Effect of short-term maximal exercise on BNP plasma levels in healthy individuals.

Many studies documented the relationship between elevated plasma concentrations of natriuretic peptides and cardiovascular diseases, especially heart failure. However, it is still uncertain whether physical exercise leads to a significant release of natriuretic peptide in healthy subjects. The aim of this study was to determine the effect of maximal physical activity on plasma BNP concentrations in healthy individuals within 3 hours after the short-term exercise. BNP plasma concentrations were measured in 15 healthy volunteers before, immediately after as well as 1 hour and 3 hours after bicycle spiroergometry. Maximal workload and exercise capacity were assessed in watts, watt-seconds, metabolic equivalents and VO(2max). Mean BNP plasma levels before, immediately after, 1 hour and 3 hours post-exercise were 19.4+/-2.5; 30.6+/-4.7; 17.9+/-2.5 and 18.7+/-3.1 pg/ml, respectively. The increase of BNP concentrations immediately after exercise was statistically significant (p=0.0017) compared to baseline values. We did not find any correlation between the post-exercise increase of BNP levels and age, body mass index, maximal workload or exercise capacity. In conclusion, short-term maximal physical exercise in healthy individuals led to a fast and transient rise of plasma BNP concentrations, which remained well within normal range and far below the cut-off value for heart failure (100 pg/ml).

[Anaemia in chronic heart failure]. / Anémie pri chronickém srdecním selhání.

Anaemia is a relatively frequent co-morbidity of chronic heart as well as chronic renal failure. In both conditions, it represents a strong and independent predictor of increased morbidity and mortality. Aetiology of this anaemia is multi-factorial. A number of various factors play a role in its development, e.g. inadequate erythropoietin production in the kidneys, bone marrow inhibition, iron deficiency as well as haemodilution associated with fluid retention. Treatment strategies aim at two directions. One is the stimulation of erythropoiesis with recombinant human erythropoietin or its analogues such as darbepoetin alpha. The other involves iron substitution, administered preferably intravenously for improved efficacy and tolerability. Clinical studies evaluating treatment of anaemia in chronic heart failure with erythropoiesis-stimulating agents conducted so far were ofa small scale, were not controlled with placebo and usually assessed proxy parameters. Their results suggested that effective treatment of anaemia in patients with chronic heart failure improves exertion tolerance, clinical status (NYHA class) as well as the quality of life and reduces the need for blood transfusions. Recently completed TREAT study was the first large morbidity and mortality study evaluating treatment of anaemia with an erythropoietin analogue compared to placebo. On a sample of more than 4000 patients with diabetes mellitus, chronic renal failure and significant anaemia, this study has shown that effective treatment of anaemia with darbepoetin alpha did not affect at all the incidence of cardiovascular and renal events; on the other hand, it had lead to a nearly two-fold increase in the incidence of cerebrovascular events. Some doubts about the safety of treatment with erythropoiesis-stimulating agents have occurred in the past based on the studies of anaemia treatment in patients with cancer and renal diseases. An answer to the question whether the treatment of anaemia associated with chronic heart failure affects positively the patient prognosis will be provided following the completion of the currently running morbidity and mortality RED-HF study.

Natriuretic peptides - physiology, pathophysiology and clinical use in heart failure.

The natriuretic peptides - atrial, brain and C-type - were discovered during the last twenty years. Their effects on cardiovascular, renal, cerebral and other tissues through guanylyl cyclase were uncovered. Over the past decade natriuretic peptides (NPs) became a very useful tool in the management of heart failure patients. Results of many clinical trials have shown that BNP and NT-proBNP are helpful for diagnosis of heart failure. They are also independent markers of prognosis not only in heart failure patients but also in patients with other cardiovascular diseases. Recently published data document the utility of NPs in guiding treatment of heart failure patients. In this article, we focus on basic biochemical and physiological characteristics of NPs as well as on their significance in management of heart failure patients. Some limitations and pitfalls of NPs levels interpretation in diagnosing heart failure are also discussed.

[Will the therapy of chronic heart failure be guided by plasma levels of natriuretic peptides?]. / Budeme lécit srdecní selhání podle plazmatické koncentrace natriuretických peptidu?

Natriuretic peptides, especially BNP and NT-proBNP became useful tool for both, the diagnostics and the estimation of prognosis in chronic heart failure. As the plasma levels of natriuretic peptides copy changes in clinical status, an attractive hypothesis was formed saying that BNP/NT-proBNP guided therapy could have better clinical outcomes than therapy guided by patients' clinical status (symptoms). In past few years this hypothesis was tested in several randomized controlled clinical trials (STARS-BNP, TIME-CHF, PRIMA). However, results of these trials are very controversial. There are preliminary results of clinical trial OPTIMA referred in this paper, too. This one-centre study was performed at the authors' institution. Altogether 52 patients with chronic heart failure were randomized to one of the above mentioned treatment strategies. The rate of cardiovascular events was lower in the patients in whom the treatment was guided by BNP values compared to the patients in whom the treatment was guided by their clinical status. However, the difference was not statistically significant.

[To treat or not to treat with statins patients with chronic heart failure?]. / Lécit, ci nelécit nemocné s chronickým srdecním selháním statiny?

Two clinical trials--CORONA and GISSI-HF--have been conducted to resolve uncertainties about the effects of statins in patients with chronic heart failure and justified suspicions that treatment with statins in these patients might be detrimental. The CORONA trial researched the effects of 10 mg rosuvastatin compared to placebo on the incidence of serious cardiovascular events in 5,011 patients with systolic heart failure of ischemic aetiology, above 60 years of age and in the NYHA functional class II-IV. Even though rosuvastatin reduced the mean LDL-cholesterol plasma concentrations by 45.0% (p < 0.001) and high-sensitivity C-reactive protein (hsCRP) concentrations by 37.1% (p < 0.001), the incidence of cardiovascular events was not importantly affected (HR = 0.92; p = 0.12). Rosuvastatin had no effect on overall mortality. The treatment resulted only in a reduction of the number of hospitalizations for cardiovascular causes (p < 0.001). The GISSI-HF trial involved 4,574 patients with chronic heart failure irrespective of aetiology and the ejection fraction value randomised to take either 10 mg of rosuvastatin or placebo. The results were almost identical. Rosuvastatin had no effect on the incidence of the primary end-point--the sum of cardiovascular mortality and hospitalizations (HR = 1.01; p = 0.903). The overall mortality was not affected either. Administration of rosuvastatin in both studies was safe, the number of adverse events, including myopathies and renal failure, was no different from placebo. However, recent results from the CORONA trial subtrials have suggested that important interactions exist in patients with chronic heart failure between the effects of rosuvastatin and natriuretic peptide and hsCRP plasma concentrations. Rosuvastatin provides clinical benefit in patients with relatively low concentrations of natriuretic peptides, i.e. relatively well-controlled, while it has no clinical effect in patients with high natriuretic peptide concentrations. Similarly, rosuvastatin provides clinical benefit in patients with high hsCRP but has no effect in patients with normal hsCRP (< 2 mg/l).

[Recurrent peripheral arterial embolism from metastatic lung choriocarcinoma]. / Opakované embolizace do periferních tepen z plicní metastázy choriokarcinomu.

A case of patient with choriocarcinoma, most likely of ovarian origin, with lung metastasis is presented. The disease manifested by recurrent embolism into peripheral arteries. Publications on this topic are reviewed.

Incorporation of labelled amino acids into proteins, from rabbit reticulocytes, retained on heparin-sepharose.

Fractions of rabbit reticulocyte lysates retained on heparin-Sepharose 4B catalyze incorporation of labelled amino acids into proteins in the absence of ribosomes, and several characteristics of this reaction are identical with peptide bond formation mediated by aminoacyl-tRNA-protein transferases. At least five different proteins become labelled, as revealed by polyacrylamide gel electrophoresis. Active fractions synthesize aminoacyl-tRNA which is utilized by transferase. Aminoacyl-tRNA-protein transferase activity may be uncoupled from that of aminoacyl-tRNA synthetase by puromycin or lysyl-phenylalanine which both inhibit the transferase activity only. Adenosine and phosphate inhibit aminoacyl-tRNA synthetase as well as the incorporation of labelled amino acids into proteins. This indicates that the incorporation must be preceded by charging of tRNA with amino acids. Presence of three different aminoacyl-tRNA-protein transferases, each of them specific for a group of four amino acids, was demonstrated. Serum albumin stimulates the incorporation of amino acids and a labelling of this protein was demonstrated in mixtures into which it had been added. Addition of both ribosomal subunits and globin messenger ribonucleoprotein significantly changes the pattern of labelled proteins, and synthesis of globin was demonstrated by polyacrylamide gel electrophoresis. Density-gradient analysis revealed formation of a 48 S ribosomal complex and the formation of polyribosomes. Systems composed of active fractions retained on heparin-Sepharose supplemented with ribosomes and globin messengers apparently catalyze the translation of this message, but interactions do exist between the ribosome-mediated peptide synthesis and non-ribosomal incorporation of amino acids into proteins.

Different binding of poly(A)-containing and poly(A)-free fractions of nuclear ribonucleic acid to ribosomes from rat liver.

Total nuclear RNA extracted from nuclei of rat liver cells by phenol/chloroform in the presence of sodium dodecyl sulphate was separated by combined gel filtration on Sepharose 4 B and affinity chromatography on poly(U) Sepharose into fractions differing in their molecular weights and contents of poly(A) sequences. The poly(A)-containing 45-S RNA became labelled most rapidly if rats were administered [3H] orotic acid. This fraction showed a high template activity when added to postmitochondrial supernatants of the Krebs ascites tumour. Fractions of nRNA, free of poly(A) sequences, had no stimulating effect on protein synthesis in this system. The 45-S RNA-containing poly(A) was readily bound to crude polyribosomes from rat liver at 0 degrees C and both ATP and GTP were necessary for this reaction. Sucrose gradient analyses provided evidence that this RNA species is bound predominantly to 80-S ribosomes. No binding was obtained with polyribosomes washed with 0.5 M KCl. The binding ability of washed polyribosomes was restored by the addition of the ribosomal wash fraction or rat liver cytosol. Crude polyribosomes bound significantly lower quantities of nRNA species free of poly(A) when compared with poly(A)-45-S RNA. The label was scattered through the whole ribosomal sedimentation pattern with no predominant peaks and the binding reaction required neither soluble factors nor nucleotide cofactors. The labelling kinetics and high template activity of poly(A)-45-S nRNA indicate that this fraction contains precursors of cytoplasmic mRNA. Requirements for soluble factors and nucleotide cofactors in the binding of this RNA species to 80-S ribosomes suggest that this binding, unlike that of other nRNA species, has a specific mechanism resembling that of mRNA binding during peptide initiation.

Purification and some properties of a cholesterol esterase from rat liver.

A cholesterol esterase operating at a slightly alkaline pH was purified to electrophoretic homogeneity from rat liver cytosol. The enzyme has a molecular weight of 260 000 and is composed of four active subunits of identical molecular weight. The purified enzyme is not able to synthesize cholesteryl esters. Trihydroxy bile salts are absolutely required for the hydrolysis of cholesteryl esters and apparently convert enzyme tetramers into active monomers. They may regulate the esterase activity by maintaining a balance between enzyme monomers and polymers the synthesis of bile acids.

[Recommendations for the treatment of tobacco dependence]. / Doporucení pro lécbu závislosti na tabáku.

This first Czech version of guidelines formulated by the working group of mentioned medical associations is based on current literature and international guidelines. They are aimed mainly on clinical medicine and on incorporation of this treatment into the health care system according to WHO recommendations. They should serve to the treatment of tobacco dependence at any level: during any contact with the smoking patient (short intervention), in specialised centres or for the health care providers or health system itself.

Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial--FAT).

OBJECTIVE: It has been repeatedly proven that statins improve endothelial function in isolated hypercholesterolaemia but there is far less evidence in the case of combined hyperlipidaemia. Studies assessing the effects of fibrates on endothelium have been neglected. Therefore, we conducted a trial in which the effects of fenofibrate and atorvastatin monotherapy on both endothelium-dependent vascular reactivity and biochemical parameters were compared in patients with combined hyperlipidaemia. METHODS: 29 otherwise healthy males (aged 47.4+/-7.8 years) with combined hyperlipidaemia (total cholesterol 7.55+/-1.20 mmol/l, triglycerides 5.41+/-4.54 mmol/l) were included into the randomised, single-blind, cross-over study to receive either 200 mg of micronised fenofibrate or 10 mg of atorvastatin daily--each of the drugs for a period of 10 weeks. Analysed biochemical parameters were as follows: serum total-, LDL- and HDL-cholesterol, apolipoproteins A-I and B, triglycerides, fibrinogen, uric acid, C-reactive protein (CRP), insulin, and homocysteine. Endothelial function was investigated by duplex Doppler ultrasonography at the brachial artery. Two indices of endothelial-dependent postischaemic changes were used - the recently introduced index of peak blood flow (PBF) representing the level of reactive hyperaemia and traditional flow-mediated dilatation (FMD). RESULTS: We observed a small improvement in FMD after both fenofibrate and atorvastatin (from 2.26% to 2.98% and 2.87%, respectively; NS). PBF increased from 448 ml/min to 536 ml/min after fenofibrate (P=0.04) and to 570 ml/min after atorvastatin (P=0.03). The effects of both fenofibrate and atorvastatin on endothelial function did not differ significantly (P-values of 0.82 and 0.47 for FMD and PBF, respectively). Significant correlations (P<0.01) between the changes of vascular reactivity and biochemical indices were found between FMD and CRP (r=-0.60) and between both FMD and PBF, and insulinaemia (r=-0.48 and -0.56, respectively) only during treatment with fenofibrate. CONCLUSIONS: Both fenofibrate and atorvastatin significantly improved endothelium-dependent vascular reactivity without mutual difference. The PBF was superior to FMD for the detection of this improvement. The beneficial effect of both drugs did not correlate with the change of lipid profile during therapy. The improvement of vascular reactivity during treatment with fenofibrate (opposed to atorvastatin) was related to the reduction of indirect marker of chronic vessel wall inflammation and of insulin resistance. The PBF was more reproducible than FMD because of considerably lower intra-subject variability.

CTP can replace GTP in reactions catalyzed by eukaryotic peptide elongation factor 1.

In several reactions catalyzed by highly purified peptide elongation factor 1 from rabbit reticulocytes, GTP may be fully replaced by CTP but not by ATP or UTP. This holds true for the factor-dependent binding of aminoacyl-tRNA to ribosomes, GTPase activity, GTP-dependent autophosphorylation of the factor protein and binding of cholesteryl 14-methylhexadecanoate by the factor.

Purification of mRNA for immunoglobulin kappa-chains from myeloma and hybridoma cells using hybridization to immobilized complementary DNA.

The principle of mRNA purification by hybridization to an immobilized DNA fragment was applied to the isolation of mRNA coding for immunoglobulin kappa-chains of mouse myeloma MOPC 21 and mouse hybridoma PTF-02. The DNA fragment comprising the 3'-untranslated region and a part of the constant region of the kappa-chain gene was covalently attached to diazobenzyloxymethyl-cellulose and used as an affinity adsorbent. A homogeneous 14S mRNA species was obtained by hybridization of total mRNA to the affinity adsorbent at 52 degrees C and by elution at 60 degrees C. Addition of the purified mRNA to a fractionated cell-free translation system resulted in a significant increase in the radioactivity immunoprecipitated by pig anti-mouse immunoglobulin antibodies. A single radioactive polypeptide of apparent Mr of 25,000, corresponding obviously to the kappa-chain, was identified as the only translation product.

Long-term echocardiographic follow-up of acromegalic heart disease.

Heart muscle disease in acromegaly manifests usually as cardiac hypertrophy. Based on a retrospective analysis, it was suggested that cardiac hypertrophy is slowly reversible after normalization of plasma growth hormone levels. The reversibility of acromegalic heart muscle disease during and after treatment of acromegaly was studied prospectively. A cohort of 78 patients was examined echocardiographically in 1981, and 38 survivors of this group were reexamined 10 years later. Patients were classified according to original hormonal activity in 1981, and change in hormonal activity during follow-up into the following 4 groups: group I--hormonally inactive for entire follow-up (n = 10); group II--hormonally active for entire follow-up (n = 11); group III--initially hormonally inactive with later resurgence (n = 6); and group IV--initially hormonally active with later normalization of growth hormone levels (n = 11). No significant echocardiographic changes occurred during follow-up in group I. Left ventricular posterior wall and septal diastolic thickness, and left ventricular mass increased significantly (all p < 0.05) in group II. Left ventricular posterior wall thickness, mass and diastolic volume increased significantly (p < 0.05, < 0.01 and < 0.001, respectively) in group III. On the contrary, there were significant decreases in left ventricular mass, and both diastolic and systolic left ventricular volumes (p < 0.01, < 0.05 and < 0.05, respectively) in group IV. It is concluded that both hypertrophy and dilatation of the left ventricle in acromegaly are slowly reversible after successful treatment. On the contrary, continuing or relapsed hyperproduction of growth hormone causes further deterioration of acromegalic heart disease.

Regression of acromegalic left ventricular hypertrophy after lanreotide (a slow-release somatostatin analog).

A group of 13 acromegalic patients was treated with lanreotide for 18 months and followed-up echocardiographically; these patients showed significant correlations between the decrease of both growth hormone (GH) and insulin-like growth factor-1 and the decrease of left ventricular mass index. This documents a regression of left ventricular hypertrophy in acromegaly after lanreotide treatment, the degree of which is dependent on the magnitude of the decrease of GH and insulin-like growth factor-1 serum levels.

Microsome-mediated stimulation of the aminoacylation of rat liver initiator transfer ribonucleic acid by benzo[alpha]pyrene and 3,3-dimethyl-1-phenyltriazene.

The charging of initiator tRNAmetF with L-methionine was significantly stimulated by pre-incubation of unfractionated tRNA from rat liver with benzo [alpha]pyrne (BP) or 3,3-dimethyl-1-phenyltriazine (DMPT). The presence of microsomal enzymes from rat liver and of NADPH was absolutely required for this effect. Maximum enhancement was obtained after 60 min of incubation with 10(-4)-10(-8) mumol/ml of either compound tested. It appears that either proximate carcinogen, BP or DMPT, must be converted by microsomal enzymes into its direct-acting metabolites (ultimate carcinogens) which interact with initiator tRNA and thereby specifically modulate its aminoacylation.

Detoxication products of the carcinogenic azodye Sudan I (solvent yellow 14) bind to nucleic acids after activation by peroxidase.

The C-hydroxyderivatives of the carcinogenic dye Sudan I, 1-phenylazo-2,6-dihydroxynaphthalene and 1-(4-hydroxyphenylazo)-2-hydroxynaphthalene, which are considered to be detoxication products of this dye bind to DNA or tRNA after oxidation into active metabolites by peroxidase and H2O2 in vitro. The 32P-postlabeling analysis of DNA modified by active metabolites of both Sudan I derivatives provides evidence that the covalent binding to DNA is the principal type of DNA modification. Since the urinary bladder is rich in peroxidases, the participation of these enzymes in activation of detoxicating products of Sudan I may be involved in the initiation of Sudan I-carcinogenesis in this organ.

Valsartan and atenolol in patients with severe essential hypertension.

The aim of this study was to evaluate the efficacy and tolerability of valsartan, a new angiotensin II receptor antagonist, versus atenolol in the treatment of severe primary hypertension. A total of 103 adult out-patients were randomised to receive either valsartan 160 mg or atenolol 100 mg once daily for 6 weeks. If necessary, additional blood pressure (BP) control could be provided as add-on therapy. Both valsartan and atenolol decreased mean sitting diastolic BP (DBP) and mean sitting systolic BP (SBP): least squares mean change from baseline in DBP; valsartan, -20.0 mm Hg; atenolol, -20.4 mm Hg: in SBP; valsartan, -30.0 mm Hg; atenolol, -25.5 mm Hg. There was no statistically significant difference between the treatment groups. Add-on hydrochlorothiazide (HCTZ) 25 mg was required by 97.2% of patients receiving atenolol and 83.6% of patients receiving valsartan; additional verapamil SR 240 mg was also required by 58.3% of patients receiving atenolol and 64.2% receiving valsartan. Valsartan was well tolerated, with a comparable incidence of treatment-related adverse experiences in both groups. In conclusion valsartan 160 mg is as well tolerated and effective as atenolol 100 mg in lowering BP in severely hypertensive patients.

Alterations of cholesteryl ester metabolism characteristic for cancer.

Earlier as well as recent evidence obtained in our laboratory is reviewed indicating that specific changes in cholesteryl ester metabolism are related to tumor growth. Some properties of cholesteryl 14-methylhexadecanoate, an unknown lipid discovered and identified in our laboratory are described and its fundamental role as an essential cofactor in protein synthesis is emphasized. Increased quantities of this ester are present in tissues of tumor-bearing animals and the elevation of its level in serum is proportional to the tumor growth. Evidence has been presented that it may be a useful and reliable marker of malignant tumors in humans. This compound is synthesized in liver cells by enzymes that were recently purified to homogeneity from rat liver. The activity of these enzymes is significantly enhanced in tumor-bearing rats in a close proportion to the tumor growth. Activity of these preparations from normal rat liver may be greatly enhanced by the addition in vitro of serum from cancer patients. Since the enzymes are of lecithin-cholesterol acyl transferase type, apparently cancer serum contains some peculiar molecular species of these phospholipids. Because these lipids may be specific products of tumor cells, attempts are now in progress in this laboratory to identify them and the possibility is studied for their utilization as specific tumor markers.

Activity of cholesterol-esterifying enzymes from rat liver cytosol is affected by malignant growth.

Three cholesterol-esterifying enzymes purified recently to apparent homogeneity from rat liver cytosol (Hradec, et al: J Chromatogr B 681: 55-62, 1996) showed in vitro an absolute requirement for natural mixtures of phosphatidylcholines. These phospholipids may be replaced by the addition of minute quantities of serum from cancer patients but not by that of healthy individuals. Individual enzymes showed different sensitivities in this respect. They utilized only phosphatidylcholines containing saturated fatty acids as substrates but not those containing unsaturated fatty acids. As revealed by high-performance liquid chromatography, products of the esterification were esters with saturated C12-C18 fatty acids (including odd-numbered) in comparable proportions. If cancer serum was added as the only source of substrate, enzymes synthesized predominantly cholesteryl 14-methylhexadecanoate. The enzymatic activity and nature of reaction products thus depended on the availability of particular phosphatidylcholines present in the cancer serum but not (or in lower quantities) in the serum of healthy individuals. These results may be of significance for further studies on metabolic changes accompanying the growth of malignant tumours.