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Biomedical subjects

J G McCormack

Publications and source records attributed to J G McCormack.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cat-scratch disease with paravertebral mass and osteomyelitis.

The case of a 9-year-old girl with cat-scratch disease (CSD) complicated by development of a paravertebral mass and osteomyelitis is presented. Following multiple scratches and inguinal lymphadenopathy, she developed back pain, and imaging demonstrated a paravertebral mass with evidence of osteomyelitis involving vertebra T9. The diagnosis was made on the basis of detection of Bartonella henselae by use of molecular techniques on an aspirate from the vertebral column and supportive serology for infection with B. henselae. Eleven other cases of this unusual manifestation associated with CSD have been reported in the literature and are reviewed. The patient was treated with gentamicin, followed by rifampicin and trimethoprim-sulfamethoxazole, orally and made a favorable recovery over 7 months. This is comparable with other case reports, regardless of the choice of antibiotic therapy. CSD in immunocompetent hosts is not always self-limiting, and tissues beyond the lymph nodes can be involved.

Bartonella henselae↗
PubMed1999

Are antipseudomonal antibiotics really beneficial in acute respiratory exacerbations of cystic fibrosis?

BACKGROUND: Although anti-pseudomonal antibiotics are routinely used in the treatment of acute respiratory exacerbations of adult cystic fibrosis (CF), the specific efficacy of such treatment remains uncertain, the mechanism of action of these agents is not fully understood, and the role of sputum susceptibility testing in clinical decision making is controversial. AIMS: We investigated the relationship between susceptibility testing and clinical outcome in adult CF patients colonised with Pseudomonas aeruginosa. METHODS: Sputum samples were collected before, during and after respiratory exacerbations from 31 admissions (17 patients). Sputum colony counts and MIC of P. aeruginosa were performed. RESULTS: Sputum colony counts did not change significantly during or after intravenous (IV) antibiotic therapy. Clinical outcome parameters (lung function, 12-minute walking distance, sputum weight and quality of life) were compared with susceptibility of P. aeruginosa colonies isolated at admission to the antibiotics used, and no correlation was evident. There was no evidence for the development of cross-resistance and there was no change in the proportion of mucoid colonies with therapy. CONCLUSIONS: While this study has a small patient sample size, it highlights the inconsistency of the role of antipseudomonal drugs also shown in other similar studies. The presence of P. aeruginosa in sputum of acutely ill CF patients prompts us to prescribe i.v. antipseudomonal drugs. If this approach was valid, we would expect to find a reduction in sputum colony counts and improvement in clinical parameters with the use of antibiotics to which the organisms were sensitive. The fact that such a relationship cannot be consistently demonstrated in this and other studies suggests that the use of antipseudomonal therapy in these patients requires more critical bacteriological and clinical evaluation.

Acute Disease↗
PubMed1999

Cytokines and inflammatory mediators do not indicate acute infection in cystic fibrosis.

Various treatment regimens and difficulties with research design are encountered with cystic fibrosis (CF) because no standard diagnostic criteria exist for defining acute respiratory exacerbations. This study evaluated the role of serial monitoring of concentrations of selected cytokines and inflammatory mediators in serum and sputum as predictors of respiratory exacerbation, as useful outcome measures for CF, and to guide therapy. Interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-alpha), neutrophil elastase-alpha-1-protease inhibitor complex (NE complex), protein, and alpha-1-protease inhibitor (alpha-1-PI) were measured in serum and sputum collected from CF patients during respiratory exacerbations and periods of well-being. Levels of NE complex, protein, and alpha-1-PI in sputum rose during respiratory exacerbations and fell after institution of antibiotic therapy (P = 0.078, 0.001, and 0.002, respectively). Mean (+/- standard error of the mean) levels of IL-8 and TNF-alpha were extremely high in sputum (13,780 +/- 916 and 249.4 +/- 23.5 ng/liter, respectively) but did not change significantly with clinical deterioration of the patient (P > 0.23). IL-8 and TNF-alpha were generally undetectable in serum, and therefore these measures were unhelpful. Drop in forced expiratory volume in 1 s was the only clinical or laboratory parameter that was close to being a determinant of respiratory exacerbation (P = 0.055). This study provides evidence of intense immunological activity occurring continually within the lungs of adult CF patients. Measurement of cytokines and inflammatory mediators in CF sputum is not helpful for identifying acute respiratory exacerbations.

Acute Disease↗
PubMed1998

Cytomegalovirus retinitis, human immunodeficiency virus antibody positivity and normal T helper cell numbers.

We describe a 46-year-old man in whom retinitis was diagnosed as his initial HIV and AIDS defining illness. A diagnosis of CMV infection was made based on the clinical appearance of the fundus and confirmed by DNA polymerase chain reaction (PCR) on his vitreous biopsy. His CD4+ T lymphocyte count at the time was 580 x 10(6)/l (16%) with a CD4:CD8 ration of 0.28. He had a splenectomy following trauma more than 20 years earlier. He responded very well to intravenous and oral ganciclovir and remains recurrence-free almost 2 years later. This case and others highlight two issues: (i) CMV retinitis in HIV positive is not confined to those with very low CD4+ T lymphocyte counts; (ii) previous splenectomy may have an impact on CD4+ cell numbers and function.

AIDS-Related Opportunistic Infections↗
PubMed1998

The effect of subinhibitory concentrations of antibiotics on adherence of Pseudomonas aeruginosa to cystic fibrosis (CF) and non-CF-affected tracheal epithelial cells.

OBJECTIVES: this project investigated the proposition that Pseudomonas aeruginosa binds preferentially to cystic fibrosis (CF) respiratory cells. In addition, disadherence of P. aeruginosa by subinhibitory concentrations of antibiotics was examined as a possible explanation for clinical improvement seen in chronically colonized patients when treated with anti-pseudomonal agents. METHODS: we used a distinctive HPV-transformed respiratory cell line to compare adherence of two strains of P. aeruginosa to CF and non-CF respiratory cells. The effect of subinhibitory concentrations of antipseudomonal antibiotics on adherence of P. aeruginosa to cell monolayers was measured. RESULTS: piliated P. aeruginosa bound significantly better to CF than non-CF-affected cells (P=0.003). Adherence was significantly reduced when organisms were preincubated in subinhibitory concentrations of antibiotics overnight (P<0.001). CONCLUSIONS: these results support the presence of an altered receptor present on CF-affected cells that binds piliated strains of P. aeruginosa. Bacterial disadherence due to subinhibitory concentrations of antibiotics may partially explain why clinical improvement is observed in CF patients with acute respiratory exacerbations.

Anti-Bacterial Agents↗
PubMed1998

Ranolazine: a novel metabolic modulator for the treatment of angina.

1. Ranolazine shifts ATP production away from fatty acid oxidation toward glucose oxidation. 2. Because more oxygen is required to phosphorylate a given amount of ATP during fatty acid oxidation than during carbohydrate oxidation, the ranolazine-induced shift in substrate selection reduces the cell's demand for oxygen without decreasing its ability to do work. The shift also maintains coupling of glycolysis to glucose oxidation during ischemia, thus reducing tissue acidosis. 3. This unique, non-hemodynamic mechanism offers the potential to treat angina without reducing blood pressure, heart rate or myocardial contractility. 4. At least three double-blind, randomized, placebo-controlled clinical trials have yielded data consistent with this hypothesis.

Acetanilides↗
PubMed1998

Zoonotic disease in Australia caused by a novel member of the paramyxoviridae.

Twenty-three horses and three humans in Queensland, Australia, were infected with a novel member of the Paramyxoviridae family of viruses in two geographically distinct outbreaks. Two of the humans died-one died of rapid-onset respiratory illness, and the other died of encephalitis. The third infected human developed an influenza-like illness and made a complete recovery. All infected humans had close contact with sick horses. Since the two outbreaks occurred at sites 1,000 km apart and no known contact between the two groups of humans and horses occurred, extensive testing of animals and birds common to the two areas was conducted. Fruit bats (Pteropus species) were found to carry a virus identical to that found in the infected humans and horses. Although there was no contact between the infected humans and the bats, some form of close contact between the horses and bats is the likely mode of infection.

Adult↗
PubMed1997

Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions.

It is now clear that the availability of different metabolic substrates can have a profound influence on the extent of damage incurred during episodes of cardiac ischaemia, and on cardiac functional recovery on reperfusion following ischaemia. In particular, increases in fatty acid availability and oxidation, compared to glucose oxidation, under such conditions leads to a worsening of outcome. Therefore metabolic interventions aimed at enhancing glucose utilisation and pyruvate oxidation at the expense of fatty acid oxidation is a valid therapeutic approach to the treatment of myocardial ischaemia. In particular, the development of agents which will promote full glucose oxidation as opposed to glycolysis alone, offer clear advantages. This can be accomplished by different means, including direct or indirect inhibition of CPT-I or inhibition of fatty acid beta-oxidation, or by direct or indirect activation of PDH. It is not yet clear which of these approaches offers the best treatment of cardiac ischaemia. To date, trimetazidine and carnitine have received limited approval in Europe for the treatment of angina; large scale clinical trials with the other agents mentioned above have not been completed. The increasing availability of agents affecting these specific sites, and the increasingly sophisticated techniques for assessing myocardial metabolism, should allow elucidation of the optimum metabolic targets and development of novel pharmacological agents for the treatment of ischaemic heart disease.

Animals↗
PubMed1997

Regulation of energy substrate metabolism in the diabetic heart.

The effects of diabetes on myocardial metabolism are complex in that they are tied to the systemic metabolic abnormalities of the disease (hyperglycemia and elevated levels of free fatty acid and ketone bodies), and changes in cardiomyocyte phenotype (e.g., down-regulation of glucose transporters and PDH activity). The cardiac adaptations appear to be driven by the severity of the systemic abnormalities of the disease. The diabetes-induced changes in the plasma milieu and cardiac phenotype both cause impaired glycolysis, pyruvate oxidation, and lactate uptake, and a greater dependency on fatty acids as a source of acetyl CoA. Studies in isolated hearts suggest that therapies aimed at decreasing fatty acid oxidation, or directly stimulating pyruvate oxidation would be of benefit to the diabetic heart during and following myocardial ischemia.

Animals↗
PubMed1997

Home intravenous therapy in cystic fibrosis: a prospective randomized trial examining clinical, quality of life and cost aspects.

In this study, we set out to determine if home intravenous (i.v.) antibiotic therapy in adult patients with cystic fibrosis (CF) is a feasible, effective and less costly alternative to hospitalization, and to assess the impact of home therapy on quality of life. The study was a prospective, randomized, two-factor mixed design involving adults presenting with respiratory exacerbations of CF. Patients were randomized such that they were discharged home after 2-4 days, or remained in hospital. Seventeen patients had 31 admissions (13 home and 18 hospital). Following 10 days of therapy, there were no significant differences between home or hospital arms with respect to body weight, 12 minute walking distance, sputum weight, pulse oximetry, or improvement in lung function (forced expiratory volume in one second (FEV1), or forced vital capacity (FVC)). Patients who remained in hospital were less fatigued and noted a greater degree of mastery. Patients discharged early noted less disruption to their family life, personal life and sleeping pattern. The total cost for the home therapy arm was approximately half that of the hospital therapy arm. Home intravenous antibiotic therapy in patients with cystic fibrosis was a feasible, cost-effective alternative to receiving therapy in hospital. Although there was no clinical compromise associated with home therapy, there were advantages and disadvantages in terms of quality of life.

Adolescent↗
PubMed1996

Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts.

BACKGROUND: Ranolazine is a novel antianginal agent that may reduce symptoms without affecting hemodynamics and has shown cardiac antiischemic effects in in vivo and in vitro models. In one study it increased active pyruvate dehydrogenase (PDHa). Other agents that increase PDHa and so increase glucose and decrease fatty acid (FA) oxidation are beneficial in ischemic-reperfused hearts. Effects of ranolazine on glucose and palmitate oxidation and glycolysis were assessed in isolated rat hearts. METHODS AND RESULTS: Working hearts were perfused with Krebs-Henseleit buffer plus 3% albumin under normoxic conditions and on reperfusion after 30-minute no-flow ischemia and under conditions designed to give either low [low (Ca) (1.25 mmol/L), high [FA] (1.2 mmol/L palmitate; with/without insulin] or high (2.5 mmol/L Ca, 0.4 mmol/L palmitate; with/without pacing) glucose oxidation rates; Langendorff-perfused hearts (high Ca, low FA) were subjected to varying degrees of low-flow ischemia. Glycolysis and glucose oxidation were measured with the use of [5-3H/U-14C]-glucose and FA oxidation with the use of [1-14C]- or [9,10-3H]-palmitate. In working hearts, 10 micromol/L ranolazine significantly increased glucose oxidation 1.5-fold to 3-fold under conditions in which the contribution of glucose to overall ATP production was low (low Ca, high FA, with insulin), high (high Ca, low Fa, with pacing), or intermediate. In some cases, reductions in FA oxidation were seen. No substantial changes in glycolysis were noted with/without ranolazine; rates were approximately 10-fold glucose oxidation rates, suggesting that pyruvate supply was not limiting. Insulin increased basal glucose oxidation and glycolysis but did not alter ranolazine responses. In normoxic Langendorff hearts (high Ca, low FA; 15 mL/min), all basal rates were lower compared with working hearts, but 10 micromol/L ranolazine similarly increased glucose oxidation; ranolazine also significantly increased it during flow reduction to 7, 3, and 0.5 mL/min. Ranolazine did not affect baseline contractile or hemodynamic parameters or O2 use. In reperfused ischemic working hearts, ranolazine significantly improved functional outcome, which was associated with significant increases in glucose oxidation, a reversal of the increased FA oxidation seen in control reperfusions (versus preischemic), and a smaller but significant increase in glycolysis. CONCLUSIONS: Beneficial effects of ranolazine in cardiac ischemia/reperfusion may be due, at least in part, to a stimulation of glucose oxidation and a reduction in FA oxidation, allowing improved ATP/O2 and reduction in the buildup of H+, lactate, and harmful fatty acyl intermediates.

Acetanilides↗
PubMed1996

On the roles of long-chain acyl carnitine accumulation and impaired glucose utilization in ischaemic contracture development and tissue damage in the guinea-pig heart.

It has been proposed that the presence of increasing concentrations of fatty acids may accelerate the development of ischaemic contracture and cardiac damage, and that this may be due to long-chain acyl carnitine accumulation and/or impairment of glucose utilization. In isolated guinea-pig papillary muscles, palmitoyl (DL) carnitine was found to have a positive inotropic effect, with a slow onset of action suggestive of an intracellular site of action, and with a maximal effect of about two-fold at a concentration of 5-10 microM; higher concentrations led to decreased contraction, probably due to increasing detergent-like effects. In isolated fura-2-loaded chick cardiomyocytes, palmitoyl carnitine increased intracellular [Ca2+]; it is proposed that this is the means by which it increases contraction. The main hypothesis above was studied using isolated guinea-pig hearts perfused with either 11.7 mM or 5 mM glucose, and either albumin alone (3%) or albumin bound palmitate (1.5 mM) during low-flow ischaemia (92% reduction in flow) for up to 60 min. With 11.7 mM glucose, the presence of palmitate caused contracture development and increased enzyme release during ischaemia. Contracture also developed when the glucose concentration was reduced to 5 mM in the absence of fatty acid, however, in its presence contracture developed to a greater extent and with increased enzyme release. Long-chain acyl carnitine accumulation was similar in both groups. These studies show that long-chain acyl carnitine accumulation has the potential to induce contracture during ischaemia, although a reduction in glucose availability may also contribute.

Animals↗
PubMed1996

Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism.

Ranolazine has shown anti-anginal efficacy in humans and cardiac anti-ischaemic activity in models, but without affecting haemodynamics or baseline contraction. In isolated normoxic rat hearts, Langendorff-perfused for 30 min with 11 mM glucose, 3% albumin, and 0.4 mM or 0.8 mM palmitate, 20 microM ranolazine significantly increased active, dephosphorylated, pyruvate dehydrogenase (PDHa), but not with no palmitate or 1.2 mM palmitate. Dichloroactetate (DCA, 1 mM), a PDHa kinase inhibitor, significantly increased PDHa in hearts perfused with 0, 0.4 or 0.8 mM but not 1.2 mM palmitate. PDHa was significantly increased with 1.2 mM palmitate by DCA plus ranolazine, and additive effects were also seen at 0.8 mM palmitate. Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may be anti-ischaemic nonhaemodynamically. Extensive studies with extracted enzymes and isolated rat heart mitochondria failed to demonstrate any effects of ranolazine on PDH kinase or phosphatase, or on PDH catalytic activity, whereas effects of other known effectors (such as DCA) were readily demonstrable, suggesting that ranolazine activates PDH indirectly. Further analyses of the hearts revealed that ranolazine reduced acetyl CoA content under all conditions where fatty acid was present, and +/- DCA which itself had little effect. In the absence of fatty acid, ranolazine and/or DCA raised acetyl CoA. In perfusions where octanoate (+/- albumin) replaced palmitate, ranolazine still decreased acetyl CoA, but not when acetate replaced palmitate. In octanoate-perfused hearts, the contents of the C4, C6 and C8 CoA esters were all increased by ranolazine. This is consistent with ranolazine causing an inhibition of fatty acid beta-oxidation leading to decreased acetyl CoA and activation of PDH.

Acetanilides↗
PubMed1996

Pyruvate dehydrogenase activity and malonyl CoA levels in normal and ischemic swine myocardium: effects of dichloroacetate.

The purposes of this study were to: (1) assess myocardial pyruvate dehydrogenase (PDH) activity and substrate exchange under well-perfused and ischemic conditions; (2) determine the metabolic effects of an intra-coronary infusion of the PDH activator, dichloroacetate (DCA); and (3) measure the effects of ischemia and DCA on malonyl CoA levels. Experiments were performed in anesthetised open-chest swine under non-ischemic conditions, followed by 40 min with a 60% reduction in left anterior descending coronary artery (LAD) blood flow. Myocardial needle biopsies for measurement of PDH activity were taken after an intracoronary infusion of either saline or DCA (1 mM in LAD blood) under aerobic conditions, and after 37 min of ischemia. Pyruvate dehydrogenase activity was measured with and without maximal activation by swine PDH phosphatase. Malonyl CoA and acetyl CoA were measured after 40 min of LAD ischemia in myocardium from the ischemic DCA- or saline-treated LAD bed, and the non-ischemic untreated left circumflex coronary artery (CFX) perfusion bed. Net glucose, lactate and free fatty acid (FFA) uptakes were measured across the LAD perfusion bed throughout the study. Dichloroacetate treatment increased the amount of active dephosphorylated PDH to 88% of the total activity under aerobic conditions, compared to 55% with saline (P < 0.01). Ischemia did not significantly change PDH activation state in either group. Acetyl CoA and malonyl CoA contents were significantly elevated in ischemic DCA-treated myocardium compared to saline-treated ischemic myocardium. Dichloroacetate treatment significantly lowered rates of myocardial FFA uptake under both aerobic and ischemic conditions, but did not effect glucose uptake or lactate exchange. Free fatty acid uptake was negatively correlated to malonyl CoA levels (r = -0.68) during ischemia. It is proposed that the inhibition of FFA uptake observed with DCA in ischemic myocardium is due to malonyl CoA inhibition of carnitine palmitoyl transferase I.

Animals↗