Adverse effects of biologic anti-inflammatory agents on the respiratory system: A review.

The therapy of autoimmune rheumatological conditions has undergone significant changes with the introduction of biologic antiinflammatory agents including cytokine antagonists and agents that interfere with the function of T and B cells or those that inhibit intracellular enzymes such as Janus kinase (JAK). Although useful to control inflammation, these agents may be associated with druginduced lung disease, which may be difficult to differentiate from pulmonary disorders caused by the underlying autoimmune diseases. This review aims to provide a description of lung disease, both infectious and non-infectious, that may be induced by the administration of biologic anti-inflammatory agents with emphasis on inhibitors of tumour necrosis factor, interleukin-1, interleukin-6 and JAK.

Burning issues in the prevention of heart failure

Chronic heart failure is common, debilitating, and often the culmination of pervasive cardiovascular insults that systematically undermine the heart's circulatory capacity and invoke counterproductive neuro-hormonal compensatory changes. Prevention of chronic heart failure therefore requires minimising the impact of traditional cardiovascular risk factors with incisive treatment of hypertension and type II Diabetes Mellitus (T2DM) and prompt lifestyle interventions for smoking, lack of exercise, obesity and hypercholesterolemia. This review is narrative, with selected emphasis on major studies, rather than structured on a specific clinical question, and should be read as such

Burning issues in blood pressure control

Globally more than 1 billion people have hypertension and it is predicted that because of ageing populations and increasing sedentary lifestyles, this figure will rise to about 1.5 billion by 2025. Elevated blood pressure (BP) is the leading cause of premature death and morbidity due to stroke and ischemic heart disease. Hypertension is also a major risk factor for heart failure, atrial fibrillation, chronic kidney disease, peripheral arterial disease and cognitive decline. This article discusses the current evidencebased treatment guidelines and pressing temporal issues in optimal blood pressure control

The reliability of chest radiographs in predicting left atrial enlargement.

INTRODUCTION: Estimates of left atrial size in patients with suspected cardiac disease play an important role in predicting prognosis and events, as well as treatment decisions. Two methods are commonly used to estimate left atrial size: chest radiography and cardiac ultrasound. This study aims to determine the test characteristics by comparing the use of radiographs to cardiac ultrasound (the gold-standard test). METHODS: Data from patients older than 18 years admitted to Steve Biko Academic Hospital during 2000-2003 who had both chest radiographs and cardiac ultrasound were included in this cross-sectional, retrospective analysis. Chest radiographs were classified into three quality classes, and the sub-carinal angle (SCA) and sub-angle distance (SAD) were measured twice in all available radiographs by two observers. Intra- and inter-observer variability (three methods) as well as the predictive value of the carinal angle and sub-angle distance measurements were determined using logistic regression (with left atrial enlargement - determined by ultrasound as comparator). RESULTS: Data for 159 patients were available (154 cardiac ultrasounds and 178 chest radiographs). Intra-observer variability for chest radiograph measurements was low with almost perfect concordance (p = 0.000). Inter-observer variability was higher for supine radiographs. Using logistic regression, a linear model was identified which was statistically significant only for erect radiographs. While goodness-of-fit analysis showed that the model fits the data, performance characteristics were poor, with high sensitivity and low specificity, and an area under the ROC curve of 0.62-0.63, depending on type of radiograph and measurement (SCA or SAD). Linearity in the logit of the dependent variable was assessed, and found to be present at the extremes of SCA measurements for the supine radiograph data and in the first three quartiles for erect radiograph data. A nonlinear model determined by fractional polynomial analysis did not perform significantly better than the original linear model. Cut-off values for the SCA of 72° and 84° (erect and supine radiographs, respectively) were found to give the best compromise between sensitivity and specificity. The corresponding cut-off values for SAD were 24.1 and 26.9 mm. CONCLUSION: Assessment of either SCA or SAD to determine left atrial size was equivalent and repeatable, both with the same observer and between two observers (less so for supine radiographs). While this measure was precise, it was found not to be very accurate. Therefore, chest radiographs are not reliable in predicting left atrial enlargement.

Decision-making using absolute cardiovascular risk reduction and incremental cost-effectiveness ratios: a case study.

BACKGROUND: Many clinical guidelines have adopted a multifactorial cardiovascular risk assessment to identify high-risk individuals for treatment. The Framingham risk chart is a widely used risk engine to calculate the absolute cardiovascular risk of an individual. Cost-effective analyses are typically used to evaluate therapeutic strategies, but it is more problematic for a clinician when faced with alternative therapeutic strategies to calculate cost effectiveness. AIM: We used a single simulated-patient model to explore the effect of different drug treatments on the calculated absolute cardiovascular risk. METHODS: The Framingham risk score was calculated on a hypothetical patient, and drug treatment was initiated. After every drug introduced, the score was recalculated. Single-exit pricing of the various drugs in South Africa was used to calculate the cost of reducing predicted cardiovascular risk. RESULTS: The cost-effective ratio of an antihypertensive treatment strategy was calculated to be R21.35 per percentage of risk reduction. That of a statin treatment strategy was R22.93 per percentage of risk reduction. U sing a high-dose statin, the cost-effective ratio was R12.81 per percentage of risk reduction. Combining the antihypertensive and statin strategy demonstrated a cost-effective ratio of R23.84 per percentage of risk reduction. A combination of several drugs enabled the hypothetical patient to reduce the risk to 14% at a cost-effective ratio of R17.18 per percentage of risk reduction. CONCLUSION: This model demonstrates a method to compare different therapeutic strategies to reduce cardiovascular risk with their cost-effective ratios.

NT-proBNP measurements in high-risk diabetic patients--a case series from Mamelodi (Gauteng).

UNLABELLED: The prevalence of raised BNP values is unknown in South African urban black populations at risk for heart failure. This study determined the frequency of raised NT-proBNP and the correlates of NT-proBNP in a high-risk diabetic population. METHODS: A cross-sectional convenience sample of diabetic patients at the Mamelodi Hospital diabetes clinic was examined. Data on clinical, biometric, biochemical and a sixminute walk test were collected. RESULTS: Sixty patients (38 female) were examined. The frequency of elevated NT-proBNP was 22% (95% CI; 12-34%). Univariate analysis found systolic blood pressure (BP) (p = 0.007) and duration of diabetes (p = 0.005) to be predictive of an elevated NT-proBNP.

The heart remembers: observations of cardiac memory in the Dorper sheep heart.

Memory is a property common to a diverse range of tissues. Cardiac memory has been demonstrated in the human, dog, rat and rabbit. This is a peculiar phenomenon, reflected in the T wave of the electrocardiogram. The heart is able to remember periods of alterations in the sequence of ventricular activation and once there is a return to a normal sequence of ventricular activation the T waves may manifest memory. Cardiac memory is noted when the T wave during normal ventricular activation retains the vector of the previous abnormal QRS complex, caused by a period of altered ventricular activation. Possible mechanisms of memory in the heart are alterations of the transient outward potassium current (I10) in ventricular myocytes and new protein synthesis inside myocytes. These two mechanisms operate in short- and long-term cardiac memory respectively. Currently, it is unknown whether memory may have adverse structural consequences in the heart. We were able to demonstrate memory in the hearts of Dorper wethers and this is the first report of cardiac memory in Dorper sheep.

An educational intervention to improve the quality of care of diabetic patients.

OBJECTIVE: As few studies have addressed intervention for in-hospital care of diabetes mellitus (DM) patients, we set out to investigate whether an educational intervention targeting doctors could improve the quality of care for diabetic patients. DESIGN: An observational interventional study conducted at Pretoria Academic Hospital, a tertiary care hospital. SUBJECTS: Doctors working in the Department of Internal Medicine were the subjects of two interventional sessions on diabetic care, and all diabetic patients admitted to the wards in the above Department were evaluated. OUTCOME MEASURES: A Diabetes Attitude Scale (DAS-3) and a Diabetes Practice Scale (DPS) were completed by each doctor before and after the interventional educational sessions. Data from diabetic patients in the wards were collected for 5 weeks before and 5 weeks after the interventional training, and these two sets of data were compared to measure the effect of the interventional training. RESULTS: Subscales of the DAS-3 showed an improvement, with a statistically significant improvement in attitude regarding seriousness of DM (P = 0.03), and a trend towards improvement in attitude regarding need for special training and patient autonomy. Most of the items on the DPS improved significantly (P < 0.05). CONCLUSIONS: A short educational intervention resulted in an improvement in attitude, knowledge and clinical management of diabetic patients.

Regulation of calcium homeostasis in activated human neutrophils--potential targets for anti-inflammatory therapeutic strategies.

OBJECTIVES: The objectives of the current study were to: (i) present an integrated model for the restoration of calcium homeostasis in activated human neutrophils based on current knowledge and recent research; and (ii) identify potential targets for the modulation of calcium fluxes in activated neutrophils based on this model and to investigate the effects of intracellular probes which target key processes involved in calcium homeostasis and pro-inflammatory activity in these cells. DESIGN AND SETTING: Laboratory-based experimental research using purified human neutrophils from healthy, adult human volunteers. OUTCOME MEASURES: Calcium metabolism and pro-inflammatory activity of neutrophils. RESULTS: Modulation of calcium fluxes in activated human neutrophils can be achieved by cAMP-dependent upregulation of the activity of the endomembrane Ca(2+)-ATPase which resequesters cytosolic Ca2+. Formoterol, a long-acting beta 2-agonist, elevates intracellular cAMP levels, accelerates Ca2+ restoration in activated neutrophils and downregulates the pro-inflammatory responses of these cells. Alterations in the membrane potential of activated neutrophils may play a role in regulating calcium reuptake into the cells as attenuation of the membrane depolarisation response is associated with accelerated calcium influx. CONCLUSIONS: Modulation of the activity of the endomembrane Ca(2+)-ATPase in human neutrophils represents an important target for anti-inflammatory

The anti-inflammatory interactions of epinephrine with human neutrophils in vitro are achieved by cyclic AMP-mediated accelerated resequestration of cytosolic calcium.

This study was designed to evaluate the effects of epinephrine (0.01-1 microM) on superoxide production by, and release of elastase from human neutrophils activated with the chemotactic tripeptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) (1 microM) in vitro, and to relate alterations in these responses to changes in adenosine 3,5' cyclic monophosphate (cAMP) and cytosolic free Ca(2+). Cyclic AMP, superoxide production and elastase release were measured by radioimmunoassay, lucigenin-enhanced chemiluminescence, and a colorimetric procedure respectively. Cytosolic Ca(2+) fluxes were measured by fura-2 spectrofluorimetry in combination with radiometric procedures that enable distinction between net efflux and influx of the cation. Epinephrine treatment of neutrophils resulted in increased cAMP and dose-related inhibition of both superoxide production and elastase release, which was potentiated by the type 4 phosphodiesterase inhibitor, rolipram, and attenuated by propranolol, but not by selective beta(1)-, alpha(1)- or alpha(2)-adrenoreceptor antagonists. Although epinephrine did not affect the FMLP-activated abruptly-occurring increase in fura-2 fluorescence intensity, indicating no effects on the release of Ca(2+) from neutrophil intracellular stores, this agent accelerated the rate of decline in fluorescence in the setting of decreased efflux and a reduction in store-operated influx of Ca(2+). These effects of epinephrine on the clearance of Ca(2+) from the cytosol of FMLP-activated neutrophils were attenuated by propranolol, and are compatible with enhancement of the activity of the cAMP-dependent Ca(2+) sequestering/resequestering endo-membrane Ca(2+)-ATPase. We conclude that epinephrine down-regulates the pro-inflammatory activities of neutrophils by cAMP-mediated enhancement of the clearance of cytosolic Ca(2+).

Apparent involvement of the A(2A) subtype adenosine receptor in the anti-inflammatory interactions of CGS 21680, cyclopentyladenosine, and IB-MECA with human neutrophils.

This study was undertaken to identify the adenosine receptor (AR) subtypes which down-regulate the proinflammatory activities of human neutrophils, as well as the involvement of adenosine 3',5'-cyclic monophosphate (cAMP) and its relationship to cellular handling of Ca(2+) in mediating these effects. Neutrophils were treated with varying concentrations (0.01-1 microM) of AR agonists operative at A(1) (N(6)-cyclopentyladenosine, CPA), A(2A) (2(4-[(2-carboxyethyl)phenyl]ethylamino)-5'-N-ethylcarboxamidoadenosi ne, CGS 21680), and A(3) (N(6)-(3-iodobenzyl-5'-N-methylcarbamoyladenosine, IB-MECA) receptors, after which they were activated with the chemoattractant, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP, 1 microM). Intracellular cAMP, superoxide, and elastase were assayed using radioimmunoassay, lucigenin-enhanced chemiluminescence (LECL), and colorimetric procedures, respectively, while changes in the concentrations of cytosolic Ca(2+) were monitored by fura-2-based spectrofluorimetry. CGS 21680, at all concentrations tested, inhibited superoxide production in a dose-related manner, while CPA and IB-MECA were effective only at the highest concentrations tested (0.5-1 microM). The release of elastase from activated neutrophils was also inhibited by all three AR agonists, but was more sensitive to CGS 21680 and IB-MECA than was superoxide production. The inhibitory effects of all 3 agonists on superoxide production and elastase release were associated with accelerated clearance of Ca(2+) from the cytosol of activated neutrophils, and were effectively neutralized by pretreatment of the cells with the highly selective A(2A)R antagonist, ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1, 2,4]triazolo[2,3-a][1,3,5]triazin-5yl amino]ethyl)phenol). Increased cAMP was detected in neutrophils treated with CGS 21680 and IB-MECA (1 microM). These data support the involvement of the A(2A)R subtype in the suppression of superoxide production and degranulation by activated human neutrophils, probably by cAMP-mediated alterations in Ca(2+) handling.

Ambulatory blood pressure monitoring--comparison with office blood pressure in patients on antihypertensive therapy in private practice.

INTRODUCTION: Available data on the use of 24-hour ambulatory blood pressure recordings in private practice are limited. For this purpose we studied 39 consecutive hypertensive patients on treatment in a private practice. METHOD: Office blood pressure, 24-hour ambulatory blood pressure, daytime ambulatory blood pressure and M-mode echocardiography were undertaken in 39 consecutive hypertensive patients (21 men, 18 women) on treatment. RESULTS: Mean 24-hour ambulatory blood pressure and mean daytime ambulatory blood pressure were lower than office blood pressure, similar to findings seen in academic settings. A blood pressure load of more than 50% was seen in 12 out of 39 patients (31%). Left ventricular hypertrophy, assessed by means of Framingham criteria, was seen in 33% of patients. A white-coat effect was seen in 15.4% of patients. CONCLUSIONS: A large proportion (33%) of patients on treatment for hypertension had left ventricular hypertrophy, despite normal electrocardiograms. Ambulatory blood pressure measurements identified a blood pressure load of more than 50% in 31% of patients on treatment for hypertension.

Exercise-induced asthma in a group of South African schoolchildren during physical education classes.

OBJECTIVES: The study was conducted to ascertain whether physical education teachers, using a peak flow meter, could reliably screen for exercise-induced asthma (EIA) in children during free running. DESIGN, SETTING AND SUBJECTS: The study was conducted using a convenience sample of male pupils between the ages of 12 and 18 years. They were tested with a peak flow meter for peak expiratory flow rate (PEFR) and with a flow-volume curve for forced expiratory flow in 1 second (FEV1) before and 10 minutes after a self-paced free running test during physical education classes. Testing was undertaken by teachers using the peak flow meter and by a medical doctor using a flow-volume curve. RESULTS: Using a 10% decrease in flow parameters (PEFR and FEV1), teachers detected EIA in 14.9% of pupils and the doctor detected EIA in 21.7% of pupils. CONCLUSION: We conclude that EIA is common and that teachers using a peak flow meter can detect EIA and thus screen for it; they do, however, underestimate the true magnitude of the problem.

Respiratory muscle endurance in heart failure--the effect of clinical severity.

UNLABELLED: In chronic heart failure there is no single explanation for reduced effort tolerance. Recently, abnormalities of skeletal muscles, which include respiratory muscles, have been described in cases of chronic heart failure. The aim of this study was to investigate the effect of clinical severity of heart failure, measured by means of the Boston score, on respiratory muscle performance (strength and endurance). METHODS: Using the Boston score, we compared 20 patients with chronic heart failure and low ejection fraction to 20 normal people, measuring maximal inspiratory mouth pressures (MIPs), maximal expiratory mouth pressures (MEPs) and endurance. Endurance was measured by repeated maximal static contractions of MIP and MEP as well as maximal voluntary ventilation (MVV). RESULTS: Inspiratory strength (MIP 75 +/- 34 cmH2O) but not expiratory strength (MEP 116.9 +/- 43.7 cmH2O) were reduced in heart failure patients, compared with controls (MIP 96.2 +/- 29.2, MEP 120.4 +/- 31 cmH2O). Endurance of inspiratory muscles was significantly reduced (P < 0.007) but not of expiratory muscles (P > 0.25). Clinical severity did not correlate with reduced endurance. CONCLUSION: Endurance of the inspiratory muscles was reduced in chronic heart failure unrelated to clinical severity.