Interaction between nonsteroidal anti-inflammatory drug intake and calcium-channel blocker-based antihypertensive treatment in the Syst-Eur trial.

OBJECTIVE: To assess the relationship between chronic intake of nonsteroidal anti-inflammatory drugs (NSAID) and outcome, in particular (gastrointestinal) bleeding and to investigate whether the effect of chronic NSAID intake was similar in untreated and treated elderly hypertensives. METHODS: Eligible patients (> or = 60 years, with systolic blood pressure 160-219 mm Hg and diastolic blood pressure < 95 mm Hg) were randomised to active treatment or placebo. Active treatment consisted of nitrendipine, with the possible addition of enalapril, hydrochlorothiazide, or both, titrated or combined to reduce the sitting systolic blood pressure by at least 20 mm Hg to below 150 mm Hg. Patients never taking NSAIDs (n = 2882) were compared with patients on chronic NSAID intake (n = 861), defined as reporting NSAID intake on at least 50% of the patient forms. RESULTS: There was a tendency towards lower mortality (relative hazard rate (95% confidence interval (CI), 0.77 (0.56-1.06)) and higher incidence of bleeding (1.13 (0.63-2.05) with chronic NSAID intake. Although there was no significant interaction between calcium-channel blocker (CCB)-based treatment and chronic NSAID intake for any of the end points, chronic NSAID intake tended to be associated with a lower incidence of bleeding on active treatment as compared to placebo (P-value of the interaction term = 0.07). CONCLUSION: The effect of chronic NSAID intake on outcome was similar in patients on active treatment based on a dihydropyridine CCB or on placebo. However, chronic NSAID intake might have a less deleterious effect on bleeding on active treatment as compared to placebo.

Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.

BACKGROUND: In the outcome trials that provided information on renal function in older hypertensive patients, diuretics and beta-blockers were mostly used as first-line drugs. The long-term renal effects of calcium-channel blockers remain unclear. OBJECTIVE: To compare the changes in renal function in 2,258 treated and 2,148 untreated patients with isolated systolic hypertension, of whom 455 had diabetes mellitus and 390 had proteinuria. METHODS: We performed a post-hoc analysis of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Active treatment was initiated with nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), or both, titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg, to less than 150 mmHg. The main outcome measures were serum creatinine concentration and creatinine clearance calculated by the formula of Cockroft and Gault. RESULTS: Serum creatinine concentration at the time when participants were randomly allocated to study groups was less than 176.8 micromol/l (2.0 mg/dl), averaging 88 micromol/l. At the time of the last serum creatinine measurement, the blood pressure difference (P< 0.001) between the two groups was 11.6/4.1 mmHg. In the intention-to-treat analysis (11,427 patient-years), serum creatinine and the calculated creatinine clearance were not influenced by active treatment. However, in the patients assigned randomly to receive active treatment, the incidence of mild renal dysfunction (serum creatinine at least 176.8 mmol/l) decreased by 64% (P= 0.04) and that of proteinuria by 33% (P= 0.03). Active treatment reduced the risk of proteinuria more in diabetic than in non-diabetic patients: by 71%, compared with 20% (P= 0.04). In non-proteinuric patients, active treatment did not influence serum creatinine, whereas in patients with proteinuria at entry to the study, serum creatinine decreased on active treatment (P< 0.001). Furthermore, in on-randomized treatment comparison stratified for risk at baseline, serum creatinine concentration did not change (P= 0.98) in patients continuing to receive monotherapy with nitrendipine, whereas it increased by 6.73 mmol/l (P < 0.001) in patients who received hydrochlorothiazide alone or in combination with other study medication (P < 0.001 for difference in trends). CONCLUSIONS: In older patients with isolated systolic hypertension, antihypertensive treatment starting with the dihydropyridine calcium-channel blocker, nitrendipine, did not decrease blood pressure at the expense of renal function and prevented the development of proteinuria, especially in diabetic patients.

Hypertension in the Very Elderly Trial (HYVET): protocol for the main trial.

A number of trials and meta-analyses have demonstrated clear benefits of blood pressure (BP) reduction in patients aged <80 years with regard to the reduction in stroke and cardiovascular events. However, a variety of studies have suggested that the positive relationship between BP and cardiovascular mortality is weakened or indeed reversed in the very elderly. Most intervention trials to date have either excluded or not recruited sufficient patients aged > or =80 years to determine whether there is a significant benefit from treatment in this age group. A meta-analysis of intervention trials that recruited patients aged > or =80 years has suggested a benefit in terms of stroke reduction but has also raised the possibility of an increase in total mortality. The benefit to risk ratio therefore needs to be clearly established before recommendations can be made for treating very elderly patients with hypertension. The Hypertension in the Very Elderly Trial (HYVET) pilot recruited 1283 patients aged > or =80 years and showed the feasibility of performing such a trial in this age group. It was a Prospective Randomised Open Blinded End-Points (PROBE) design but the main trial has additional pharmaceutical sponsorship to run a double-blind trial. Therefore, the main trial is a randomised, double-blind, placebo-controlled trial designed to assess the benefits of treating very elderly patients with hypertension. It compares placebo with a low dose diuretic (indapamide sustained release 1.5mg daily) and additional ACE inhibitor (perindopril) therapy if required. As in the pilot trial, the primary end-point is stroke events (fatal and non-fatal) and the trial is designed to determine whether or not a 35% difference occurs between placebo and active treatment. The main objective will be achieved with 90% power at the 1% level of significance. Secondary outcome measures will include total mortality, cardiovascular mortality, cardiac mortality, stroke mortality and skeletal fracture. 2100 patients aged > or =80 years are to be recruited and followed up for an average of 5 years. Entry BP criteria after 2 months of a single-blind placebo run-in period are a sustained sitting systolic BP (SBP) of 160 to 199mm Hg and a diastolic BP of 90 to 109mm Hg. The standing SBP must be >140mm Hg. The trial will be carried out in accordance with the principles of Good Clinical Practice. We describe in detail the protocol for the main trial and discuss the reasons for the changes from the pilot, the use of the drug regimen, and the BP criteria to be used in the trial.

Influence of acute copper deficiency, cold-restraint stress and the H2 blocker ranitidine on the severity of acute gastric mucosal lesions and lipid peroxidation in rats.

Acute copper deficiency produces disturbances in the microcirculation and structure of extracellular matrix proteins, causes an increase in mast cell population, which is followed by an increased content of their degranulation products, produces disturbances in histamine metabolism and decreases the activity of some antioxidant enzymes. These pathogenic mechanisms are similar to the processes underlying stress ulcer formation. The histamine H2-receptor antagonist ranitidine, a drug with the highest application for stress ulcer prophylaxis, has the ability to helate the copper ion and to influence its tissue distribution and the processes of generation and neutralization of reactive oxygen species (ROS). In order to determine the interrelation between the disturbances of copper homeostasis, stress ulcers and ranitidine, we investigated the impact of a short-term diet with powdered milk in combination with cold-restraint stress with or without ranitidine on the severity of acute gastric mucosal lesions, copper content, lipid peroxidation and the activity of superoxide dismutase and catalase in the stomachs of rats.

[Two cases of insulinoma treated as a psychiatric disease]. / Dva sluchaia na insulinom, tretirani kato psikhichno zaboliavane.

The insulin producing tumors are rare diseases and sometimes the diagnostics is very difficult. We present two cases of insulinoma treated as psychiatric diseases. We discuss the difficulties and particularities in the diagnostic process.

Reduced concentrations of soluble adhesion molecules after antioxidant supplementation in postmenopausal women with high cardiovascular risk profiles--a randomized double-blind study.

BACKGROUND: One of the suggested mechanisms of increased cardiovascular risk in postmenopause is a loss of the antioxidant effects of estrogens. It has been shown that classical cardiovascular risk factors increase oxidative stress on the arterial wall, and that endothelial cells react to this insult by increased expression of cellular adhesion molecules (CAM), which in turn are markers of arterial wall inflammation. METHODS: A randomized, placebo-controlled, double-blind study was performed in 60 postmenopausal women with high cardiovascular risk profiles, but free from clinical atherosclerotic disease. Patients were randomized to either antioxidant supplementation (using a combination of natural antioxidants; n = 30) or placebo (n = 30), and followed for 12 weeks. The concentrations of the adhesion molecules sVCAM-1 and sICAM-1 were measured by ELISA at baseline and at the end of the study, as well as total cholesterol, LDL, HDL, triglycerides and blood pressure. RESULTS: 27 women in the antioxidant supplementation group and 29 on placebo completed the study. At baseline, there were no significant differences in measured parameters between the groups: sICAM-1 concentrations were 341.8 +/- 116.9 vs. 349.9 +/- 104.6 ng/ml (active treatment vs. placebo; p = n.s.) and sVCAM-1 concentrations were 780.5 +/- 325.8 vs. 761.0 +/- 333.7 ng/ml (p = n.s.). In contrast, at the end of the study, sICAM-1 concentrations were 301.6 +/- 56.0 vs. 356.0 +/- 134.8 ng/ml (active treatment vs. placebo; p = 0.053) and sVCAM-1 concentrations were 656.0 +/- 326.5 vs. 818.5 +/- 381.0 ng/ml (p = 0.04). There were no significant differences between or changes within the groups in measured cholesterol and blood pressure. CONCLUSION: Antioxidant supplementation reduces serum concentrations of endothelium-derived adhesion molecules sICAM-1 and sVCAM-1 in postmenopausal women with high cardiovascular risk profiles.

Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators.

CONTEXT: The clinical use of ambulatory blood pressure (BP) monitoring requires further validation in prospective outcome studies. OBJECTIVE: To compare the prognostic significance of conventional and ambulatory BP measurement in older patients with isolated systolic hypertension. DESIGN: Substudy to the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial, started in October 1988 with follow up to February 1999. The conventional BP at randomization was the mean of 6 readings (2 measurements in the sitting position at 3 visits 1 month apart). The baseline ambulatory BP was recorded with a noninvasive intermittent technique. SETTING: Family practices and outpatient clinics at primary and secondary referral hospitals. PARTICIPANTS: A total of 808 older (aged > or =60 years) patients whose untreated BP level on conventional measurement at baseline was 160 to 219 mm Hg systolic and less than 95 mm Hg diastolic. INTERVENTIONS: For the overall study, patients were randomized to nitrendipine (n = 415; 10-40 mg/d) with the possible addition of enalapril (5-20 mg/d) and/or hydrochlorothiazide (12.5-25.0 mg/d) or to matching placebos (n = 393). MAIN OUTCOME MEASURES: Total and cardiovascular mortality, all cardiovascular end points, fatal and nonfatal stroke, and fatal and nonfatal cardiac end points. RESULTS: After adjusting for sex, age, previous cardiovascular complications, smoking, and residence in western Europe, a 10-mm Hg higher conventional systolic BP at randomization was not associated with a worse prognosis, whereas in the placebo group, a 10-mm Hg higher 24-hour BP was associated with an increased relative hazard rate (HR) of most outcome measures (eg, HR, 1.23 [95% confidence interval [CI], 1.00-1.50] for total mortality and 1.34 [95% CI, 1.03-1.75] for cardiovascular mortality). In the placebo group, the nighttime systolic BP (12 AM-6 AM) more accurately predicted end points than the daytime level. Cardiovascular risk increased with a higher night-to-day ratio of systolic BP independent of the 24-hour BP (10% increase in night-to-day ratio; HR for all cardiovascular end points, 1.41; 95% CI, 1.03-1.94). At randomization, the cardiovascular risk conferred by a conventional systolic BP of 160 mm Hg was similar to that associated with a 24-hour daytime or nighttime systolic BP of 142 mm Hg (95% CI, 128-156 mm Hg), 145 mm Hg (95% CI, 126-164 mm Hg) or 132 mm Hg (95% CI, 120-145 mm Hg), respectively. In the active treatment group, systolic BP at randomization did not significantly predict cardiovascular risk, regardless of the technique of BP measurement. CONCLUSIONS: In untreated older patients with isolated systolic hypertension, ambulatory systolic BP was a significant predictor of cardiovascular risk over and above conventional BP.

Serum level of IgG autoantibodies against oxidized low density lipoproteins and lag-phase of serum oxidation in coronary heart disease--inverse correlation.

High affinity IgG autoantibodies (ABs) against oxLDLs and lag-phase of serum oxidation were tested in patients with coronary heart disease (CHD). Fifty one (37 M/14 F) patients with CHD defined as Q-wave myocardial infarction and/or stenosis of more than 50% and 51 (34 M/17 F) healthy blood donors as controls participated in this study. LDLs were isolated by gradient ultracentrifugation and oxidized with CuSO4. The modified LDLs (oxLDLs) or native LDLs (nLDLs) were used as antigens in an enzyme immunoassay (ELISA) to detect IgG ABs in both groups. The serum was oxidized by CuSO4 and the oxidation was monitored spectrophotometrically at lambda = 234 nm to follow the formation of conjugated diens. The lag-phase (in minutes) is the interval between the addition of CuSO4 to the serum and the beginning of extensive oxidation (increasing absorbance at 234 nm). The concentrations of total cholesterol, triglycerides, HDL-cholesterol, apo-A and apo-B were measured as well. The mean level of ABs against oxLDLs (expressed as optical density units) was 0.590 +/- 0.330 in CHD-patients vs 0.244 +/- 0.200 in controls (p < 0.001). The lag-phase in minutes was 47.00 +/- 27.19 in CHD-patients and 80.23 +/- 26.30 in controls (p < 0.001). A negative correlation between ABs levels and lag-phase was established in CHD-patients (r = -0.69, p < 0.001) and controls (r = -0.62, p < 0.001). A poor correlation was established between ABs levels or lag-phase, on one hand, and other measured parameters. In conclusion, the lag-phase of serum oxidation by Cu2+ could be informative for LDL susceptibility to modification and the extent of consequent humoral immune response.

Systolic Hypertension in Europe (Syst-Eur) trial phase 2: objectives, protocol, and initial progress. Systolic Hypertension in Europe Investigators.

The Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (> or = 60 years) patients with isolated systolic hypertension (systolic BP > or = 160 mm Hg and diastolic BP < 95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Ci: 0.8 to 2.6 mm Hg; P < 0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P < 0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and active-treatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst-Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, will be monitored and validated by blinded experts.

Correlates of cognitive status of old patients with isolated systolic hypertension: the Syst-Eur Vascular Dementia Project.

OBJECTIVE: To assess cognitive functions and their correlates for a dementia-free cohort of old patients with isolated systolic hypertension. DESIGN: Cross-sectional data from the randomization period of the European Trial in Elderly with Systolic Hypertension (Syst-Eur Vascular Dementia Project). SETTING: Sixteen European countries and Israel. PARTICIPANTS: We studied 2252 patients aged 60-100 years (mean 70). MAIN OUTCOME MEASURES: Mini Mental State Examination (MMSE) and Spearman correlation of MMSE scores to demographic data or blood pressure. RESULTS: The MMSE was successfully completed for 1474 women and 751 men. The baseline blood pressure averaged 173 +/- 10/86 +/- 6 mmHg (means +/- SD). Median age at which education of patients at school had stopped was 15 years. Men and women who consumed alcohol (28%) had median intakes of 8 and 3 g/day, respectively. The median MMSE score was 29 (range 15-30). The maximum score of 30 was attained by 609 (30%) subjects. Fifty-nine (3%) patients had a MMSE score of 23 or less. The MMSE score decreased with advancing age (r = -0.21, P < 0.001). Both for men and for women, it was positively correlated to the level of education (r = 0.30 and r = 0.32, P < 0.001). For women after adjustment for age and the level of education, the score was correlated negatively to systolic blood pressure (r = -0.07, P < 0.05) but positively to intake of alcohol (r = 0.06, P < 0.05). CONCLUSION: In a cohort of elderly patients with isolated systolic hypertension, baseline cognitive function measured in terms of the MMSE score was high, probably due to selective recruitment of patients who were not clinically demented. Blood pressure was a weak contributor to cognitive status compared with age and level of education. Baseline cognitive function of women was negatively and independently correlated to systolic blood pressure.

Calcium channel blockade and cardiovascular prognosis in the European trial on isolated systolic hypertension.

In the double-blind Systolic Hypertension in Europe (Syst-Eur) Trial, active treatment was initiated with nitrendipine (10 to 40 mg/d) with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d) titrated or combined to reduce sitting systolic blood pressure by at least 20 mm Hg to <150 mm Hg. In the control group, matching placebos were used similarly. In view of persistent concerns about the use of calcium channel blockers as first-line antihypertensive drugs, this report explored to what extent nitrendipine, administered alone, prevented cardiovascular complications. Age at randomization averaged 70.2 years and systolic/diastolic blood pressure 173.8/85.5 mm Hg. Of 2398 actively treated patients, 1327 took only nitrendipine (average dose, 23.4 mg/d), and 1042 progressed to other treatments including nitrendipine (n=757; 35.7 mg/d), enalapril (n=783; 13.4 mg/d), and/or hydrochlorothiazide (n=294; 21.0 mg/d). Compared with the whole placebo group (n=2297), patients receiving monotherapy with nitrendipine had 25% (P=0.05) fewer cardiovascular end points, and those progressing to other active treatments showed decreases (P

Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly.

BACKGROUND: In 1989, the European Working Party on High Blood Pressure in the Elderly started the double-blind, placebo-controlled, Systolic Hypertension in Europe Trial to test the hypothesis that antihypertensive drug treatment would reduce the incidence of fatal and nonfatal stroke in older patients with isolated systolic hypertension. This report addresses whether the benefit of antihypertensive treatment varied according to sex, previous cardiovascular complications, age, initial blood pressure (BP), and smoking or drinking habits in an intention-to-treat analysis and explores whether the morbidity and mortality results were consistent in a per-protocol analysis. METHODS: After stratification for center, sex, and cardiovascular complications, 4695 patients 60 years of age or older with a systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg were randomized. Active treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d) and/or hydrochlorothiazide (12.5-25 mg/d), titrated or combined to reduce the sitting systolic BP by at least 20 mm Hg, to below 150 mm Hg. In the control group, matching placebo tablets were employed similarly. RESULTS: In the intention-to-treat analysis, male sex, previous cardiovascular complications, older age, higher systolic BP, and smoking at randomization were positively and independently correlated with cardiovascular risk. Furthermore, for total (P = .009) and cardiovascular (P = .09) mortality, the benefit of antihypertensive drug treatment weakened with advancing age; for total mortality (P = .05), the benefit increased with higher systolic BP at entry, while for fatal and nonfatal stroke (P = .01), it was most evident in nonsmokers (92.5% of all patients). In the perprotocol analysis, active treatment reduced total mortality by 24% (P = .05), reduced all fatal and nonfatal cardiovascular end points by 32% (P<.001), reduced all strokes by 44% (P = .004), reduced nonfatal strokes by 48% (P = .005), and reduced all cardiac end points, including sudden death, by 26% (P = .05). CONCLUSIONS: In elderly patients with isolated systolic hypertension, stepwise antihypertensive drug treatment, starting with the dihydropyridine calcium channel blocker nitrendipine, improves prognosis. The per-protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths, 54 major cardiovascular end points, 29 strokes, or 25 cardiac end points. The effects of antihypertensive drug treatment on total and cardiovascular mortality may be attenuated in very old patients.

New competitive enzyme-linked immunosorbent assay for determination of metallothionein in tissue and sera.

Very little information is available concerning the relationship between metallothionein (MT) and diseases in humans. Several methods to measure MT levels exist but many of these assays are not sensitive to measure MT in human sera. A new sensitive competitive ELISA system has been developed using MT labeled with horseradish peroxidase as a conjugate and high-titre polyclonal antibodies obtained from rabbit immunoglobulin G for MT determination in human sera. The cELISA proposed here permits a reliable determination of MT in the range 10-2 000 000 pg ml(-1). The method was compared with Cd-hem assay and showed good agreement of results. The recovery of the assay was determined by spiking rat MT into rat and human sera, and comparing it with spiked diluent controls. The overall recoveries of the added MT were 101% for rat sera and 89% for human sera. The variation within-assay and between assay were 3 and 6%, respectively. A significant difference (P<0.001) was found between the MT-level in human sera from patient with essential hypertension (646+/-223 ng ml(-1), n=90) and normotensive subjects (21+/-18 ng ml(-1), n=236). A correlation between arterial hypertension and MT-level seems possible. A very sensitive new cELISA method was presented for determination of MT in sera and tissues. It enables investigation of possible correlations between sera MT-concentration and certain diseases.

Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.

BACKGROUND: Isolated systolic hypertension occurs in about 15% of people aged 60 years or older. In 1989, the European Working Party on High Blood Pressure in the Elderly investigated whether active treatment could reduce cardiovascular complications of isolated systolic hypertension. Fatal and non-fatal stroke combined was the primary endpoint. METHODS: All patients (> 60 years) were initially started on masked placebo. At three run-in visits 1 month apart, their average sitting systolic blood pressure was 160-219 mm Hg with a diastolic blood pressure lower than 95 mm Hg. After stratification for centre, sex, and previous cardiovascular complications, 4695 patients were randomly assigned to nitrendipine 10-40 mg daily, with the possible addition of enalapril 5-20 mg daily and hydrochlorothiazide 12.5-25.0 mg daily, or matching placebos. Patients withdrawing from double-blind treatment were still followed up. We compared occurrence of major endpoints by intention to treat. FINDINGS: At a median of 2 years' follow-up, sitting systolic and diastolic blood pressures had fallen by 13 mm Hg and 2 mm Hg in the placebo group (n = 2297) and by 23 mm Hg and 7 mm Hg in the active treatment group (n = 2398). The between-group differences were systolic 10.1 mm Hg (95% CI 8.8-11.4) and diastolic, 4.5 mm Hg (3.9-5.1). Active treatment reduced the total rate of stroke from 13.7 to 7.9 endpoints per 1000 patient-years (42% reduction; p = 0.003). Non-fatal stroke decreased by 44% (p = 0.007). In the active treatment group, all fatal and non-fatal cardiac endpoints, including sudden death, declined by 26% (p = 0.03). Non-fatal cardiac endpoints decreased by 33% (p = 0.03) and all fatal and non-fatal cardiovascular endpoints by 31% (p < 0.001). Cardiovascular mortality was slightly lower on active treatment (-27%, p = 0.07), but all-cause mortality was not influenced (-14%; p = 0.22). INTERPRETATION: Among elderly patients with isolated systolic hypertension, antihypertensive drug treatment starting with nitrendipine reduces the rate of cardiovascular complications. Treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major cardiovascular endpoints.

Therapy in old patients with isolated systolic hypertension: fourth progress report on the Syst-Eur trial.

The Syst-Eur trial is a multicentre, randomized, double-blind, placebo controlled therapeutical trial in patients at least 60 years old and with isolated systolic hypertension. Its scope is to investigate the effects of modern antihypertensive drug treatment on morbidity and mortality and to assess possible adverse effects of the drugs used. Patients were recruited in 22 countries in western and eastern Europe and Israel. At three run-in visits 1 month apart their sitting systolic blood pressure (SBP) on single-blind placebo treatment averaged 180-219 mm Hg with diastolic blood pressure (DBP) lower than 95 mm Hg. After stratification for sex and the presence of cardiovascular complications, the patients were randomized either to active treatment or placebo. Active treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day) and/or hydrochlorothiazide (12.5-25 mg/day), titrated or combined to reduce the sitting SBP by at least 20 mm Hg to below 150 mm Hg. Matching placebos were employed similarly. The present progress report is based on the data received at the Coordinating Office before 1 March 1996. At that time 3433 subjects had been randomized. A total of 2015 patients had been followed for at least 1 year on double-blind treatment and 1298 patients for at least 2 years. At baseline BP was similar in both treatment groups and averaged 174/86 mm Hg. According to a per-protocol analysis at 1 year, BP fell (P < 0.001) on average by 22.6 +/- 15.7/6.0 +/- 8.0 mm Hg in the active treatment group and by 12.2 +/- 15.9/1.7 +/- 7.3 mm Hg in the placebo group. At 2 years BP was 10.2/5.7 mm Hg lower (P < 0.001) on active treatment than on placebo. At 1 year the percentage of patients who had reached goal BP was 19.9% in the placebo group and 41.4% in the active treatment group. At 2 years these percentages were 20.9 and 43.2 respectively.

Oxidation of low density lipoproteins leads to disturbance of their binding with alpha-tocopherol.

The dynamics of binding of exogenous alpha-tocopherol (alpha-T) added to native or oxidatively modified LDLs (LDLs or oxLDLs) were investigated. Venous blood from 31 clinically healthy blood donors (15 males and 16 females) was used. LDLs were isolated by density gradient ultracentrifugation. LDLs were oxidized in vitro by CuSO4. LDLs or oxLDLs were enriched with exogenous alpha-T (initial concentrations: 0; 10; 20; 50; or 100 nmol per mg protein). The contents of alpha-T in LDLs or in oxLDLs were measured by HPLC. Lag-phase of LDL oxidation before or after saturation with alpha-T was recorded. Correlation analysis of the lag-phase of LDL oxidation and alpha-T content in LDLs was carried out by the method of Esterbauer et al. The experimental results demonstrated that: (i) alpha-T was incorporated into native LDLs to a higher extent as compared to oxLDLs. (ii) A saturation of LDLs and oxLDLs with alpha-T was observed. (iii) A positive correlation was observed between the duration of the lag-phase of LDL oxidation in vitro and the content of alpha-T in LDLs. (iv) Based on LDL saturation with alpha-T, the persons could be classified in two groups: LDLs from group I of 26 persons were found to incorporate exogenous alpha-T to the extent of 1.8 to 3 times its initial concentration; LDLs from group II of 5 persons incorporated little or no exogenous alpha-T. In the first group, oxidation of LDLs lead to a considerable decrease in alpha-T dependent variable k and to a moderate reduction of alpha-T-independent variable alpha in the equation of Esterbauer et al.: lag-phase = k.[alpha-tocopherol]+alpha. In the second group, oxidation of LDLs lead to insignificant changes in k, as well as in a. (v) According to the levels of k and a the native LDLs from the second group of 5 persons were very close to oxLDLs from the first group of 26 persons. Presumably, native LDLs from the second group of persons were initially oxidatively modified, and probably this will be a risk group in relation to atherogenic disorders.

Complexes of zinc with picolinic and aspartic acids inactivate free varicella-zoster virions.

Zn(II) picolinate and aspartate, Zn(pic)(2) and Zn(asp)(2), have been shown to inhibit key steps of the replication of HSV-1. In the present study we describe the effect of Zn(pic)(2) and Zn(asp)(2) on the replication of VZV and on the infectivity of free virions. The experiments are done using BHK-21 cells, a clinical isolate of VZV and Zn-complexes in concentration of 10 muM. When Zn-complexes are present during the whole period of infection, the yield of infectious virus progeny decreases up to 98%. The infectivity of VZV is completely restored after the removal of zinc. The virucidal effect is manifested at the 2nd h of contact, when 90% of the virions are inactivated. The results show that both Zn(pic)(2) and Zn(asp)(2) specifically inactivate free VZV virions with no effect on viral replication.

The diagnostic value of conventional X-ray examination of the lungs in comparison with high-resolution computed tomography (HRCT), isotope perfusion scintigraphy and the diffusion capacity in patients with pneumoconiosis.

A precise diagnosis of initial reticular forms of pneumoconioses is very difficult. The present study focuses on 30 patients with initial reticular forms of silicosis, asbestos induced interstitial lung fibrosis, mixed dust pneumoconioses and pneumoconioses of electrowelders. The anterior-posterior chest radiography (according to the ILO International Radiological Classification of Pneumoconioses, 1980), high-resolution computed tomography (HRCT), perfusion scintigraphy with 99mTc and the changes in the diffusion capacity were compared. The diagnostic value of these methods was assessed. The study continues by expanding the groups of patients examined and by including the membrane component of diffusion.

Oxidative modifications of blood serum in humans with coronary artery disease.

Oxidative modifications of blood serum in humans with and without coronary artery disease were investigated. Four parameters were analyzed: the intensity of serum fluorescence, which is indicative of the content of lipofuscine-like lipid peroxidation products; the content of thiobarbituric acid-reactive substances; the lag-phase of serum oxidation by azo-compounds; and the content of lipophilic natural antioxidants--alpha-tocopherol, beta-carotene and ubiquinol-9(10). It was found that coronary artery disease resulted in a significant increase of serum fluorescence and the content of TBARS. The atherogenic disorders in humans with coronary artery disease drastically decreased the lag-phase of serum oxidation in the presence of 2,2'-azo-bis-(2-amidinopropane) dihydrochloride. The oxidative modifications of serum were in close correlation with the balance of natural lipophilic antioxidants in blood serum, i.e. alpha-tocopherol, ubiquinols and beta-carotene. The contents of all antioxidants tested in serum were significantly decreased in patients with coronary artery disease.