Each cell types or tissues contain certain “physiological” levels of R-2-hydroxyglutarate (2HG), as well as enzymes for its synthesis and degradation. 2HG accumulates in certain tumors, possessing heterozygous point mutations of isocitrate dehydrogenases IDH1 (cytosolic) or IDH2 (mitochondrial) and contributes to strengthening their malignancy by inhibiting 2-oxoglutaratedependent dioxygenases. By blocking histone de-methylation and 5-methyl-cytosine hydroxylation, 2HG maintains cancer cells de-differentiated and promotes their proliferation. However, physiological 2HG formation and formation by non-mutant IDH1/2 in cancer cells were neglected. Consequently, low levels of 2HG might play certain physiological roles. We aimed to elucidate this issue and found that compared to highest 2HG levels in hepatocellular carcinoma HepG2 cells and moderate levels in neuroblastoma SH-SY5Y cells, rat primary fibroblast contained low basal 2HG levels at early passages. These levels increased at late passage and likewise 2HG/2OG ratios dropped without growth factors and enormously increased at hypoxia, reaching levels compared to cancer HepG2 cells. Responses in SH-SY5Y cells were opposite. Moreover, external 2HG supplementation enhanced fibroblast growth. Hence, we conclude that low 2HG levels facilitate cell proliferation in primary fibroblasts, acting via hypoxia-induced factor regulations and epigenetic changes., A. Dvořák, J. Zelenka, K. Smolková, L. Vítek, P. Ježek., and Obsahuje bibliografii
Baroreflex control of heart rate was studied in inbred salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) Dahl rats that were subjected to chronic dietary sodium chloride loading (for 4 weeks) either in youth or only in adulthood, i.e. from the age of 4 or 12 weeks. Using phenylephrine administration to pentobarbital-anesthetized male rats we have demonstrated the decreased baroreflex sensitivity (lower slope for reflex bradycardia) in young prehypertensive SS/Jr rats fed a low-salt diet as compared to age-matched SR/Jr animals. High salt intake further suppressed baroreflex sensitivity in young SS/Jr but not in SR/Jr rats. Baroreflex sensitivity decreased with age in SR/Jr rats, whereas it increased in SS/Jr rats fed a low-salt diet. Thus at the age of 16 weeks baroreflex sensitivity was much higher in SS/Jr than in SR/Jr animals. High salt intake lowered baroreflex sensitivity even in adult SS/Jr rats without affecting it in adult SR/Jr rats. Nevertheless, baroreflex sensitivity was significantly lower in young SS/Jr rats with a severe salt hypertension than in adult ones with a moderate blood pressure elevation. It is concluded that the alterations of baroreflex sensitivity in young inbred SS/Jr rats (including the response to high salt intake) are similar to those described earlier for outbred salt-sensitive Dahl rats. We have, however, disclosed contrasting age-dependent changes of baroreflex sensitivity in both inbred substrains of Dahl rats., J. Nedvídek, J. Zicha., and Obsahuje bibliografii
1a_It has been known for many years that baroreflex sensitivity is lowered in hypertensive patients. There are several known factors implicating this association, e.g. high blood pressure leads to remodeling of the carotid arterial wall, to its stiffness and to a diminished activation of baroreceptors; leptin released from a fatty tissue activates the sympathetic nervous system etc. On the other hand, low baroreflex sensitivity (BRS, usually quantified in ms/mmHg) can be inborn. Studies on primary hypertension in children and adolescents have brought new information about the role of baroreflex in the development of an early stage of primary hypertension. BRS lower than 3.9 ms/mmHg was found in 5 % of healthy subjects. This value approaches the critical value for the risk of sudden cardiac death in patients after myocardial infarction and corresponds to the value present in hypertensive patients. A decreased BRS and BRSf (baroreflex sensitivity expressed in mHz/mmHg, index independent of the mean cardiac interval), was found not only in children with hypertension, but also in those with white-coat hypertension. This is in accordance with a single interpretation. The decrease of BRS/BRSf precedes a pathological blood pressure increase., 2a_The contribution of obesity and BRS/BRSf to the development of hypertension in adolescents was also compared. Both factors reach a sensitivity and a specificity between 60 % and 65 %, but there is no correlation between the values of the body mass index and BRS either in the group of hypertensive patients or in healthy controls. If a receiver operating curve (sensitivity versus specificity) is plotted for both values together using logistic regression analysis, a sensitivity higher than 70 % and a specificity over 80 % are reached. This means that low baroreflex sensitivity is an independent risk factor for the development of primary hypertension. Studies demonstrate that adolescents with increased blood pressure and with BRS under 7 ms/mmHg should be given care and intensively motivated to change their lifestyle including a change in diet and increase in physical activity., and N. Honzíková, B. Fišer.
Sympathetic overactivity and low parasympathetic activity is an autonomic dysfunction (AD) which enhances cardiac mortality. In the present study, the impact of AD on the mortality in patients after myocardial infarction was evaluated. We examined 162 patients 7-21 days after myocardial infarction, 20 patients of whom died in the course of two years. Baroreflex sensitivity (BRS) was estimated by spectral analysis of spontaneous fluctuations of systolic blood pressure and cardiac intervals (Finapres, 5 min recording, controlled breathing 20/min). The heart rate variability was determined as SDNN index (mean of standard deviations of RR intervals for all 5-min segments of 24-hour ECG recordings). BRS < 3 ms/mm Hg and/or SDNN index < 30 ms were taken as markers of AD. The risk stratification was performed according to the number of the following standard risk factors of increased risk of cardiac mortality (SRF): ejection fraction < 40 %, positive late potentials and the presence of ventricular extrasystoles > 10/h. No difference in mortality between patients with AD (4 %) and without AD (4.5 %) was found in 92 patients without SRF, the mortality in 6 patients with three SRF was 66.6 %. Five of these patients had AD. Out of 64 patients with one or two SRF, 32 had AD. The mortality of patients without AD was 6.25 % and 31.2 % of those with AD (p<0.025). It is concluded that AD enhanced two-years mortality five fold in our patients with moderate risks., N. Honzíková, B. Semrád, B. Fišer, R. Lábrová., and Obsahuje bibliografii
At present, there are insufficient information about baroreflex sensitivity (BRS) and factors that determine BRS in premature newborns. The objective of this study was to determine the relationship between BRS and the characteristics that reflecting the intrauterine development (gestational age and birth weight), as well as postnatal development (postconception age and the actual weight of the child at the time of measurement). We examined 57 premature infants, who were divided into groups according to gestational age and postconception age as well as birth weight, and weight at the time of measurement. Continuous and noninvasive registration of peripheral blood pressure (BP) was perf ormed in every child within 2-5 m in under standard conditions using a Portapres (FMS) device. The results showed a close correlation of baroreflex sensitivity, heart rate and respiratory rate with gestational age, postconception age, birth weight and actual weight at the time of measureme nt premature newborns. An increase in the characteristics (ages and weights) resulted in increased BRS and diastolic arterial pressure (DAP), and in decreased heart and respiratory rates. Baroreflex sensitivity in the first week was in the group of very premature newborns the lowest (4.11 ms/mmHg) and in the light premature newborns was almost double (8.12 ms/mmHg). BRS increases gradually in relation to postnatal (chronological) and to postconception age as well as to birth and actual weight. The multifact or analysis of BRS identified birth weight and postconception age as the best BRS predictors. The two independent variables together explained 40 % of interindividual BRS variability., K. Haskova, M. Javorka, B. Czippelova, M. Zibolen, K. Javorka., and Obsahuje bibliografii
Prenatal exposure to methamphetamine (METH) increases nociceptive sensitivity in adult rats. As the strong analgesics have high abuse potential and drugs of abuse are known to have analgesic properties, the aim was to study analgesic effect of different psychostimulants in control and prenatally METHexposed rats. Latencies of withdrawal reflexes of hind limbs and the tail on thermal nociceptive stimuli were repeatedly measured in 15-min intervals after the application of 5 mg/kg s.c. of amphetamine (AMPH), methamphetamine (METH), cocaine (COC), 3,4-methylenedioxymethamphetamine (MDMA) or morphine (MOR). In all groups, AMPH induced on hind limbs stronger analgesia than METH and MDMA whereas COC and MOR were practically without any effect. On the tail, effect of AMPH did not differ from that of MOR. All psychostimulants increased defecation in comparison with MOR and in all groups the number of defecation boluses positively correlated with analgesia of the hind limbs. We did not confirm that prenatal exposure to METH makes adult rats more sensitive either to same drug or to other psychostimulants. The different analgesic potencies of psychostimulants and MOR at different body sites indicate the possible existence of a somatotopic organization of pain inhibition, which is controlled by different mechanisms., A. Yamamotová, R. Šlamberová., and Obsahuje seznam literatury
The study investigated whether specific changes in phase synchrony in the beta 2 frequency band of EEG (25-35 Hz) occurred during a recognition task. The level of synchrony was examined between one hundred and eighty loci in the frontal and temporal lobes of eight epileptic patients with intracerebral electrodes; the EEG records were obtained during a visual oddball task. In each pair of records, the correlation curves were created from the sequence of correlation coefficients calculated. These curves consisted of irregular oscillations between the maximal and minimal r-values. Transient highly synchronized activity was observed during the whole time course of the experiment in all record pairs investigated and a significant relationship was found between the number of such episodes and the mean correlation coefficient (Spearman R 0.84; N 3240; p<0.001). On averaged curves, which were calculated using stimulus onsets as the trigger of averaging, a significant increase of the mean correlation coefficient in the post-stimulus epoch was found (p<0.01 after both target and non-target stimuli; t-test for dependent samples). As the cognitive demand significantly increases after stimulus presentation, the results are considered to be the first evidence from intracranial recording of increased synchronization in the beta 2 frequency band related to the cognitive activity., M. Kukleta ... [et al.]., and Obsahuje seznam literatury
In this study, we focused on an analysis of biguanides effects on mitochondrial enzyme activities, mitochondrial membrane potential and membrane permeabili ty transition pore function. We used phenformin, which is more efficient than metformin, and evaluated its effect on rat liver mitochondria and isolated hepatocytes. In contrast to prev iously published data, we found that phenformin, after a 5 min pr e-incubation, dose-dependently inhibits not only mitochondrial complex I but also complex II and IV activity in isolated mitochondria. The enzymes complexes inhibition is paralleled by the decreased respiratory control index and mitochondrial membrane potent ial. Direct measurements of mitochondrial swelling revealed that phenformin increases the resistance of the permeability transition pore to Ca 2+ ions. Our data might be in agreement with the hypothesis of Schäfer (1976) that binding of biguanides to membrane phospholipids alters membrane properties in a non-specific manner and, subsequently, different enzyme activities are modified via lipid phase. However, our measurements of anisotropy of fluorescence of hydrophobic membrane probe diphenylhexatriene have not shown a measurable effect of membrane fluidity with the 1 mM concentration of phenformin that strongly inhibited complex I activity. Our data therefore suggest that biguanides could be considered as agents with high efficacy but low specifity., Z. Drahota ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
The incidence of diabetes mellitus is rising worldwide. The aim of this prospective epidemiological study was to compare the effects of natural and surgical menopause on parameters of glucose metabolism. In a group of 587 repeatedly examined women, with a baseline age of 45-55 years, the following subgroups of women were separated: those after bilateral oophorectomy (BO, n=37) and those in natural menopause (NAT, n=380) including women menopausal already at baseline (POST, n=89). The study parameters including glycemia, insulinemia, HOMA-IR and betacell function using HOMA-β were determined at baseline and 6 years later. Over the study period, there was a marked rise in prediabetic and diabetic values of fasting glycemia; the percentage of women with diabetic values increased in the NAT (from 0.8 % to 3.9 %) and POST (from 2.2 % to 9.0 %) subgroups, with the highest prevalence in the BO subgroup (from 8.1 % to 10.8 %). While, among women with non-diabetic fasting glycemia, an increase in fasting glycemia was observed in all study subgroups, it was more marked in the BO subgroup than in the NAT and POST ones (p=0.02 both). This difference between NAT and BO was also found in the long-term trend of development of glycemia in non-diabetic women (p=0.014). Compared with natural menopause, bilateral oophorectomy may have an adverse effect on glucose metabolism., M. Lejsková, J. Piťha, S. Adámková, O. Auzký, T. Adámek, E. Babková, V. Lánská, Š. Alušík., and Obsahuje bibliografii
The complex architecture of the liv er biliary network represents a structural prerequisite for the formation and secretion of bile as well as excretion of toxic substances through bile ducts. Disorders of the biliary tract affect a significant portion of the worldwide population, often leading to cholestatic liver diseases. Cholestatic liver disease is a condition that results from an impairment of bile formation or bile flow to the gallbladder and duodenum. Cholestasis leads to dramatic changes in biliary tree architecture, worsening liver disease and systemic illness. Recent studies show that the preva lence of cholestatic liver diseases is increasing. The availability of well characterized animal models, as well as development of visualization approaches constitutes a critical asset to develop novel pathogenetic concepts and new treatment strategies., L. Sarnova, M. Gregor., and Obsahuje bibliografii