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PURPOSE: Tuberculosis is still a major threat to global health. New tools and strategies to produce disease-related proteins are quintessential for the development of novel vaccines and diagnostic markers. EXPERIMENTAL DESIGN: To obtain recombinant proteins from Mycobacterium tuberculosis (Mtb) for use in clinical applications, a standardized procedure was developed that includes subcloning, protein expression in Mycobacterium smegmatis and protein purification using chromatography. The potential for the different protein targets to serve as diagnostic markers for tuberculosis was established using multiplex immunoassays. RESULTS: Twelve soluble proteins from Mtb, including one protein complex, were purified to near-homogeneity following recombinant expression in M. smegmatis. Protein purity was assessed both by size exclusion chromatography and MS. Multiplex serological testing of the final protein preparations showed that all but one protein displayed a clear antibody response in serum samples from 278 tuberculosis patients. CONCLUSION AND CLINICAL RELEVANCE: The established workflow comprises a simple, cost-effective, and scalable pipeline for production of soluble proteins from Mtb and can be used to prioritize immunogenic proteins suitable for use as diagnostic markers.

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BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitors have been used for more than a decade to treat high blood pressure, despite the lack of data from randomised intervention trials to show that such treatment affects cardiovascular morbidity and mortality. The Captopril Prevention Project (CAPPP) is a randomised intervention trial to compare the effects of ACE inhibition and conventional therapy on cardiovascular morbidity and mortality in patients with hypertension. METHODS: CAPPP was a prospective, randomised, open trial with blinded endpoint evaluation. 10,985 patients were enrolled at 536 health centres in Sweden and Finland. Patients aged 25-66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were randomly assigned captopril or conventional antihypertensive treatment (diuretics, beta-blockers). Analysis was by intention-to-treat. The primary endpoint was a composite of fatal and non-fatal myocardial infarction, stroke, and other cardiovascular deaths. FINDINGS: Of 5492 patients assigned captopril and 5493 assigned conventional therapy, 14 and 13, respectively, were lost to follow-up. Primary endpoint events occurred in 363 patients in the captopril group (11.1 per 1000 patient-years) and 335 in the conventional-treatment group (10.2 per 1000 patient-years; relative risk 1.05 [95% CI 0.90-1.22], p=0-52). Cardiovascular mortality was lower with captopril than with conventional treatment (76 vs 95 events; relative risk 0.77 [0.57-1-04], p=0.092), the rate of fatal and non-fatal myocardial infarction was similar (162 vs 161), but fatal and non-fatal stroke was more common with captopril (189 vs 148; 1.25 [1-01-1-55]. p=0.044). INTERPRETATION: Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality. The difference in stroke risk is probably due to the lower levels of blood pressure obtained initially in previously treated patients randomised to conventional therapy.

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The Captopril Prevention Project (CAPPP) is an ongoing intervention study conducted in 11,019 hypertensive patients in Sweden and Finland. Patients have been randomized to receive either conventional antihypertensive therapy (diuretics and/or beta-blockers) or captopril-based treatment. A prospective, randomized, open, blinded-endpoint evaluation (PROBE) study design is used to compare these two therapeutic regimens as regards cardiovascular morbidity and mortality. The rationale for the CAPPP Study are the many observations of beneficial effects of ACE inhibition, as compared to diuretics and beta-blockers, on intermediary endpoints such as insulin sensitivity, serum lipoproteins, left ventricular hypertrophy and renal function. Captopril has also been shown to be markedly effective in the treatment of left ventricular dysfunction as well as congestive heart failure. The hypothesis is that these differences might result in improved risk reduction when ACE inhibitors are used in the treatment of hypertension. The present paper describes the baseline data and the changes in blood pressure during the first year in the total cohort. During the first year the average blood pressure was reduced by 11/8 mm Hg. A number of substudies have been conducted in the CAPPP Study. In one of these insulin sensitivity was compared in a subgroup of the patients using the euglycemic insulin clamp technique. In another substudy the ACE gene was sequenced and some new polymorphisms were discovered. Several other substudies are in progress or in the planning phase. The main results of the CAPPP Study should be available by mid-1998. Some of the intended anayses of the final results as well as other planned substudies are briefly described here.

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The increased viscosity of blood of hypertensive patients can be assumed to be a risk factor for the development of cardiovascular diseases. The aim of the present study was to elucidate whether anti-hypertensive treatment has any impact on blood rheology. Twenty patients with previously untreated hypertension who consecutively attended our outpatient hypertension clinic were included in this prospective, open, cross-over study. The patients were randomly selected to treatment with amlodipine or metoprolol. The anti-hypertensive therapy was switched after 4 months. Haemorheological and haemodynamic variables were measured with rotational viscometry and impedance cardiography, respectively. Fifteen and 16 patients could be evaluated after amlodipine or metoprolol treatment respectively. The mean blood pressure (BP) decreased from 159 +/- 22/105 +/- 7 to 139 +/- 21/91 +/- 6 mm Hg on amlodipine and from 162 +/- 22/104 +/- 5 to 145 +/- 24/90 +/- 8 mm Hg on metoprolol therapy. After amlodipine treatment, the total peripheral resistance index decreased whereas metoprolol treatment was accompanied by a decrease in the cardiac index. Decreases in whole blood viscosity, haematocrit and serum erythropoietin were found after amlodipine as well as metoprolol treatment. After amlodipine the plasma viscosity decreased and the erythrocyte deformability increased in the majority of patients. Plasma fibrinogen decreased after metoprolol treatment. Despite the differences in haemodynamic mechanisms underlying the decrease in BP, amlodipine and metoprolol exert beneficial effects on blood viscosity. Haemodilution and a decrease in serum erythropoietin may be factors underlying this decrease in blood viscosity.

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A daily dose of 20 mg of protriptyline can improve daytime arterial blood gas tensions in chronic obstructive pulmonary disease (COPD). Its usefulness is limited by anticholinergic side-effects. This study examined whether a daily dose of 10 mg of protriptyline improved daytime arterial oxygen tension (PaO2) and quality of life in patients with stable mild or moderate hypoxaemia caused by COPD. Twenty six patients were randomized to receive protriptyline or placebo in a double-blind parallel-group trial for 12 weeks, following a run-in period of 4 weeks, in order to assess the stability of hypoxaemia. Patients with a change in PaO2 of > 0.7 kPa during the run-in were excluded. Spirometry, quality of life and dyspnoea score were measured at randomization and after 12 weeks, whilst arterial blood gas tensions were also measured 2 and 6 weeks after randomization. No improvement in arterial blood gas tensions, spirometry values, dyspnoea score, or quality of life was found in either the protriptyline or the placebo group. The majority of patients receiving protriptyline experienced anticholinergic side-effects, which necessitated the withdrawal of the drug in one patient. We conclude that there was no evidence that a daily dose of 10 mg of protriptyline had a significant effect on daytime arterial oxygen tension in stable mild and moderate hypoxaemia caused by COPD. Despite the low dose, anticholinergic side-effects occurred in most patients.

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The primary objective in this multicentre, double-blind randomised, parallel study was to compare the metabolic effects of 12 months of treatment with an ACE inhibitor (enalapril) with those of a selective beta-blocker (atenolol) in patients with mild hypertension. The patients (35-69 years of age) were included if they were without antihypertensive drugs and after six months of nonpharmacological treatment had supine DBPs between 90 and 104 mmHg; 220 patients were randomised to enalapril (20 or 40 mg/day) and 218 to atenolol (50 or 100 mg/day). After 12 months of treatment, atenolol significantly increased the glucose concentrations at 60, 90 and 120 minutes after an oral intake of 75 g glucose (P < 0.01), while enalapril did not. Atenolol significantly increased fasting blood glucose and insulin concentration 120 minutes after glucose intake, while enalapril did not. Plasma total cholesterol and triglycerides increased significantly in patients having atenolol but not in those having enalapril. HDL cholesterol decreased significantly in the atenolol group but not in the enalapril group. The proportions of patients with clinical adverse experiences were similar in both treatment groups. These results indicate that enalapril does not influence either glucose tolerance or lipoprotein metabolism while atenolol does. These findings are consistent over the 12 month treatment period and confirm earlier short-term study results.

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Thiazide diuretics are widely used in the drug treatment of hypertension but their dose-response curves for the antihypertensive and adverse metabolic effects differ. To characterize the lower end of the dose-response curve a double-blind, parallel group trial was performed as multicentre study in Scandinavia. One hundred and eleven patients with newly diagnosed or previously treated mild to moderate hypertension (untreated diastolic blood pressure of 95-115 mmHg after 4 weeks placebo) were randomly allocated to various doses of hydrochlorothiazide (3, 6, 12.5 or 25 mg) or placebo for 6 weeks. Blood pressure and biochemical variables (plasma renin activity, serum potassium, magnesium, urate, fasting glucose, total cholesterol, HDL-cholesterol, triglycerides and apolipoproteins A1 and B were measured. 12.5 mg hydrochlorothiazide had a borderline effect on blood pressure whilst 25 mg had a definite antihypertensive effect. Biochemical changes were seen in plasma renin activity, serum potassium and urate after the 12.5 and 25 mg dose. Three and 6 mg had no effect on blood pressure or metabolic parameters.

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Diltiazem is a calcium channel blocker with antihypertensive and antiarrhythmic actions. In the present study 24 hypertensive patients were treated with diltiazem (180-360 mg daily) for 6 months. The effects on the electrocardiogram (ECG) were studied and were related to the serum levels of diltiazem. Treatment with diltiazem induced a non-significant reduction in heart rate with 3 beats min-1 and decreased blood pressure (-11/-9 mm Hg, p < 0.001). The treatment also induced a prolongation of the PQ-interval (+1.4 cs, p < 0.02), a prolongation only being weakly related to the plasma levels of diltiazem (r = 0.28, not significant) and its metabolite MA (r = 0.37, p = 0.07). Neither was the induced increase in the QT-interval (+0.9 cs, p < 0.05), significantly related to the plasma levels of diltiazem. In conclusion, the plasma levels of diltiazem were not clearly related to the induced changes at the ECG during antihypertensive treatment.

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OBJECTIVES: The viscosity of blood is increased in patients with essential hypertension. The aim of the present study was to investigate the importance of the different variables of blood rheology to total peripheral resistance, and to elucidate whether inappropriate regulation of the formation of erythropoietin could be important. DESIGN: Nineteen consecutive patients with untreated essential hypertension were examined and compared with a group of matched healthy volunteers. METHODS: The haemorheologic variables were assessed by rotational viscometry and the haemodynamic variables by bioimpedance cardiography. The serum concentrations of erythropoietin were determined by radioimmunoassay. RESULTS: The whole blood viscosity and peripheral resistance index were elevated in the hypertensive group. The two variables were positively correlated with each other (r = 0.68, P = 0.0015). The plasma viscosity and erythrocyte aggregation tendency were increased and the erythrocyte deformability, measured as fluidity, was decreased in the hypertensive patients. In the male subpopulation (n = 12) the aggregation tendency was positively, and the deformability negatively, correlated with body mass index. The serum concentrations of erythropoietin were equal in the two groups. CONCLUSIONS: The increased total peripheral resistance in patients with essential hypertension may in part be explained by an increased blood viscosity, but the possibility of an opposite cause-effect relationship must also be taken into consideration. The haemorheological abnormalities observed in the present patients cannot be explained by high serum levels of erythropoietin.

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The interplays between calcium metabolic indices, retinal vascular status, plasma renin activity and blood pressure were examined in 67 patients with untreated essential hypertension. There was an inverse relationship between plasma ionized calcium and blood pressure (P = .002), whereas albumin-modified total serum calcium was directly related to blood pressure (P = .02). The plasma cyclic AMP level (P = .05) and the 24 h urinary excretion of cyclic AMP (P = .03) were also positively associated with blood pressure. Patients with vascular retinopathy had lower plasma ionized calcium concentrations (P = .01) and higher 24 h urinary cyclic AMP excretions (P = .05) than those without such changes, even when the differences in blood pressure, age, sex and body mass index were taken into account in analyses of covariance. Plasma renin activity did not interfere with the relationships between calcium metabolic indices and blood pressure, nor were there any associations between the renin status and the calcium metabolic indices. These findings suggest that a low concentration of plasma ionized calcium is an independent risk factor for vascular disease.

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We have previously shown that during percutaneous transluminal renal angioplasty (PTRA) there is a transient increase in plasma renin activity (PRA) that is partly mediated by adrenergic beta-receptors. Despite a concomitant increase in plasma aldosterone, no increase in blood pressure occurred. The aim of this study was to record sympathetic outflow in man during PTRA as reflected by muscle nerve sympathetic activity and arterial plasma noradrenaline. Nine patients with hypertension and unilateral renal artery stenosis underwent PTRA by the Grüntzig technique and simultaneous microelectrode recording of muscle nerve sympathetic activity in the peroneal nerve. Blood pressure and heart rate were recorded and blood specimens were drawn for determination of noradrenaline and PRA. During total occlusion of the renal artery, muscle nerve sympathetic activity and the heart rate were unchanged. In the first 6 min after occlusion PRA increased transiently, but there was no significant change in muscle nerve sympathetic activity, arterial noradrenaline, heart rate or blood pressure. From 10 min after PTRA, muscle nerve sympathetic activity was significantly increased and after 40 min there was a significant increase in noradrenaline. The heart rate remained unchanged throughout the procedure, but the blood pressure decreased progressively and the diastolic blood pressure was significantly reduced at 40 min, indicating successful dilation. Despite activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, two strong pressor systems, the only circulatory reaction was a decrease in diastolic blood pressure. These findings indicate simultaneous activation of a potent depressor mechanism during PTRA.

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Calcium plays a central role in maintaining vascular tone. Recent studies indicate that there are continuous relationships between systemic calcium metabolism and BP, as over the whole range of normal and raised BPs there is an inverse correlation between plasma ionised calcium concentration and BP. Twenty-two subjects with normal or moderately elevated BP participated in the present study, undertaken to investigate the interactions between systemic calcium metabolism and BP during a two-hour constant-rate calcium infusion in the absence and in the presence of concomitant verapamil infusion. During the infusion there was an increase in plasma ionised calcium by 0.40 mmol/l, SBP rose by 14 mmHg, and DBP by 9.7 mmHg. Higher basal plasma ionised calcium and lower basal serum parathyroid hormone concentrations were associated with a more pronounced diastolic pressor response to the calcium infusion. A greater DBP increase was also accompanied by more pronounced parathyroid hormone suppression, determined as cyclic adenosine monophosphate excretion, and greater tissue uptake of calcium during the infusion. Conversely, higher basal BPs were associated with greater tissue calcium uptake during the infusions. This relationship was abolished when verapamil was present. The present findings extend the previous observations of continuous relationships between indices of calcium metabolism and BP and indicate that both a direct effect of the calcium ion and indirect effects, as evidenced by cyclic adenosine monophosphate excretion, affect the BP response to acute hypercalcaemia.

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In a randomized, double-blind study (n = 58) with parallel groups, the effects of diltiazem (mean dose 329 mg/day) and atenolol (mean dose 67 mg/day) on carbohydrate and lipoprotein metabolism in hypertensive patients were compared. The mean systolic blood pressure (SBP)/diastolic blood pressure (DBP) reductions in the supine position were similar and satisfactory, 9/11 and 11/9 mmHg during atenolol and diltiazem treatment, respectively. Insulin-mediated glucose uptake, measured with the euglycaemic insulin clamp technique, decreased during atenolol treatment, from 7.1 to 5.6 mg/kg per min (P = 0.05). but not during treatment with diltiazem (initial value 6.8, final value 6.7 mg/kg per min; P greater than 0.8). Treatment differences between groups were statistically significant (P less than 0.05). During atenolol treatment there was a slight but significant increase in plasma glucose in the fasting state (P less than 0.05) and at the end of an intravenous glucose tolerance test (IVGTT; P less than 0.01), and in plasma insulin at the end of IVGTT (P less than 0.05). Despite increased insulin resistance the increase in insulin response was small, suggesting inhibition of insulin release. The insulin peak was decreased by 13% during diltiazem treatment (P less than 0.05). The concentrations of very-low and low-density lipoprotein triglycerides increased, whereas high-density lipoprotein cholesterol decreased and low-density lipoprotein cholesterol was unaffected during atenolol treatment. In conclusion, there was no difference between the antihypertensive effects of atenolol and diltiazem, but atenolol decreased insulin sensitivity and altered the lipid profile, thus possibly increasing the risk of diabetes mellitus and theoretically reducing the benefits of blood pressure reduction with regard to risk of coronary heart disease.

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Fifteen patients (eight men, seven women) with hypertension and renal artery stenosis underwent dilation of the stenosis by percutaneous transluminal renal angioplasty (PTRA). During and shortly after this treatment the effects on the renin-angiotensin-aldosterone system and blood pressure were studied. Plasma renin activity (PRA) was measured in peripheral blood and in renal venous blood during the PTRA. PRA increased in peripheral blood during PTRA as a result of an immediate significant rise in renal venous plasma renin activity by 132 +/- 134% (P less than 0.01) on the dilated side. PRA in the contralateral renal vein was close to that in peripheral blood. Within 10 min after PTRA there was a significant increase in serum aldosterone from 439 +/- 343 to 774 +/- 635 pmol 1-1 (P less than 0.025), while serum cortisol remained unchanged. The aldosterone increase was most probably mediated by angiotensin II. Systolic and diastolic blood pressures were unchanged during PTRA in spite of renin and aldosterone increases, suggesting that antihypertensive factors counteract the pressor effects of a physiologically relevant increase in PRA.

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1. Disturbances of calcium metabolism, mimicking mild, compensated secondary hyperparathyroidism, accompany essential hypertension, but it is not known whether these alterations are primary or only secondary to the elevated blood pressure. 2. Indices of systemic calcium metabolism were followed prospectively during 6 months' treatment with either propranolol, bendroflumethiazide or verapamil in 35 patients with essential hypertension. Multivariate statistical methods were employed to study the effects of blood pressure reduction upon the metabolic indices with adjustment for the effects of the different antihypertensive agents. 3. Propranolol treatment increased the plasma ionized calcium and serum phosphate concentrations, and reduced the serum levels of parathyroid hormone, free fatty acids and glycerol. Neither the total nor the total albumin-modified serum calcium concentration was significantly affected. Thus, presumably the decrease in free fatty acids reduced the calcium complex and the calcium binding to albumin, and consequently increased the plasma ionized calcium, thereby suppressing the secretion of parathyroid hormone. 4. Bendroflumethiazide caused a reduction of the fasting renal calcium excretion to half the pretreatment level, but produced no other significant changes in the various indices of calcium metabolism. 5. During verapamil treatment, the fasting renal excretion of calcium and magnesium increased, whereas the free fatty acids and glycerol concentrations in serum were reduced. These two changes presumably balanced each other, as the plasma ionized calcium and serum parathyroid hormone concentrations were not significantly altered. 6. There were no consistent relationships between the decrease in blood pressure and the changes in the metabolic indices, either in the total sample or within any subgroup.(ABSTRACT TRUNCATED AT 250 WORDS)

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Relationships between cytosolic free calcium ([Ca2+]i) in platelets, indices of systemic calcium metabolism and blood pressure were examined in 86 subjects; 29 patients with untreated and 29 patients with treated essential hypertension, six patients with borderline hypertension and 22 healthy reference subjects. In order to analyse interactions between the variables, multivariate statistical analyses were employed. The patients with untreated hypertension had higher [Ca2+]i values in non-activated platelets (P = 0.04) and lower levels of plasma ionized calcium (P = 0.02) than the reference subjects. In multivariate models analysing platelet [Ca2+]i mean blood pressure (MBP), plasma ionized calcium, serum parathyroid hormone (PTH) and body mass index (BMI), the relationship between platelet [Ca2+]i and blood pressure was attenuated (P = 0.13), whereas the inverse relationships between plasma ionized calcium and MBP (P = 0.01) and between platelet [Ca2+]i and serum PTH (P = 0.06) seen in univariate analyses persisted. According to the multivariate models the [Ca2+]i value explained only 5% of the MBP variability. Thus, the data from this investigation do not support a close relationship between basal platelet [Ca2+]i and blood pressure. The inverse relationship between plasma ionized calcium and blood pressure, independent of platelet [Ca2+]i and serum PTH, suggests a direct interaction between plasma ionized calcium and blood pressure regulation.

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Relations between indices of mineral metabolism and blood pressure were examined in 182 subjects, comprising 58 patients with essential hypertension (EHT) and 124 healthy subjects attending a general health survey. Multivariate techniques of statistical analysis were employed to test the hypothesis of different relationships between blood pressure and calcium metabolism within the subpopulations and to eliminate confounding effects of age, sex and obesity. Plasma ionized calcium was inversely related and the urinary calcium excretion positively related to blood pressure in the total group. This was not significantly different between the groups. Serum parathyroid hormone (PTH) was, however, related to diastolic blood pressure only in the EHT group. The EHT patients had significantly lower plasma levels of ionized calcium, significantly higher levels of PTH and significantly greater excretion of calcium in the urine than the healthy subjects. The results of this investigation support the hypothesis that among patients with EHT the renal tubular reabsorption of calcium is impaired resulting in a reduction of plasma ionized calcium and thereby stimulation of PTH. The findings of linear relationships suggests the possibility of a direct association between calcium metabolism and the regulation of blood pressure.

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Peroneal muscle sympathetic activity (MSA) was recorded during 2 min of isometric handgrip at 30% of maximal power and correlated with plasma levels of noradrenaline (NA) in venous blood from the contralateral forearm in 16 normotensive subjects and 15 previously untreated patients with essential hypertension. Resting values for MSA and NA were similar in the two groups and there was a significant positive correlation between the level of MSA (expressed either as bursts per 100 heart beats or bursts min-1) and the concentration of NA. Changes of MSA and NA during handgrip were similar in both groups. When monitored every minute in a subgroup of the material (n = 12), the number of sympathetic bursts min-1 increased maximally by 23% and total MSA (bursts min-1 X mean burst amplitude) by 67% during the second minute of handgrip. The maximal increase of venous NA concentrations was 21% and occurred 2 min later, probably reflecting a slow wash-out of NA from the neuroeffector junctions. It is concluded that: there is no difference in MSA between normotensive and hypertensive subjects at rest or during isometric handgrip, MSA is an important determinant of the concentration of NA in forearm venous plasma, and the relative change of the venous plasma NA concentration during isometric handgrip is considerably smaller than the change in total MSA.

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Eleven patients with hypertension and renal artery stenosis of fibromuscular type were investigated with renal blood flow estimations with Xenon133 wash-out technique before and after alpha-receptor blockade with infusion of phenoxybenzamine in the stenosed renal artery. During the whole investigation frequent blood samples for renal vein renin estimations were drawn from both kidneys. Immediately after the Xenon injection renal vein renin elevations on the investigated side were observed in 9/11 patients. The renin peak was reached in 10 min and the mean increase for all patients was 152%. The mean duration of the peak was 19.25 min. A neurogenic renin release mechanism triggered by renal chemoreceptors and mediated by beta-adrenergic fibres was suggested. This finding with renin release stimulation at Xenon133 infusion in the renal artery is of great importance in judging results of investigations concerning renal blood flow and renin when the Xenon wash-out technique is used. Blood samples for renin estimations should not be taken within 25 min after intrarenal Xenon133 infusions.

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