PubMed Health⌕ Search

Biomedical subjects

J B Gavin

Publications and source records attributed to J B Gavin.

At least 37 records · Page 2Linked to original sources
PubMed1992

The pathobiology of subclinical pyelonephritis--an experimental evaluation.

Clinical studies have demonstrated a poor correlation between localization tests, which are designed to determine the site of urinary tract infection, and symptoms of upper urinary tract infection. One explanation is that microorganisms may be present in the kidney but not initiate an inflammatory response with associated symptoms. An animal model has been developed to obtain quantitative information on the comparative pathobiology of lesion-inducing and non-lesion-inducing infections. In this model, non-manipulated kidneys had acquired a persistent microbial flora within 48 hours of the lower urinary tract becoming infected. This bacterial invasion was not associated with gross or histologic changes within the renal parenchyma, but minor foci of inflammatory cells were seen beneath the epithelium lining the calyces. Ureteric urines from such kidneys contained many leukocytes and high numbers of bacteria. These results showed that the kidneys were infected, rather than colonized, and the term "subclinical" infection was appropriate. Antimicrobial agents were variably successful at eradicating the infection. These experimental observations support the concept of subclinical pyelonephritis and may explain the absence of symptoms in the clinically equivalent situation in humans.

Animals↗
PubMed1992

The role of immune effector cells in flavone acetic acid-induced injury to tumor cells in EMT6 spheroids.

Inhibition of tumor blood flow appears to a major antitumor mechanism of flavone acetic acid (FAA), although non-ischemic processes may also be a significant role. To distinguish between direct and immune effector cell-mediated cytotoxicity as the basis for non-ischemic killing, effects of FAA were compared in EMT6 spheroids grown entirely in vitro and spheroids recovered from the peritoneal cavities of mice after six days of in vivo growth (ex vivo spheroids). Approximately 50% of the cells in the latter case were of host origin (macrophages and lymphocytes). Ex vivo spheroids showed specific histological changes when exposed to FAA, including tumor cell rounding, apoptosis, depression of mitotic activity and dissolution of necrotic debris in the spheroid core. Quantitation of histological changes indicated these effects to be significantly greater in ex vivo than in vitro spheroids. The histological changes in FAA treated ex vivo spheroids were partially inhibited by dexamethasone. Oxygen tension did not influence the response of spheroids to FAA. The results suggest that immune effector cells, probably macrophages, mediate blood flow-independent antitumor effects of FAA.

Animals↗
PubMed1992

Long-term preservation of explanted hearts perfused with L-aspartate-enriched cardioplegic solution. Improved function, metabolism, and ultrastructure.

The effects of supplementing oxygenated St. Thomas' Hospital cardioplegic solution No. 2 with L-aspartate and/or D-glucose for the long-term preservation of excised rat hearts were determined with isolated working heart preparations. Left ventricular function was assessed at 37 degrees C with a crystalloid perfusate, before cardioplegic arrest and after 20 hours of low-flow perfusion (1.5 ml/min) with continuing arrest at 4 degrees C, and after this period, again at 37 degrees C with a crystalloid perfusate. Four groups (n = 8/group) of hearts were studied with four cardioplegic solutions: St. Thomas' Hospital solution alone, St. Thomas' Hospital solution with aspartate 20 mmol/L, St. Thomas' Hospital solution with glucose 20 mmol/L, and St. Thomas' Hospital solution plus both aspartate and glucose (20 mmol/L each). The addition of glucose to St. Thomas' Hospital solution made no significant difference in the recovery of aortic flow rates (17.7% +/- 8.6% and 21.6% +/- 7.8% of prearrest values), but when aspartate or aspartate and glucose were present, hearts showed significant improvements (89.8% +/- 5.2% and 85.0% +/- 6.2%, respectively). These improvements were associated with a reduction in the decline of myocardial high-energy phosphates during reperfusion, a reduction in cellular uptake of Na+ and Ca++, and a reduction in ultrastructural damage. These results indicate that low-flow perfusion with St. Thomas' Hospital solution plus aspartate can considerably extend the duration of safe storage of explanted hearts.

Adenine Nucleotides↗
PubMed1991

Tumor-dependent increased plasma nitrate concentrations as an indication of the antitumor effect of flavone-8-acetic acid and analogues in mice.

The antitumor agent flavone-8-acetic acid (FAA) is remarkable because it induces hemorrhagic necrosis, altered tumor blood flow, and cytokine synthesis. We show here that FAA and structurally related analogues increase plasma nitrite plus nitrate (NO2-/NO3-) levels in mice. Dose-dependent increases in plasma NO2-/NO3- concentrations, which reached maximum levels at 12 h, were found following administration of FAA. Furthermore, the presence of a palpable s.c. Colon 38 tumor significantly enhanced the response. Tumor-dependent increases were also observed with the active FAA analogues xanthenone-4-acetic acid, 5-methyl XAA, and 5,6-dimethyl XAA, while the inactive analogue 8-methyl XAA failed to increase plasma NO2-/NO3- concentrations substantially above basal levels. Increased plasma NO2-/NO3- levels were also observed in response to endotoxin (100 micrograms/mouse) and to recombinant human tumor necrosis factor alpha (4 to 16 micrograms/mouse). NO2-/NO3- levels may signify nitric oxide production as a result of stimulation of the L-arginine-dependent pathway in activated macrophages. The tumor dependence of the response may reflect the immunological stimulus imposed by tumor implantation. A clear relationship was found between increased plasma NO2-/NO3- levels and tumor growth delays induced by FAA and xanthenone-4-acetic acid analogues. It is suggested that nitric oxide may contribute to tumor cell death by two mechanisms, alteration of blood flow contributing to tumor ischemia and direct tumor cell killing. Plasma NO2-/NO3- concentrations may be a sensitive indication of the antitumor response to this class of compounds.

Adenocarcinoma↗
PubMed1991

Oxygen content of the fixative is important in the interpretation of the ultrastructure of ischaemic myocardium.

Isolated rat hearts were subjected to 15, 45, or 60 minutes of global ischaemia and then fixed by perfusion at 37 degrees C with glutaraldehyde containing various amounts of oxygen. This either had been bubbled with 100% oxygen (PO2 620 mm Hg) or with 100% nitrogen (PO2 40 mm Hg) immediately before use, or it had been routinely prepared and stored exposed to atmospheric oxygen (PO2 245 mm Hg). The ultrastructure of myocytes and endothelial cells subjected to 15 minutes of ischaemia was not affected by the treatment of the fixative. However, when the tissue subjected to longer periods of ischaemia was fixed with routinely prepared or oxygen-bubbled glutaraldehyde, ultrastructural changes characteristic of reoxygenation damage were uniformly evident in both the microvasculature and myocytes. These qualitatively distinct changes included mitochondrial swelling, cell swelling, endothelial bleb formation, and narrowing of capillary lumina. These abnormalities were not observed in tissue fixed with nitrogen-bubbled glutaraldehyde. These findings indicate that deliberate steps should be taken to reduce or eliminate dissolved oxygen from the fixatives used to study ischaemic tissues. Otherwise artefactual reoxygenation damage in vitro may occur and make valid ultrastructural interpretation difficult or impossible.

Animals↗
PubMed1991

Interrelationships of ultrastructure and function in the microvasculature of normal and ischaemic myocardium.

This paper reviews various methods involving electron microscopy that have been used to investigate the ultrastructure of the vasculature of the normal and diseased heart. Whereas scanning electron microscopy is more commonly employed to record surface topography, it can be used to examine freeze-fracture planes within the myocardium and, using heavy-metal staining and back-scattered electron imaging, to examine large 2-mu-thick resin-embedded sections through the heart. The latter technique allows the comparison of structural alterations across the wall of the heart and thus accurate definition of the transmural progression of pathological processes. Transmission electron microscopy can then be used to provide more detailed information from precisely localised regions. Human myocardium can be usefully studied up to 12 hours post-mortem provided that suitable control material is included. Intravascular tracers including low-viscosity resin and nuclear track emulsion can be used to determine whether or not particular vessels allow flow at the time of fixation, and thus changes in the pattern of flow through the microvasculature due to ischaemia and reperfusion can be quantified and defined. Particular care is required in the fixation of ischaemic tissues because oxygen dissolved in the fixative can lead to the rapid formation of oxygen-free radicals on contact with the tissue. This produces artefactual reoxygenation damage characterised by membrane disruption and cell and organelle swelling, which has previously been attributed to ischaemic injury per se. Bubbling glutaraldehyde with nitrogen substantially reduces this artefact.

Animals↗
PubMed1991

Cardiovascular implant calcification: a survey and update.

Calcification of cardiovascular prosthetic implants is a common and important problem. This review provides an update based upon the Conference on Cardiovascular Implant Calcification held as part of the 13th World Congress of the International Society for Heart Research, 1989. A variety of cardiovascular prostheses are affected clinically by calcification, including bioprosthetic heart valves, aortic homografts and trileaflet polymeric valve prostheses. In addition, experimental studies have demonstrated calcification of artificial heart devices in ventricular assist systems in long-term calf studies. The pathophysiology of this disease process is incompletely understood. A common element between the various types of cardiovascular implant calcification is the localization of calcific deposits to devitalized cells and membranous debris. Prevention of cardiovascular implant calcification by either biomaterial modifications or regional drug therapy (controlled release) is being investigated.

Animals↗
PubMed1991

The contribution of ischaemia to the development of microvascular incompetence in the myocardium.

STUDY OBJECTIVE: The aim was to determine the contribution of ischaemia per se to the development of microvascular incompetence in the myocardium. DESIGN: Isolated, buffer perfused rat hearts were made globally ischaemic for 0-60 min, then fixed with nitrogen bubbled glutaraldehyde and perfused with nuclear track emulsion to identify and quantify competent blood vessels in scanning and transmission electron micrographs. SUBJECTS: Adult Male Wistar rats weighing between 275 and 350 g were used. MEASUREMENTS AND MAIN RESULTS: Thirty or more min ischaemia significantly (p less than 0.05) reduced the density of competent capillaries in the subendocardial third of the myocardium, as did 45 or more min in the subepicardial third and 60 min in the middle third. Following 60 min ischaemia virtually all vessels in the subendocardial third were not perfusable. Severely ischaemic myocardium showed relatively normal, open, unobstructed capillaries and an absence of the endothelial, myocyte and mitochondrial swelling which have previously been attributed to ischaemia. CONCLUSIONS: In severely ischaemic myocardium microvascular incompetence shows a transmural gradient in severity. It develops progressively, starting near the endocardium. These findings suggest that postischaemic reoxygenation may accelerate the development of microvascular incompetence.

Animals↗
PubMed1991

Influence of storage volume on functional recovery and metabolism of explanted hearts following cold cardioplegia: studies in the rat.

STUDY OBJECTIVE: The aim was to characterise the metabolic and functional recovery after extended periods of hypothermic storage of hearts in varying volume of oxygenated cardioplegic solution. DESIGN: Explanted rat hearts were arrested with and stored in 5, 10, or 100 ml of oxygenated (95% O2: 5% CO2) St Thomas's Hospital cardioplegic solution No 2 (STH) at 4 degrees C for 5 or 10 h. The isolated working heart model was used to determine the cardiac functions and the degree of functional recovery was expressed as a percentage of the prearrest value. Groups of hearts (n = 6) were rapidly freeze-clamped immediately after arrest, at end of storage, or after 30 min reperfusion for quantitation of the high energy phosphate content. SUBJECTS: 84 Male albino Wistar rats weighing 280 to 320 g (heart weight = 1.25 g) were used. MEASUREMENTS AND MAIN RESULTS: All hearts in the three different volumes of STH recovered 80% or more [mean 90 (SEM 3)%] of their prearrest aortic output after 5 h storage but after 10 h, recovery was significantly reduced [23(7)%] with no significant difference among groups. During 5 h storage the phosphocreatine content of the hearts rapidly declined from 33.2(3.1) to 5.0(0.2) mumol.g-1 dry wt in the 5 ml group but only to 16.7(1.2) mumol.g-1 dry wt in the 100 ml group. Similarly ATP preservation was improved in the latter group (81% v 63%, p less than 0.02). Extending the storage time to 10 h resulted in a further decline in high energy phosphates (ATP + phosphocreatine) to 30% of normal values in the 100 ml group and to 9% in the 5 ml group (p less than 0.01). While the total nucleotide pool did not decrease the major catabolite was inosine monophosphate (IMP) which comprised 46% of the nucleotide pool in all groups. The extent of cardiac function recovered was correlated inversely with tissue IMP (R = 0.859) and positively with ATP (R = 0.835) but showed no significant correlations with the postischaemic ADP, AMP, or phosphocreatine. CONCLUSIONS: Increased storage volume of oxygenated cardioplegic solution is superior in the preservation of ATP and phosophocreatine content in donor hearts with full recovery of cardiac function after the first 5 h of hypothermic (4 degrees C) storage.

Adenosine Triphosphate↗
PubMed1990

The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels.

EMT6 multicellular spheroids were introduced into the peritoneal cavities of mice and allowed to become vascularised, resulting in solid spherical tumours. The necrotic cores of the initially avascular spheroids were replaced by vascularised tumour tissue but the outer zones of the spheroids failed to become vascularised. The presence of both vascular and avascular components in each spheroid allowed the role of the vasculature in the antitumour action of flavone acetic acid (FAA) to be determined. Eighteen hours after treatment with FAA 0.8 mmol kg-1, the vascularised core became necrotic and haemorrhagic, while the outer avascular zone remained viable. Tumour cells which were infiltrating superficial sub-mesothelial fat did not become necrotic despite the presence of numerous thrombi in associated vessels. Injection of two fluorescent vascular markers, the first (Hoechst 33342) together with FAA, and the second (10-nonyl acridine orange) 4 h later, demonstrated that there is a marked loss of blood flow in the spheroids. These results provide further evidence that FAA kills blood vessel-dependent tumour cells by interrupting the tumour blood supply.

Acridine Orange↗
PubMed1990

Sulphinpyrazone reduces endocardial injury and mural thrombosis.

STUDY OBJECTIVE: The aim of the study was to investigate the effectiveness of sulphinpyrazone, a drug which stabilises endothelial cell membranes, in reducing endocardial injury and mural thrombosis produced by lactic acid in the left ventricle. DESIGN: The left ventricular endocardium of isolated beating rat hearts, perfused via the aorta with oxygenated Krebs-Henseleit buffer, was exposed for up to 4 h to additional lactic acid (pH 6.4), with and without sulphinpyrazone (100 ng x ml-1). After flushing with buffer, passage of 10 ml blood, and further flushing, the hearts were fixed by coronary perfusion and the endocardium examined by scanning electron microscopy. EXPERIMENTAL MATERIAL: Hearts from 48 male albino Wistar rats, weight 270-380 g, were used. MAIN RESULTS: Morphometric analysis of the surface of the papillary muscles showed that lactic acid caused membrane injury in endothelial cells, up to 30% of which exfoliated. However when sulphinpyrazone was present, endothelial cell damage was reduced and there was up to 75% reduction in the area of exposed basal lamina or connective tissue. This was associated with a corresponding reduction in the extent of platelet adhesion (79%) and thrombus formation (94%). CONCLUSIONS: The results show that sulphinpyrazone has the potential to reduce the risk of mural thrombosis following endocardial injury.

Animals↗
PubMed1990

Relation of Helicobacter pylori to the human gastric mucosa in chronic gastritis of the antrum.

The spatial relations between bacteria and the affected tissues can indicate pathogenic mechanisms. This study was undertaken to define the spatial relation of Helicobacter pylori to the human gastric mucosa. Antibodies against gastric mucus and ruthenium red were used to stabilise the glycoprotein structure of the mucus and glycocalyces in antral biopsy specimens from eight patients infected with H pylori. The location of organisms and ultrastructural features were assessed using systematic scanning and transmission electron microscopy: 92 (2)% (mean (SE] of H pylori were in the pit mucus, and 7 (3)% were in the surface mucus; 60 (12)% of H pylori were close to epithelial cells, with only 5 (2)% located near the epithelial intercellular junctions. Fine filamentous strands extended between organisms and nearby epithelial cells, with few organisms in membrane to membrane contact. H pylori were not observed between, beneath, or within cells of the gastric mucosa. The preferred location of H pylori in the gastric antrum is within the pit mucus close to the epithelial cell surface, with no evidence that they have a direct toxic effect on the mucosa.

Gastric Mucosa↗
PubMed1990

L-aspartate improves the functional recovery of explanted hearts stored in St. Thomas' Hospital cardioplegic solution at 4 degrees C.

Explanted rat hearts were subjected to cardioplegic arrest by 3 minutes' perfusion with oxygenated St. Thomas' Hospital solution no. 2 and then were stored by immersion in the same solution at 4 degrees C. Prearrest and postischemic left ventricular functions were compared by means of an isolated working heart apparatus. Hearts (n = 8 per group) arrested and stored for up to 8 hours all resumed the spontaneous rhythm of contraction during reperfusion for 30 minutes at 37 degrees C. There was good recovery of aortic flow rate (105% +/- 3%) against a pressure of 100 cm H2O, of heart rate (102% +/- 2%), and of aortic pressure (86% +/- 5% of prearrest values). Hearts stored for 10 and 20 hours showed poor or no postischemic recovery of cardiac pump function (aortic flow, 16% +/- 11% and 0%, respectively). Enrichment of St. Thomas' Hospital solution with L-glutamate (20 mmol/L) also failed to improve functional recovery of hearts subjected to 10 hours of storage, but hearts treated with St. Thomas' Hospital solution containing L-aspartate (20 mmol/L) or L-aspartate plus L-glutamate (20 mmol/L each) reestablished aortic flow rates of 99% +/- 5% and 93% +/- 4%, respectively. These results indicate that the addition of L-aspartate to St. Thomas' Hospital solution improves the functional recovery and extends the safe preservation of explanted hearts stored at 4 degrees C.

Animals↗
PubMed1989

Blood flow failure as a major determinant in the antitumor action of flavone acetic acid.

Some investigators have suggested that the marked activity of flavone acetic acid (FAA) against advanced solid tumors in mice results from an indirect effect. This study indicates that the critical effect of FAA is irreversible inhibition of tumor blood flow. Perfusion of sc Colon 38 tumors, assessed with H33342 as a fluorescent stain for functional blood vessels, was reduced to 50% of controls within 3 hours of an ip injection of 1.2 mmol of FAA/kg and was completely inhibited by 24 hours. A double-label fluorescence technique demonstrated a significant decrease in blood flow in both sc Colon 38 and im EMT-6/Ak tumors as early as 15 minutes after iv treatment with 1.2 mmol of FAA/kg, with progressively enlarging zones of perfusion failure. The rate of cell death in totally ischemic EMT-6 tumors was shown to be sufficiently rapid to represent a major component of the observed antitumor effect of FAA if the flavonoid acts via inhibition of blood flow. Further, avascular EMT-6/Ak multicellular spheroids growing in the mouse peritoneum are relatively resistant to killing by FAA administered iv or ip, despite extensive infiltration with host immune cells. These results indicate that inhibition of tumor blood flow by FAA is a necessary component of its antitumor activity against solid tumors.

Animals↗
PubMed1989

The intima of human coronary arteries.

Intimal thickness relative to that of the media (r) was measured in coronary and internal mammary arteries from 300 human subjects. Whereas this ratio remained low (less than 0.17) in the mammary arteries, coronary arteries showed progressive intimal thickening (r = 4.10 by 60 years). The intimal surfaces of 70 pairs of arteries were compared by light, transmission, and scanning electron microscopy. The mammary arteries had a continuous endothelial lining, but the coronary arteries showed incomplete coverage of the thickened intima. In affected vessels the endothelial cells showed loss of attachment to adjacent cells and to the underlying tissue. It was concluded that the progressive intimal thickening of the human coronary artery, which develops early in life and is associated with defects in the internal elastic lamina, is also associated with endothelial cell separation and detachment, with the formation of denuded areas on the intimal surface.

Adolescent↗
PubMed1989

The nature and progression of injury in the organ of Corti during ischemia.

This study has defined the nature and sequence of ultrastructural changes in the organ of Corti following severe, total cochlear ischemia. Afferent nerve endings of IHC became swollen within 15 min and eventually ruptured. Outer hair cells were swollen within 30 min and showed alterations to mitochondria, endoplasmic reticulum and the nucleus whereas IHC remained unchanged for up to 60 min. Both efferent and afferent nerve endings of OHC were unaltered until after 60 min ischemia. Regardless of the type, cells in the base of the cochlea developed abnormalities more rapidly than those in the apical turns. These results imply a differential susceptibility to ischemic damage both among the different cell types and along the organ of Corti.

Afferent Pathways↗
PubMed1989

Endocardial injury and the pathogenesis of mural thrombosis in the left ventricle.

To define the interactions between blood and endocardium damaged by lactic acid, the left ventricles of 48 isolated continuously perfused and beating hearts were exposed for 0-4 hours to Krebs Henseleit buffer (KHB) with or without 33 mumol.ml-1 of lactic acid (pH 6.4). After excising its apex, the left ventricle was flushed with KHB, followed by 10 ml of lightly heparinised blood, and then by a further 10 ml of KHB. Lactic acid caused endothelial cell membrane rupture, intercellular separation, and exfoliation with exposure of the basal lamina and underlying connective tissue. Whereas multilayered platelet aggregations formed on exposed basal lamina, fibrin deposition and incorporation of blood cells were only observed in the larger thrombi which formed on exposed collagen. These findings indicate that a metabolite which accumulates in ischaemic myocardium can cause endocardial injury which would predispose to the mural thrombosis which can complicate myocardial infarction.

Animals↗