Chronic hyperglycemia and intracranial meningiomas.

Meningiomas are among the most common primary tumors of the central nervous system. Previous research into the meningioma histological appearance, genetic markers, transcriptome and epigenetic landscape has revealed that benign meningiomas significantly differ in their glucose metabolism compared to aggressive lesions. However, a correlation between the systemic glucose metabolism and the metabolism of the tumor hasn't yet been found. We hypothesized that chronic levels of glycaemia (approximated with glycated hemoglobin (HbA1c)) are different in patients with aggressive and benign meningiomas. The study encompassed 71 patients with de novo intracranial meningiomas, operated on in three European hospitals, two in Croatia and one in Spain. Our results show that patients with WHO grade 2 meningiomas had significantly higher HbA1c values compared to patients with grade 1 lesions (P = 0.0290). We also found a significant number of patients (19/71; 26.7%) being hyperglycemic, harboring all the risks that such a condition entails. Finally, we found a significant correlation between our patients' age and their preoperative HbA1c levels (P = 0.0008, ρ(rho) = 0.388), suggesting that older meningioma patients are at a higher risk of having their glycaemia severely dysregulated. These findings are especially important considering the current routine and wide-spread use of corticosteroids as anti-edematous treatment. Further research in this area could lead to better understanding of meningiomas and have immediate clinical impact.

CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling.

Many solid cancers including pancreatic ductal adenocarcinoma (PDAC) are characterized by an extensive stromal reaction that is accompanied by infiltrating tumor-associated macrophages (TAMs). The role of TAMs in malignant tumors is only partially understood. Previously, we identified the transcription factor CUX1 as an important mediator of tumor progression in PDAC. Interestingly, we found that CUX1 is highly expressed not only in tumor cells but also in TAMs. On the basis of these data, we aimed to elucidate the effects of CUX1 in TAMs in vitro and in vivo. We analyzed the effects of CUX1 on cytokine expression using overexpression and knockdown strategies. The cytokine regulation by CUX1 was further assessed by reporter assays, DNA pulldown experiments and chromatin-immunoprecipitation. CUX1 expression in TAMs was analyzed in human pancreatic cancer tissues and in a genetic mouse model. Immunohistochemical analysis revealed strong expression levels of CUX1 in a distinct subset of TAMs in human PDAC tissues. Furthermore, its expression increased during tumor progression in a genetic mouse model of PDAC. Profiling experiments showed that CUX1 downregulates several NF-κB-regulated chemokines such as CXCL10, which have been associated with M1 polarization and inhibition of angiogenesis and tumor progression. We could demonstrate that CUX1 interacts with NF-κB p65, leading to reduced binding of NF-κB p65 to the chemokine promoters. In addition, CUX1 reduces acetylation of NF-κB p65 at K310 by recruiting HDAC1. Functionally, CUX1 expression in TAMs antagonizes T-cell attraction and enhances angiogenesis in vitro. We identified CUX1 as an important modulator of the TAMs phenotype and function by modulating NF-κB-dependent cytokines.

Combined isotope and enantiomer analysis to assess the fate of phenoxy acids in a heterogeneous geologic setting at an old landfill.

Phenoxy acid herbicides and their potential metabolites represent industrial or agricultural waste that impacts groundwater and surface waters through leaching from old landfills throughout the world. Fate assessment of dichlorprop and its putative metabolite 4-CPP (2-(4-chlorophenoxy)propionic acid) is frequently obstructed by inconclusive evidence from redox conditions, heterogeneous geologic settings (e.g. clay till) and ambiguous parent-daughter relationships (i.e. 4-CPP may be daughter product or impurity of dichlorprop). For the first time, a combination of four methods was tested to assess transformation of phenoxy acids at a contaminated landfill (Risby site): analysis of (i) parent and daughter compound concentrations, (ii) enantiomer ratios (iii) compound-specific isotope analysis and (iv) enantiomer-specific isotope analysis. Additionally, water isotopes and chloride were used as conservative tracers to delineate two distinct groundwater flow paths in the clay till. Metabolite concentrations and isotope ratios of chlorinated ethenes demonstrated dechlorination activity in the area with highest leachate concentrations (hotspot) indicating favorable conditions also for dechlorination of dichlorprop to 4-CPP and further to phenoxypropionic acid. Combined evidence from concentrations, enantiomer ratios and isotope ratios of dichlorprop and 4-CPP confirmed their dechlorination in the hotspot and gave evidence for further degradation of 4-CPP downgradient of the hotspot. A combination of 4-CPP enantiomer and isotope analysis indicated different enantioselectivity and isotope fractionation, i.e. different modes of 4-CPP degradation, at different locations. This combined information was beyond the reach of any of the methods applied alone demonstrating the power of the new combined approach.

Prominent periventricular fiber system related to ganglionic eminence and striatum in the human fetal cerebrum.

Periventricular pathway (PVP) system of the developing human cerebrum is situated medial to the intermediate zone in the close proximity to proliferative cell compartments. In order to elucidate chemical properties and developing trajectories of the PVP we used DTI in combination with acetylcholinesterase histochemistry, SNAP-25 immunocytochemistry and axonal cytoskeletal markers (SMI312, MAP1b) immunocytochemistry on postmortem paraformaldehyde-fixed brains of 30 human fetuses ranging in age from 10 to 38 postconceptional weeks (PCW), 2 infants (age 1-3 months) and 1 adult brain. The PVP appears in the early fetal period (10-13 PCW) as two defined fibre bundles: the corpus callosum (CC) and the fetal fronto-occipital fascicle (FOF). In the midfetal period (15-18 PCW), all four components of the PVP can be identified: (1) the CC, which at rostral levels forms a voluminous callosal plate; (2) the FOF, with SNAP-25-positive fibers; (3) the fronto-pontine pathway (FPP) which for a short distance runs within the PVP; and (4) the subcallosal fascicle of Muratoff (SFM) which contains cortico-caudate projections. The PVPs are situated medial to the internal capsule at the level of the cortico-striatal junction; they remain prominent during the late fetal and early preterm period (19-28 PCW) and represent a portion of the wider periventricular crossroad of growing associative, callosal and projection pathways. In the perinatal period, the PVPs change their topographical relationships, decrease in size and the FOF looses its SNAP-25-reactivity. In conclusion, the hitherto undescribed PVP of the human fetal cerebrum contains forerunners of adult associative and projection pathways. Its transient chemical properties and relative exuberance suggest that the PVP may exert influence on the development of cortical connectivity (intermediate targeting) and other neurogenetic events such as neuronal proliferation. The PVP's topographical position also indicates that it is a major site of vulnerability in hypoxic-ischaemic perinatal brain injury.

Concentrations of particulate matter and arsenic in Bor (Serbia).

Measurements of air quality in the territory of Bor (Serbia) were performed at the sampling sites in the urban-industrial, suburban and rural area during the 2003-2008 period. A high level of arsenic (As) concentration in suspended particulate matter (PM) is of a predominantly industrial origin. The major source of pollution is the copper smelter which is situated in the close vicinity of the urban area of Bor. The ambient level of PM and As is influenced by meteorological parameters as well as the remoteness from the copper smelter. Continual exceedances of the annual limit value (LV) for As (6 ng m(-3)) were recorded at the sampling sites in the urban-industrial and suburban area. Maximum annual As concentrations were recorded at Town Park (46.5 ng m(-3)) in 2004, Institute (95.4 ng m(-3)) in 2004 and Jugopetrol (74.5 ng m(-3)) in 2003. In the past 15 years not a single mean annual As concentration recorded at the sampling sites Town Park, Institute and Jugopetrol has been within the LV. When the average annual and maximum monthly As concentrations are compared, it can be concluded that the level of pollution is higher in the urban-industrial and suburban areas than in the rural area.

Does Alzheimer's disease begin in the brainstem?

Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimer's disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high-order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake-sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging - Reagan Institute (NIA-RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, beta-amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD-related neuropathological changes.

Conventional conformal radiotherapy vs intracavitary brachytherapy for the adjuvant postoperative treatment of cervical cancer: a comparative dosimetric study.

OBJECTIVES: The aim of this pilot study is to evaluate the feasibility of 3D-conformal radiotherapy (3D-CRT) in the adjuvant postoperative radiotherapy of the vaginal cuff and upper third of present vaginal tissue. METHODS: The representative patient (FIGO IB; PH: squamous cell carcinoma) was referred for adjuvant post-hysterectomy radiotherapy. A whole pelvis irradiation with concomitant high-dose-rate intracavitary brachytherapy (HDR-ICBT) was applied. HDR-ICBT total dose of 24 Gy in four fractions/one fraction per week was delivered to the vaginal cuff using two Fletcher-Suit ovoids. The feasibility of change from HDR-ICBT to CRT was evaluated by generating of three different plans using 10 MV photon beams shaped by multileaf collimator. RESULTS AND DISCUSSION: The referent volume received HDR-ICBT prescribed dose. The maximum ICBT percentage dose to the rectum and urinary bladder was 101% and 106% respectively. In all 3D-CRT plans almost 100% of planning target volume (PTV) was covered by 95% therapy isodose surface. From 12 - 13% of the rectum and 1-3% urinary bladder volume were covered by 100% isodose surface, with the highest maximum dose of 104% and 101%, respectively. Comparison of the PTV dose coverage and the maximum dose to the rectum and urinary bladder for HDR-ICBT and 3D-CRT plans showed no major difference. CONCLUSION; 3D-CRT could be considered as adequate replacement for ICBT in the adjuvant postoperative treatment of the vaginal cuff and upper thi-rd of present vaginal tissue. Time-dose-fractionation pattern for HDR-ICBT may be safely applied for 3D-CRT.

Semiclassical Dirac theory of tunnel ionization.

We present analytic tunnel ionization rates for hydrogenlike ions in ultrahigh intensity laser fields, as obtained from a semiclassical solution of the three-dimensional Dirac equation. This presents the first quantitative determination of tunneling in atomic ions in the relativistic regime. Our theory opens the possibility to study strong laser field processes with highly charged ions, where relativistic ionization plays a dominant role.

Fractal and nonfractal analysis of cell images: comparison and application to neuronal dendritic arborization.

Neurons of the rat spinal cord were stained using the Golgi impregnation method. Successfully impregnated neurons from laminae II, III, and VI were subjected to fractal and nonfractal analyses. Fractal analysis was performed using length-related techniques. Since an application of fractal methods to the analysis of dendrite arbor structures requires caution, we adopted as appropriate a nonfractal method proposing a generalized power-law model with two main nonfractal parameters: (i) the anfractuosity, characterizing the degree of dendritic deviation from straight lines; and (ii) an estimate of the total length of arbor dendrites. The anfractuosity can distinguish between two sets of drawings where the fractal methods failed. We also redefine some basic concepts of fractal geometry, present the ruler-counting method, and propose a new definition of fractal dimension.

Development of a national protocol for a high activity (192)Ir brachytherapy source calibration.

PURPOSE: Determination of the air kinetic energy released in material (KERMA) rate (commonly named source strength) or a brachytherapy source activity represents one of the first steps in the acceptance, as well as in the periodic Quality Assurance (QA) testing procedures. In this paper, calibration of an (192)Ir high-dose rate (HDR) brachytherapy source is presented. MATERIALS AND METHODS: An (192)Ir HDR brachytherapy source calibration was carried out, with two independent procedures - calibration in water and in free air. The dosimeter used consisted of a thimble ionization chamber (NE 2571) and an electrometer (NE 2670). The reference air KERMA rate was calculated according to the International Atomic Energy Agency (IAEA) and the International Commission for Radiation Units and Measurements (ICRU) protocols. All physical quantities and correction factors used were determined, calculated, and re-checked for particular chamber and source type. RESULTS: In water, the reference air KERMA rate, determined by the IAEA protocol differed by +1.0% from the manufacturer's declared value and was measured with a relative error of 1%. The reference air KERMA rate, calculated by the ICRU protocol differed by -0.4% from the manufacturer's declared value and was measured with a relative error of 1.1%. In air, the value of the reference air KERMA rate, calculated by the IAEA protocol, differed by +1.6% from the manufacturer's declared value and was measured with a relative error of 1%. The value of the reference air KERMA rate for the same source, calculated by the ICRU protocol, differed by +1.1% from the manufacturer's declared value and was measured with a relative error of 0.9%. The results showed that application of the IAEA protocol gave higher values than the application of the ICRU protocol. It stands for both calibration methods. The difference between calibration protocols was not higher than 2% (in the water 1.4% and in the air 0.5%). Finally, calibration results showed that the difference between the calibration methods (in water and in air), for both calibration protocols, was not higher than 2%. For the IAEA protocol the difference was -0.6% and for the ICRU protocol it was -1.5%. We believe that benefits can be derived from the simultaneous application of both methods. CONCLUSION: A proposal of a national protocol represents an attempt to formulate a unique protocol for brachytherapy sources calibration in Serbia. The comparison of "in water" and "in free air" calibration has shown systematic differences of in-source strength of about 2%, respectively. It would be worth suggesting to radiotherapy centres to adopt the most optimal calibration method, based on well-known international protocols.

Attosecond metrology.

The generation of ultrashort pulses is a key to exploring the dynamic behaviour of matter on ever-shorter timescales. Recent developments have pushed the duration of laser pulses close to its natural limit-the wave cycle, which lasts somewhat longer than one femtosecond (1 fs = 10-15 s) in the visible spectral range. Time-resolved measurements with these pulses are able to trace dynamics of molecular structure, but fail to capture electronic processes occurring on an attosecond (1 as = 10-18 s) timescale. Here we trace electronic dynamics with a time resolution of

Immobilisation on polystyrene of diazirine derivatives of mono- and disaccharides: biological activities of modified surfaces.

The potential of surface glycoengineering for biomaterials and biosensors originates from the importance of carbohydrate-protein interactions in biological systems. The strategy employed here utilises carbene generated by illumination of diazirine to achieve covalent bonding of carbohydrates. Here, we describe the synthesis of an aryl diazirine containing a disaccharide (lactose). Surface analysis techniques [X-ray photoelectron spectroscopy (XPS) and time of flight secondary ion mass spectroscopy (ToF-SIMS)] demonstrate its successful surface immobilisation on polystyrene (PS). Results are compared to those previously obtained with an aryl diazirine containing a monosaccharide (galactose). The biological activity of galactose- or lactose-modified PS samples is studied using rat hepatocytes, Allo A lectin and solid-phase semi-synthesis with alpha-2,6-sialyltransferase. Allo A shows some binding to galactose-modified PS but none to lactose-modified surfaces. Similar results are obtained with rat hepatocytes. In contrast, sialylation of lactose-modified PS is achieved but not with galactose-modified surfaces. The different responses indicate that the biological activity depends not only on the carbohydrate per se but also on the structure and length of the spacer.

Lead stimulates intercellular signalling between hepatocytes and Kupffer cells.

The role of intercellular signalling between liver cells in lead (Pb)(1)-induced liver toxicity was investigated in cocultures of freshly isolated and cultured rat hepatocytes and Kupffer cells. The Kupffer cells (seeded onto culture dish inserts), the hepatocytes or the two in cocultures were exposed to Pb acetate (2-50 microM) in combination with lipopolysaccharide (0.1-1000 ng/ml). In hepatocyte cultures, the combined Pb/lipopolysaccharide treatment induced no significant increase in the release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) whereas in Kupffer cell cultures and in cocultures, at low lipopolysaccharide levels (0.1 and 1 ng/ml), TNF-alpha release was synergistically increased (up to 30-fold) when compared to lipopolysaccharide exposure alone. This stimulation of Kupffer cell-derived TNF-alpha release was specific for Pb or not detectable with mercury and cadmium. As a response to the Pb/lipopolysaccharide induced release of TNF-alpha, the cocultured hepatocytes increased their nitric oxide (NO) content sixfold when compared with lipopolysaccharide alone and downregulated the negatively regulated acute phase protein albumin. This downregulation was also detectable without lipopolysaccharide and without TNF-alpha release, indicating that Pb induces additional thus far unidentified Kupffer cell-derived factors, which interact with the cocultured hepatocytes. At the time of TNF-alpha release, the viability of the hepatocytes and the Kupffer cells was not affected. However, after a 48-h treatment period, Pb induced a Kupffer cell specific toxicity without affecting the hepatocytes. Loss of hepatocyte viability after lipopolysaccharide/Pb stimulation was only detectable in the presence of cocultured Kupffer cells together with human-derived granulocytes. It is concluded that Pb stimulates intercellular signalling between Kupffer cells and hepatocytes which is synergistically enhanced in the presence of low lipopolysaccharide levels. The released Kupffer cell-derived signals (e.g. cytokines) promotes most likely proteolytic hepatocyte killing in combination with a direct cellular interaction between the granulocytes and the hepatocytes.

Optical pulse compression: bulk media versus hollow waveguides.

Optical pulse-compression systems based on bulk materials and hollow waveguides are compared by use of coupled-mode theory. Our analysis reveals an intuitive picture of the temporal and spatial nonlinear processes involved in pulse compression. Further, simple formulas are derived that give an estimate of the spatial distortions and of the self-phase modulation induced by Kerr nonlinearity. Finally, a parameter regime is identified in which self-focusing in bulk media is suppressed, resulting in a substantial improvement in the spatial beam quality of the compressed pulses.

[Effect of dunce and amnesiac genes on signal learning in Drosophila melanogaster: experiments with odors]. / Vliianie genov dunce i amnesiac na signal'noe obuchenie u plodovykh myshek Drosophila melanogaster: éksperimenty s zapakhami.

The behavior of normal Drosophila and of X-linked olfactory conditioning mutants, dunce and amnesiac, was analyzed using an olfactory search task. Normal (C-S) flies quickly learn and remember which of two odors signals the presence of food and they are capable of retaining this information for at last eight hours. Both dunce and amnesiac mutants are able to learn, whereas mutant dunce do not reach the learning level of wild type C-S flies. Also dunce flies require more than one learning trial for sizeable learning effect. Reversal learning experiments showed that normal C-S flies and amnesiac are able to switch to a new food signal in response to a new experience, while the dunce mutation inhibits the acquisition of new information in reversal learning experiments.

Kupffer cell-mediated differential down-regulation of cytochrome P450 metabolism in rat hepatocytes.

Nonparenchymal cells, particularly Kupffer cells, might play an important role in the modulation of xenobiotic metabolism in liver and its pharmacological and toxicological consequences. This intercellular communication via the exchange of soluble factors was investigated in primary rat Kupffer cells and hepatocytes. Freshly isolated rat Kupffer cells were seeded onto cell culture inserts and cocultured with 5 day old serum-free rat hepatocyte monolayer cultures at a ratio of 1:1 for 2 days. Hepatocyte cultures, Kupffer cell cultures or cocultures were treated with 0.1 ng/ml-10 microg/ml lipopolysaccharide (LPS). Within this concentration range, no significant toxicity was observed in either cell type. In LPS-exposed cocultures, tumor necrosis factor alpha (TNFalpha) levels rose up to 5 ng/ml within 5 h; nitric oxide (NO) levels increased up to 70 microM within 48 h of treatment, both in a dose-dependent fashion. The release of negative (albumin) and positive (alpha1-acid-glycoprotein) acute phase proteins from the hepatocytes was strongly down- and up-regulated, respectively. The simultaneous treatment of the cocultures with phenobarbital and LPS (10 ng/ml) or 3-methylcholanthrene and LPS (10 ng/ml) resulted in a strong down-regulation (85%) of the phenobarbital-induced cytochrome P450 (CYP) isoform CYP2B1 in the hepatocytes whereas the 3-methylcholanthrene-induced isoform CYP1A1 was only weakly affected (15%). This specific down-regulation of CYP2B1 was mediated exclusively by TNFalpha, released from the Kupffer cells. It was not linked with NO release from or inducible NO synthase activity in the hepatocytes. The TNFalpha release was not affected by the two xenobiotics. Acetaminophen tested in these cocultures showed no direct interaction with the Kupffer cells. The use of liver cell cocultures is therefore a useful approach to investigate the influence of intercellular communication on xenobiotic metabolism in liver.

[Cocultures between primary parenchymal and nonparenchymal liver cells improve the reliability of results from in vitro toxicity testing] / Kokulturen zwischen primären parenchymalen und nichtparenchymalen Leberzellen der Ratte verbessern die Aussagekraft von organspezifischen in vitro Toxizitätstests.

Conventional homotypic hepatocyte cultures do not include the possible contribution of nonparenchymal liver cells, particularly Kupffer cells, to the pharmacological and toxicological consequences after exposure to xenobiotics. Therefore the exchange of soluble factors between liver cells was investigated in cocultures between primary, freshly isolated cultured rat hepatocytes and Kupffer cells. Cocultures were exposed to endotoxins in combination with phenobarbital, 3-methylcholanthrene or lead. A strong but selective down-regulation of xenobiotic induced cytochrome P450 isoforms was detectable, mediated exclusively by TNFalphareleased from the Kupffer cells. Pb synergistically increased this endotoxin induced TNFalpha-release. The results indicate that cocultures improve the reliability of data obtained from organ specific cell cultures and that they simulate much closer the situation in the intact liver.