Secretome of apoptotic peripheral blood cells (APOSEC) attenuates microvascular obstruction in a porcine closed chest reperfused acute myocardial infarction model: role of platelet aggregation and vasodilation.

Although epicardial blood flow can be restored by an early intervention in most cases, a lack of adequate reperfusion at the microvascular level is often a limiting prognostic factor of acute myocardial infarction (AMI). Our group has recently found that paracrine factors secreted from apoptotic peripheral blood mononuclear cells (APOSEC) attenuate the extent of myocardial injury. The aim of this study was to determine the influence of APOSEC on microvascular obstruction (MVO) in a porcine AMI model. A single dose of APOSEC was intravenously injected in a closed chest reperfused infarction model. MVO was determined by magnetic resonance imaging and cardiac catheterization. Role of platelet function and vasodilation were monitored by means of ELISA, flow cytometry, aggregometry, western blot and myographic experiments in vitro and in vivo. Treatment of AMI with APOSEC resulted in a significant reduction of MVO. Platelet activation markers were reduced in plasma samples obtained during AMI, suggesting an anti-aggregatory capacity of APOSEC. This finding was confirmed by in vitro tests showing that activation and aggregation of both porcine and human platelets were significantly impaired by co-incubation with APOSEC, paralleled by vasodilator-stimulated phosphoprotein (VASP)-mediated inhibition of platelets. In addition, APOSEC evidenced a significant vasodilatory capacity on coronary arteries via p-eNOS and iNOS activation. Our data give first evidence that APOSEC reduces the extent of MVO during AMI, and suggest that modulation of platelet activation and vasodilation in the initial phase after myocardial infarction contributes to the improved long-term outcome in APOSEC treated animals.

Clinical, radiological and pathological correlates of leukoaraiosis.

INTRODUCTION: Leukoaraiosis is characterized by an abnormal appearance of the brain white matter on imaging. Its pathogenesis is still a matter of investigation. The purpose of this study was to investigate the radiological, clinical and pathological correlates of leukoaraiosis. METHODS: The study population consisted of 93 deceased patients. The pre-mortem T2W magnetic resonance images were evaluated for the presence and grading of leukoaraiosis. The clinical and pathological characteristics based on the clinical charts and autopsy reports were evaluated. Tissue specimens of the blocks of 19 brains that demonstrated severe leukoaraiosis and those of five control brains were excised and stained. RESULTS: The variables found to be significantly associated with leukoaraiosis were age and a clinical history of Parkinson's disease. Other risk factors and pathological markers of atherosclerosis were not significantly correlated with leukoaraiosis. No significant difference was found between the scoring of the myelin integrity, glial fibrillary acidic protein, cluster of differentiation 68 and smooth muscle actin. There was a significant difference with respect to thickening of vessels walls. CONCLUSIONS: Our pathological results indicate that structural vascular abnormalities characterized by vessel wall thickening are associated with leukoaraiosis, supporting the assertion that vascular changes and ischemia generate leukoaraiosis. The relations between parkinsonism and leukoaraiosis may be explicable through vascular effects on the circuitry of the basal ganglia.

Antiproliferative effect of 4-thiouridylate on OCM-1 uveal melanoma cells.

PURPOSE: Brachytherapy is a well-established, effective treatment for uveal melanoma with a failure rate of 15%. The fatal consequence of unsuccessful treatments offers reason for improvement of the method. The authors propose using an apoptosis inducing agent locally, concomitantly with the well-established therapy, to sensitize the tumor cells. The authors propose a new nontoxic moderately active apoptosis inducing agent, 4-thio-uridylate (s4UMP), for this purpose. METHODS: OCM-1 uveal melanoma cells were treated with various concentrations of s4UMP and its effect was monitored by measuring the cell viability (MTT assay). The following apoptosis detecting methods were performed to reveal the mechanism of decreased cell viability: light microscopy, DNA fragmentation assay, determination of caspase 9 activity, and FACS analysis. RESULTS: The viability of uveal melanoma cells was decreased by 32%, 40%, and 9% after 24, 48, and 72 hours of treatment with 10 microg/mL (30 microM) s4UMP. The effect was not dose dependent; it rather followed a saturation-type inhibition and the cells at lower drug concentration recovered after 72 hours. Characteristic apoptotic cell morphology and DNA fragmentation was detected in treated cells. The caspase-9 was activated upon treatment showing maximal activity at 48 hours suggesting the induction of apoptosis. The annexin binding activity further verified the apoptogenic activity of s4UMP. CONCLUSIONS: Uveal melanoma, more than other solid tumors, is resistant to most of the chemotherapeutic protocols as indicated by the high mortality rate of metastatic disease. The authors showed that s4UMP, a naturally occurring nucleotide, could induce apoptosis in uveal melanoma cells, suggesting a potential supplementary therapeutic application of the compound.

Relationship between cellular ATP, potassium, sodium and magnesium concentrations in mammalian and avian erythrocytes.

Intracellular K+/Na+ ratios of erythrocytes of various mammalian species are known to differ markedly. We have measured ATP, K+, Na+, Mg2+, H2O contents of erythrocytes of twelve mammalian and three avian species. Our results indicate that the intracellular ATP concentration in erythrocytes of different species is in close positive correlation with the K+/Na+ ratios (linear correlation coefficient, r = 0.852). Furthermore, ATP levels in erythrocytes of individual sheep with different potassium concentrations correspond with their K+/Na+ ratios (r = 0.747). Intracellular magnesium concentrations also correlate with ATP concentrations in erythrocytes of different species (r = 0.629) and in different sheep (r = 0.549).

Factors of the extrinsic pathway of blood coagulation in tumour associated macrophages.

Despite the growing evidence implicating intratumoural fibrin formation in the progression of malignant tumours, the origin of coagulation factors that participate in extravascular clotting has not been elucidated. Using immunohistochemical methods we attempted to detect and localize clotting factors of extrinsic pathway in different human malignant tumours. Coagulation factors II, V, VII and X (FII, FV, FVII and FX) were detected in a huge number of cells showing spindle-shaped or stellate morphology. By double immunohistochemical labellings it was demonstrated that cells containing these clotting factors express monocyte/macrophage differentiation marker antigens recognized by Leu M3, Ki M7 and DAKO-macrophage monoclonal antibodies, i.e. they represent monocyte-derived, phagocytic tumour associated macrophages (TAMs). These findings suggest that TAMs can be viewed as clot cells, which in addition to the initiation of extravascular clotting by expressing procoagulant activity can also provide all the components necessary for the extrinsic thrombin formation.

Acid phosphatase activity in monocytes and sera of patients with Hodgkin's disease.

Acid phosphatase (AP) levels have been found to be decreased in monocytes of 38 patients with Hodgkin's disease as compared to 16 healthy subjects. Low cellular AP activity was associated with the presence of active disease, stage IV and lymphocyte depletion type. Lactate dehydrogenase (LDH) was decreased in monocytes of patients but the difference did not reach statistical significance. In parallel, serum AP activities have been found to be increased in patients. There was an inverse correlation between the monocyte and serum AP levels which can be explained by assuming AP secretion from monocytes of patients in vivo.

Comprehensive epidemiological and clinicopathological survey of Hodgkin's disease in Hungary.

To determine the epidemiological pattern and some clinicopathological features of Hodgkin's disease in Hungary, the data of 233 consecutive patients with the disease from seven counties, diagnosed between January 1983 and July 1987, were analysed on the basis of data from four cancer centers. Large variations were noted in incidence rates between the different regions of Hungary. The epidemiological pattern seems to vary from those reported in developed and developing countries. A sharp rise in the incidence of Hodgkin's disease occurred at the end of the second decade of patients' lives. More of our Hodgkin's patients are at advanced clinical stages, with systemic symptoms and a histological type of mixed cellularity, at the time of diagnosis, than in the western hemisphere. On the average, there is a 6-month period between the appearance of the first sign or symptom and the diagnosis. There is a lack of data outlining the epidemiological differences in the pattern of Central Europa. The aim of this study is to supply data for the etiopathogenetic research of Hodgkin's disease, as there is an important task to improve the unfavourable home situation, and to strive for earlier diagnosis in this disease.

Nuclear magnetic resonance relaxation parameters of muscle in malignant hyperthermia-susceptible swine.

RATIONALE AND OBJECTIVES: The malignant hyperthermia (MH) syndrome involves characteristic changes in metabolism that have a significant effect on the postmortem properties of muscle tissue. We investigated the 1H nuclear magnetic resonance (MR) relaxation parameters of muscle tissue from normal (MH-) and malignant hyperthermia-susceptible (MH+) swine taken before their death to identify whether postmortem metabolic differences would be accompanied by changes in relaxation parameters. METHODS: Muscle samples from 63 MH-susceptible swine were characterized by proton MR relaxation times (T1 and T2). The water content, pH, conducting, and the "subjective meat" quality were assessed in order to differentiate the meat into one of three groups: normal, pale-soft-exudative, and dark-firm-dry. RESULTS: The T2 relaxation of MH- and MH+ muscles was significantly different, but no significant changes were detected in the water content and corresponding T1 relaxation times. CONCLUSION: These data suggest that MH-susceptible swine can be distinguished from normal swine using nuclear MR relaxometry. The results of relaxation measurements and the multiexponential analysis of the T2 curves suggest a shift between the different water compartments during MH that might predict the increased water loss of muscle tissue after death.

T and B lymphocytes in lymph nodes and spleen of patients with Hodgkin's disease.

Lymphocyte surface markers of 100 tissue specimens (67 lymph nodes and 33 spleens) of 40 patients with Hodgkin's disease were studied by means of spontaneous E-rosette formation and direct immunofluorescence method. The occurrence of active and total T cells was signigicantly higher (p less than 0.001) in the tumor-involved lymph nodes and spleens, while the frequency of B cells was practically the same in the histologically negative lymph nodes and spleens. In the tumorous spleen of 6 untreated patients the frequency of active and total T cells was higher in the tumorous tissue specimens than in the surrounding histologically negative tissue specimens. No correlation has been found between the simultaneously investigated peripheral T and B cell counts, clinical stage and the histological type of the tumor.

In vivo assessment of breast muscle, abdominal fat and total fat volume in meat-type chickens by magnetic resonance imaging.

Measurements were performed on commercial broiler chickens by magnetic resonance imaging (MRI) tomography. A total of 72 chickens were scanned at the age of 6, 7, 8, 10, 16 and 20 weeks. MRI scans based on spin echo sequence were taken in the three orthogonal planes. The volume of the pectoral muscles increased from 259 cm3 to 1035 cm3 in males and from 250 cm3 to 875 cm3 in females between 6 and 20 weeks of age. Abdominal fat volume increased from 18.9 cm3 to 153.2 cm3 in males and from 19.3 cm3 to 267.0 cm3 in females between 7 and 20 weeks of age. Total body fat volume increased from 129 cm3 to 557 cm3 in males and from 171 cm3 to 1321 cm3 in females between 6 and 20 weeks of age. The correlation coefficients between the total volume of fat pixels and the amount of abdominal fat determined in the coronal plane by MRI were 0.85 and 0.95 in the male and female sex, respectively. Changes found in the pectoral muscles (mm. pectorales) as well as in total and abdominal fat volume were in close agreement with dissection data obtained at the slaughterhouse and with laboratory data based on the measurement of total body chemical composition in both sexes. This MRI method can be a good complement to computed tomography (CT) scanning in the transversal plane.

The bulk of ATP is associated to proteins in the living cell: a release kinetics study.

The analysis of the nonionic detergent induced release kinetics of intracellular components is a promising approach to obtain information on the possible molecular interactions inside the living cell. The molecular interactions of ATP were studied by monitoring the nonionic detergent-induced release kinetics of ATP from cultured human cells. The observed rapid mobilization rate in the presence of Triton X 100 and the retarded release in the presence of Brij 58 were in good agreement with the detergent-induced release kinetics of proteins and K+ reported earlier. These data are consistent with the idea that the bulk of ATP is associated to the protein macromolecules of the living cell.

Cation distribution in mammalian red blood cells: interspecies and intraspecies relationships between cellular ATP, potassium, sodium and magnesium concentrations.

The intracellular K+/Na+ ratio of erythrocytes of different mammalian species are known to differ markedly. These differences are sustained despite plasma potassium and sodium concentrations being almost identical, i.e. high [Na+] and low [K+], in all mammalian species. Conventional cell theory couples intracellular K+ and Na+ concentrations with Na+/K(+)-dependent ATPase activity. Ling's Association-Induction (AI) hypothesis couples intracellular K+ and Na+ concentrations with the concentration of ATP, by way of an inductive adsorption of both monovalent cations on the available terminal and lateral carboxyl groups of proteins. Based on the working hypothesis, different relationships are expected between the erythrocyte K+ and Na+ concentrations and ATP levels. Our results indicate that the intracellular ATP level in erythrocytes of different species corresponds with intracellular K+ and Na+ levels, K+/Na+ ratios and total K+ + Na+ levels. Similar relationships were revealed between the erythrocyte ATP and monovalent cation contents of different individual sheep.

[Management of vomiting induced by polychemotherapy in Hodgkin's disease]. / Polychemoterápia okozta hányás és kezelése Hodgkin-kórban.

Sixty patients with Hodgkin's disease were treated with a polychemotherapy regimen including very emetic dacarbazine and adriamycin in addition to bleomycin and vincristine on 622 treatment days during the last 10 years. Nausea in 97% and severe vomiting in 91% were observed during the treatment causing considerable distress to patients which led to patient noncompliance in 26.6%. Among the used antiemetic agents haloperidol was less active than high-dose metoclopramide alone or with high-dose methylprednisolone which were extremely effective. The control and prevention of drug-induced emesis is a major problem for cancer patients and their oncologists. The present situation and the home tasks are also discussed on the basis of literature and their observations.

[Method and use of intracranial cine MR imaging]. / Intracranialis mozgóképes magmágneses rezonanciás vizsgálatok és alkalmazásaik.

The authors introduce a dynamic, non-invasive MR method for the examination of liquorspaces and liquor flow in 221 patients. This method is suitable not only for a dynamic imaging of liquor-flow but also for the semi-quantitative evaluation of flow through the aqueduct. This later measurement can help to select the shuntresponsive NPH cases as well. Cine MR examination along with the routine protocol seems to be most helpful in the differential-diagnostics of different hydrocephalus cases.

[Principles of functional MRI imaging and its possibilities in the study of cerebral cortex activation]. / A funkcionális MR képalkotás elve és lehetöségei a kérgi aktivációk vizsgálatában.

While MR imaging of anatomic structures has long been widely appreciated, the emergence of functional magnetic resonance imaging (FMRI) methods for localising brain activity has emerged in the beginning of the 90s. This new MRI technique produces images of activated brain regions by detecting the indirect effects of neural activity on local blood volume, flow and oxygen saturation, and it is a promising new tool for further understanding of the relationships among brain structure, function and pathology. The information revealed by FMRI is partially overlapping with PET and SPECT, but it is non-invasive and has a better spatial and temporal resolution. The authors briefly summarise the concept and basics of FMRI and demonstrate the first successful FMRI examination performed in Hungary. The potential role of FMRI in the clinical practice is presented.

[Refsum disease]. / Refsum-kór.

For the first time in literature the authors interpret the pathography of Refsum's disease, in the case of their patient, as pseudo-hypervitaminosis A. The biochemical basis of the clinical picture is a defect in the activity of phytanic-acid-alpha-hydrolase belonging to the peroxisomal system. As a consequence, phytanic acid accumulates in the serum and in the parenchymal tissues. Retinol, an alcohol with high molecular weight, is a natural ligand of nuclear RXR (retinoid-X-receptor), which plays an important role in the regulation of peroxisoma synthesis. In Refsum's disease the phytanic acid accumulated because of the enzyme defect competes with the biotransformation derivates (all-trans-retinoic acid, 9-cis-retinoic acid) of the all-trans-retinol (vitamin A) for the nuclear RX receptor binding sites, and as a very potent receptoractivator it causes the intestinal symptoms of hypervitaminosis A. The authors review the procedure of fatty-acid chromatography necessary for the establishment of the diagnosis and discuss--in addition to dietary restrictions--recent therapeutic possibilities, like plasmapheresis, cascade filtration, lipapheresis and oral batylalcohol treatment.

[Chiari I. malformation, a new childhood disease?]. / Chiari I. malformáció, egy "új" gyermekbetegség?

From July 1, 1994 to July 1, 1997 a total of 17 children with Chiari I malformation diagnosed by MRI was seen in our hospital. Six of them underwent craniocervical decompression and tonsilar resection. The major complaints of all these children were gait ataxia and persisting (longer than 6 month) headache, and one child had acutely presenting vertigo and problem of swallowing. The MRI showed that in all cases the tonsils were displaced below the level of CI. Hydrocephalus or syrinx was not seen. At surgery the tonsils were resected. All the patients can be considered cured and symptom free at an average follow up of 13 month.

[Dynamic MR examination of the breast--histological correlations]. / Az emló dinamikus MR-vizsgálata--szövettani korreláció.

The authors outline dynamic MR mammography (dMRM) as a highly sensitive diagnostic method for the examination of the breast. In a retrospective study relating to 84 processed cases, in the knowledge of the cytological-histological findings the diagnostic accuracy of the examinations was determined. The role of the method in detecting benign and malignant changes of the breast has been estimated. Misdiagnosed cases have been analysed and recommendations for the application of the method are included. The MR proved to be positive in 32 cases and negative in 3 cases of the analysed 35 malignant tumors. Benign lesions were found at microscopy in 49 cases, of which MR correctly diagnosed 40. The sensitivity and the specificity of dynamic MR mammography were 91% and 82%.

[Comprehensive epidemiologic and clinico-pathologic study of Hodgkin's disease]. / Reprezentatív epidemiológiai és klinikopatológiai felmérés Hodgkin-kórban.

To determine the epidemiologic pattern and some clinicopathologic features of Hodgkin's disease (HD) in Hungary, the data of 233 consecutive patients with HD, diagnosed between January 1983 and July 1987 from seven county were analysed on the basis of data from 4 cancer centers. Large variations have shown in incidence rates within different regions of Hungary. The epidemiologic pattern seems to vary from those reported in developed and developing countries. A sharp rise in HD incidence occurs already at the end of second decade. More Hodgkin's patients have advanced clinical stages, systemic symptoms, mixed cellularity histologic type at the time of diagnosis than in Western hemisphere. On the average, there is a six months period between the appearance of the first sign or symptom and the diagnosis. There is a lack of data outlining the epidemiologic difference in the pattern of Central Europe. The aim of this study was to supply data for the etiopathogenetic research of HD. There is an important task to improve the unfavourable home situation, to strive to earlier diagnosis in HD.

[The benzodiazepine story]. / A benzodiazepin történet.

Benzopyrylium salt (3) was converted by means of excess of hydrazine hydrate into a substance of a composition C22H26N2O4. The structure of this compound was elucidated by means of detailed NMR and mass-spectroscopic studies and the structure of 1-(3,4- dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine (4) has been proved. Conformation analysis was performed as well and it has been established that two conformers (A and B) exist in reversible equilibrium. The molecule contains a chiral centre and the enantiomers were separated via optical resolution. Two different 14C-labelled 4 were prepared for pharmacological studies. The compound is known as GrandaxinR in the medicinal practice (INN = tofisopam).