Pioglitazone Alters Ace/Ace 2 Balance to Favour Ace2 Independently Of Glycaemia Levels in Diabetic Rat Heart.

The activation of the renin-angiotensin system (RAS) contributes to the pathogenesis of cardiac damage during diabetes. In the present study, we investigated the role of pioglitazone, dapagliflozin and their combination on RAS components in streptozotocin-induced diabetic cardiomyopathy in Wistar rats. Blood glucose, serum lipids, and ACE (angiotensin-converting enzyme), ACE2 levels were determined. mRNA levels of Myh6 (myosins heavy chain), Myh7, Ace, Ace2, Nppa, Nppb (natriuretic peptide A, B) and Ppars (peroxisome proliferator activating receptors) genes in the heart were determined by real-time PCR (polymerase chain reaction). Protein expression of ACE and ACE2 was assessed by western blotting. After six weeks pioglitazone suppressed Ace mRNA and protein levels (p<0.05) and modified the Ace/Ace2 ratio (p<0.05) in the cardiac tissue of diabetic rats. Pioglitazone significantly decreased serum lipids (p<0.05) but did not significantly influence blood glucose and ACE serum levels of diabetic animals. Dapagliflozin had a significant glucose-lowering action (p<0.05) however, it had no impact on the Ace/Ace2 ratio. The combination of both compounds markedly improved blood glucose (p<0.05) as well as the Myh6/Myh7 ratio (p<0.05) but had no further impact on the Ace to Ace2 balance in cardiac tissue compared to pioglitazone monotherapy. We found that pioglitazone improves the cardiac Ace/ Ace2 ratio in diabetic rats suggesting a potential cardioprotective effect. This effect is independent of its antidiabetic and metabolic effects.

Electrocardiography in two models of isoproterenol-induced left ventricular remodeling.

We studied the ability of the ECG to detect pathological changes in isoproterenol-induced remodeling of rat heart. Myocardial hypertrophy in rats was induced by repeated injections of isoproterenol (5 mg/kg s.c. 7 days, Iso5, n=7). Single overdose of isoproterenol (150 mg/kg s.c., Iso150, n=7) evoked myocardial infarction followed with ventricular remodeling. The electrocardiograms were recorded in anesthetized animals (thiopenthal 45 mg/kg i.p.) and myocardial contractile performance was analyzed in isolated hearts perfused according to Langendorff. The hypertrophic hearts were characterized by increased heart and left ventricular (LV) weight as well as by thicker LV free wall and interventricular septum. Mean values of LV contraction did not significantly differ from controls. Longer QT interval, QRS complex, negative Q and S waves, higher R amplitude were typical characteristics for Iso5 rats. Iso150 animals showed tendency to decreased systolic blood pressure and heart frequency. Decrease in the thickness of LV compared to Iso5 as well as impaired LV function were related to the dilated left ventricle. Iso150 ECG showed longer QRS and QT, deepened negativity of S wave and mild decrease of R(II) compared to Iso5. Voltage criteria showed that Sokolow-Lyon index is a good predictor of left ventricular hypertrophy in isoproterenol-induced cardiac remodeling without systemic hypertension.

Realisation of Bologna Declaration at the Slovak medical schools.

Implementation of Bologna Declaration should result in development and facilitating of the education system. Following tasks need to be done: (1) Establish committees of expert, at the level of institutes, schools and universities, which would compare and harmonize syllabus and credits of individual courses with the aim to maximally support students' and teachers' mobility. (2) It is necessary to re-evaluate the transformation of medical education in Slovakia in the near future, so as key identical courses within Slovak schools of medicine have similar syllabus, number of hours and number of given credits. Then medical study at the School of Medicine Comenius University Bratislava will be comparable to study at Slovak, Czech and other European schools of medicine. (3) Harmonize academic titles within European Union. (4) Finish all syllabi of new study programs according the programs of European Union. (5) Evaluate the prerequisites and consider the variability of some study programs. (6) Maintain flexibility of theory and practice in relation 1:2 in theoretical and practical study. (7) Determine possible forms of thesis, their content and forms, technical equipment considering experience in student's research activity. (8) Develop conditions for an adequate teachers input. (9) Objectively validate and evaluate students' gained knowledge regarding their use in practice. (10) Solve transparent conditions of support and economic guarantee of higher education for universities, teachers and students by Ministry of Education of Slovak Republic (Ref. 18). Full Text (Free, PDF) www.bmj.sk.

Position of information science in the medical and health studies curricula.

Innovation of both the content and forms of informatics teaching directed on exploitation of technical facilities and methods of information and communication technologies (ICT) in non-informatics universities study programmes and in life-long education is still actual today. Expanding knowledge base of the life and health sciences requires to form new skills to educate the end-users and facilitate an immediate information access. Theoretical and practical teaching in pregradual medical and health studies includes the basic contacts of students with the modern technique and special medical devices supported or completed by computers. The teaching of information science and corresponding subjects represents small but important part of medical and health studies curricula at all medical faculties in Slovakia (Fig. 2, Ref. 8).

The role of medical physics in the scheme of diagnostic and therapeutic processes by keeping safety and hygienic regulations.

According to Standards of European Union the pregradual education should tend toward preparation of multidisciplinary working teams that can manage the health service using principles of evidence-based medicine, nowadays. The primary aims of teaching process is to direct the students to acquire, identify, analyze, process and select the reproducible results of physical measurements, to that the medical interpretation will be assigned. Our scientific research was directed at the existing conditions for professional use of different types of medical technique in the surgical and internal disciplines in health service institutions in all the regions of Slovakia. It also looked at the possibilities of eliminating the various unwanted effects of certain physical factors (Fig. 3, Ref. 9).

The preparation of students of medical faculties and other public colleges for educative activities within the national programme of health support.

The tradition of education of physicians at the Medical Faculty of Comenius University (MFCU) has been developing for more than 85 years. Currently, the education has been widened by non-medical fields of study (nursing, obstetrical assistance, rehabilitation, public health care and laboratory and examination methods). After joining EU, the accreditation study programmes have been subject to transformation in compliance with current world trends in education. In accord with the transformation of content and forms of medical physics training, the authors demonstrate the main objectives and goals of this process. The goal is to prepare the graduates on high theoretical and practical levels, to teach them to work in team, and to prepare them for whole-life education. Practical skills in pre-clinical and clinical disciplines are being strengthened. One of the important outputs of pre-graduate education is the readiness of graduates for educative activities in favour of the National Programme of Health Support. (Tab. 1, Fig. 1, Ref. 7.)

Interactive dynamic system of didactic means in medical studies.

Didactic means are an integral part of teaching also in the process of healthcare and doctoral education. They are applied not only in teaching of theoretical, but also in that of clinical subjects at medical faculties. The forms and levels of the use of didactic aids are subject to a dynamic process of transformation. They take place in form of conceptions, projects, realizations, results and effects. A part of them represent a domain of professionals, others are affected by basically non-professional teachers. The results and effects are influenced by students. The authors of this study present the didactic means used at the Faculty Medicine of Comenius University (FMCU) in Bratislava. (Tab. 1, Ref. 11.).

Study of the content of heavy metals related to environmental load in urban areas in Slovakia.

UNLABELLED: It is natural for the man to take care of his environment so the negative influences of intensification of industrial and agricultural production and the entire process of pollution are kept at minimum or eliminated as early as possible. However, they must first be identified. BACKGROUND: companion animals, for example dogs, are a very good indicator of the pollution load on the environment. They inhabit the same space as humans and are exposed to the action of the same pollutants. The most important role in contamination of the environment with heavy metals is played by emissions of different origin. For that reason it is appropriate and advantageous to evaluate the load on the man by parallel evaluation of the heavy metal load on dogs, particularly in large town agglomerations. MAIN PURPOSE: the aim of the study was to compare and evaluate the content of three heavy metals, cadmium, arsenic and lead, in the hair of dogs from two largest town agglomerations of Slovakia, Bratislava and Kosice. In addition to that, an effort was made to compare the environmental load in Bratislava and Kosice by using the dog as a bioindicator of environmental pollution with heavy metals and to quantify the content of heavy metals in dog' hair. METHODS: The generally low level of heavy metals in biological material makes it impossible to use common analytical methods. In our study the samples of dog hair were analysed using the method of atomic absorption spectrometry. The measurements were carried out on a Perkin-Elmer spectrometer, model 5000, using the following wavelengths: 228.8 nm for Cd, 193.7 nm for As and 283.3 nm for Pb. The results of analyses are presented as means. The concentrations of Cd, As and Pb are expressed in microg/kg dog hair. Statistical evaluation of results was carried out by means of Student's t-test. RESULTS: The mean values of heavy metals in the set of dogs from Bratislava reached the following levels: 38.09 microg/kg for Cd, 111.07 microg/kg for As, and 729.59 microg/kg for Pb. The set of dogs from Kosice allowed us to detect the following mean values: 22.21 microg/kg for Cd, 79.87 microg/kg for As, and 542.49 microg/kg for Pb. The mean values for the entire Slovak territory reached 27.39 microg/kg for Cd, 90.06 microg/kg for As, and 601.96 microg/kg for Pb. The comparison of the first two experimental sets of data with the Slovak mean values showed highly significant differences in arithmetic means (p < 0.01) for Cd and significant (p < 0.05) for As with the Bratislava set reaching higher values. No statistically significant differences were observed with regard to Pb. CONCLUSION: The study confirms the need for further research in this area with the dog as a bioindicator involving also other environmental loads not only that resulting from heavy metals. It indicates the importance of risk assessment in relation to environmental pollution. As the studies on animals are applicable also to the human population it appears very appropriate to use also this indirect way to point out to the negative impact of the polluted environment. Lead, cadmium and arsenic are the heavy metals that raise particular concern because of their wide-spectrum negative influences on live organisms. (Tab. 4, Fig. 5, Ref 28.)

[Autologous transplantation of peripheral hematopoietic cells and subsequent maintenance therapy with interferon alpha or interferon alpha and dexamethasone in patients with multiple myeloma--results from the 4W randomized clinical trial of the Czech Myeloma Group]. / Autologní transplantace periferních hemopoetických bunek a následná udrzovací terapie interferonem alfa nebo interferonem alfa a dexamethasonem u nemocných s mnohocetným myelomem--prubezné výsledky randomizované klinické studie 4W Ceské myelomové skupiny.

In the clinical 4W study patients with newly diagnosed multiple myeloma are included where the state of the disease calls for treatment, while high dose chemotherapy is not contraindicated. Treatment according to protocol 4W comprises induction chemotherapy VAD, mobilization of haematopoietic cells (cyclophosphamide 5 g/m2). This is followed by autologous transplantation (as a conditioning regime melfalan 200 mg/m2 is administered). The patients are randomized into two groups, the first one is given interferon alpha as maintenance treatment, in the second group alternates cyclically interferon alpha and dexamethasone treatment. So far between 1996 and Aug. 31 2000 in the 4W clinical study 167 patients were included. 113 patients after transplantation were evaluated incl. 13 (12%) who achieved complete remission of the disease (absence of paraprotein, negative immunofixation), 63 patients (56%) with remission of the disease (decline of paraprotein, by more than 75%). Another 24 patients (21%) achieved partial remission (decline of paraprotein by more than 50% but less than 75%). The peritransplantation mortality is 2.67%. So far there is no significant difference between the two groups on maintenance treatment as regards the mean period before a relapse of the disease (p = 0.567). The median of the mean survival was not reached so far. The authors describe the results of the internal analysis of data incl. statistical processing.

[Cystatin C in estimates of glomerular filtration in patients with renal disease--initial experience]. / Cystatin C v odhadu glomerulární filtrace u pacientu s nemocemi ledvin, první zkusenosti.

Cystatin is reported in the literature with increasing frequency as a new reliable parameter for estimates of glomerular filtration. The authors examined cystatin C by the PET method of DAKO Co. in 151 patients from the nephrological out-patient clinic. 91 patients had normal renal functions, 60 suffered from renal insufficiency of different severity. Between cystatin C and glomerular filtration assessed by creatinine clearance was a close correlation, R = -0.787 according to Pearson. The authors evaluated separately a group of 36 patients with glomerulonephritis, 34 diabetic patients with diabetic nephropathy, 38 patients with tubulointerstitial nephritis and 43 subjects with other kidney diseases. The groups did not differ significantly when compared with the whole group nor mutually (p = n.s.). The authors of the study confirmed that a good correlation of cystatin with creatinine filtration is not influenced by the type of basic nephrological disease. The effect of administration of insulin, antihypertensive drugs, cyclosporin A and glucocorticoids was not proved in the investigated group. The published method is accurate, not demanding from the technical aspect. The examined subject is not restricted by conditions ensuring the accuracy of assessment and seems thus useful and perspective for nephrological patients.

[Treatment of multiple myeloma with high-dose chemotherapy and transplantation of autologous hematopoietic stem cells and subsequent maintenance therapy with interferon alfa-2b or interferon alfa 2b and dexamethasone. Report of the ongoing study of the "4W" Czech Myeloma Group]. / Lécba mnohocetného myelomu vysokodávkovanou chemoterapií s transplantací autologních kmenových hemopoetických bunek a následující udrzovací lécbou interferonem alfa-2b nebo interferonem alfa-2b a dexametazonem. Zpráva o probíhající studii "4w" Ceské myelomové skupiny.

We report our results with high-dose chemotherapy in previously untreated multiple myeloma patients (4 courses of VAD chemotherapy, collection of PBSC after priming with cyclophosphamide, 5 g/m2, high-dose chemotherapy with melphalan, 200 mg/m2). Second transplantation was indicated only for patients who did not achieve remission after the first high-dose therapy (paraprotein lower than 25% of the pretreatment value). For the second transplantation melphalan (200 mg/m2) with methylprednisolone (1.5 g for 5 days) were used as conditioning regimen. After high-dose therapy all patients were randomized into two arms of maintenance therapy: interferon alpha-2b or sequential maintenance therapy (interferon alpha-2b for 3 months followed after 4 week pause by 40 mg of dexamethasone days 1-4, 10-13 and 20-23. The administration of interferon alpha was resumed four weeks after the last dexamethasone for next three months. The maintenance therapy continued for 48 months or until the progression. Fifty-five patients were enrolled in the study from January 1996 to August 1997. Thirty-five patients have undergone the first transplantation and 57% of them reached complete remission. There were 10% of non-responders after the first high-dose regimen. The mean time to reach white blood cell count above 1 x 10(9)/L after the application of high dose melphalan and platelets more than 50 x 10(9)/L were 12.2 (range 6-16 days) and 12.4 (range 0-25 days), respectively. Grade 4 mucositis according to SWOG classification requiring total parenteral nutrition was presented in 40% of the patients. The mean number of 1 unit of platelets and 2 units of packed red blood cells transfusions were given within the posttransplant period. Early transplant related mortality was 3%. This paper describes the response and tolerance of each particular step of therapy. The follow-up has been too short to evaluate event-free and overall survivals.

[Difficulties in the therapy of primary amyloidosis]. / Obtízná lécba primární amyloidózy.

The therapy of primary amyloidosis is still unsatisfactory. The response rate after the cytostatics, dimethylsulphoxide, colchicin and vitamin E is usually low. None of these treatment modalities prolongs significantly the survival in majority of treated patients. The success of interferon alpha in the maintenance therapy of follicular non-Hodgkin's lymphoma and in the remission of multiple myeloma, as well as successful treatment of primary cryoglobulinaemia, brought us to the idea to test interferon alpha in the therapy of primary amyloidosis. Interferon alpha-2b was administered to the patient with three years history of primary amyloidosis. Interferon alpha was used in the dose of 3 x 10(6) daily for the treatment period of 10 weeks. The evaluation of the response was based on the weekly assessment of the light chain lambda concentration in the morning spot of urine. No significant decrease of the light chain concentration during the course of the therapy was observed. The administration of interferon alpha-2b was interrupted in the 10th week of the therapy because of manic psychosis. The question is, whether a higher dose than 3 x 10(6) IU daily would be able to decrease the light chain production, or if this disease is resistant to interferon alpha therapy. Because of the low incidence of primary amyloidosis, the experiences will be collected on the base of small groups of case reports.

[Lower cardiotoxicity of adriamycin during continuous administration in patients with refractory multiple myeloma treated with cyclophosphamide, vincristine, adriamycin and dexamethasone (C-VAD)]. / Nizsí kardiotoxicita adriamycinu pri kontinuálním podání u nemocných s refrakterním mnohocetným myelomem lécených cyklofosfamidem, vincristinem, adriamycinem a dexamethazonem (C-VAD).

Standard treatment of refractory myeloma is combined VAD treatment (vincristine, adriamycin and dexamethasone). In recent years adriamycin was sometimes replaced by mitoxanthrone which caused greater myelotoxicity. As a positive feature of the exchange of adriamycin for mitoxanthrone, authors using it, report its lower cardiotoxicity. In the literature there are, however, occasional reports on a lower cardiotoxicity of adriamycin when administered in a continuous infusion. In the submitted work the authors sought answers to two questions. 1. Is the cardiotoxicity of adriamycin administered in a continuous infusion lower than the cardiotoxicity of adriamycin administered as a bolus? 2. Is it possible to add to VAD chemotherapy cyclophosphamide without increasing the toxicity excessively? After echocardiographic evaluation of the diastolic and systolic function following a cumulative dose of 200 mg the authors observed smaller changes of the above functions in the group treated with adriamycin a in a continuous infusion (patients with multiple myeloma) than in the group with bolus therapy (patients with non-Hodgkin lymphomas and acute leukaemia). Addition of 600 mg cyclophosphamide on the 5th, 10th and 20th day to the classical VAD pattern made treatment more intensive without causing a deteriorated tolerance of this treatment.

[Lack of therapeutic effect on primary amyloidosis by interferon-alpha]. / Effektlose Therapie der primären Amyloidose mit Interferon alpha.

The therapy of primary amyloidosis is still unsatisfactory. The response rate after cytostatics, dimethylsulphoxide, colchicin and vitamin E is usually low. None of these treatment modalities prolongs significantly the survival in the majority of treated patients. The success of interferon alpha in the maintenance therapy of follicular non-Hodgkin's lymphoma and in the remission of multiple myeloma, as well as successful treatment of primary cryoglobulinemia, brought us to the idea to test interferon alfa in the therapy of primary amyloidosis. Interferon alpha-2b was administered to a patient with three years history of primary amyloidosis. Interferon alpha was used in the dose of 3 x 10(6) i. V. daily for a treatment period of 10 weeks. The evaluation of the response was based on the weekly assessment of the light chain lambda concentration in the morning spot of urine. No significant decrease of the light chain concentration during the course of the therapy was observed. The administration of interferon alpha-2b was interrupted in the 10th week of the therapy because of manic psychosis. The question is, whether a higher dose than 3 x 10(6) IU daily would be able to decrease the light chain production, or if this disease is resistant to interferon alpha therapy. Because of the low incidence of primary amyloidosis, the experiences will be collected on the base of small groups of case reports.

Treatment of refractory multiple myeloma with vincristine, adriamycin, dexamethasone, and with repeated application of cyclophosphamide (C-VAD).

The quick reduction of differentiated myeloma cells by VAD chemotherapy (vincristine, adriamycin, dexamethasone) causes, according to the investigation by Bell et al., the acceleration of the proliferation of myeloma stem cells. In 1990 Bell demonstrated that this proliferation could be stopped by administering 500 mg of cyclophosphamide in 1-week intervals. We therefore modified the classical VAD scheme to the following "C-VAD" scheme:vincristine 0.5 mg/day in continuous infusion on the first to the 4th day, adriamycin 9 mg/m2/day in continual infusion on the 1st to the 4th day, dexamethasone 40 mg p.o. or i.v. always on 4 days starting with the 1st, 10th and 20th days, cyclophosphamide 600 mg i.v. on the 5th, 10th and 20th days). A further cycle follows on the 28th day. In the present paper the effect and the tolerance of this C-VAD scheme is evaluated: In the group of 21 patients with refractory myeloma 9 remissions were achieved, 5 partial remissions, in 6 patients the disease progressed, 1 patient died after the 2nd cycle without the possibility of evaluating the therapeutic response. The mean remission length was 10.2 months. The tolerance of chemotherapy was satisfactory, C-VAD chemotherapy did not cause any serious drop in the number of leucocytes and thrombocytes. Echocardiographically lower adriamycin cardiotoxicity was demonstrated in continual administration in comparison with the bolus administration. The C-VAD scheme is considered to be suitable for comparison with the VAD chemotherapy in a randomized study.

[Determination of beta 2-microglobulin in the serum and cerebrospinal fluid using radial immunodiffusion (comparison with the Elisa Pharmacia method)]. / Stanovení beta 2-mikroglobulinu v séru a likvoru metodou radiální imunodifuze. (Srovnání s referencní metodou Elisa Pharmacia)

The authors elaborated a method of radial immunodiffusion for assessment of beta 2-microglobulin serum and cerebrospinal fluid levels in patients. The method is based on a modified procedure of staining and decolouration. The antibody produced by USOL Co. which was used for the purpose was not modified. Comparison of 90 sera and 27 cerebrospinal fluid samples where also the reference method ELISA Pharmacia was used revealed almost absolute agreement, the correlation coefficient was 0.98. The method is used for clinical monitoring in patients with myelomas and renal insufficiencies.