Atrial fibrillation: Epigenetic aspects and role of sodium-glucose cotransporter 2 inhibitors.

Atrial fibrillation (AF) is the most frequent arrhythmia and is associated with substantial morbidity and mortality. Pathophysiological aspects consist in the activation of pro-fibrotic signaling and Ca2+ handling abnormalities at atrial level. Structural and electrical remodeling creates a substrate for AF by triggering conduction abnormalities and cardiac arrhythmias. The care of AF patients focuses predominantly on anticoagulation, symptoms control and the management of risk factors and comorbidities. The goal of AF therapy points to restore sinus rhythm, re-establish atrioventricular synchrony and improve atrial contribution to the stroke volume. New layer of information to better comprehend AF pathophysiology, and identify targets for novel pharmacological interventions consists of the epigenetic phenomena including, among others, DNA methylation, histone modifications and noncoding RNAs. Moreover, the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in diabetic and non-diabetic patients at cardiovascular risk as well as emerging evidence on the ability of SGLT2i to modify epigenetic signature in cardiovascular diseases provide a solid background to investigate a possible role of this drug class in the onset and progression of AF. In this review, following a summary of pathophysiology and management, epigenetic mechanisms in AF and the potential of sodium-glucose SGLT2i in AF patients are discussed.

Acute medication poisoning causing hospital admissions in childhood: a 3-year prospective observational single-center study.

Although the risks of medication poisoning in children are often reported, there is a lack of studies addressing this issue. The majority of papers deal with a wide range of xenobiotics poisoning and, in particular, alcohol intoxications. All hospital admissions during three years were prospectively recorded. Patients younger than 19 years of age admitted for acute drug intoxications were further evaluated. A total of 15,069 children were admitted. Of them, 55 were hospitalized for acute medication poisoning. The condition was more common in girls (72.7 % vs. 27.3 %, p<0.01). Toddlers were the largest patient group (36.4 %). Non-steroidal anti-inflammatory drugs (NSAIDs) were the most frequently used agents, with ibuprofen being the leading drug (20 % of all cases). The route of intoxication was almost exclusively oral. Solid drug forms were involved in 40 (72.7 %) cases. There was one fatal accidental poisoning. The highest occurrence of accidental drug intoxications was in the age group from one to three years. Attempted suicides were most frequent among adolescents. We are currently actively dealing with the issue. The cohort has been expanded to include a period of ten years and is being analyzed.

Radiotherapy in lymphoepithelioma-like carcinoma of the skin: review of the literature and report of a recurrent and metastatic case.

Primary lymphoepithelioma-like carcinoma of the skin (LELCS) is a very rare cutaneous neoplasm. Only about 70 cases have been documented in the literature. There are no prospective data regarding treatment methods. Surgical excision is sufficient therapy in the majority of cases. Radiation therapy is sometimes used in case of recurrence or positive margins after surgery. The metastatic potential of LELCS is extremely low and only five previously documented cases of lymph node spread have been reported. We present the case of an 80-year-old male with a tumor primarily located on the lower eyelid, with two regional recurrences and cervical lymph node spread after surgery, treated with concurrent chemoradiation. According to the available data, this is the first case of lymph node spread from an eyelid location and the first nodal recurrence after surgery.

Prognostic factors in patients with T1 glottic cancer treated with radiotherapy.

PURPOSE: Presentation of long-term results of radiation treatment in patients with T1 glottic cancer and evaluation of prognostic factors. METHODS: We performed a retrospective analysis in a group of 569 patients with T1 squamous cell glottic carcinoma treated with radiotherapy at the Center of Oncology in Cracow between 1977 and 2007. In all, 503 (88%) patients presented with T1a stage disease and 66 (12%) with T1b. Anterior commissure infiltration was present in 179 (31%) patients. Average hemoglobin level prior to therapy was 13.9 g/dl. Using the body mass index (BMI), 114 (20%) patients were underweight, and 91 (16%) were overweight. Median time between collecting tumor specimen and beginning of radiotherapy was 56 days (range 14-145 days). Treatment regimen was normofractionated with single fraction ≤2 Gy in 102 (18%) and hypofractionated in 467 (82%) patients. RESULTS: The 5­ and 10-year overall survival (OS), disease-specific survival (DSS) and local control (LC) rates were 85 and 68%, 88 and 86%, 89 and 87%, respectively. Multivariate analysis showed that tobacco smoking, low hemoglobin level (<13 g/dl), anterior commissure infiltration, fraction dose ≤2 Gy and time from collecting specimen to beginning of therapy longer than 30 days had negative impact on LC and DSS. Patients' age over 60 years, worse performance status and malnutrition (BMI <18.5) had negative impacts on OS. CONCLUSIONS: Radiotherapy is a highly effective treatment method in patients with T1N0M0 glottic cancer. LC and DSS may be improved following hypofractionation, smoking cessation, and shortening of waiting-time until start of treatment. OS was mainly influenced by nutritional and performance status.

[Pharmacokinetics of carbapenems]. / Farmakokinetika karbapenemu

Carbapenems, beta-lactam antibiotics, are ideal candidates for the treatment of serious nosocomial infections including sepsis for their exceptionally broad antibacterial spectrum and high efficiency. They are administered parenterally by intravenous infusion. Carbapenems penetrate well and rapidly into many different tissue compartments and the interstitial fluid. They are metabolized by renal dihydropeptidase-1. Therefore, imipenem must be co-administered with an inhibitor of dihydropeptidase-1. Other carbapenems registered in the Czech Republic (meropenem, ertapenem and doripenem) are more stable to this enzyme. Carbapenems are mainly eliminated via the kidneys and dose adjustment in patients with renal impairment is necessary. The elimination half-life of most carbapenems is around 1 hour with the exception of ertapenem, with 3.8-hour half-life, which allows its once-daily use. Carbapenems are a group of antibiotics with time-dependent effect. Their typical pharmaceutical property is a limited stability in solution after dilution. Administration in the prolonged infusion appears to be a convenient strategy to achieve higher efficiency. Pharmacokinetic parameters of carbapenems may vary individually, especially in critically ill patients and those treated by renal replacement therapy. Therefore, individualization of dosing regimens based on knowledge of pharmacokinetic parameters of individual patients may be useful.

Resident cardiac stem cells.

The introduction of stem cells in cardiology provides new tools in understanding the regenerative processes of the normal and pathologic heart and opens new options for the treatment of cardiovascular diseases. The feasibility of adult bone marrow autologous and allogenic cell therapy of ischemic cardiomyopathies has been demonstrated in humans. However, many unresolved questions remain to link experimental with clinical observations. The demonstration that the heart is a self-renewing organ and that its cell turnover is regulated by myocardial progenitor cells offers novel pathogenetic mechanisms underlying cardiac diseases and raises the possibility to regenerate the damaged heart. Indeed, cardiac stem progenitor cells (CSPCs) have recently been isolated from the human heart by several laboratories although differences in methodology and phenotypic profile have been described. The present review points to the potential role of CSPCs in the onset and development of congestive heart failure and its reversal by regenerative approaches aimed at the preservation and expansion of the resident pool of progenitors.

Acute cholestatic hepatitis induced by fenofibrate.

We report a case of acute liver injury probably due to fenofibrate. A 50-year-old female without a history of liver disease developed cholestatic hepatitis during her second week of fenofibrate treatment. Laboratory tests on admission showed serum bilirubin 534.0 mcmol/L (conjugated 444.0), alkaline phosphatase (AP) 8.76, gamma-glutamyl traspeptidase (GGT) 20.92, alanine aminotransferase (ALT) 2.6, aspartate aminotransferase (AST) 3.64 mckat/L. Fenofibrate withdrawal and ursodeoxycholic acid (750 mg daily) administration was rapidly followed by a favourable outcome.

New laboratory markers in diagnosis of alzheimer dementia.

OBJECTIVES: The aim of our work was to assess the role of tau protein, beta amyloid and cystatin C in diagnosis of Alzheimer dementia (AD) and other neurodegenerative diseases (NDs). METHODS: The levels of tau protein, beta amyloid and cystatin C were assessed in a set of 79 patients with ND (38 men and 41 women; aged 22-90 years; mean, 61.6 +/- 15.6 years) and in a control group of 79 subjects with a healthy central nervous system (38 men and 41 women; aged 20-91 years; mean, 61.5 +/- 15.1 years). RESULTS: When compared with the subjects in the control group, a statistically significant decrease in tau protein levels was found in patients with ND, an increase in tau protein levels in patients with AD and an increase in cystatin C cerebrospinal fluid/serum index in the ND + AD group. DISCUSSION: Our work only confirmed the previously reported results in part. Although tau protein seems to be a quite reliable marker of AD, the role of beta amyloid in AD diagnosis remains at the least questionable. In the case of cystatin C, our results would seem to confirm the views of certain authors that cystatin C will probably not become a new 'revolutionary' marker contributing to differential diagnostics.

The assessment of beta amyloid, tau protein and cystatin C in the cerebrospinal fluid: laboratory markers of neurodegenerative diseases.

To assess the role of tau protein, beta-amyloid(1-42) and cystatin C in the diagnostics of Alzheimer dementia (AD) and other neurodegenerative diseases (ND) by comparing to the control groups (CG). The levels of tau protein, beta-amyloid(1-42) and cystatin C were assessed in the set of 69 patients (AD + ND, 33 males, 36 females, aged 22-90, mean 60.5 + 16.1 years), and in a control group of 69 subjects without the affection of the central nervous system (CGAD + CGND, 33 males, 36 females, aged 20-91, mean 60.5 + 16.0 years). Statistically significant increased tau protein levels (P = 0.0001) and index tau/beta-amyloid(1-42) levels (P = 0.0002) were shown in the group of AD patients, compared to the group of ND patients. One-way ANOVA analysis with Bonferonni post hoc test did not show any significant differences of the cystatin C values between any of the compared groups. ROC analysis showed at least one tie between the positive actual state group (AD) and the negative actual state group (ND) by CSF cystatin C and at least one tie between the positive actual state group and the negative actual state group by CSF tau protein. Our study confirmed previously reported results only in part. While tau protein seems to be quite a reliable marker of AD, the role of beta-amyloid(1-42) and cystatin C in AD diagnosis remains at least questionable.

Influence of third-generation cephalosporin utilization on the occurrence of ESBL-positive Klebsiella pneumoniae strains.

BACKGROUND: Klebsiella pneumoniae belongs to important nosocomial pathogens causing mainly hospital-acquired infections. Beta-lactam antibiotics are frequently used in the treatment of infections caused by K. pneumoniae, but by their selection pressure the bacteria become resistant. Excessive use of third-generation cephalosporins is a risk factor for the occurrence and spread of ESBL-producing bacterial strains. The goal of this study was to describe the utilization of third-generation cephalosporins and to analyse their selection pressure on K. pneumoniae in the University Hospital in Olomouc. METHODS: Data on the utilization of antibiotics in the hospital were obtained for the period 1997-2005 from the computerized database and expressed in defined daily doses per 100 bed-days (DBD). The data were processed according to the ATC/DDD system. Klebsiella pneumoniae strains were isolated from clinical material obtained from hospitalized patients. RESULTS: Consumption of third-generation cephalosporins, which was 1.79 DBD in 1997, decreased to 0.93 in 1999, remained stable until 2002, and then increased to 2.40 DBD in 2005. During the 9-year period analysed, a total of 9564 strains of K. pneumoniae were isolated. The ESBL-positive K. pneumoniae strains frequency increased from 8% to 18%. CONCLUSIONS: Increasing utilization of third-generation cephalosporins was associated with a statistically and clinically significant increased incidence of ESBL-positive K. pneumoniae strains.

The influence of antibiotic use on the occurrence of vancomycin-resistant enterococci.

BACKGROUND: Several studies have documented the influence of antibiotic selective pressure, mainly from the use of glycopeptides, third-generation cephalosporins, quinolones and lincosamides, on the frequency of vancomycin-resistant enterococci (VRE) occurrence in hospitals. The aim of this study was to evaluate the relationship between VRE occurrence and antibiotic use in the Department of Hemato-Oncology of the Teaching Hospital in Olomouc (DHO), Czech Republic, over a 6-year period under standard and unchanged hygienic and epidemiological conditions. METHODS: During the period of 1998-2003, Enterococcus sp. strains and VRE were isolated by standard methods from clinical samples taken from DHO in-patients. The frequency of VRE occurrence was expressed as the number of isolated strains per 100 bed-days/year. DHO antibiotic consumption data were processed according to the anatomical therapeutic chemical (ATC)/defined daily dose (DDD) system valid in 2003 and expressed in defined daily dose per 100 bed-days (DDD/100 bed-days) for each year of the period. RESULTS: Since 1998, the occurrence of VRE decreased significantly (from 0.28 to 0.17 VRE/100 bed-days in 2001). Between 2001 and 2003, a significant (P < 0.05) increase from 0.17 to 0.38 was observed. The antibiotic use decreased from 205.2 in 1998 to 161.0 DDD/100 bed-days in 1999 and after an increase in 2001 (to 181.8 DDD/100 bed-days) it remained relatively stable. A significant decrease was observed in third-generation cephalosporins and quinolones (from 29.5 to 9.7 and from 42.2 to 30.2 DDD/100 bed-days respectively) between 1998 and 1999. In 2002-2003, the use of third-generation cephalosporins and glycopeptides increased substantially (from 10.1 to 13.9 and from 11.3 to 15.2 DDD/100 bed-days respectively). The Pearson correlation value was significantly positive (P < 0.05) for VRE occurrence and the use of glycopeptides and third-generation cephalosporins. CONCLUSIONS: While our study confirms the effect of use of glycopeptides and third-generation cephalosporins on occurrence of VRE, no influence of quinolones and lincosamides over the 6-year period was shown.

Cognitive performance in people with Parkinson's disease and mild or moderate depression: effects of dopamine agonists in an add-on to L-dopa therapy.

In a randomized prospective multi-centre study, we evaluated the cognitive performances of a group of 41 non-demented patients, all with advanced Parkinson's disease (PD) and a current depressive episode, in whom the effects of pramipexole (PPX) and pergolide (PRG) in an add-on to l-dopa therapy were also studied and published with regard to motor symptoms of PD, motor complications and depression. The Trail Making Test, the Stroop test and four subtests (arithmetic, picture completion, digit symbols and similarities) of the Wechsler Adult Intelligence Scale-Revised were performed prior to and 8 months after the administration of either PPX or PRG. We found no statistically significant difference between the two tested drugs or between the first and the last visit in any of the above-listed neuropsychological tests. All patients' motor outcomes significantly improved and we conclusively demonstrated the anti-depressive effect of PPX. The dissociation of dopaminomimetic effects on the different tested domains indicates that there are different pathological mechanisms of cognitive, motor and affective disturbances in advanced PD patients. In our non-demented group of fluctuating depressed PD subjects, both PPX and PRG administration in combination with l-dopa were safe in terms of the effect on cognitive performance.

Comparison of ultrasonography, CT angiography, and digital subtraction angiography in severe carotid stenoses.

Digital subtraction angiography (DSA) is considered to be the 'gold standard' for confirmation of severe (70-99%) stenoses of internal carotid arteries (ICAs). However, it is associated with a risk of complications. The aim of this study was to assess the accuracy of ultrasonography (US), computed tomographic angiography (CTA), and their combined use for the detection and quantification of severe carotid stenoses, when compared with DSA. Severe ICA stenoses were diagnosed by US in a set of 29 patients. All patients also underwent CTA and DSA. Sensitivity, specificity, positive (PPV), negative predictive values (NPV), and Pearson's correlation coefficient were used in the evaluation of the percentage of stenosis results. Homogeneity chi2 test was applied when assessing statistical significance. Severe stenosis was diagnosed in 34 ICAs. Two ICAs with uninterpretable CTA finding were excluded. The number of ICAs with stenoses 70-99%/<70%- US 32/0; CTA 29/3; US + CTA 29/3; DSA 24/8. Pearson's correlation coefficient - US 0.601; CTA 0.725; US + CTA 0.773. Sensitivity/specificity/PPV/NPV - US 1.0/0.75/0.75/xxx; CTA 1.0/0.844/0.828/1.0; US + CTA 1.0/0.844/0.828/1.0. Homogeneity chi2 test results - US, P = 0.002; CTA, P = 0.098; US + CTAG, P = 0.098. US in combination with CTA can be used for relatively secure diagnostics of severe ICA stenoses. Thus, invasive DSA can be avoided in a substantial number of patients.

Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study.

An 8-month multicentre prospective randomized study aimed at comparing the effects of dopamine receptor agonists pramipexole (PPX; Mirapexin) and pergolide (PRG; Permax) as add-on to L-dopa therapy on depression [Montgomery and Asberg Depression Rating Scale (MADRS)] in 41 non-demented patients (25 men, 16 women) suffering from both mild or moderate depression and advanced Parkinson's disease (PD). The assessment was performed by a blinded independent observer. Motor symptoms (UPDRS III), motor complications (UPDRS IV), activities of daily living (UPDRS II and VI) and depressive symptoms as measured by Self - Rating Depression Scale by Zung were evaluated in an open-label design. The average value of Zung scores decreased significantly in both groups with no statistical difference between both groups. A significant decrease in the average value of MADRS scores was present only in the PPX group. The average UPDRS scores decreased significantly with no statistical difference between both groups at the comparable average total daily dose of both preparations. In both cases, the total daily dose of L-dopa decreased significantly but the decrease was statistically more pronounced in the PRG group. Our results demonstrate the antidepressant effect of PPX in patients with PD while we can't make any conclusions with regard to antidepressant effect of PRG.

Facilities for acute stroke patients care in the Czech Republic: nationwide epidemiological study.

BACKGROUND AND PURPOSE: Stroke is the third most common cause of death in the Czech Republic (CR). Specialized in-patient stroke unit care improves the outcome of stroke patients. The aim of the study was to chart and improve the current facilities. METHODS: Neurological in-patient departments exist in 75% of the districts in the CR, and in the capital Prague. Questionnaires were sent to all 79 neurological in-patient departments. A chi2 test was used for the evaluation of statistical significance. RESULTS: There is better access to intensive/intermediary care beds (statistically not significant) and to angiography (statistically significant) in the districts with a population density of over 151 inhabitants per km2 than in districts with a lower population density (p = 0.09 and p = 0.008). Stroke patients have access within 1 hour to computed tomography of the brain in all but one, and to laboratory tests in all districts with a neurological in-patient department(s). There is no statistically significant difference in the availability of ultrasound examination of extracranial brain arteries between the sparse, and more populated districts (p = 0.715). CONCLUSIONS: Facilities for the establishment of stroke units are quite good in the majority of highly populated areas; however, they are worse in some of the larger towns. The results of the study must be used to further improve the development of stroke care in the CR.

The occurrence of vancomycin-resistant enterococci in hematological patients in relation to antibiotic use.

Very important bacterial pathogens found in hematological patients at present are vancomycin-resistant enterococci (VRE). The main goal of this retrospective study was to assess their occurrence in relation to antibiotic use. We isolated 1918 Enterococcus strains, in toto, 138 (7.2%) of which proved to be VRE. The VRE most frequently identified were Enterococcus faecium VanA (77%) and Enterococcusfaecalis VanB (12%), mostly isolated from stools (57%). Comparing the development of the selection pressure of antibiotics and percentage of VRE in each period of observation, an effect of the administration of each antibiotic group on the occurrence of VRE can be presumed. A reduction in the administration of third generation cephalosporins, glycopeptides and fluoroquinolones and its replacement by penicillin antibiotics combined with inhibitors of bacterial beta-lactamases, contributed to the cessation of VRE incidence and succeeding reduced occurrence from 15.1% in the second half of 1998 to 6.1% in the first half of 2000.

Pharmacokinetic study of iodine-labeled silibinins in rat.

The very low bioavailability of silibinin (silybin, SB), the main antioxidant flavonolignan of silymarin from Silybum marianum L. (Asteraceae), requires sensitive methods to study the modulation of silibinin bioavailability. To evaluate the potential for use of radiolabeled silibinin, two silibinin derivatives, separated by HPLC after iodination ((125)I-SB(1) and (125)I-SB(2)) and their complexes 1 : 1 with phosphatidylcholine ((125)I-SPC(1) and (125)I-SPC(2)) were administered concurrently with a single intragastric dose of 5.0 mg or 50 mg of unlabeled silibinin (alone or as a constituent of the complex) per kg of body weight in a comparative study of bioavailability in the rat. Pharmacokinetic parameters as well as organ uptake of (125)I-SB(1)-derived radioactivity showed a dose-response pattern. The parameters of bioavailability after (125)I-SPC(1) intake were not influenced by unlabeled silibinin (complexed with phosphatidylcholine), since maximal levels were achieved by the lower dose of unlabeled compound. The superior bioavailability of (125)I-SPC(1) was obvious at the lower dose of unlabeled compound as elevated AUC and RA(max) (maximal percentage of administered radioactivity), and increased radioactivity in liver, kidney, spleen and heart. An absence of these characteristics with (125)I-SB(2) and (125)I-SPC(2) suggests the use of(125)I-SB(1) for studies of modulation of its bioavailability in vivo in rat.