by 4'-(9-acridinylamino)methanesulfon-m-anisidide.

In order to elucidate the mechanism by which the intercalative antineoplastic drug 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) stabilizes the covalent topoisomerase II-DNA cleavage complex, the effect of the drug on the DNA cleavage/religation reaction of the type II enzyme from Drosophila melanogaster was examined. At a concentration of 60 microM, m-AMSA enhanced topoisomerase II mediated double-stranded DNA breakage approximately 5-fold. Drug-induced stabilization of the enzyme-DNA cleavage complex was readily reversed by the addition of EDTA or salt. When a DNA religation assay was utilized, m-AMSA was found to inhibit the topoisomerase II mediated rejoining of cleaved DNA approximately 3.5-fold. This result is similar to that previously reported for the effects of etoposide on the activity of the Drosophila enzyme [Osheroff, N. (1989) Biochemistry 28, 6157-6160]. Thus, it appears that structurally disparate classes of topoisomerase II targeted antineoplastic drugs stabilize the enzyme's DNA cleavage complex primarily by interfering with the ability of topoisomerase II to religate DNA.

Aminacrine↗
PubMed1990

Contractile responses to endothelin in feline cortical vessels in situ.

In this study in chloralose-anaesthetised cats, the vasomotor responses of individual pial vessels on the cortical surface to perivascular subarachnoid microapplication of endothelin were examined. Endothelin (3 x 10(-10) -3 x 10(-6) M) induced marked vasoconstriction of pial arterioles (-33.5 +/- 3.8% at 3 x 10(-6) M) and pial veins (-35.1 +/- 2.7% at 3 x 10(-6) M). The concentration of endothelin inducing half-maximal response was in the nanomolar range, with pial veins being slightly more sensitive to the peptide than pial arterioles. Vasoconstrictions induced by endothelin were extremely prolonged, persisting for approximately 90 min after a single microapplication. Arterioles constricted by endothelin remained responsive to perivascular microapplication of K+ (10 mM) or alkalotic CSF (pH 7.48).

Animals↗
PubMed1990

Outcome after acute osteomyelitis in preterm infants.

Eight cases of skeletal infection in preterm infants were studied. All the infants were systemically unwell, with polymorpholeucocytosis. Diagnosis was by blood culture, and any radiographic changes were apparent at the time of presentation. Infection was often multifocal, with sites around the knee being most commonly affected. Staphylococcus aureus was the pathogen isolated in six of the eight cases; in these treatment with fusidic acid was effective and well tolerated, even at doses that were less than the recommended therapeutic minimum. Even with prompt diagnosis and aggressive treatment orthopaedic sequelae are common.

Acute Disease↗
PubMed1990

Markers of serious illness in infants under 6 months old presenting to a children's hospital.

Six hundred and eighty two assessments were performed on 641 babies under 6 months of age who presented to the emergency department of the Royal Children's Hospital, Melbourne, to try and determine the best markers of serious illness in young infants. Detailed, specific questions that quantified a baby's functional response to illness gave the most useful information. As a group, the six most common predictive symptoms of serious illness were: taking less than half the normal amount of feed over the preceding 24 hours, breathing difficulty, having less than four wet nappies in the preceding 24 hours, decreased activity, drowsiness, and a history of being both pale and hot. The presence of the corresponding sign on examination increased the predictive value of the symptom by 10-20%. Specific, highly predictive (though less common) signs included moderate to severe chest wall recession, respiratory grunt, cold calves, and a tender abdomen. A list of low, medium, and high risk symptoms has been constructed and the five measurements that were most useful in predicting serious illness in young infants have been detailed.

Causality↗
PubMed1990

Calcium antagonists in the management of subarachnoid haemorrhage.

The development of delayed cerebral ischaemia and hence neurological deficit remains a serious problem following subarachnoid haemorrhage. Over recent years, attention has focussed on the use of the dihydropyridine class of calcium channel blocking agents ("calcium antagonists"), in particular nimodipine, as drug therapy in the prophylaxis and treatment of this condition. The theoretical basis for this is briefly discussed and then the clinical experience of the use of calcium antagonists following subarachnoid haemorrhage reviewed. In particular, attention is focussed on the randomised controlled trials that have eventually been able to show that such treatment is beneficial, both in terms of reduction of ischaemic deficit attributable to cerebral "vasospasm" and in clinical outcome, when given prophylactically, although not apparently therapeutically once deficit has developed. The evidence of the mode of action of calcium antagonists in this situation is discussed, again with particular reference to clinical data obtained in situ in the course of such trials. Although the mechanism of action remains unclear, it appears likely that it is at least in part due to the selective cerebral vasodilation induced by these compounds. The necessity for large well-controlled, prospective, randomised clinical trials in the assessment of therapeutic efficacy is stressed.

Brain Ischemia↗
PubMed1989

Malignant fibrous histiocytoma (giant cell type) of the pancreas. A distinctive variant of osteoclast-type giant cell tumor of the pancreas.

Malignant giant cell tumors of the pancreas are rare neoplasms which have been generally thought to represent epithelial malignancies of either acinar or ductal epithelium. The authors have studied a tumor of the pancreas that was characterized histologically by a proliferation of benign-appearing osteoclast-type giant cells in association with atypical, often bizarre mononuclear cells. Immunohistochemical studies demonstrated negative staining of the tumor cells with epithelial markers, including low-molecular weight keratins, carcinoembryonic antigen and epithelial membrane antigen, and positive staining with vimentin antibodies, supporting a fibroblastic line of differentiation. Electron microscopic examination also showed absence of ultrastructural features of epithelial differentiation such as microvilli, intercellular junctions, or desmosomes. The authors believe the current case represents a true sarcoma of the pancreas, currently best classified as a malignant fibrous histiocytoma, giant cell type. This tumor should be distinguished from the epithelial type of osteoclastic giant cell tumor of the pancreas.

Aged↗
PubMed1989

Nongranulomatous involvement of the bone marrow in lepromatous leprosy.

Bone marrow involvement in lepromatous leprosy has been characterized histologically by a proliferation of foamy histiocytes containing lepra bacilli, the so-called Virchow cells. The authors have studied three patients with biopsy-proven lepromatous leprosy in whom Fite stain, performed on histologic sections of bone marrow aspirates, demonstrated numerous bacilli lying free in the interstitium in the absence of Virchow cells or focal collections of foamy macrophages. Two of the patients had a recent diagnosis of lepromatous leprosy by skin biopsy; the third patient had a 33-year history of lepromatous leprosy that had been treated. Bone marrow aspirates were performed in all three patients for evaluation of anemia. The findings indicate that the bone marrow may act as a reservoir for viable organisms in the absence of a host response in treated and untreated patients with lepromatous leprosy. The persistence of viable organisms in the bone marrow in patients with lepromatous leprosy may account for the high rate of relapse and/or recrudescence of the disease following cessation of specific therapy. Bone marrow examination with the Fite modification of the acid-fast stain is therefore indicated in such patients to evaluate bone marrow involvement and the efficacy of treatment.

Adult↗
PubMed1989

Malignant endovascular papillary angioendothelioma (Dabska tumor). A case report and review of the literature.

Malignant endovascular papillary angioendothelioma is a rare vascular tumor of childhood that was first defined by Dabska in 1969. Microscopically, this tumor is composed of anastomosing vascular channels, some of which contain papillary projections or tuft-like structures sometimes resembling renal glomeruli. Although cases have been reported with metastases to regional lymph nodes, the long term prognosis for patients with these tumors is generally good. We have studied this tumor by light and electron microscopy as well as immunohistochemical techniques in a 10-year-old boy. A review of the literature on this rare entity is presented.

Back↗
PubMed1989

Pediatric bowenoid papulosis: risks and management.

A 34-month-old Haitian girl had a six-month history of asymptomatic vulvar papules. Histologic features and DNA probe studies were diagnostic of bowenoid papulosis. Resolution of the lesions was enhanced by cryotherapy. This is the third reported patient with prepubertal bowenoid papulosis. Sexual abuse should be suspected, but not assumed, in pediatric patients with this condition. Our patient had no evidence of sexual abuse. Bowenoid papulosis has been associated with cervical intraepithelial neoplasia and rarely with squamous cell carcinoma. Close gynecologic follow-up is recommended.

Bowen's Disease↗
PubMed1989

Spindle cell carcinoma of the renal pelvis. Immunohistochemical and ultrastructural study of a case demonstrating coexpression of keratin and vimentin intermediate filaments.

A carcinoma of the renal pelvis characterized histologically by a spindle cell sarcomatoid morphological growth pattern was studied by electron microscopy and immunohistochemical techniques. Ultrastructural examination revealed abundant perinuclear cytoplasmic tonofilament bundles in association with prominent rough endoplasmic reticulum. Immunohistochemical study demonstrated coexpression of keratin and vimentin, two intermediate filaments thought to be specific for epithelial and nonepithelial cells, respectively. It is proposed that the spindle transformation of the epithelial cells in such cases may be explained on the basis of the development by the tumor cells of nonepithelial characteristics, such as the expression of vimentin intermediate filaments, that may be responsible for the adoption of the morphological growth pattern characteristic of neoplasms following mesenchyme-derived lines of differentiation.

Aged↗
PubMed1988

Histiocytic lymphophagocytic panniculitis. An unusual extranodal presentation of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease).

A 72-year-old woman presented with the sudden onset of multiple, large, firm, subcutaneous nodules in her right arm and left thigh. Biopsy of the lesions revealed a septal and lobular panniculitis of unknown cause. The lesions regressed spontaneously without therapy over a period of a few weeks. A follow-up review of the microscopic slides from the biopsy disclosed a lymphohistiocytic and plasma cell proliferation with lymphophagocytosis by histiocytes, the characteristic morphological features of sinus histiocytosis with massive lymphadenopathy. This diagnosis was further supported by the immunocytochemical demonstration of S100 protein reactivity within the histiocytic cells. A seven-year follow-up has failed to reveal any evidence of recurrence or progression of the disease. Sinus histiocytosis with massive lymphadenopathy should be entertained in the differential diagnosis of cutaneous lesions presenting with septal and lobular panniculitis.

Aged↗