A multi-centre retrospective study of Nocardia speciation and antimicrobial susceptibility in Queensland, Australia.

The study aims to characterise the species identification and antimicrobial susceptibility testing (AST) results of Nocardial isolates from adult patients across major public hospitals in Queensland, Australia, over a 15-year period. A multi-centre retrospective observational study of Nocardia sp. isolates was conducted from 7 major public hospitals in Queensland, Australia, over a 15-year period. Clinical samples from patients aged ≥ 18 years that isolated Nocardia sp. were included. Demographic and clinical data were collected, along with species identification and AST results. Overall, 484 Nocardia sp. were isolated. Most patients were male (297, 61%) with a mean (IQR) age of 60 (51-75) and a median (IQR) Charlson Comorbidity Index of 4 (2-6). Of these, 239 (49%) patients were immunosuppressed. Organisms were most frequently isolated from sputum (174, 36%), and superficial swabs (102, 21%). Patients presented with pulmonary infections (165, 35%) and superficial skin and soft tissue infections (87, 18%) most commonly. One hundred (21%) isolates were deemed pulmonary colonisation and were not treated. Of the speciated organisms, N. nova complex was the most common (93, 19%), followed by N. farcinica complex (79, 16%). Organisms were reliably susceptible to linezolid (240/245, 98%), amikacin (455/470, 97%), and trimethoprim/sulfamethoxazole (459/476, 96%), but less so to imipenem (243/472, 51%) and ceftriaxone (261/448, 58%). This is the largest Australian description of Nocardia sp. to date. Given antimicrobials are often commenced prior to AST results and sometimes even speciation, characterisation of local species and antibiogram data is important to guide empiric choices and local guidelines.

Reporting guidelines and journal quality in otolaryngology.

OBJECTIVES: Journals increasingly use reporting guidelines to standardise research papers, partly to improve quality. Although defining journal quality is difficult, various calculated metrics are used. This study investigates guideline adoption by otolaryngology journals and whether a relationship exists between this and journal quality. DESIGN, SETTING, PARTICIPANTS: Retrospective MEDLINE database review for English language, Index Medicus, journals of interest to otolaryngologists (October 2013). MAIN OUTCOME MEASURES: The resulting journals were examined for the number of guidelines endorsed and then tabulated against surrogate measures of journal quality (Impact factor, Eigenfactor, SCImago, Source-Normalised rank). The primary outcome measure was the number of recognised reporting guidelines endorsed per journal. This was then correlated against journal quality scores. For comparison, a further small sample correlation was performed with 6 randomly selected and 6 high-profile clinical non-otolaryngology journals. RESULTS: 37 otolaryngology journals were identified. Number of guidelines used and quality scores were not normally distributed. Mean guideline usage was 1.0 for otolaryngology journals, 1.5 for randomly selected, and 5.5 for the high-profile journals. Only 18/37 (49%) otolaryngology journals endorsed any guidelines, compared with 11/12 non-otolaryngology journals. Within otolaryngology, Eigenfactor positively correlated with guideline use (r = 0.4, n = 44, p < 0.01) otherwise no correlation was found between guideline endorsement and journal quality. CONCLUSIONS: Reporting guideline endorsement within otolaryngology journals is low. Although it might be expected that use of reporting guidelines improved quality, this is not reflected in the derived quality scores in otolaryngology. This may reflect low levels of use/enforcement, that quality indicators are inherently flawed, or that generalised guidelines are not always appropriate or valued by editors.

Endothelial function is impaired in fit young adults of low birth weight.

OBJECTIVE: Non-insulin-dependent diabetes, hypertension and ischaemic heart disease, with insulin resistance, are associated with low birth weight (the 'Small Baby Syndrome'). Common to these adult clinical conditions is endothelial dysfunction. We tested the hypothesis that endothelial dysfunction could precede their development in those of low birth weight. METHODS: Endothelial function was measured by ultrasonic 'wall-tracking' of flow-related brachial artery dilatation in fit 19-20 year old subjects randomly selected (blind to the investigators throughout the study) from low (< 2.5 kg) and normal (3.0-3.8 kg) birth weight subjects in the 1975-7 cohort of the Cardiff Births Survey and with no known cause for endothelial dysfunction. RESULTS: Flow-related dilatation was impaired in low birth weight relative to normal birth weight subjects (median 0.04 mm [1.5%] [n = 22] cf. 0.11 mm [4.1%] [n = 17], p < 0.05; 0.04 mm [1.5%] [n = 15] cf. 0.12 mm [4.4%] [n = 12], p < 0.05 after exclusion of inadvertently included ever-smokers). CONCLUSION: The findings suggest that endothelial dysfunction is a consequence of foetal malnutrition, consistent with contributing to the clinical features of the 'Small Baby Syndrome' in later adult life.

Syndrome X and endothelial dysfunction.

OBJECTIVE: Syndrome X (angina, normal coronary arteriogram and positive exercise test) remains an enigma with unexplained features and apparent conflicts of evidence. The present study addressed whether (i) the Syndrome is characterised by generalised flow-related endothelial dysfunction, (ii) myocardial thallium201 defects reflect myocardial or microvascular dysfunction, (iii) endothelial dysfunction and its consequences can be improved by oral L-arginine. METHODS: Flow-mediated brachial artery dilatation was measured by ultrasonic 'wall-tracking' in 7 Syndrome X patients, further characterised as having thallium201 defects and no known cause of endothelial dysfunction, and a normal control group. Syndrome X patients entered a 4-week randomised double-blind placebo-controlled cross-over trial of oral L-arginine (7 g twice daily), with brachial artery studies, exercise tests and technetium99 tetrafosmin scans. RESULTS: Flow-mediated dilatation was absent in Syndrome X vs. normal. Stress technetium99 tetrafosmin and thallium201 scans showed similar defects. Flow-mediated dilatation, symptom-limited exercise duration and peak oxygen consumption (VO2max) were increased but rate-pressure-product (RPP) and radionuclide defects were unchanged after L-arginine vs. placebo. CONCLUSIONS: The study supports coronary microvascular rather than myocardial dysfunction and shows loss of flow-mediated dilatation in systemic arteries. Oral L-arginine improved flow-mediated dilatation, exercise capacity and VO2max (by ca. 17%) despite unchanged RPP. The findings support generalised endothelial dysfunction. The arginine effects imply NO-mediated improvement of skeletal muscle perfusion suggesting improved homogeneity of microvascular distribution.

The cardiac endothelium: cardioactive mediators.

Endothelial cells within the heart release a number of substances that modulate myocardial contractile function. These agents include nitric oxide, endothelin, prostanoids, adenylpurines, and other substances that have so far been characterized only in bioassay studies. A notable feature of many of these agents is that they influence contractile behavior predominantly by modifying cardiac myofilament properties rather than altering cytosolic Ca2+ transients. A consequence of this subcellular action is often a disproportionate effect on myocardial relaxation and diastolic tone. The paracrine modulation of cardiac myocyte function by endothelial cell factors is likely to be an important mechanism contributing to the overall regulation of cardiac contractile function, both physiologically and in pathological states.

Impaired matching of perfusion and ventilation in heart failure detected by 133xenon.

In severe chronic heart failure (CHF) the ventilatory cost of CO2 elimination during exercise (VE/VCO2) is increased, suggesting ventilation/perfusion (V/Q) mismatch. The relationship of exercise VE/VCO2 regression slope m to deadspace ventilation was studied in 15 patients with CHF who underwent cardiopulmonary exercise testing and arterial blood gas monitoring. Regional lung ventilation and perfusion was studied, using 133xenon, at rest and peak exercise in a further group of 10 CHF patients and in five normal subjects. VE/VCO2 slope m correlated well with deadspace ventilation at peak exercise in the 15 patients with CHF. We therefore used exercise VE/VCO2 slope m to categorize CHF patients undergoing 133xenon imaging into groups with increased (slope m > 36) or normal (slope m < 36) exercise deadspace ventilation. In normals, resting V/Q determined by 133xenon showed a gravitational gradient, which improved on exercise as a result of relative increases and of relative reductions in regional perfusion; no significant changes in regional ventilation distribution were detected. In patients with CHF who had normal slope m (n = 5), rest and exercise V/Q were similar to the normal subjects. In CHF patients with increased slope m (n = 5) however, the resting gravitational gradient of V/Q was lost, and there were no significant changes in relative perfusion distribution on exercise. These findings suggest that the increased ventilatory cost of CO2 elimination found in certain patients with CHF is related to inability to coordinate and optimise the relative distribution of lung perfusion with respect to ventilation during exercise.

Flosequinan in chronic heart failure: how is exercise capacity improved?

OBJECTIVE: Diuretics, angiotensin converting enzyme inhibitors and digoxin have become "standard" triple therapy for many patients with chronic cardiac failure. Flosequinan increases exercise duration and improves symptoms when added to standard triple therapy. Despite intensive study, the clinical pharmacology of flosequinan remains uncertain. SETTING: The University Hospital of Wales, a Regional Cardiac Centre. PATIENTS: Twenty four patients with chronic heart failure who remained symptomatic despite standard therapy including ACE inhibitors. METHODS: A double-blind placebo-controlled parallel group study of 100 mg daily of flosequinan. We measured changes in exercise duration using cardiorespiratory exercise testing and changes in large artery distensibility using Doppler ultrasound. RESULTS: Exercise duration after 8 weeks flosequinan treatment was significantly greater than following placebo treatment. The flosequinan-related increase in exercise duration (+14%) was associated with a significant reduction in VE/VCO2 slope (-16%). Brachial-radial pulse wave velocities were unaltered by flosequinan treatment. CONCLUSIONS: Our results confirm that flosequinan improves exercise duration in patients with chronic heart failure. They suggest that this observed beneficial effect is independent of any change in large artery distensibility and that in the presence of ACE inhibitors, this improvement may be independent of any vasodilating action of flosequinan. Although this study confirms the beneficial symptomatic effects of flosequinan in chronic cardiac failure, clinical trials have subsequently demonstrated an overall increase in mortality in patients treated with 100 mg flosequinan daily. This has resulted in the withdrawal of flosequinan from routine clinical use.

Endothelial control of arterial distensibility is impaired in chronic heart failure.

BACKGROUND: Vascular tone is a determinant of conduit artery distensibility. The aim of this study was to establish whether endothelium-derived relaxing factor (EDRF) influences the distensibility of conduit arteries and whether endothelium-mediated increases in distensibility are impaired in chronic heart failure (CHF). METHODS AND RESULTS: Conduit artery distensibility was measured by two methods in healthy subjects and in nine patients with CHF caused by dilated cardiomyopathy. In the first method, pulse-wave velocity (PWV) was measured in the right common iliac artery at rest and during local infusions of acetylcholine (10(-7) to 10(-5) mol/L) or adenosine (2 x 10(-7) to 2 x 10(-5) mol/L), with correction for systemic effects. Acetylcholine induced concentration-dependent local reductions of PWV in healthy subjects (-5%, -15%, and -26%) but not in CHF patients (3%, 1%, -4%, P < .01), whereas adenosine induced similar reductions of PWV in healthy subjects and CHF patients. In the second method, brachial artery diameter, blood flow, and blood pressure were measured noninvasively by high-resolution ultrasound, continuous-wave Doppler, and photoplethysmography during reactive hyperemia in the hand and after sublingual glyceryl trinitrate (GTN, 400 micrograms). Hyperemic flow, similar in healthy subjects and CHF patients, was associated with increases in diameter and distensibility in healthy subjects (8.8% and 18.4%, respectively) but not in CHF patients (0.3% and -4.5%), whereas GTN induced similar effects in healthy subjects and CHF patients. CONCLUSIONS: These data indicate that conduit artery distensibility is increased by acetylcholine and increased blood flow in healthy subjects but not in CHF patients, whereas the effects of adenosine and GTN on distensibility are preserved in CHF patients. This implies that EDRF-mediated increases in distensibility are impaired in CHF patients, thus adding to cardiac work.

Endothelial control of myocardial function.

The newly described phenomenon of endothelial control of myocardial contraction is reviewed. Endothelium both from endocardium and from coronary microvessels releases an unidentified contraction-prolonging agent and can be stimulated to release a contraction-abbreviating agent which is nitric oxide which elevates myocardial cyclic GMP content: these act by increasing and decreasing contractile protein sensitivity to cytosolic calcium respectively. The phenomenon has been confirmed in vitro and in vivo, with physiological and potential pathophysiological and pharmacological consequences for cardiac pump function.

Effects of the correction of renal anaemia by erythropoietin on physiological changes during exercise.

The effects of treating the anaemia of end-stage renal failure with erythropoietin were studied in nine dialysis patients. The increase in haemoglobin concentration (by 59% from 7.0 +/- 1.2 to 11.1 +/- 1.1 g dl-1) was associated with increases in exercise duration (by 41%) and maximum oxygen consumption (by 34%). Treatment reduced resting heart rate but did not significantly alter heart rate at maximum exercise, nor resting or exercise blood pressure. Resting arterial potassium concentrations were slightly increased after treatment, but they increased similarly in relation to minute ventilation during exercise. Lactic acidaemia developed during exercise at both levels of haemoglobin, and was accompanied by similar reductions in arterial pH and bicarbonate levels but constant PaO2 and PaCO2. Ventilation was coupled to the metabolic rate of carbon dioxide production, ventilatory dead-space and arterial PCO2 before and after treatment of anaemia, the ventilatory requirement for carbon dioxide elimination being unchanged. Treatment of anaemia did not alter resting arterial lactate concentration; the concentration of lactate at maximum exercise was increased slightly following treatment but this increase did not reach statistical significance. The rate of increase in arterial lactate concentration as a function of oxygen consumption, assessed both with respect to the 'lactate threshold' and 'lactate slope index', was significantly delayed by treatment. Treatment of anaemia also delayed the 'anaerobic threshold', and there was good correlation between lactate and anaerobic thresholds. Treatment of renal anaemia by erythropoietin thus results in improved tissue oxygen supply during exercise, reflected by delay in the onset of lactic acidaemia.

The ventilatory cost of exercise compared in chronic heart failure and chronic renal anaemia.

The cardiorespiratory responses to maximal treadmill exercise were compared in matched groups of patients with chronic renal anaemia or treated chronic heart failure, and in normal controls. Exercise capacity was similarly reduced in both patient groups compared to normal controls, the raised respiratory exchange ratio at peak exercise implying anaerobic metabolism due to limited oxygen delivery in heart failure and limited oxygen carrying capacity in anaemia. Minute ventilation (VE) was related linearly to minute CO2 production (VCO2) in all subjects (each r > 0.92) from all three groups. The slope of the VE/VCO2 relationship was normal in anaemia but steeper in heart failure, reflecting ventilation/perfusion mismatching in chronic heart failure.

Syndrome X and hyperventilation.

The cardiorespiratory responses to exercise and forced hyperventilation were measured in 17 unselected patients with syndrome X (angina, positive exercise test, normal coronary arteriogram, no other cardiovascular disease) and compared with those in 15 healthy subjects. Forced hyperventilation produced hypocapnia and metabolic alkalosis but no chest pain or electrocardiographic change. Patients with syndrome X showed reduced maximum oxygen consumption with an increased respiratory exchange ratio at peak exercise, confirming that exercise was limited by skeletal muscle perfusion--and thus that the increase in cardiac output with exercise is limited in syndrome X as in heart failure. Arterial carbon dioxide tension (PCO2) homoeostasis during exercise was normal but the ventilatory cost of carbon dioxide excretion was increased in syndrome X (as in heart failure). End tidal PCO2 measurements correlated only poorly with arterial PCO2 in individual patients with syndrome X, providing a possible explanation for previous reports, based on end tidal PCO2 of inappropriate hyperventilation. Patients with syndrome X did not show inappropriate hyperventilation but they did show hyperventilation that was appropriate to maintain normal arterial PCO2 in the face of reduced cardiac reserve.

Hyperinsulinaemia and microvascular angina ("syndrome X")

Glucose and insulin responses to a glucose load in 11 patients with angina attributed to microvascular coronary dysfunction were compared with those in 11 healthy subjects matched for age, sex, and body mass. Stimulated hyperinsulinaemia was demonstrated in the microvascular angina group. The findings suggest a role for increased concentrations of insulin in coronary microvascular dysfunction.