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Biomedical subjects

J G McCormack

Publications and source records attributed to J G McCormack.

At least 73 records · Page 4Linked to original sources
PubMed1993

Changes in mitochondrial matrix free calcium in perfused rat hearts subjected to hypoxia-reoxygenation.

Reperfusion or reoxygenation of ischaemic or hypoxic cardiac tissue results in increases in total cell calcium and cell lysis both of which are dependent on mitochondrial function. Although changes which occur during this period of exposure of the tissue to hypoxia predispose the heart to take up calcium on reoxygenation, the mechanisms involved are not well understood. In the present study we have investigated the effects of hypoxia and reoxygenation on the concentration of intramitochondrial (matrix) free Ca2+ ([Ca2+]m) using mitochondria loaded in the intact heart with fura-2. During periods of up to 80 min hypoxia, total tissue calcium content was unchanged. Over this period [Ca2+]m rose from an initial value of 156 +/- 26 nM to 360 +/- 33 nM and 574 +/- 62 nM at 50 and 80 min of hypoxia, respectively; values that are within the expected physiological range for [Ca2+]m. Reoxygenation after 50 min hypoxia resulted in no further change in [Ca2+]m whereas reoxygenation after 80 min hypoxia resulted in a 10-fold increase in this parameter. These results provide clear evidence that [Ca2+]m increases during hypoxia and suggest that the ability of the cell to maintain Ca2+ homeostasis is lost on reoxygenation after prolonged hypoxia with the result that [Ca2+]m exceeds the normal physiological range.

Adenosine Triphosphate↗
PubMed1993

Protective effects of ranolazine in guinea-pig hearts during low-flow ischaemia and their association with increases in active pyruvate dehydrogenase.

1. In isolated Langendorff-perfused, electrically-paced, hearts of guinea-pigs, global low-flow-ischaemia (LFI; at 0.7 ml min-1) resulted in marked increases in the rates of release of lactate, lactate dehydrogenase (LDH) and creatine kinase (CK) over a 30 min period. At the end of the LFI period, tissue ATP content was significantly reduced from a control value of 11.8 +/- 0.8 (5) to 5.6 +/- 0.8 (5) mumol g-1 dry weight. 2. The presence of ranolazine [(+/-)-N-(2,6-dimethyl-phenyl)-4[2-hydroxy-3-(2-methoxy-phenoxyl)- propyl] - l-piperazine acetamide dihydro-chloride; RS-43285-193] at 10 microM, from 20 min prior to and during LFI, resulted in significant reductions in the release of lactate, LDH and CK during the ischaemic period and a significant preservation of tissue ATP (9.0 +/- 1.1 (6) mumol g-1 dry wt.). Ranolazine did not prevent the reductions in creatine phosphate or glycogen observed in LFI, nor did it have any significant effects on any contractile parameters before or during the LFI period. 3. Neither ranolazine nor LFI affected the total amounts of tissue pyruvate dehydrogenase (PDH) activity; however, the significant reduction in the amount of active, non-phosphorylated PDH caused by LFI (from 88.2 +/- 5.5 to 44.2 +/- 3.2% of total activity) was partially but significantly prevented by ranolazine (67.2 +/- 6.8%). This effect of ranolazine on PDH may be part of the mechanism whereby the compound reduces lactate release and preserves tissue ATP during ischaemia.

Acetanilides↗
PubMed1993

Inhibition of adherence of mucoid Pseudomonas aeruginosa by alginase, specific monoclonal antibodies, and antibiotics.

The adherence of pseudomonal species was investigated by using a newly developed radiometric dacron fiber microcolumn assay. Pseudomonas aeruginosa, P. stutzeri, and Xanthomonas maltophilia were more adherent (approximately 20%) than P. pseudomallei, P. fluorescens, and P. cepacia (approximately 10%). Mucoid strains of P. aeruginosa were consistently more adherent than nonmucoid strains (30% versus 20%). Alginase was shown to inhibit the adherence of mucoid but not nonmucoid P. aeruginosa. Monoclonal antibodies to alginate were also shown to inhibit the adherence of mucoid but not nonmucoid P. aeruginosa. In addition, antibiotics active against P. aeruginosa were shown to inhibit the adherence of both mucoid and nonmucoid strains. Furthermore, synergism between dyadic combinations of monoclonal antibodies and antibiotic (ciprofloxacin), as well as alginase and antibiotic, was also observed. These results indicate that bacterial alginate has an intrinsic role in the adherence of mucoid P. aeruginosa and may have evolved not only for protection against dehydration in the water and soil ecosystem of this bacterium, but also as a means of attaching to soil substrates in the same ecosystem to enhance survival. They also suggest that synergistic combinations of antibiotics with alginase or monoclonal antibodies to alginate may be of value in the therapy of some pseudomonal infections.

Alginates↗
PubMed1993

Suppression of lymphocyte and neutrophil functions by Pseudomonas aeruginosa mucoid exopolysaccharide (alginate): reversal by physicochemical, alginase, and specific monoclonal antibody treatments.

The mucoid exopolysaccharide (MEP or alginate) of Pseudomonas aeruginosa is thought to be a virulence factor for this organism by virtue of its ability to suppress local host defense mechanisms. We purified MEP from clinical isolates of mucoid P. aeruginosa, subjected it to degradation by ultrasonication, heat, alkali, and alginase, and reacted it with monoclonal antibodies specific for MEP epitopes. Partial reversal or complete abrogation of the inhibitory effects of alginate on human neutrophil random migration, chemotaxis, and hexose monophosphate shunt activity and lymphocyte transformation were observed following most of these treatments. Physicochemical analysis of degraded MEP revealed a positive correlation between changes in molecular size and viscosity and loss of biological properties. The biological properties of MEP were also shown to be dependent on the structural integrity of the O-acetyl groups substituted for the mannuronic acid residues. The results show that the capacity of MEP to suppress neutrophil and lymphocyte functions is dependent on its acetyl content and the physical properties of large size and viscosity and may provide part of the explanation for the propensity of mucoid P. aeruginosa to persist in the airways of patients with cystic fibrosis. These findings highlight the important role of MEP as one of the virulence factors in the pathogenesis of inflammatory damage and subsequent pulmonary destruction in cystic fibrosis.

Alginates↗
PubMed1993

Mitochondrial Ca2+ transport and the role of intramitochondrial Ca2+ in the regulation of energy metabolism.

The mitochondrial inner membrane of all mammalian tissues, including brain tissues, has specific active transport systems for the uptake and egress of Ca2+. The primary role of this transport system is to relay changes in cytosolic [Ca2+], which stimulates energy-requiring processes in the cytosol (e.g. secretion), into the mitochondrial matrix where it stimulates several key steps in energy production. Thus using the same second-messenger molecule, the latter events allow energetic homeostasis to be maintained under conditions of cell stimulation. This appears to be brought about by a co-ordinated enhancement of steps throughout the pathways of oxidative phosphorylation, including substrate supply to the respiratory chain by dehydrogenase activation, activation of the respiratory chain itself by a mechanism which appears to involve changes in the matrix volume, and also possibly activation of the ATP synthetase where the release of a specific inhibitory subunit has been proposed.

Animals↗
PubMed1992

The effect of protein kinase C activation on muscarinic-M3- and K(+)-evoked release of [3H]noradrenaline and increases in intracellular Ca2+ in human neuroblastoma SH-SY5Y cells.

Short-term pretreatment (9 min) with the phorbol ester 12-myristate 13-acetate (PMA) alone had no effect on the basal release of [3H]noradrenaline ([3H]NA), but enhanced K+ (100 mM)-, acetylcholine (0.1 mM)-, carbachol (1 mM)-, muscarine (1 mM)- and arecoline (1 mM)-evoked release by 2.3-, 6.4-, 3.0-, 2.0- and 2.0-fold respectively in SH-SY5Y cells. Maximum effects of PMA were observed after a 10 min preincubation at a concentration of 0.1 microM. There was a 4-fold decrease in the EC50 values (concentration required for 50% of maximal stimulation) observed for carbachol- and acetylcholine-evoked release of [3H]NA in the presence of PMA. The inactive phorbol ester 4 alpha-phorbol 12,13-didecanoate did not alter the K(+)- or carbachol-evoked release of [3H]NA. The enhancement of release in the presence of PMA was more potently inhibited by the protein kinase C inhibitors RO 31-7549 [concentration required for 50% inhibition (IC50) = 0.18 microM/bd and RO 31-8220 (IC50 = 0.56 microM) than by either polymyxin-B or H-7. Furthermore, in the absence of PMA, both K(+)- and carbachol-evoked release was inhibited by these antagonists. Atropine, hexahydro-sila-difenidol and pirenzepine antagonized the PMA-enhanced carbachol-evoked release of [3H]NA, with Ki values of 2.75 +/- 0.25 nM, 2.6 +/- 0.64 nM and 294 +/- 17 nM respectively. These values were consistent with the coupling of an M3 muscarinic receptor to the release of [3H]NA in SH-SY5Y cells. Whereas pretreatment with PMA (5 min) enhanced M3-evoked release of [3H]NA, it decreased the muscarinic-agonist-evoked initial peak (greater than 85%) and plateau phase in intracellular Ca2+. These results suggest that noradrenaline release evoked by muscarinic agonists was triggered not only by relatively small changes in Ca2+ but also by activation of protein kinase C.

Calcium↗
PubMed1992

The loading of fura-2 into mitochondria in the intact perfused rat heart and its use to estimate matrix Ca2+ under various conditions.

When rat hearts were perfused with a medium containing 10 microM fura-2/AM for 1 hr at 37 degrees C a significant amount of the derived fura-2 could be detected in subsequently isolated mitochondria. This procedure allowed the measurement of matrix free Ca2+ concentration ([Ca2+]m) of mitochondria rapidly isolated from whole hearts by a method which avoids artefactual redistribution of Ca2+. [Ca2+]m in mitochondria prepared from control hearts and incubated with respiratory substrates and EGTA was found to be 172 +/- 23 nM (mean +/- S.E.M.). When hearts were subjected to either increased mechanical work or treatment with 1 microM L-epinephrine (for 2 mins) [Ca2+]m increased to 916 +/- 138 nM and 727 +/- 65 nM respectively. The presence of ruthenium red (2.5 microM) in the perfusion medium prior to and during inotropic intervention diminished these increases in [Ca2+]m(to 316 +/- 28 nM and 218 +/- 18 nM respectively) but did not affect control values. Addition of Na+ ions to incubated mitochondria to enhance mitochondrial Ca2+ egress diminished these increases in [Ca2+]m due to pre-treatment with positive inotropes (compared to controls). These changes in [Ca2+]m were broadly parallelled by changes in the active non-phosphorylated form of pyruvate dehydrogenase (PDH) under all circumstances. These results provide further evidence that the activation of PDH by positive inotropes is accomplished by, and at least in part due to, raised mitochondrial matrix free [Ca2+] and that such increases can be maintained in isolated and suitably incubated mitochondria.

Animals↗
PubMed1992

Clinical features of human infection with Scedosporium inflatum.

We report on 17 Australian cases of human infection or colonization with Scedosporium inflatum. The spectrum of clinical manifestations was similar to that in infection caused by Scedosporium apiospermum. The patients were classified into three groups. Four immunocompetent patients who presented with localized infections of a joint, nail bed, eye, or sphenoidal sinus made up the first group. Our first case, in a boy with posttraumatic septic arthritis, responded to surgical drainage with amphotericin B followed by treatment with itraconazole. The other three cases were cured by surgery alone. The second group consisted of five immunocompromised patients who presented with disseminated infections in a variety of sites. Four of these patients did not respond to antifungal therapy and died. The fifth apparently responded to antifungal drugs after correction of his neutropenia. The third group included eight patients with asymptomatic colonization in the external ear (five cases) or respiratory secretions (three cases). The nine isolates of S. inflatum tested by both disk and agar dilution methods were resistant to antifungal drugs. In our first case, which responded clinically to itraconazole, the MIC of this drug for the fungal isolate was 25 micrograms/mL. Thus S. inflatum can cause a broad spectrum of human infections whose severity and prognosis depend largely on the host's immune status.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Severe amoebic colitis requiring colonic resection.

A 54 year old Australian man presented with fulminant amoebic colitis. Although the amoebae were eradicated, his colonic function did not recover. Colectomy was required. Situations where the surgeon may encounter amoebiasis are discussed.

Biopsy↗
PubMed1991

Subdural and epidural empyema: diagnostic and therapeutic problems.

OBJECTIVE: A clinical and microbiological review of cases of subdural and epidural empyema. DESIGN, SETTING, PATIENTS: A 10-year retrospective review of patients with subdural and epidural empyema in all Brisbane hospitals with neurosurgical units. In this period there were 14 cases. RESULTS: The paranasal sinuses were the primary focus in 8 of the 14 cases, the middle ear in 3 and a surgical or traumatic wound in 2. One case occurred as a complication of Haemophilus influenzae meningitis. Streptococci, particularly Streptococcus milleri, were the causative organisms in all cases of sinus origin, most of which occurred in the second decade of life. An intracranial collection was considered in the differential diagnosis within 24 hours of admission in all 3 cases of otic origin but in only 2 of the 10 sinus or post-traumatic cases. The most common initial diagnosis was viral or partially-treated bacterial meningitis (8 of 13 cases). The initial computed tomographic (CT) scan was not diagnostic in 3 of 11 patients. No patient was successfully treated without surgery, and all 3 deaths in the series were associated with delayed surgery. CONCLUSIONS: Subdural and epidural empyema is an uncommon condition. The majority of the cases in this series were associated with sinusitis, and Streptococcus milleri was the commonest organism identified. The condition remains a diagnostic challenge; CT scanning cannot be relied upon although the use of intravenous contrast and more modern scanners has improved the diagnostic yield. Surgical drainage and early aggressive antimicrobial therapy are essential to avoid significant morbidity and mortality.

Adolescent↗
PubMed1991

Branhamella (Moraxella) catarrhalis: pathogenic significance in respiratory infections.

OBJECTIVES: To assess the pathogenic significance of Branhamella catarrhalis isolates in patients with respiratory infections and to define the clinical characteristics of such patients. DESIGN AND SETTING: Respiratory specimens were assessed in a three-year prospective study performed in a Brisbane metropolitan hospital. Assessment of the pathogenic significance of isolates of B. catarrhalis was based on four predetermined criteria: (i) clinical evidence of respiratory infection based on history, examination and chest x-ray; (ii) isolation of B. catarrhalis as the sole potential pathogen; (iii) absence of antibiotic treatment in the previous two weeks; and (iv) subsequent clinical response to an antibiotic to which the isolate was sensitive. RESULTS: B. catarrhalis was identified in 118 respiratory samples, 92 (78%) being from patients less than 10 years old. Infection with B. catarrhalis was more commonly seen in winter months and was community-acquired in two-thirds of cases. Isolation of this organism was associated with a broad variety of upper and lower respiratory tract syndromes. Isolates were considered to be of pathogenic significance (all four above criteria satisfied) in 35% of cases and of possible significance (the first and fourth criteria satisfied) in a further 15% of cases. Isolates were more likely to be of pathogenic significance in older patients and in those with pre-existing cardiorespiratory disease; however, a number of serious infections were observed in previously-well children. Expectorated sputum and tracheal aspirates were more likely to yield a clinically significant isolate than nasopharyngeal aspirates. Production of beta-lactamase was demonstrated in 88% of isolates. CONCLUSION: B. catarrhalis causes respiratory infection more frequently than is generally appreciated. Isolation of this organism from the respiratory tract had pathogenic significance or possible pathogenic significance in 50% of our patients. If therapy is indicated in patients with respiratory infection caused by this organism, traditional beta-lactam regimens cannot be relied upon, as shown by the high rate of beta-lactamase production in this study; a tetracycline, erythromycin, a second or third generation cephalosporin, or the combination of a penicillin derivative and beta-lactamase inhibitor should be considered.

Adolescent↗
PubMed1991

Effects of glycogen stores and non-esterified fatty acid availability on insulin-stimulated glucose metabolism and tissue pyruvate dehydrogenase activity in the rat.

The effects of increased tissue glycogen stores on insulin sensitivity, and on the response of insulin-stimulated glucose utilisation to an acute elevation in plasma fatty acid levels (approximately 1.5 mmol/l), were investigated in conscious rats using the hyperinsulinaemic euglycaemic clamp. Studies were performed in two groups of rats; (a) fasted 24 h; (b) fasted 4.5 h, but infused with glucose for 4 h (0.5 g/h) of this period before the clamp (fed, glucose infused rats). Clamp glucose requirement and 3-3H-glucose turnover were 20-25% lower in the fed, glucose-infused rats. In these rats, elevation of plasma fatty acid levels resulted in impaired suppression of hepatic glucose output (residual hepatic glucose output: 41 +/- 4 vs 8 +/- 6 mumol.min-1.kg-1, p less than 0.001) but did not further decrease 3-3H-glucose turnover. Elevated non-esterified fatty acid levels had no significant effect on glucose kinetics in 24 h fasted rats. In the fed glucose-infused rats, at low plasma fatty acid levels, there was no deposition of glycogen in muscle during the clamp and liver glycogen levels fell. With elevation of non-esterified fatty acid levels muscle glycogen deposition was stimulated in both groups, and there was no fall in liver glycogen during the clamps in the fed glucose-infused rats. Increased non-esterified fatty acid availability during the clamps decreased pyruvate dehydrogenase activity in liver, heart, adipose tissue and quadriceps muscle, in both groups of rats. The findings are consistent with an inhibition of glycolysis in liver, skeletal muscle and heart by increased fatty acid availability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗