Katalin Nagy

Hungarian experience with Langerhans Cell Histiocytosis in childhood

The Langerhans cell histiocytosis (LCH) in children is relatively rare and the long-term analysis of therapy results has not been done yet in Hungary. The aim of this study was to investigate the incidence, clinical features, prognostic risk factors, and treatment results of childrens LCH in Hungary in a 20-year period. Children less than 18 years of age with newly diagnosed LCH in Hungary were entered in this study. Clinical data of all children with LCH were reported to the National Childhood Cancer Registry in Hungary from 1981 to 2000. The clinical files were collected and abstracted for information regarding age at diagnosis, gender, disease characteristics, treatment, and outcome of treatment. Median follow-up duration of surviving patients is 10.98 years. Between January 1981 and December 2000, 111 children under 18 years of age were newly diagnosed with LCH in Hungary. The annual incidence of LCH in children younger than 18 years of age was 2.24/million children. The male–female ratio was 1.36:1; the mean age was 4 years 11 months. Thirty-eight children had localized disease and in 73 cases systemic dissemination was found already at the time of diagnosis. Twenty-two patients were treated only by local surgery, 7 by surgery with local irradiation, and 5 children got only local irradiation. In 2 cases remission was achieved with local steroid administration. Seventy-five patients received chemotherapy. In the 20 years of the study 14 children died, 9 due to the progression of the disease. Sixteen patients had relapse with a mean of 2.16 ± 1.29 years after the first diagnosis. Three patients with relapse got chemotherapy generally used in lymphoma and remission was achieved. The overall survival of all patients (n = 111) was 88.3 ± 3.1% at 5 years and 87.3 ± 3.2% at 10 and 20 years. Childhood LCH is a well-treatable disease and the survival rate is high. Even disseminated diseases have a quite good prognosis in childhood.

[125I]SD-7015 reveals fine modalities of CB1 cannabinoid receptor density in the prefrontal cortex during progression of Alzheimer's disease

The cannabinoid type-1 receptor (CB₁R) is one of the most abundant members of the G protein-coupled receptor family in the central nervous system. Once activated by their cognate ligands, endocannabinoids, CB₁Rs generally limit the timing of neurotransmitter release at many cortical synapses. Prior studies have indicated the involvement of CB₁R in neurodegeneration and in various neuronal insults, with an emphasis on their neuroprotective role. In the present study we used a novel selective CB₁R radioligand to investigate regional variations in CB₁R ligand binding as a factor of progressive Braak tau pathology in the frontal cortex of Alzheimers disease (AD) patients. The frontal cortex was chosen for this study due to the high density of CB₁Rs and their well-characterized involvement in the progression of AD. Post-mortem prefrontal cortex samples from AD patients from Braak stages I to VI and controls were subjected to CB₁R autoradiography with [¹²⁵I]SD-7015 as radioligand. Regional concentration of [¹²⁵I]SD-7015, corresponding to, and thereby representing, regional CB₁R densities, were expressed in fM/g_tissue. The results show that CB₁R density inversely correlates with Braak tau pathology with the following tendency: controls <AD Braak stage V-VI <AD Braak stage III-IV <AD Braak stage I-II. Differences were significant between control and AD Braak stage I-II groups, as well as between controls and the AD group comprising all Braak stages. These findings indicate an up-regulation of the tissue binding of the selective CB₁R radioligand [¹²⁵I]SD7015 in human brains, allowing the detection of fine modalities of receptor expression and radioligand binding during the progression of AD.

On the useful role of OH free radicals in differentiation of cultured human fibroblasts

The working hypothesis assuming that oxygen free radicals cannot be considered only as harmful by-products of the oxidative metabolism has been experimentally tested. Human fibroblasts were grown in culture from the following five types of tissues: (1) normal orbital fat; (2) orbital fat of patients with endocrine ophtalmopathy (EOP); (3) normal orbital muscle; (4) orbital muscle of EOP patients; (5) skin. These fibroblasts (second to 12th passages) were treated for 2x72 h with the Fenton reactants: ADP-Fe(2+)-complex (0.1 mM for iron) and H(2)O(2) (0.055 mM), final concentrations. This treatment caused a slowing down of the cell proliferation, induced various morphological signs of differentiation, and significantly increased (40-150%) the total superoxide dismutase (SOD) and catalase (CAT) activities of the fibroblasts. Authors suggest that the increased expression of these enzymes may play a general role in the cell differentiation mechanisms, meaning that the generation of oxygen free radicals is an essential, useful factor even during the early phases of development, and may not be taken only as a harmful process during aging.

New Prognostic Score for the Prediction of 30-Day Outcome in Spontaneous Supratentorial Cerebral Haemorrhage

Aims. The purpose of the present study was to evaluate predictors of outcome in primary supratentorial cerebral haemorrhage. Furthermore, we aimed to develop a prognostic model to predict 30-day fatality. Methods. We retrospectively analyzed a database of 156 patients with spontaneous supratentorial haemorrhage to explore the relationship between clinical and CT characteristics and fatal outcome within 30 days using multiple logistic regression analysis. The analyzed factors included volumetric data assessed by neuropathological and CT volumetry. A second CT scan in survivors or neuropathological ABC/2 volumetry in nonsurvivors was used along with the baseline CT to assess the growth index of haematoma. Results. Systolic blood pressure, serum potassium and glucose levels, platelet count, absolute and relative haematoma volumes, and presence and size of intraventricular haemorrhage statistically significantly predicted the fatal outcome within 30 days. Based on our results we formulated a six-factor scoring algorithm named SUSPEKT to predict outcome. Conclusions. After validation the SUSPEKT score may be applicable in general clinical practice for early patient selection to optimize individual management or for assessment of eligibility for treatment trials.

An in vitro model of aging: the influence of increasing physical density on enzyme activities of trypsin, xanthine oxidase and superoxide dismutase

The enzyme activities of trypsin (using an artificial substrate, Nalpha-benzoyl-L-arginine-ethylester = BAEE), xanthine oxidase (XOD) and superoxide dismutase (SOD) were measured in the absence and presence of various concentrations of the following inert, water-soluble polymer viscogens: polyvinylpyrrolidone (PVP-40), polyethyleneglycol (PEG-6000) and bovine serum albumin (BSA). Enzyme activities measured in the absence of viscogens were taken as 100%. In the presence of the viscogens, enzyme activities decreased considerably as follows: (i) Trypsin: to 2 or 12% in reaction mixtures containing 64 mg/ml PVP-40 or 481 mg/ml PEG-6000, respectively. (ii) XOD: to 29.3% in a reaction mixture containing 116 mg/ml PVP-40, to 68.9% in a medium containing 266 mg/ml PEG-6000, and 38.1% in the presence of 138 mg/ml BSA. (iii) SOD: to 40.0, 19.9 and 16.6% in the same media as listed for XOD, respectively. The observations are consistent with the predictions of the molecular enzyme kinetic model (MEKM), and are also of importance for the membrane hypothesis of aging, since the latter explains the loss of cell functions by an age-dependent increase of intracellular density which may cause serious enzyme inhibitions.

The involvement of hydroxyl free radicals in differentiation of the PC-12 rat pheochromocytoma cell line.

These experiments tested the differentiation properties of the PC-12 cell line under conditions of in vitro generation of OH&z.rad; free radicals by Fenton reaction. This involves the simultaneous addition of the following reactants: ADP-Fe(2+)-complex (0.1 mM for iron) and H(2)O(2) (0.025 mM), final concentrations. Superoxide dismutase activity, the increase of which is considered as a marker of differentiation, catalase and glutathione peroxidase enzyme activities were investigated, which all displayed significant increases after single and repeated interventions with hydroxyl free radicals, while the cell number remained nearly at the starting-value. It is known that the differentiation takes place when the cell number has reached a plateau. These data, therefore, suggest that hydroxyl free radicals can induce in vitro cell differentiation, and that they play a more complex role in cell physiology than simply causing oxidative damages. It is interesting that the cells can maintain high levels of these enzyme activities for a relatively long time (2 or 4 days) after a very short flux of hydroxyl free radicals.

Age-dependence of free radical-induced oxidative damage in ischemic-reperfused rat heart

Oxygen free radical-induced oxidative damage is involved in both aging and ischemia-reperfusion. The purpose of this study was to determine the aging-induced oxidative alterations in rat heart as well as the age-dependence of heart injury following ischemia-reperfusion. A comparative study was performed on young and old ischemic-reperfused rat hearts. Protein oxidation and the ascorbyl radical level in heart tissue were determined in order to characterize the oxidative stress. Comparing the control conditions, old hearts have 31% more oxidized proteins as measured by protein carbonyl content, and 18% lower ascorbyl radical level as determined by ESR, than young ones. The extent of increase of protein oxidation and ascorbyl free radical depletion induced by ischemia-reperfusion is less pronounced in the old hearts (7 and 8% respectively), as compared to the young ones (55 and 21% respectively). Pre-treatment with a free radical scavenger, such as centrophenoxine, diminished the ischemia-reperfusion injury in both young and old rat hearts.

In vitro evidence for competitive tspo binding of the imaging biomarker candidates vinpocetine and two iodinated daa1106 analogues in post mortem autoradiography experiments on whole hemisphere human brain slices

Earlier in vivo PET experiments have demonstrated the binding of the neuroprotective alkaloid vinpocetine to the peripheral benzodiazepine receptor (PBR) or, with other terminology, the TSPO (18kDa translocator protein). With the aim of demonstrating the direct binding of vinpocetine to TSPO in vitro, two different ionidated versions of the novel TSPO ligand DAA1106 were used in autoradiographic experiments on human postmortem whole hemisphere brain slices. Vinpocetine effectively blocked the binding of both [125I]desmethoxy-DAA1106 and [125I]desfluoro-DAA1106 to TSPO, the decrease in binding reaching 30 % to 64 % in various brain structures. This present findings yield further evidence to vinpocetines direct binding to the TSPO in the human brain in vitro as well as to the possible use of its radiolabelled versions as imaging biomarkers. The results also support the usefulness of two ionidated versions of DAA1106 as biomarkers of TSPO for in vitro and in vivo studies in neurological diseases accompanied with microglia activation.