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.

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.

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.

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.

Events related to microembolism during extracorporeal perfusion in man: effectiveness of in-line filtration recorded by ultrasound.

Microparticle generation during cardiopulmonary bypass was monitored continuously in 60 adult patients who underwent open-heart operations. Echo-ultrasound transducers of 5 mHz frequency were interposed in a bubble oxygenator arterial line proximal and distal to a commercially available micropore filter. Ordinary perfusion events correlated with an increase in embolic counts and were recorded graphically. Calculation of filter efficiency revealed that all filters decreased measurable embolic counts. Platelet and leukocyte determinations and plasma hemoglobin values were not altered beyond limits ordinarily encountered during perfusion without filters. No patient in any filter group experienced postoperative respiratory distress, diffuse pulmonary infiltrate, or low PaO2. The 20 mu woven nylon mesh filter and the Dacron-wool filter showed greater than 90% effectiveness in removing recorded particles. Insertion of a cardiotomy filter did not appreciably alter recorded embolic counts distal to the arterial line filter.

Antibiotic selective pressure and development of bacterial resistance.

This study evaluates the development of resistance in Gram-negative rods to cefotaxime and ceftazidime, ofloxacin and ciprofloxacin, gentamicin and amikacin, meropenem and ampicillin/sulbactam over a five year period of use (1994-1998) at the University Hospital in Olomouc, Czech Republic. The development of bacterial resistance was linked with antibiotic use and hence selective pressure which was specific for the type of antibiotic and the bacterial species. Statistically significant correlations were found for the use of ofloxacin and resistance in Escherichia coli, Proteus vulgaris and Providencia rettgeri; cefotaxime and Enterobacter cloacae; ceftazidime and Acinetobacter spp., Enterobacter agglomerans and Proteus vulgaris; and gentamicin and Proteus mirabilis.

[Radiological findings in pseudohypoparathyroidism]. / Radiologische Befunde beim Pseudohypoparathyreoidismus.

Clinical and radiodiagnostic changes in pseudohypoparathyroidism are described in three members of one family. Radiodiagnostic changes consist of symmetric calcifications in basal ganglia, perivascular calcifications in soft tissues, and of alterations on the skeleton--Albright's osteodystrophy. Bone changes include a combination of osteoproductive and osteomalacic alterations. All these changes were observed in both brothers, their mother had only calcifications localised in upper and lower extremities.

Luminol-dependent chemiluminiscence of monocytes and granulocytes in multiple sclerosis: the effect of autologous thrombocytes.

The luminol-dependent chemiluminiscence of monocytes and granulocytes and the effect of autologous thrombocytes upon the chemiluminiscence activity were investigated in multiple sclerosis patients, patients with other neurological diseases and healthy controls. The spontaneous monocyte chemiluminiscence was found to be significantly higher in multiple sclerosis patients than in healthy controls. However, no differences were found between multiple sclerosis patients and the group of other neurological diseases. Addition of autologous thrombocytes did not substantially alter both the spontaneous and the zymozan-stimulated monocyte chemiluminiscence. No significant differences in granulocyte spontaneous and stimulated chemiluminiscence were found between the multiple sclerosis patients and both control groups. In all multiple sclerosis patients the addition of autologous thrombocytes markedly depressed the spontaneous and stimulated granulocyte chemiluminiscence and a similar effect was observed in most of the patients with other neurological diseases. In healthy controls, the effect of autologous thrombocytes was rather more heterogenous and both a thrombocyte-dependent increase and a decrease of the granulocyte chemiluminiscence were found. The results suggest that platelets are able to suppress the granulocyte oxidative burst and that this scavenger mechanism can be activated in multiple sclerosis and some other neurological diseases.

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.

The role of adhesion molecules in allotransplanted islet cells rejection. Prolongation of islet cells allograft survival by antiadhesion treatment.

Insulin-dependent diabetes mellitus is an autoimmune disease caused by the selective destruction of islet beta cells. Allo or xeno transplantation of islet cells may establish a novel promising method of IDDM therapy. Understanding how lymphocytes recognize beta cell antigens is essential for the elucidation of the pathogenesis of islet dysfunction. Leukocyte adhesion to the target cells (endothelium, islets) via adhesion molecule pathways plays an important role in auto and allo/xeno antigen recognition and effector cytodestruction of target cells. However, the expression of these molecules on the endothelium and islet cells during the rejection process still remains unclear. There are some publications describing possible roles of these antigens in the response to the graft. The expression of some of adhesion molecules may contribute to a new method for the diagnosis of graft rejection and its therapy when adhesion blocking substances are used for the treatment.

Hyperhomocysteinemia as a risk factor for cardiovascular diseases. The association of hyperhomocysteinemia with diabetes mellitus and renal transplant recipients.

Hyperhomocysteinemia has been recognised as an independent risk factor for cardiovascular, cerebrovascular and peripheral artery disease. There is strong evidence suggesting that hyperhomocysteinemia accelerates the process of atherogenesis. Possible explanations for this will be shortly reviewed. Recently a growing interest has been focused on the association of hyperhomocysteinemia with diabetes mellitus and with chronic renal disease, including renal transplant recipients. Some clinical aspects of this occurrence, such as interactions with insulin, metformin, and cyclosporine and also with some vitamins, will be described. The issue of hyperhomocysteinemia in heart transplant patients will also be mentioned. Last of all, the interaction of homocysteine concentration with some beverages will be considered.

[A modeling analysis of possible generic substitutions in an inpatient facility]. / Modelová analýza moznosti generické substituce v luzkovém zarízení.

The paper presents an example of a sectional analysis of drug consumption in a large in-patient health-service facility which is to be used as a foundation for making decisions about the measures to decrease the costs of drugs. Consumption of industrially produced pharmaceutical preparations at a selected facility for a period of four months was analyzed. The authors evaluated possible substitution of administered important preparations by cheaper equivalents and by means of model analysis they calculated expected savings when using the cheapest available mass-produced pharmaceutical preparations. In the preparations under study, possible savings of costs in the extent of 2.2% of the spent sum were found. On the basis of the results of the analysis, the hospital formulary authors consider the positive list with a quality system of objective monitoring of drug consumption to be the most suitable way of introduction of more rational prescription of industrially produced drugs in an in-patient facility.

Proliferation of reticuloendothelial system (RES) in rats with altered vision or smell (to the hypothetic neural regulation of the RES).

A long-term administration of an azo-dye, trypan blue, induced a reactive proliferation of RES in rats. Reaction of the RES was followed in rats whose optical analyzer was eliminated by enucleation of bulbs after the birth, in rats whose smell analyzer was altered by a repeated long-term exposition to ammoniac and in normal rats. Blind rats showed a striking proliferation of histiocytes of the RES in the liver, while the reaction was weak in the spleen and lymph nodes. In contrary to that, rats with altered smell and also the normal rats exhibited standard reactive changes in the spleen and lymph nodes and distinctly weaker reaction in the liver. The obtained results support an idea that vegetative neural mechanisms play a role in control and coordination of RES reactions.

[Immunopathology of a model inflammation]. / Prispevek k inumopatologii modelového zánetu

A series of 32 healthy individuals has been examined, in whom a large number of model inflammatory lesions of the "skin window" type had been produced. Physiological salina solution and diptheriac toxoid were administered by dropping as well as by intradermal injection into the lesioned areas of these individuals. The cover slips were removed after 12, 24 and 48 hours. The control inflammation without antigenic stimulation was characterized by the presence of neutrophilic granulocytes, monocytogenic macrophages and, later, also by epitheloid cells and foreign body giant cells. Celluization of the immune conditioned inflammation mainly consisted of rather small mononuclear cells related to the lymphatic series on the basis of their morphological and cytochemical features. In addition, neutrophils were also found, as well as typical macrophages, epitheloid and foreign body gaint cells. In the 24 and 48 hour preparations, particularly in those obtained from lesions following intradermal antigen administration, basophilic and eosinophilic granulocytes were a regular finding. The ftndings show a variability of the mutual proportions of immunocompetent and immunoneutral cells in the inflammatory cellulization under various condition.

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.