Eva Cermakova

Lymphatic vasculature is increased in heart valves, ischaemic and inflamed hearts and in cholesterol-rich and calcified atherosclerotic lesions.

Eur J Clin Invest 2011; 41 (5): 487–497

Out-of-hospital cardiac arrests in patients with acute ST elevation myocardial infarctions in the East Bohemian region over the period 2002-2004.

Background: Early reperfusion by direct percutaneous coronary intervention (PCI) in patients with ST segment elevation acute myocardial infarctions (STEMI) with an out-of-hospital cardiac arrest (OHCA) reduces hospital and longterm mortality. Aims: Evaluating the significance of direct PCI for the short-term (discharge from acute hospitalization) and 1-year survival in patients with acute STEMI after OHCA. Methods: In this prospective study, from April 1, 2002 up to August 31, 2004, a total of 26 hospitalized individuals (22 men, 4 women, aged 35–79 years, median 58.5) from the East Bohemian region with OHCA (primary group of 718 individuals) with acute STEMI were included. Urgent coronary angiography was performed in 20 individuals, and direct PCI was done in 19 of them. The remaining 6 patients did not undergo angiography. Results: Fifteen patients (57.7%) survived acute hospitalization, of whom 11 were without neurological deficits. In the subgroup with urgent coronary angiography 14 patients (70%) survived hospitalization, and in the subgroup without coronarography only 1 patient survived hospitalization (16.7%). In the subgroup with PCIs, 13 out of the 19 patients survived (68.4%). None of the patients died during the 1-year follow-up after being discharged from acute hospitalization. According to the urgent coronarography the artery most commonly responsible for the infarction was the left anterior descending artery (50%). Initial TIMI flow grade 0–I was found in 17 patients and grade II–III in 3 individuals. After PCI, irrespective of stent implantation, an optimal angiographic success (TIMI flow grade II–III) was obtained in 17 cases. Conclusion: Short-term survival of patients after OHCA with STEMI treated with direct PCI was found to be 68.4%. Out of 6 patients not receiving reperfusion therapy 1 survived (16.7%). Over the course of the 1-year follow-up none of the patients died.

Glycine serum level in schizophrenia: Relation to negative symptoms

Glycine acts as an endogenous selective co-agonist at the glycine modulatory site of the NMDA (N-methyl-d-aspartate) receptor. Significantly decreased glycine serum levels were reported in patients with schizophrenia in comparison to healthy controls. Administration of glycine improved negative symptoms in patients with schizophrenia treated with antipsychotics in some clinical trials. We hypothesized that glycine serum levels might be associated with intensity of negative symptoms in schizophrenia. Fifty outpatients with the diagnosis of schizophrenia as defined by ICD-10 and fifty age- and gender-matched healthy controls were recruited into the study. Glycine serum levels were measured by high performance liquid chromatography (HPLC). We used the Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) to assess the symptoms of schizophrenia in the patients. We found mean glycine serum levels to be significantly lower in patients than in controls. This difference was only caused by findings in the male study population. Glycine serum levels were negatively associated with intensity of negative symptoms assessed by the PANSS negative subscale and the SANS total scores in the patients. These data suggest a possible implication of NMDA receptor dysfunction in the pathogenesis of negative symptoms in schizophrenia.

Prognostic impact of hemoglobin level prior to radiotherapy on survival in patients with glioblastoma.

Purpose:To evaluate prognostic factors in patients with glioblastoma treated with postoperative or primary radiotherapy.Patients and Methods:From 1989 to 2000, a total of 100 patients underwent irradiation as part of their initial treatment for glioblastoma. All patients had undergone surgery or biopsy followed by conventional external-beam radiotherapy. 85 patients who received the planned dose of irradiation (60 Gy in 30 fractions) were analyzed for the influence of prognostic factors. 73/85 (86%) of patients were given postoperative irradiation, while 12/85 (14%) of patients were primarily treated with radiotherapy after biopsy.Results:The median overall survival was 10.1 months (range, 3.7–49.8 months), the 1- and 2-year survival rates were 41% and 5%, respectively. Univariate analysis revealed age ≤ 55 years (p < 0.001), pre-radiotherapy hemoglobin (Hb) level > 12 g/dl (p = 0.009), and pre-radiotherapy dose of dexamethasone ≤ 2 mg/day (p = 0.005) to be associated with prolonged survival. At multivariate analysis, younger age (p < 0.001), higher Hb level (p = 0.002), lower dose of dexamethasone (p = 0.026), and a hemispheric tumor location (p = 0.019) were identified as independent prognostic factors for longer survival. The median survival for patients with an Hb level > 12 g/dl was 12.1 months compared to 7.9 months for those with a lower Hb level. Contingency-table statistics showed no significant differences for the two Hb groups in the distribution of other prognostic factors.Conclusion:The results indicate that lower Hb level prior to radiotherapy for glioblastoma can adversely influence prognosis. This finding deserves further evaluation.Ziel:Evaluation prognostischer Faktoren bei Patienten mit Glioblastom, die mit postoperativer oder primärer Strahlentherapie behandelt wurden.Patienten und Methodik:Bei 100 Patienten mit Glioblastom wurde in den Jahren 1989–2000 die Strahlentherapie im Rahmen der Primärbehandlung angewandt. Bei allen Patienten wurde eine Operation oder Biopsie mit nachfolgender konventioneller perkutaner Bestrahlung durchgeführt. Der Einfluss der prognostischen Faktoren wurde bei 85 Patienten, die die geplante Strahlendosis (60 Gy in 30 Fraktionen) erhielten, evaluiert. 73/85 Patienten (86%) wurden mit postoperativer Bestrahlung, 12/85 Patienten (14%) mit primärer Strahlentherapie und Biopsie behandelt.Ergebnisse:Die mittlere Überlebenszeit betrug 10,1 (3,7–49,8) Monate, die Überlebenszeit nach 1 und 2 Jahren lag bei 41% bzw. 5%. Mittels der univariaten Analyse stellten sich folgende Faktoren dar, die mit einer längeren Überlebenszeit verbunden sind: ein Alter ≤ 55 Jahre (p < 0,001), eine Hämoglobin-(Hb-)Konzentration zu Beginn der Strahlentherapie > 12 g/dl (p = 0,009) und eine prätherapeutische Dexamethasondosis ≤ 2 mg/Tag (p = 0,005). Die multivariate Analyse ermittelte ein jüngeres Alter (p < 0,001), eine höhere Hb-Konzentration (p = 0,002), eine niedrigere Dexamethasondosis (p = 0,026) und eine hemisphärische Tumorlokalisation (p = 0.019) als unabhängige prognostische Faktoren für eine längere Überlebenszeit. Die mittlere Überlebenszeit bei Patienten mit einer Hb-Konzentration > 12 g/dl betrug 12,1 Monate, bei Patienten mit einem niedrigeren Blut-Hb-Wert dagegen nur 7,9 Monate. Die Kontingenztabellenstatistik zeigte keine signifikanten Unterschiede in der Distribution der anderen prognostischen Faktoren bei beiden Hb-Gruppen.Schlussfolgerung:Die Ergebnisse weisen darauf hin, dass eine niedrigere Hb-Konzentration vor Beginn der Strahlentherapie wegen Glioblastoms einen negativen Einfluss auf die Prognose haben kann. Diese Beobachtung verdient weitere Aufmerksamkeit.

L-rhamnose and L-fucose suppress cancer growth in mice

It is documented that deficient fucosylation may play an important role in the pathogenesis of cancer. Since the supplementation of L-fucose could restore fucosylation in both in vitro and in vivo conditions, our intent was to examine the effect of intraperitoneal administration of L-fucose and L-rhamnose (a similar deoxysaccharide) on tumour growth, mitotic activity and metastatic setting of a solid form of Ehrlich carcinoma as well as on the survival rate of tumour bearing mice. Both L-fucose and L-rhamnose exerted a significant suppressive effect on tumour growth (P<0.05). After 10 days of therapy, the greatest inhibition of tumour growth expressed as a percentage of controls was observed in L-rhamnose at a dose of 3 g/kg/day (by 62%) and L-fucose at a dose of 5 g/kg/day (by 47%). Moreover, the mitotic index decreased with increasing doses of L-fucose and L-rhamnose. Prolonged survival of tumour bearing mice was observed after 14 consecutive days of daily administering L-rhamnose. Its optimal dose was estimated to be 3.64 g/kg/day. L-Fucose, however, displayed only a slight effect on the survival of the mice. Our results suggest that L-fucose and especially L-rhamnose have anticancer potential. This study is the first to demonstrate the tumour-inhibitory effect of L-rhamnose.

Antipsychotic drugs as a risk factor for venous thromboembolism

Objective. We assessed whether antipsychotic drugs represent a risk factor for venous thromboembolism by comparing the prevalence of antipsychotic drugs use in a population of patients with venous thromboembolism versus a group of individuals treated for hypertension. Methods. We identified 266 patients (141 women) diagnosed as having venous thromboembolism at the average age of 43.1±11 years who had been hospitalized in the University Hospital in Hradec Králové from 1 January 1996 to 31 December 2004. Two hundred and seventy-four patients (140 women) with arterial hypertension, with an average age of 48.3±8.8 years, represented the control population. Results. Use of antipsychotic drugs was moderately more frequent in the group of patients with venous thromboembolism as compared with the control group subjects (4.89 vs. 1.82%; odds ratio 2.76; 95% confidence interval=1.01–7.55). Discussion. We discuss the possible mechanisms of venous thromboembolism induced by antipsychotic agents – hypoactivity, blood status, obesity, abnormal coagulation, autoimmune mechanisms, and hyperhomocysteinemia. Conclusion. Our results indicate the possibility of an increased risk for venous thromboembolism in patients using antipsychotic drugs. It is necessary to seriously consider this possible adverse effect owing to its potentially fatal consequences.

Venous Thromboembolism in Young Female While on Oral Contraceptives: High Frequency of Inherited Thrombophilia and Analysis of Thrombotic Events in 400 Czech Women:

Oral contraceptive use is a common risk factor for venous thromboembolism in women of reproductive age. The presence of inherited thrombophilia further increases this risk. Methods: We analyzed a large group of 400 Czech women with venous thromboembolism in association with oral contraceptive with regard to duration of use at the time of manifestation of venous thromboembolism, the frequency of inherited and acquired thrombophilia, the frequency of eliciting risk factor for thrombosis including immobilization, surgery, administration of plaster cast, long travel, and so on, and the type of thrombosis. The mean age of the women was 26 years, and the average duration of use was 45 months at the onset of thrombosis. Results: Venous thrombosis solely due to the pill occurred in 57% of the women, and in the other 43%, an additional transient eliciting factor was recognized. Among the clinical manifestation, distal thrombosis prevailed (N = 231, 58%) followed by proximal deep vein thrombosis (N = 65, 16%), pulmonary embolism (N = 21, 5%), and thrombosis in unusual sites (N = 20, 5%). Inherited or acquired thrombophilia was diagnosed in 195 (49%) women: factor V Leiden mutation in 35%, congenital deficiency of antithrombin in 1.8%, protein C in 0.8%, protein S in 1%, F IIG20210A in 5%, and antiphospholipid syndrome (APS) in 5.3%. Among the most common risk factors were immobilization of lower limb, minor and major surgery, and trauma. Conclusion: The results confirm that venous thromboembolism is a multifactorial disease in which thrombophilia screening is needed in young symptomatic women on the pill with thrombosis. The results also emphasize the value of proper thromboprophylaxis in women while on oral contraceptive in situations of increased risk for venous thromboembolism.

Comparative study of various subpopulations of cytotoxic cells in blood and ascites from patients with ovarian carcinoma

Aim of the study A number of observations have indicated that the immune system plays a significant role in patients with epithelial ovarian cancer (EOC). In cases of EOC, the prognostic significance of tumour infiltrating lymphocytes has not been clearly explained yet. The aim is to determine the phenotype and activation molecules of cytotoxic T cell and NK cell subpopulations and to compare their representation in malignant ascites and peripheral blood in patients with ovarian cancer. Material and methods Cytotoxic cells taken from blood samples of the cubital vein and malignant ascites were obtained from 53 patients with EOC. Their surface and activation characteristics were determined by means of a flow cytometer. Immunophenotype multiparametric analysis of peripheral blood lymphocytes (PBLs) and tumour infiltrating lymphocytes (TILs) was carried out. Results CD3+ T lymphocytes were the main population of TILs (75.9%) and PBLs (70.9%). The number of activating T cells was significantly higher in TILs: CD3+/69+ 6.7% vs. 0.8% (p < 0.001). The representation of (CD3–/16+56+) NK cells in TILs was significantly higher: 11.0% vs. 5.6% (p = 0.041); likewise CD56bright and CD–56bright from CD56+ cells were higher in TILs (both p < 0.001). The activation receptor NKG2D was present in 45.1% of TILs vs. 32.3% of PBLs (p = 0.034), but we did not find a significant difference in the numbers of CD56+/NKG2D+ in TILs and PBLs. Conclusions These results prove that the characteristics and intensity of anti-tumour responses are different in compared compartments (ascites/PBLs). The knowledge of phenotype and functions of effector cells is the basic precondition for understanding the anti-tumour immune response.

Different serine and glycine metabolism in patients with schizophrenia receiving clozapine

Dysfunction of the N-methyl-d-aspartate receptor, which is modulated by excitatory amino acids (EAA), is involved in the pathophysiology of schizophrenia. The effects of antipsychotics on EAA metabolism are uncertain. Positive clinical effects of treatment with antipsychotics were not always associated with changes in EAA serum levels in patients with schizophrenia in clinical trials. To examine EAA serum levels in relation to the intensity of psychotic symptoms and the type of medication received we compared these variables among patients with schizophrenia (n = 49) treated with first (FGA) or second (SGA) generation antipsychotics or clozapine. Glutamate, aspartate, glycine, total serine and d-serine serum levels were measured by High Performance Liquid Chromatography. The Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) were used to assess symptoms of schizophrenia. Lower average levels of glycine and total serine were found in the serum of patients receiving clozapine when compared to the groups of patients treated with FGA or SGA. There were no differences in serum glutamate, aspartate or d-serine levels or in the intensity of schizophrenic symptoms assessed by PANSS or SANS among the groups of patients treated with FGA or SGA or clozapine. Lower glycine and total serine serum levels could be caused by the particular characteristics of the population of patients receiving clozapine rather than as an effect of the clozapine. The results suggest selective deficiency of l-serine synthesis in the patients with resistance to non-clozapine treatment. It might be an unique biochemical and pathophysiological characteristic of the treatment-resistance in schizophrenia.

Chlorambucil conjugates of dinuclear p-cymene ruthenium trithiolato complexes: synthesis, characterization and cytotoxicity study in vitro and in vivo

Four diruthenium trithiolato chlorambucil conjugates have been prepared via Steglich esterification from chlorambucil and the corresponding trithiolato precursors. All conjugates are highly cytotoxic towards human ovarian A2780 and A2780cisR cancer cell lines with IC50 values in the nanomolar range. The conjugates exhibit selectivity towards A2780 cells as compared to non-cancerous HEK293 cells, while being only slightly selective for RF24 and A2780cisR cells. In vivo, the conjugate [10]BF4 suppressed the growth of a solid Ehrlich tumor in immunocompetent NMRI mice but did not prolong their overall survival. The reactivity of the chlorambucil conjugates with glutathione, a potential target of the dinuclear ruthenium motive, and with the 2-deoxyguanosine 5′-monophosphate (dGMP—a model target of chlorambucil) was studied by mass spectrometry and NMR spectroscopy. The conjugates did not show catalytic activity for the oxidation of glutathione nor binding to nucleotides, indicating that glutathione oxidation and DNA alkylation are not key mechanisms of action.Graphical abstractFour highly cytotoxic diruthenium trithiolato chlorambucil conjugates have been prepared. All conjugates exhibit selectivity towards A2780 cells as compared to HEK293 cells, while being only slightly active in RF24 and A2780cisR cells. In vivo, the best candidate suppressed the growth of a solid Ehrlich tumor in immunocompetent NMRI mice but did not prolong their overall survival.