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T McDonagh

Publications and source records attributed to T McDonagh.

At least 19 recordsLinked to original sources
PubMed2003

Clinical applications of B-type natriuretic peptide (BNP) testing.

Many claims have been made in recent years regarding the utility of plasma B-type natriuretic peptide (BNP) concentration measurements in the diagnosis, risk stratification and monitoring of patients with heart failure. This paper summarizes the current evidence and provides guidance for practising clinicians. Overall, plasma BNP testing appears to be of most value in the diagnostic arena, where it is likely to improve the performance of non-specialist physicians in diagnosing heart failure. In clinical practice, BNP testing is best used as a 'rule out' test for suspected cases of new heart failure in breathless patients presenting to either the outpatient or emergency care settings; it is not a replacement for echocardiography and full cardiological assessment, which will be required for patients with an elevated BNP concentration. Although work is ongoing in establishing the 'normal' values of BNP, heart failure appears to be highly unlikely below a plasma concentration of 100 pg/ml. However, as BNP levels rise with age and are affected by gender, comorbidity and drug therapy, the plasma BNP measurement should not be used in isolation from the clinical context.

Ambulatory Care↗
PubMed2003

Survival differences between heart failure in general practices and in hospitals.

OBJECTIVES: To compare the survival of patients thought to have heart failure in general practice (GP-HF) with that of patients with heart failure in hospital (hospital-HF), patients with heart disease but without heart failure (non-HF), and a control group without heart disease. DESIGN AND SETTING: Cross sectional study from general practice with a prospective follow up from 5.3 to 7.4 years. PARTICIPANTS: 2157 community participants, 1999 of whom lived outside nursing homes, were selected because they were registered with four general practitioners at entry. Study participants were divided into the four groups after a review of general practice case notes, questionnaires, and interviews. MAIN OUTCOME MEASURES: Five year survival and multivariate predictors of all cause mortality. RESULTS: Five year survival was 76% in the control group (n = 571, mean age at entry 74.1 years), 71% in non-HF patients (n = 218, 74.4 years), 61% in GP-HF patients (n = 67, 75.8 years), and 39% in hospital-HF patients (n = 33, 76.7 years). The median survival times were 6.8 years for GP-HF patients and 3.9 years for hospital-HF patients. Significant predictors of mortality in the multivariate Cox model of 1979 patients living outside nursing homes were hospital-HF (hazard ratio (HR) 2.1, p = 0.002), GP-HF (HR 1.7, p = 0.004), non-HF heart disease (HR 1.4, p = 0.03), previous myocardial infarction (HR 1.6, p = 0.04), no response to questionnaire (HR 2.0, p < 0.0001), higher age (for every 10 years, HR 2.4, p < 0.0001), and male sex (HR 2.1, p < 0.0001). Other factors such as atrial fibrillation, hypertension, and diabetes were not significant. CONCLUSION: Heart failure in general practice is associated with a worse survival than that seen in the control group but is better than for patients who have been treated at least once for heart failure in a hospital.

Adult↗
PubMed2000

Solution structure of N-TRADD and characterization of the interaction of N-TRADD and C-TRAF2, a key step in the TNFR1 signaling pathway.

TRADD is a multifunctional signaling adaptor protein that is recruited to TNFR1 upon ligand binding. The C-terminal of TRADD comprises the "death domain" that is responsible for association of TNFR1 and other death domain-containing proteins such as FADD and RIP. The N-terminal domain (N-TRADD) promotes the recruitment of TRAF2 to TNFR1 by binding to the C-terminal of TRAF2, leading to the activation of JNK/AP1 and NF-kappa B. The solution structure of N-TRADD was determined, revealing a novel protein fold. A combination of NMR, BIAcore, and mutagenesis experiments was used to help identify the site of interaction of N-TRADD with C-TRAF2, providing a framework for future attempts to selectively inhibit the TNF signaling pathways.

Amino Acid Sequence↗
PubMed2000

The effect of amlodipine on respiratory and pulmonary vascular responses to hypoxia in mountaineers.

Calcium antagonists are known to reduce the incidence of high-altitude pulmonary oedema, but the mechanism is unclear. The aim of this study was to examine the effects of the calcium antagonist, amlodipine, on cardiac and respiratory responses in normoxia and hypoxia. Fourteen normal subjects aged 31+/-4 yrs who had climbed to altitudes of 5,000-7,500 m without problems were randomly assigned to a double-blind crossover trial of amlodipine versus placebo, using sea-level inspiratory hypoxia to simulate altitude. Doppler echocardiographic estimates of resting pulmonary haemodynamics and cycle ergometer test results of cardiorespiratory responses to exercise were recorded in normoxia and hypoxia. It was found that, although hypoxic pulmonary vasoconstriction (HPV) was not significantly reduced by amlodipine, the effect of the drug on HPV was inversely related to the serum level of amlodipine. Amlodipine did not alter left ventricular function measured echocardiographically. During exercise, amlodipine increased breathlessness, measured using standard scales, in both normoxia and hypoxia but had no effect on ventilatory variables. It was concluded that amlodipine has the potential to block hypoxic pulmonary vasoconstriction as evidenced by a drug concentration-related decrease in resting tricuspid regurgitation jet velocity without any change in resting myocardial contractility. However, with amlodipine, the subjects felt more breathless during exercise. The reasons for this increase in breathlessness are not clear.

Adult↗
PubMed1999

Echocardiography overestimates left ventricular mass in hemodialysis patients relative to magnetic resonance imaging.

UNLABELLED: Echocardiography overestimates left ventricular mass in hemodialysis patients relative to magnetic resonance imaging. BACKGROUND: Left ventricular hypertrophy (LVH) is a common finding and a strong adverse prognostic factor in patients with chronic renal failure. An accurate method of measuring left ventricular mass (LV mass) is therefore a prerequisite in the management of these patients. Recent evidence has suggested that echocardiography overestimates LV mass in patients with essential hypertension, and this error increases with increasing LV mass. METHODS: We studied 35 patients on maintenance hemodialysis within 24 hours of their last dialysis. LV mass was measured by both echocardiography and magnetic resonance imaging (MRI) performed less than three hours apart. Clinic and ambulatory blood pressure (ABPM), resting echocardiogram, and blood sampling were performed at the same visit. RESULTS: Thirty-two patients had results from both methods. Clinic blood pressure, ABPM, and QT dispersion all correlated with LV mass, with a stronger correlation observed for MRI values. Intraobserver and interobserver variability were significantly greater for echocardiography (although similar to other published data). Comparing the two methods, the difference in LV mass values (echo minus magnetic resonance) increased in a linear fashion with an increasing mean mass and chamber diameter. CONCLUSIONS: Echocardiography significantly overestimates LV mass relative to MRI in the presence of LVH and dilation. This overestimation is the result of assumptions made in the calculation of mass from echocardiography M-mode images, which are invalid when LV geometry is abnormal. This error is therefore amplified in dialysis patients, the majority of whom have LVH and in whom intravascular volume is constantly changing.

Adult↗
PubMed1998

Solution structure and membrane interactions of the C2 domain of cytosolic phospholipase A2.

The amino-terminal, 138 amino acid C2 domain of cytosolic phospholipase A2 (cPLA2-C2) mediates an initial step in the production of lipid mediators of inflammation: the Ca2+-dependent translocation of the enzyme to intracellular membranes with subsequent liberation of arachidonic acid. The high resolution solution structure of this Ca2+-dependent, lipid-binding domain (CaLB) has been determined using heteronuclear three-dimensional NMR spectroscopy. Secondary structure analysis, derived from several sets of spectroscopic data, shows that the domain is composed of eight antiparallel beta-strands with six interconnecting loops that fits the "type II" topology for C2 domains. Using a total of 2370 distance and torsional restraints, the structure was found to be a beta-sandwich in the "Greek key" motif. The solution structure of cPLA2-C2 domain is very similar to the X-ray crystal structure of the C2 domain of phospholipase-C-delta and phylogenetic analysis clarifies the structural role of highly conserved residues. Calorimetric studies further demonstrate that cPLA2-C2 binds two Ca2+ with observed Kds of approximately 2 microM in an entropically assisted process. Moreover, regions on cPLA2-C2 interacting with membranes were identified by 15N-HSQC-spectroscopy of cPLA2-C2 in the presence of low molecular weight lipid micelles. An extended binding site was identified that binds the phosphocholine headgroup in a Ca2+-dependent manner and also interacts with proximal regions of the membrane surface. Based upon these results, a structural model is presented for the mechanism of association of cPLA2 with its membrane substrate.

Amino Acid Sequence↗
PubMed1998

Independent folding and ligand specificity of the C2 calcium-dependent lipid binding domain of cytosolic phospholipase A2.

The Ca(2+)-dependent lipid binding domain of the 85-kDa cytosolic phospholipase A2 (cPLA2) is a homolog of C2 domains present in protein kinase C, synaptotagmin, and numerous other proteins involved in signal transduction. NH2-terminal fragments of cPLA2 spanning the C2 domain were expressed as inclusion bodies in Escherichia coli, extracted with solvent to remove phospholipids, and refolded to yield a domain capable of binding phospholipid vesicles in a Ca(2+)-dependent manner. Unlike other C2 domains characterized to date, the cPLA2 C2 domain bound preferentially to vesicles comprised of phosphatidylcholine in response to physiological concentrations of Ca2+. Binding of the cPLA2 C2 domain to vesicles in the presence of excess Ca2+ chelator was induced by high concentrations of salts that promote hydrophobic interactions. Despite the selective hydrolysis of arachidonyl-containing phospholipid vesicles by cPLA2, the cPLA2 C2 domain did not discriminate among phospholipid vesicles containing saturated or unsaturated sn-2 fatty acyl chains. Moreover, the cPLA2 C2 domain bound to phospholipid vesicles containing sn-1 and -2 ether linkages and sphingomyelin at Ca2+ concentrations that caused binding to vesicles containing ester linkages, demonstrating that the carbonyl oxygens of the sn-1 and -2 ester linkage are not critical for binding. These results suggest that the cPLA2 C2 domain interacts primarily with the headgroup of the phospholipid. The cPLA2 C2 domain displayed selectivity among group IIA cations, preferring Ca2+ approximately 50-fold over Sr2+ and nearly 10,000-fold over Ba2+ for vesicle binding. No binding to vesicles was observed in the presence of greater than 10 mM Mg2+. Such strong selectivity for Ca2+ over Mg2+ reinforces the view that C2 domains link second messenger Ca2+ to signal transduction events at the membrane.

Amino Acid Sequence↗
PubMed1998

The reproducibility of symptoms during a submaximal exercise test in chronic heart failure.

AIMS: The aim of this study was to evaluate the use of a submaximal test with a symptom limited endpoint and to measure the reproducibility of symptoms in patients with CHF. METHODS: Ten patients with chronic heart failure were studied. Based on two maximal treadmill tests an individual protocol using a constant work rate at a submaximal intensity was derived. The projected maximum treadmill time for the constant workrate was between 8 and 17 min. Tests were carried out 1, 2, 4 and 6 weeks after the maximum tests. Every 2.5 min during the submaximal test patients recorded their symptoms of breathlessness and fatigue using computer automated visual analogue (VAS) and Borg CR10 scales. The measure of reproducibility used was the proportion of total variability explained by the between subject variability. RESULTS: Using the VAS scale, general fatigue was reasonably reproducible ranging from 77-86%. For VAS breathlessness reproducibility ranged from 66% to 83%. Reproducibility for breathlessness and fatigue for the Borg CR10 scale was much lower than the VAS scale. Reproducibility for the treadmill times was 51% but increased to 76% if one test of one subject was excluded. CONCLUSIONS: The use of the VAS during submaximal exercise offers a useful means of evaluating symptoms in CHF and potentially their response to treatment. These findings show that individual submaximal protocols can be easily prescribed for CHF patients. Using such an approach, clinically desirable tests lasting around 12 min can be developed. These tests are reasonably reproducible and may provide a useful means of assessing patient disability and the impact of treatment.

Aged↗
PubMed1998

Candoxatril improves exercise capacity in patients with chronic heart failure receiving angiotensin converting enzyme inhibition.

AIMS: To assess the effect of candoxatril, a novel neutral endopeptidase inhibitor, on exercise capacity, clinical status and quality of life in patients with mild to moderate chronic heart failure receiving angiotensin converting enzyme inhibition. METHODS AND RESULTS: Patients were recruited from 16 centres throughout the United Kingdom. Following a 4-week single-blind placebo 'run-in' phase of weekly exercise tests, patients underwent double-blind randomization to receive either candoxatril (100 mg twice daily) or placebo for the next 84 days. Patients were then reassessed every 28 days. Of 110 patients randomized, 56 received candoxatril and 54 placebo. Over the study period, the overall improvement in mean total exercise time in the candoxatril group in comparison to the placebo group was 34.1 s (P=0.02: 95% confidence interval: 5.1 to 63.0). There were no significant changes in functional class, clinical status or quality of life scores between the two groups. There was a trend for a small reduction in blood pressure in the candoxatril group. CONCLUSION: Candoxatril confers an improvement in exercise capacity in patients with chronic heart failure who are receiving maintenance angiotensin converting enzyme inhibitor therapy.

Aged↗
PubMed1997

Solution structure of recombinant human interleukin-6.

Interleukin-6 (IL-6) is a 185 amino acid cytokine which exerts multiple biological effects in vivo and whose dysregulation underlies several disease processes. The solution structure of recombinant human interleukin-6 has now been determined using heteronuclear three and four-dimensional NMR spectroscopy. The structure of the molecule was determined using 3044 distance and torsion restraints derived by NMR spectroscopy to generate an ensemble of 32 structures using a combined distance geometry/simulated annealing protocol. The protein contains five alpha-helices interspersed with variable-length loops; four of these helices constitute a classical four-helix bundle with the fifth helix located in the CD loop. There were no distance violations greater than 0.3 A in any of the final 32 structures and the ensemble has an average-to-the-mean backbone root-mean-square deviation of 0.50 A for the core four-helix bundle. Although the amino-terminal 19 amino acids are disordered in solution, the remainder of the molecule has a well defined structure that shares many features displayed by other long-chain four-helix bundle cytokines. The high-resolution NMR structure of hIL-6 is used to rationalize available mutagenesis data in terms of a heteromeric receptor complex.

Antigens, CD↗
PubMed1996

Complete 1H, 15N and 13C assignments, secondary structure, and topology of recombinant human interleukin-6.

Essentially complete backbone and side-chain 1H, 15N and 13C resonance assignments for the 185-amino-acid cytokine interleukin-6 (IL-6) are presented. NMR experiments were performed on uniformly [15N]- and [15N,13C]-labeled recombinant human IL-6 (rIL-6) using a variety of heteronuclear NMR experiments. A combination of 13C-chemical shift, amide hydrogen-bond exchange, and 15N-edited NOESY data allowed for analysis of the secondary structure of IL-6. The observed secondary structure of IL-6 is composed of loop regions connecting five alpha-helices, four of which are consistent in their length and disposition with the four-helix bundle motif present in other related cytokines and previously postulated for IL-6. In addition, the topology of the overall fold was found to be consistent with a left-handed up-up-down-down four-helix bundle based on a number of long-range interhelical NOEs. The results presented here provide deeper insight into structure-function relationships among members of the four-helix bundle family of proteins.

Amino Acid Sequence↗
PubMed1996

Two cases of paraduodenal hernia, a rare internal hernia.

Paraduodenal hernia is a rare congenital internal hernia which arises from an error of rotation of the midgut with entrapment of the small intestine beneath the developing colon. It is important as it usually presents as intestinal obstruction, and before laparotomy is often misdiagnosed. Mortality increases significantly with delays in surgical treatment. Two cases are presented: an 8 year old boy and a 52 year old man. Both presented with a short history of abdominal pain and an acute abdomen. With prompt surgical treatment, they recovered rapidly.

Abdominal Pain↗
PubMed1995

Doppler assessment of hypoxic pulmonary vasoconstriction and susceptibility to high altitude pulmonary oedema.

BACKGROUND: Subjects with previous high altitude pulmonary oedema may have stronger than normal hypoxic pulmonary vasoconstriction. Susceptibility to high altitude pulmonary oedema may be detectable by echo Doppler assessment of the pulmonary vascular reactivity to breathing a hypoxic gas mixture at sea level. METHODS: The study included 20 healthy controls, seven subjects with a previous episode of high altitude pulmonary oedema, and nine who had successfully climbed to altitudes of 6000-8842 m during the 40th anniversary British expedition to Mount Everest. Echo Doppler measurements of pulmonary blood flow acceleration time (AT) and ejection time (ET), and of the peak velocity of the tricuspid regurgitation jet (TR), were obtained under normobaric conditions of normoxia (fraction of inspired oxygen, FIO2, 0.21), of hyperoxia (FIO2 1.0), and of hypoxia (FIO2 0.125). RESULTS: Hypoxia decreased AT/ET by mean (SE) 0.06 (0.01) in the control subjects, by 0.11 (0.01) in those susceptible to high altitude pulmonary oedema, and by 0.02 (0.02) in the successful high altitude climbers. Hypoxia increased TR in the three groups by 0.22 (0.06) (n = 14), 0.56 (0.13) (n = 5), and 0.18 (0.1) (n = 7) m/s, respectively. However, AT/ET and/or TR measurements outside the normal range, defined as mean +/- 2 SD of measurements obtained in the controls under hypoxia, were observed in only two of the subjects susceptible to high altitude pulmonary oedema and in five of the successful high altitude climbers. CONCLUSIONS: Pulmonary vascular reactivity to hypoxia is enhanced in subjects with previous high altitude pulmonary oedema and decreased in successful high altitude climbers. However, echo Doppler estimates of hypoxic pulmonary vaso-constriction at sea level cannot reliably identify subjects susceptible to high altitude pulmonary oedema or successful high altitude climbers from a normal control population.

Adult↗
PubMed1993

Trends in hospitalization for heart failure in Scotland 1980-1990.

Heart failure is a growing public health problem in industrialized countries with ageing populations. Scotland has a relatively stable population of approximately 5 million and a well described system for recording details of hospitalizations (Scottish Hospital In-Patients Statistics-SHIPS). We have examined SHIPS data for hospitalizations for heart failure in Scotland 1980-1990. Discharges for heart failure as the primary diagnosis increased by almost 60%, from 1.30 to 2.12/1000 population in this period (as either primary or secondary diagnosis the rate increased from 2.51 to 4.24/1000). Seventy-eight percent of discharges were in persons aged > or = 65 years and 48% of discharges were male. Heart failure (primary diagnosis) accounted for almost 4% of all general (internal) medicine discharges. In-patient case fatality was 18% in 1990. Mean duration of in-patient stay on Internal Medicine wards was approximately 11 days. The number of hospitalizations for heart failure is now almost identical to those for myocardial infarction. These trends mirror those recently reported from the United States. Heart failure is an increasingly common and costly cause of hospitalization in Scotland. Approaches which can reduce this burden on the hospital service require urgent attention.

Adult↗
PubMed1987

What follows diagnosis by computed tomography of solitary brain tumour? Audit of one year's experience in South East Scotland.

The referral rate to neurosurgeons after diagnosis by computed tomography (CT) of solitary brain tumour (SBT) was audited for South East Scotland in 1985. 142 patients had SBT diagnosed by CT, but histological confirmation by biopsy or open operation was sought in only 67. Among these the CT diagnosis of glioma proved to be incorrect in 3 of 44 cases and that of solitary metastasis in 4 of 8 cases. Since CT diagnosis of SBT is not fully reliable, biopsy should be considered in all cases.

Adult↗
PubMed1981

Induction of twin-calving by non-surgical embryo transfer: a field trial.

Non-surgical embryo transfers were carried out on nine farms to 84 previously inseminated recipient cows. Insemination and transfers were at a fixed time after synchronisation. Forty-nine (58 pr cent) of the 84 cows calved to the fixed insemination and transfer, producing a total of 69 calves or 1.4 calves per cow calving. The twinning rate was 41 per cent in cows calving. Transferred embryo survival was high (59 per cent) in pregnant cows. Data on calf and calving performance are given.

Animals↗