Mortality in Patients Treated for Tuberculous Pericarditis in Sub-Saharan Africa

Objective: To determine the mortality rate and its predictors in patients with a presumptive diagnosis of tuberculous pericarditis in sub-Saharan Africa. Design: Between 1 March 2004 and 31 October 2004; we enrolled 185 consecutive patients with presumed tuberculous pericarditis from 15 referral hospitals in Cameroon; Nigeria; and South Africa; and observed them during the 6-month course of antituberculosis treatment for the major outcome of mortality. This was an observational study; with the diagnosis and management of each patient left at the discretion of the attending physician. Using Cox regression; we have assessed the effect of clinical and therapeutic characteristics (recorded at baseline) on mortality during follow-up. Results: We obtained the vital status of 174 (94) patients (median age 33; range 14-87 years). The overall mortality rate was 26. Mortality was higher in patients who had clinical features of HIV infection than in those who did not (40versus 17; P=0.001). Independent predictors of death during follow-up were: (1) a proven non-tuberculosis final diagnosis (hazard ratio [HR] 5.35; 95confidence interval 1.76 to 16.25); (2) the presence of clinical signs of HIV infection (HR 2.28; 1.14-4.56); (3) co-existent pulmonary tuberculosis (HR 2.33; 1.20-4.54); and (4) older age (HR 1.02; 1.01-1.05). There was also a trend towards an increase in death rate in patients with haemodynamic instability (HR 1.80; 0.90-3.58) and a decrease in those who underwent pericardiocentesis (HR 0.34; 0.10-1.19). Conclusion : A presumptive diagnosis of tuberculous pericarditis is associated with a high mortality in sub-Saharan Africans. Attention to rapid aetiological diagnosis of pericardial effusion and treatment of concomitant HIV infection may reduce the high mortality associated with the disease

Serum lipid parameters and the prevalence of corneal arcus in a dyslipidaemic patient population.

AIM: To determine whether an association exists between plasma lipoprotein constituents and the prevalence of corneal arcus in dyslipidaemic patients. METHODS: Adult patients (n = 115) were included if their fasting total serum cholesterol concentrations exceeded the 95th percentile or their serum low-density lipoprotein (LDL) : high density lipoprotein (HDL) ratios exceeded 5. Slit-lamp assessment of the corneas was performed. RESULTS: The study group divided into a subgroup with arcus 37% (43) and a subgroup without arcus 63% (72). Total serum cholesterol and triglyceride levels were not associated with corneal arcus. A significant difference was found (p < 0.05) between the mean levels of LDL cholesterol (LDL-C) in the group without arcus (5.61 +/- 1.74 mmol/l) and the group with arcus (5.96 +/- 1.71 mmol/l). The mean serum HDL-cholesterol (HDL-C) in the group with corneal arcus was 1.04 +/- 0.30 mmol/l as opposed to 1.31 +/- 0.38 mmol/l in the group without arcus (p < 0.005 for difference). The mean LDL-C : HDL-C ratio in the group without arcus was 4.28 (SD: 1.99), and 5.73 (SD: 2.09) in the group with a corneal arcus (p < 0.05). CONCLUSIONS: Low HDL-C levels, high LDL-C levels and LDL-C : HDL-C ratios > 5 have been implicated as risk factors of numerous circulatory diseases. The observations in this study suggest that the presence of corneal arcus in the dyslipidaemic patient correlates strongly with these same risk indicators.

Abnormal serum lipoprotein levels as a risk factor for the development of human lenticular opacities.

AIM: To determine whether an association exists between the different plasma lipoprotein constituents and the prevalence of lenticular opacities in dyslipidaemic subjects. METHODS: Adult patients (n = 115) of both genders were included if their fasting total serum cholesterol concentrations exceeded the 95th percentile of normal or their serum low-density lipoprotein (LDL): high-density lipoprotein (HDL) ratios exceeded 5. Patients were excluded if they suffered from any condition known to cause, or predispose them to, elevated lipoprotein levels or lenticular opacification. Lenticular changes were assessed by means of a slit-lamp through the fully dilated pupil. RESULTS: An extremely strong association (p<0.0001) was found to exist between HDL cholesterol levels and the development of lens opacities. Below an HDL-C level of 1.5 mmol/l subjects had a seven-fold higher calculated probability of falling in the lens opacity subgroup than those with HDL-C levels above 1.5 mmol/l [odds ratio =7.33 (95% CI = 2.06-26.10; p = 0.0001)]. An equally strong association was found between high (>5) LDL:HDL ratios and the development of lens opacities (p<0.0003). The risk of falling into the cataract subgroup if the individual's LDL:HDL ratio exceeded 5 was 2.35 (95% CI = 1.09-5.04; p = 0.014). CONCLUSION: This study strongly suggests that an association exists between low levels of HDL cholesterol and high LDL:HDL ratios on one hand and the development of adult lens opacification on the other.

Effect of statins on bone mineral density and bone histomorphometry in rodents.

Statins have been postulated to affect bone metabolism. We investigated the effects of different doses of simvastatin (1, 5, 10, and 20 mg. kg(-1). d(-1)), atorvastatin (2.5 mg. kg(-1). d(-1)), and pravastatin (10 mg. kg(-1). d(-1)) administered orally for 12 weeks to intact female Sprague-Dawley rats and the effect of 20 mg. kg(-1). d(-1) simvastatin in sham-operated and ovariectomized rats on femoral bone mineral density (BMD) and quantitative bone histomorphometry (QBH) and compared them with controls. BMD was decreased by 1 mg. kg(-1). d(-1) simvastatin (P=0.042), atorvastatin (P=0.0002), and pravastatin (P=0.002). The effect on QBH parameters differed with different doses of simvastatin (ANOVA, P=0.00012). QBH parameters of both bone formation and resorption were equivalently and markedly increased by 20 mg. kg(-1). d(-1) simvastatin in 2 separate groups of intact rats and were reflected by a relatively unchanged BMD. At lower doses, 1 mg. kg(-1). d(-1) simvastatin decreased bone formation while increasing bone resorption, as reflected by a marked decrease in BMD. Ovariectomized animals receiving 20 mg. kg(-1). d(-1) simvastatin showed no change in BMD relative to the untreated, ovariectomized controls; their increase in bone formation was smaller than in sham-operated rats receiving simvastatin, and there was no change in bone resorption. Dose-response curves of simvastatin for bone formation and resorption differed. These studies indicate that (1) statins decrease BMD in rodents, (2) high-dose simvastatin increases bone formation and resorption, (3) low-dose simvastatin decreases bone formation and increases bone resorption, (4) the effects of simvastatin on QBH differ at different dosages, (5) the effects of simvastatin seen in intact rats are not observed in ovariectomized rats, and (6) simvastatin is unable to prevent bone loss caused by ovariectomy.

Cortical lens opacities in the young patient--an indication for a lipogram?

AIM: To determine the characteristics and prevalence of lenticular opacification in patients with underlying dyslipidaemia. METHODS: Eighty patients of both genders and all ages (18-90 years) were enrolled in the trial if they met the inclusion criteria for dyslipidaemia. Patients were included if their fasting serum cholesterol and triglyceride concentrations were > 5.2 mmol/l and > 2.3 mmol/l, respectively, when measured on three separate occasions over a 1-month period. Patients were excluded if they suffered from any condition known to cause or predispose them to elevated lipid levels or lenticular opacification. Lenticular changes were assessed by means of a slit-lamp through the fully dilated pupil and other physical signs were documented subsequent to thorough physical evaluation. RESULTS: In addition to the classic clinic signs of dyslipidaemia, 31% of patients had cortical lens opacities. Cortical opacities were twice as prevalent as Achilles tendon thickening (16.3%) in our study, the second most prevalent sign of elevated lipid levels. In the subgroup of patients aged under 50 years, 55% had lenticular opacities, predominantly cortical (80%). CONCLUSIONS: Cortical lens opacification was the most prevalent sign of dyslipidaemia and it occurred at a relatively young age in our trial population in those patients who were affected. Cortical lenticular opacification should be regarded as an indication for blood lipid profile evaluation.

The TETAMI trial: the safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and of tirofiban versus placebo in the treatment of acute myocardial infarction for patients not thrombolyzed: methods and design.

Patients with acute myocardial infarction (AMI) who do not receive early reperfusion therapy are at high risk of reinfarction or death, and the efficacy and safety of antithrombotic therapy in this group of patients has not been evaluated. Enoxaparin is a low-molecular-weight heparin (LMWH) that has previously been shown to reduce the incidence of ischemic events in patients with unstable angina or non-Q-wave MI. The principal aims of the TETAMI study are to investigate the efficacy and safety of treatment with enoxaparin or tirofiban (a glycoprotein IIb/IIIa receptor antagonist) alone or in combination for 2 to 8 days in patients with AMI who are not eligible for early reperfusion therapy. In this 2 by 2 factorial design study approximately 900 patients will be randomly assigned, in a blinded manner, to one of four treatments: enoxaparin alone, enoxaparin plus tirofiban, unfractionated heparin (UFH), or UFH plus tirofiban, with appropriate matched placebos. The primary end point is the composite of death, recurrent AMI, and recurrent angina, analyzed at 30 days after AMI. The design and methods of the TETAMI study are described in this article.

Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestry.

The South African population harbors genes that are derived from varying degrees of admixture between indigenous groups and immigrants from Europe and the East. This study represents the first direct mutation-based attempt to determine the impact of admixture from other gene pools on the familial hypercholesterolemia (FH) phenotype in the recently founded Coloured population of South Africa, a people of mixed ancestry. A cohort of 236 apparently unrelated patients with clinical features of FH was screened for a common mutation causing familial defective apolipoprotein B-100 (FDB) and seven low-density lipoprotein receptor (LDLR) gene defects known to be relatively common in South Africans with FH. Six founder-type 'South African mutations' were responsible for FH in approximately 20% of the study population, while only 1 patient tested positive for the familial defective apolipoprotein B-100 mutation R3500Q. The detection of multiple founder-type LDLR gene mutations originating from European, Indian and Jewish populations provides direct genetic evidence that Caucasoid admixture contributes significantly to the apparently high prevalence of FH in South African patients of mixed ancestry. This study contributes to our knowledge of the biological history of this unique population and illustrates the potential consequences of recent admixture in populations with different disease risks.

Efficacy and safety of cerivastatin for type 2 diabetes and hypercholesterolaemia. Hyperlipidaemia in Diabetes Mellitus investigators.

BACKGROUND: The prevalence of coronary heart disease (CHD) is markedly increased in diabetic patients compared with non-diabetic individuals, and its prognosis is less good. Serum total and low-density lipoprotein (LDL) cholesterol concentrations have been shown to be powerful predictors of CHD morbidity and mortality in patients with type 2 diabetes. The available data suggest that the target cholesterol concentration in patients with diabetes should be similar to that in non-diabetic individuals with a previous myocardial infarction. This led us to investigate the efficacy, tolerability and safety of a new, highly potent statin, cerivastatin, in diabetic hyperlipidaemia. METHODS: This was a multinational, multicentre, double-blind, randomized study in type 2 diabetic patients with hypercholesterolaemia (LDL cholesterol >3.35 mmol/l; triglycerides <4.56 mmol/l). Eligible patients were randomly assigned to groups to receive cerivastatin 0.1 mg or 0.3 mg or placebo in a ratio of 2:2:1 for 12 weeks. They were monitored in the clinic every 4 weeks. RESULTS: Of the 453 patients screened, 265 were allocated to the study groups. Fifty-one received placebo and 107 patients were assigned to each active treatment group (0.1 mg and 0.3 mg cerivastatin). At the close of the study, total cholesterol had decreased by 13.7% and 23.5%, LDL cholesterol decreased by 20.2% and 33.8%, and triglyceride concentrations decreased by 3.9% and 12.3% in the cerivastatin 0.1 mg and 0.3 mg groups, respectively. There was no significant difference between the groups in haemoglobin A1c, adverse events or increases in liver and muscle enzymes during the study period. CONCLUSIONS: Hypercholesterolaemic patients with type 2 diabetes had a significant reduction in LDL cholesterol and total cholesterol concentrations after cerivastatin treatment once daily. The dose of 0.3 mg cerivastatin is effective in diabetic hypercholesterolaemia, with co-reduction of triglyceride concentrations. The effect of cerivastatin on coronary morbidity and mortality is currently being investigated in clinical trials.

Increased efficacy and tolerability with losartan plus hydrochlorothiazide in patients with uncontrolled hypertension and therapy-related symptoms receiving two monotherapies.

The efficacy and tolerability of losartan 100 mg/hydrochlorothiazide (HCTZ) 25 mg and enalapril 10 mg/HCTZ 25 mg were compared in a double-blind, randomized trial in hypertensive patients inadequately controlled and experiencing side effects on prior therapy. Patients with moderate or severe hypertension, currently treated with at least two single-agent drugs (excluding angiotensin-converting enzyme inhibitors), with a sitting diastolic blood pressure (DBP) above 90 mm Hg, and at least one undesirable drug-related symptom were randomized to once-daily treatment with one of the combinations for 12 weeks. Losartan/HCTZ lowered sitting DBP from the prior therapy baseline by 13.7 mm Hg and sitting systolic blood pressure 19.3 mm Hg; similar reductions occurred with enalapril/HCTZ. Trough sitting DBP was reduced to normal levels (< 90 mm Hg) in 63% of patients switched to the losartan combination and in 58% of those treated with the enalapril combination. Each combination was associated with improved tolerability compared with prior therapy, although fewer patients reported each of 24 undesirable symptoms after 12 weeks of losartan/HCTZ. The improvement from prior therapy in the occurrence of cough was significantly greater with losartan/HCTZ (P = .005). Enalapril/HCTZ, but not losartan/HCTZ, increased serum uric acid levels at week 12. In conclusion, the combination of losartan 100 mg/HCTZ 25 mg offers a beneficial therapeutic option for patients with a history of moderate to severe hypertension whose blood pressure is not adequately controlled or who exhibit side effects while on two or more single-agent antihypertensive drugs. In this population, the switch from prior antihypertensive therapies to once daily losartan 100 mg/HCTZ 25 mg improves blood pressure control and reduces side effects.

Isoenzymes of adenosine deaminase in pleural effusions: a diagnostic tool?

SETTING: Tygerberg Hospital, an academic teaching hospital, Republic of South Africa. OBJECTIVE: To identify the adenosine deaminase (ADA) isoenzymes as a diagnostic tool for tuberculosis in pleural effusions with increased ADA activity. DESIGN: Patients (n = 157) with exudative effusions and ADA activities >20 U/l, due to causes which satisfied predetermined diagnostic criteria, participated in the study. They consisted of 87 tuberculous effusions, 27 infective effusions (12 empyematous and 15 non-empyematous), 37 malignant effusions and six other exudative effusions (systemic lupus erythematosus, pancreatitis and lung embolus). In each case the ADA isoenzymes in the pleural fluid were identified using polyacrylamide gel electrophoresis. In addition, microbiology and cytology (including differential cell counts) were also carried out. RESULTS: Although ADA1c and ADA2 were the predominant isoenzymes observed in tuberculous effusions, while ADA1c and ADA1m were predominant in infective non-empyematous effusions, no additional diagnostic value was obtained. In the case of neoplastic effusions and other exudates, determination of ADA isoenzyme patterns also did not assist in diagnosing these conditions. CONCLUSION: Determination of patterns of ADA isoenzymes does not enhance the overall diagnostic value of ADA activity in pleural effusions.

Combined use of pleural adenosine deaminase with lymphocyte/neutrophil ratio. Increased specificity for the diagnosis of tuberculous pleuritis.

UNLABELLED: Increased pleural fluid adenosine deaminase (ADA) activity is classically associated with tuberculous pleuritis. However, increased activity can also occur in a number of other diseases and this may negatively affect the diagnostic utility of ADA measurements and decrease its specificity for the diagnosis of tuberculosis (TB). The presence of ADA in pleural fluids reflects the cellular immune response in the pleural cavity and in particularly, the activation of T lymphocytes. Different disease entities are typically associated with the presence of particular types of leukocytes. OBJECTIVE: To determine whether the combined use of ADA activity and differential cell counts would provide a more efficient means for diagnosing tuberculous pleurisy than the use of ADA levels alone. METHODS: Biochemistry, cytology, and microbiology studies were performed on 472 consecutive pleural fluids. ADA and differential cell counts were determined on all exudative effusions. RESULTS: ADA activity in tuberculous effusions was significantly higher than in any other diagnostic group (p < 0.005). At a level of 50 U/L, the sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv), and efficiency for the identification of TB were calculated at 91%, 81%, 84%, 89%, and 86%, respectively. When the additional requirement of a lymphocyte neutrophil ratio of 0.75 or greater was included, the sensitivity, specificity, ppv, npv, and efficiency for the identification of TB were calculated at 88%, 95%, 95%, 88%, and 92%, respectively. CONCLUSION: ADA, especially when combined with differential cell counts and lymphocyte/neutrophil ratios, remains a useful test in the diagnosis tuberculous pleuritis.

A comparison of the metabolic effects of captopril and atenolol on glucose, insulin and lipoproteins in patients with mild-to-moderate essential hypertension.

The metabolic effects of captopril 25 mg twice daily and atenolol 50 mg daily on glucose, insulin and lipids were compared in 83 otherwise healthy mild-to-moderate hypertensive between the ages of 25 and 60 years in a randomised double-blind trial. Hourly glucose and insulin levels were measured during a 2-hour 75 g oral glucose tolerance test at baseline and after 12 weeks of treatment. Lipid profiles including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, HDL2, HDL3, triglycerides, apoprotein (Apo)A1, ApoB, and Apo(a) were obtained before and after the treatment period. Blood pressure decreased significantly and equivalently in both treatment groups. The glucose and insulin levels and glucose x insulin product at 2 hours after the glucose load increased after 12 weeks of treatment with atenolol compared with the baseline values, but these parameters all decreased after the treatment period with captopril compared with their baseline values. These results indicate an improvement in insulin sensitivity with captopril and a deterioration with atenolol. HDL-cholesterol and HDL3 decreased in the atenolol group but increased in the captopril group. We conclude that captopril has more favourable effects than atenolol on glucose, insulin and lipid metabolism in the treatment of mild-to-moderate hypertension.

Comparative analysis of the biochemical parameters used to distinguish between pleural transudates and exudates.

UNLABELLED: The differentiation between exudates and transudates is the initial step in the analysis of pleural effusions as it often gives an indication of the underlying pathophysiologic process, the differential diagnosis, and the need for further investigations. Four classifications have been suggested in the literature: Light's criteria, serum-effusion albumin gradient, effusion cholesterol concentration, and pleural/serum bilirubin concentration. AIM OF STUDY: To compare the various biochemical parameters used to identify exudates. PATIENTS AND METHODS: A study was carried out from February 1993 to March 1994 at Tygerberg Hospital, South Africa. Five hundred pleural effusions and serum specimens were analyzed. After discharge, the hospital records of all patients were reviewed for a diagnosis. RESULTS: A reliable diagnosis could be made in 393 cases (270 exudates and 123 transudates). Using the criteria of Light and associates 93% of the effusions were correctly classified, yielding a sensitivity and specificity of 98% and 83%, respectively, to detect exudates. The serum-effusion albumin gradient at a cutoff level of 12 g/L yielded the following results: accuracy, 89%; sensitivity, 87%; and specificity, 92%. Using a cutoff level of 1.55 mmol/L, the effusion cholesterol concentration yielded results of 70%, 54%, and 92%, respectively. The results improved at lower cutoff levels for effusion cholesterol level. Use of the pleural/serum bilirubin ratio as a means for identifying exudates produced results of 75%, 81%, and 61%, respectively. CONCLUSION: The criteria of Light et al remain the best method for distinguishing exudates from transudates. The serum-effusion albumin gradient is useful when patients are receiving concurrent diuretic therapy.

Use of adenosine deaminase as a diagnostic tool for tuberculous pleurisy.

BACKGROUND: A statistical audit of adenosine deaminase (ADA) in pleural effusions was undertaken. METHODS: ADA analysis, cytological and microbiological examinations, and differential cell counts were performed on 462 pleural fluid samples. RESULTS: ADA activity in tuberculous effusions was higher than in any other diagnostic group. At a level of 50 U/l the sensitivity and specificity for the identification of tuberculosis was 90% and 89%, respectively. CONCLUSIONS: ADA activity remains a useful test in the evaluation of pleural effusions.