a1_In a series of studies in the late 1950s and early 1960s, Jan Bures introduced cortical spreading depression to the field of behavioral neuroscience (eg. Bures 1960). This technique offered a unique way to study the role of cortex in learning and memory, and attracted the attention of many who began their graduate studies at that time, including one of us (LN, cf. Nadel 1966). An NIH postdoctoral fellowship to study with the master himself brought LN to Prague in September 1967. Thus began a relationship that included science, politics, and personal life, and has lasted over 30 years1,2. The first scientific exchange began with Jan pulling a piece of paper from his desk with a long list of possible experiments written on it -- “pick one”, he said. This led to a series of studies on interhemispheric transfer of learning under conditions of monocular input, demonstrating, amongst other things, that such transfer is not a uniform process. Depending on the kind of trials given with both hemispheres intact, and the eye which remained open to input, transfer can either be non-specific, likely involving some kind of procedural knowledge, or highly specific, likely involving knowledge about the trained discrimination itself (Nadel and Buresova, 1970). These studies anticipated LN’s future work on multiple memory systems, a research enterprise pursued in the following decades by many labs (including LN’s: e.g. Nadel and O’Keefe 1974, O’Keefe et al. 1975). In this paper we focus on several scientific issues that Jan has been thinking about for the past 25 years. In particular, we consider spatial learning, the hippocampus, and memory. To this mix we add stress, something well known to anyone living in Prague in 1968., a2_LN left Prague after the 1968 invasion and stayed in London for seven months, during which time arrangements were made for an eventual return to the Medical Research Council Cerebral Functions Research Group in 1970. Thus it was that LN happened to be down the hall when John O’Keefe and Jonathan Dostrovsky discovered place cells (O’Keefe and Dostrovsky 1971) and began the program of research leading to the cognitive map theory of hippocampal function (O’Keefe and Nadel 1978)., L. Nadel, J.D. Payne., and Obsahuje bibliografii
The relationship is shown between a concentration of urinary iodine and serum thyroglobulin in population studies carried out on a general population that was randomly selected from the registry of the General Health Insurance Company (individuals aged 6-98 years, 1751 males, 2420 females). The individuals were divided into subgroups with a urinary iodine concentration of <50, 50-99, 100-199, 200-299 and ≥300 μg/l. The mean and median of thyroglobulin were calculated in these subgroups. Tg concentrations were dependent on gender (males<females), age (thyroglobulin increased with age) and statistically significant negative relationship was observed between thyroglobulin and urinary iodine in individuals with urinary iodine <300 μg/l and the age under 65 years. Upper nonparametric tolerance limits of thyroglobulin in relation to iodine intake were calculated in subgroup of normal individuals (n=1858, thyroglobulin, urinary iodine, thyrotropin and free thyroxine were within the normal reference range). Upper limits were dependent on gender and age. The total value of upper limits is 44 μg/l; for individuals aged 6-17 years it is 39.1 μg/l; 18-65 years = 51.4 μg/l and 66-98 years = 60.6 μg/l. In general, thyroglobulin serum concentrations higher than 40 μg/l should be an indicator for determining urinary iodine., R. Bílek, J. Čeřovská, V. Zamrazil., and Obsahuje bibliografii
The system of IGF-I and its binding proteins may be involved in the pathogenesis of vascular damage in Type 1 diabetes. The aim of this study was to analyze the relationship between this system and the microvascular reactivity in Type 1 diabetes as measured by laser-Doppler flowmetry. Twenty-two Type 1 diabetic patients (13 women and 9 men) with microangiopathy and fifteen healthy subjects (8 women and 7 men) were examined clinically, underwent laser-Doppler flowmetry and intima-media thickness measurements. Fasting serum levels of IGF-I, free IGF-I, IGFBPs and lipids were examined. The microvascular reactivity was impaired in Type 1 diabetic patients. Maximal perfusion during post-occlusive reactive hyperemia (PORHmax) and during thermal hyperemia (THmax) was significantly decreased in Type 1 diabetes (p<0.01). Percentage perfusion increase in both tests (PORH and TH) was lower in Type 1 diabetes mellitus (p<0.01) and the reaction after heating was slower in diabetic patients (THmax/t) (p<0.01). We did not find any significant dependence of microvascular reactivity on the parameters of IGF-I or its binding proteins. We conclude that the microvascular reactivity is impaired in Type 1 diabetes mellitus, but this impairment is not clearly dependent on the activity of the IGF-I system. It is probably only a complementary pathogenic factor., M. Kršek, M. Prázný, J. Škrha, V. Justová, Z. Lacinová, T. Haas., and Obsahuje bibliografii
We introduce a new magnetic resonance (MR) method based on a pixel-by-pixel image processing to examine relationships between metabolic and structural processes in the pathologic hippocampus. The method was tested for lateralization of the epileptogenic zone in patients with temporal lobe epilepsy (TLE). Twenty patients with drug-resistant TLE and fifteen healthy controls were examined at 3T. The measurement protocol contained T2-weighted MR images, spectroscopic imaging, diffusion tensor imaging and T2 relaxometry. Correlations between quantitative MR parameters were calculated on a pixelby- pixel basis using the CORIMA program which enables automated pixel identification in the normal tissue according to control data. All MR parameters changed in the anteroposterior direction in the hippocampus and correlation patterns and their slopes differed between patients and controls. Combinations of T2 relaxation times with metabolite values represent the best biomarkers of the epileptogenic zone. Correlations with mean diffusivity did not provide sufficiently accurate results due to diffusion image distortions. Quantitative MR analysis noninvasively provides a detailed description of hippocampal pathology and may represent complementary tool to the standard clinical protocol. However, the automated processing should be carefully monitored in order to avoid possible errors caused by MR artifacts., D. Wagnerová, V. herynek, M. Dezortová, P. Marusič, P. Kršek, J. Zámečník, F. Jírů, A. Škoch, M. Hájek., and Obsahuje bibliografii
To understand the pathogenesis of hypercholesterolemia in Prague hereditary hypercholesterolemic (PHHC) rat, we analyzed the response of hepatic transcriptome to dietary cholesterol in PHHC and control Wistar rats. Male PHHC and Wistar rats were fed chow (C), 5 % fat (palm kernel oil) (CF) or 1 % cholesterol + 5 % fat (CHOL) diet for three weeks. Hepatic transcriptome was analyzed using Affymetrix GeneChip arrays. No differences were found in the effect of both control diets (C and CF) on lipid metabolism and gene expression of 6500 genes. Therefore, these data were pooled for further analysis. Dietary cholesterol induced accumulation of cholesterol and triacylglycerols in the liver in both strains and hypercholesterolemia in PHHC rats. However, there were no differences in response of hepatic transcriptome to CHOL diet. On the other hand, several genes were found to be differently expressed between both strains independently of the diet. Two of those genes, Apof and Aldh1a7, were studied in more detail, and their role in pathogenesis of hypercholesterolemia in PHHC rats could not been corroborated. In conclusion, the hypercholesterolemia in PHHC rats is due to physiological response of hepatic transcriptome to dietary cholesterol in different genetic background., M. Vlachová, M. Heczková, M. Jirsa, R. Poledne, J. Kovář., and Obsahuje bibliografii
Numerous hypotheses have been proposed about the pathogenesis of the polycystic ovarian syndrome (PCOS). However, hormonal control of persistent follicles has not be enestablished. The objective of the present study was to compare the follicular structure and hormonal profiles of rats treated with the adrenocor ticotrophic hormone (ACTH) with two experimental models of PCOS. ACTH-treated animals were compared with those exposed to continuous light, those treated with estradiol valerate, and with control (in proestrous and diestrous). Serum hormone levels, histomorphometrical changes, and immunoexpression of vimentin, cytokeratins, cadherins, and proliferating cell nuclear antigen (PCNA) were examined. Treatment with ACTH resulted in an elevation of corticosterone secretion with LH reduction but without changes in ovarian morphology. Although stress (or ACTH) stimulation may be only one of pathophysiological mechanisms involved in follicular cystathogenesis in other species, we do not have important evidence to suppose that this would happen in rats., C. Bavaralle, N. R. Salvetti, G. A. Mira, J. A. Lorente, H. H. Ortega., and Obsahuje bibliografii a bibliografické odkazy
Carbon dioxide interacts both with reactive nitrogen species and reactive oxygen species. In the presence of superoxide, NO reacts to form peroxynitrite that reacts with CO2 to give nitrosoperoxycarbonate. This compound rearranges to nitrocarbonate which is prone to further reactions. In an aqueous environment, the most probable reaction is hydrolysis producing carbonate and nitrate. Thus the net effect of CO2 is scavenging of peroxynitrite and prevention of nitration and oxidative damage. However, in a nonpolar environment of membranes, nitrocarbonate undergoes other reactions leading to nitration of proteins and oxidative damage. When NO reacts with oxygen in the absence of superoxide, a nitrating species N2O3 is formed. CO2 interacts with N2O3 to produce a nitrosyl compound that, under physiological pH, is hydrolyzed to nitrous and carbonic acid. In this way, CO2 also prevents nitration reactions. CO2 protects superoxide dismutase against oxidative damage induced by hydrogen peroxide. However, in this reaction carbonate radicals are formed which can propagate the oxidative damage. It was found that hypercapnia in vivo protects against the damaging effects of ischemia or hypoxia. Several mechanisms have been suggested to explain the protective role of CO2 in vivo. The most significant appears to be stabilization of the iron-transferrin complex which prevents the involvement of iron ions in the initiation of free radical reactions., A. Veselá, J. Wilhelm., and Obsahuje bibliografii
a1_Vascular resistance in the mammalian pulmonary circulation is affected by many endogenous agents that influence vascular smooth muscle, right ventricular myocardium, endothelial function, collagen and elastin deposition, and fluid balance. When the balance of these agents is disturbed, e.g. by airway hypoxia from high altitude or pulmonary obstructive disorders, pulmonary hypertension ensues, as characterized by elevated pulmonary artery pressure (PPA). Among neuropeptides with local pulmonary artery pressor effects are endothelin-1 (ET-1), angiotensin II (AII), and substance P, and among mitigating peptides are calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), atrial natriuretic peptide (ANP), vasoactive intestinal peptide (VIP) and ET-3. Moreover, somatostatin28 (SOM28) exacerbates, whereas SOM14 decreases PPA in hypoxic rats, with lowering and increasing of lung CGRP levels, respectively. Pressure can also be modulated by increasing or decreasing plasma volume (VIP and ANP, respectively), or by induction or suppression of vascular tissue remodeling (ET-1 and CGRP, respectively). Peptide bioavailability and potency can be regulated through hypoxic up- and down- regulation of synthesis or release, activation by converting enzymes (ACE for AII and ECE for ET-1), inactivation by neutral endopeptidase and proteases, or by interaction with nitric oxide (NO). Moreover, altered receptor density and affinity can account for changed peptide efficacy. For example, upregulation of ETA receptors and ET-1 synthesis occurs in the hypoxic lung concomitantly with reduced CGRP release. Also, receptor activity modifying protein 2 (RAMP2) has been shown to confer ADM affinity to the pulmonary calcitonin-receptor-like receptor (CRLR). We recently detected the mRNA encoding for RAMP2, CRLR, and the CGRP receptor RDC-1 in rat lung., a2_The search for an effective, lung selective treatment of pulmonary hypertension will likely benefit from exploring the imbalance and restoring the balance between these native modulators of intrapulmonary pressure. For example, blocking of the ET-1 receptor ETA and vasodilation by supplemental CGRP delivered i. v. or via airway gene transfer, have proven to be useful experimentally., I. M. Keith., and Obsahuje bibliografii
Recent studies focused on epicardial fat, formerly relatively neglected component of the heart, have elucidated some of its key roles. It possesses several properties that can distinguish it from other adipose tissue depots. Its unique anatomical location in the heart predisposes the epicardial fat to be an important player in the physiological and biochemical regulation o f cardiac homeostasis. Obesity is associated with an increase in epicardial fat mass. Excess of cardiac fat can contribute to greater left ventricular mass and work, diastolic dysfunction and attenuated septal wall thickening. Imbalance in adipokines levels secreted in autocrine or paracrine fashion by epicardial fat can contribute to the activation of the key atherogenic pathways in the setting of metabolic syndrome. Epicardial fat has also been identified as an important source of pro-inflammatory mediato rs worsening endothelial dysfunction, eventually leading to coronary artery disease. Increased production of pro-inflammatory factors by epicardial fat can also contribute to systemic insulin resistance in patients undergoing cardiac surgery. Here we revie w the most important roles of epicardial fat with respect to heart disease in the context of other underlying pathologies such as obesity and type 2 diabetes mellitus., Z. Matloch, T. Kotulák, M. Haluzík., and Obsahuje bibliografii
Ferritin and increased iron stores first appea red on the list of cardiovascular risk factors more than 30 years ago and their causal role in the pathogenesis of atherosclerosis has been heavily discussed since the early 1990s. It seems that besides traditional factors such as hyperlipoprotein emia, hyp ertension, diabetes mellitus, obesity, physical inactivity, smoking and family history, high iron stores represent an additional parameter that could modify individual cardiovascular risk. The role of iron in the pathogenesis of atherosclerosis was origina lly primarily associated with its ability to cataly ze the formation of highly reactive free oxygen radicals and the oxidation of atherogenic lipoproteins. Later, it became clear that the mechanism is more complex. Atherosclerosis is a chronic fibroprolife rative inflammatory process and iron, through increased oxidation stress as well as directly, can control both native and adaptive immune responses. Within the arterial wall, iron affects all of the cell types that participate in the atherosclerotic proces s (monocytes/macrophages, endothelial cells, vascular smooth muscle cells and platelets). Most intracellular iron is bound in ferritin, whereas redox-active iron forms labile iron pool. Pro-inflammatory and anti-inflammatory macrophages within arterial plaque differ with regard to the amount of intracellular iron and most probably with regard to their labile iron pool. Yet, the relation between plasma ferritin and intracellular labile iro n pool has not been fully clarified. Data from population studies document that the consumption of meat and lack of physical activity contribute to increased iron stores. Patients with hereditary h emochromatosis, despite extreme iron storage, do not show i ncreased manifestation of atherosclerosis probably due to the low expression of hepcidin in macrophages., P. Kraml., and Obsahuje bibliografii