Perivascular vital cells in the ablation center after multibipolar radiofrequency ablation in an in vivo porcine model.

Multibipolar radiofrequency ablation (RFA) is an advanced ablation technique for early stage hepatocellular carcinoma and liver metastases. Vessel cooling in multibipolar RFA has not been systematically investigated. The objective of this study was to evaluate the presence of perivascular vital cells within the ablation zone after multibipolar RFA. Multibipolar RFA were performed in domestic pigs in vivo. Three internally cooled bipolar RFA applicators were used simultaneously. Three experimental settings were planned: (1) inter-applicator-distance: 15 mm; (2) inter-applicator-distance: 20 mm; (3) inter-applicator-distance: 20 mm with hepatic inflow occlusion (Pringle maneuver). A vitality staining was used to analyze liver cell vitality around all vessels in the ablation center with a diameter > 0.5 mm histologically. 771 vessels were identified. No vital tissue was seen around 423 out of 429 vessels (98.6%) situated within the central white zone. Vital cells could be observed around major hepatic vessels situated adjacent to the ablation center. Vessel diameter (> 3.0 mm; p < 0.05) and low vessel-to-ablation-center distance (< 0.2 mm; p < 0.05) were identified as risk factors for incomplete ablation adjacent to hepatic vessels. The vast majority of vessels, which were localized in the clinically relevant white zone, showed no vital perivascular cells, regardless of vessel diameter and vessel type. However, there was a risk of incomplete ablation around major hepatic vessels situated directly within the ablation center. A Pringle maneuver could avoid incomplete ablations.

Influence of interapplicator distance on multibipolar radiofrequency ablation during physiological and interrupted liver perfusion in an in vivo porcine model.

Radiofrequency ablation (RFA) is a curative treatment option for early stage hepatocellular carcinoma (HCC). Vascular inflow occlusion to the liver (Pringle manoeuvre) and multibipolar RFA (mbRFA) represent possibilities to generate large ablations. This study evaluated the impact of different interapplicator distances and a Pringle manoeuvre on ablation area and geometry of mbRFA. 24 mbRFA were planned in porcine livers in vivo. Test series with continuous blood flow had an interapplicator distance of 20 mm and 15 mm, respectively. For a Pringle manoeuvre, interapplicator distance was predefined at 20 mm. After liver dissection, ablation area and geometry were analysed macroscopically and histologically. Confluent and homogenous ablations could be achieved with a Pringle manoeuvre and an interapplicator distance of 15 mm with sustained hepatic blood flow. Ablation geometry was inhomogeneous with an applicator distance of 20 mm with physiological liver perfusion. A Pringle manoeuvre led to a fourfold increase in ablation area in comparison to sustained hepatic blood flow (p < 0.001). Interapplicator distance affects ablation geometry of mbRFA. Strict adherence to the planned applicator distance is advisable under continuous blood flow. The application of a Pringle manoeuvre should be considered when compliance with the interapplicator distance cannot be guaranteed.

A diagnostic evaluation of modeled mercury wet depositions in Europe using atmospheric speciated high-resolution observations.

This study is part of the Global Mercury Observation System (GMOS), a European FP7 project dedicated to the improvement and validation of mercury models to assist in establishing a global monitoring network and to support political decisions. One key question about the global mercury cycle is the efficiency of its removal out of the atmosphere into other environmental compartments. So far, the evaluation of modeled wet deposition of mercury was difficult because of a lack of long-term measurements of oxidized and elemental mercury. The oxidized mercury species gaseous oxidized mercury (GOM) and particle-bound mercury (PBM) which are found in the atmosphere in typical concentrations of a few to a few tens pg/m(3) are the relevant components for the wet deposition of mercury. In this study, the first European long-term dataset of speciated mercury taken at Waldhof/Germany was used to evaluate deposition fields modeled with the chemistry transport model (CTM) Community Multiscale Air Quality (CMAQ) and to analyze the influence of the governing parameters. The influence of the parameters precipitation and atmospheric concentration was evaluated using different input datasets for a variety of CMAQ simulations for the year 2009. It was found that on the basis of daily and weekly measurement data, the bias of modeled depositions could be explained by the bias of precipitation fields and atmospheric concentrations of GOM and PBM. A correction of the modeled wet deposition using observed daily precipitation increased the correlation, on average, from 0.17 to 0.78. An additional correction based on the daily average GOM and PBM concentration lead to a 50% decrease of the model error for all CMAQ scenarios. Monthly deposition measurements were found to have a too low temporal resolution to adequately analyze model deficiencies in wet deposition processes due to the nonlinear nature of the scavenging process. Moreover, the general overestimation of atmospheric GOM by the CTM in combination with an underestimation of low precipitation events in the meteorological models lead to a good agreement of total annual wet deposition besides the large error in weekly deposition estimates. Moreover, it was found that the current speciation profiles for GOM emissions are the main factor for the overestimation of atmospheric GOM concentrations and might need to be revised in the future. The assumption of zero emissions of GOM lead to an improvement of the mean normalized bias for three-hourly observations of atmospheric GOM from 9.7 to 0.5, Furthermore, the diurnal correlation between model and observation increased from 0.01 to 0.64. This is a strong indicator that GOM is not directly emitted from primary sources but is mainly created by oxidation of GEM.

Acetylcholinesterase-R increases germ cell apoptosis but enhances sperm motility.

Changes in protein subdomains through alternative splicing often modify protein-protein interactions, altering biological processes. A relevant example is that of the stress-induced up-regulation of the acetylcholinesterase (AChE-R) splice variant, a common response in various tissues. In germ cells of male transgenic TgR mice, AChE-R excess associates with reduced sperm differentiation and sperm counts. To explore the mechanism(s) by which AChE-R up-regulation affects spermatogenesis, we identified AChE-R's protein partners through a yeast two-hybrid screen. In meiotic spermatocytes from TgR mice, we detected AChE-R interaction with the scaffold protein RACK1 and elevated apoptosis. This correlated with reduced scavenging by RACK1 of the pro-apoptotic TAp73, an outcome compatible with the increased apoptosis. In contrast, at later stages in sperm development, AChE-R's interaction with the glycolytic enzyme enolase-alpha elevates enolase activity. In transfected cells, enforced AChE-R excess increased glucose uptake and adenosine tri-phosphate (ATP) levels. Correspondingly, TgR sperm cells display elevated ATP levels, mitochondrial hyperactivity and increased motility. In human donors' sperm, we found direct association of sperm motility with AChE-R expression. Interchanging interactions with RACK1 and enolase-alpha may hence enable AChE-R to affect both sperm differentiation and function by participating in independent cellular pathways.

Comment on "temperature dependence of the Casimir effect".

Recently, Brevik [Phys. Rev. E, 71, 056101 (2005)] adduced arguments against the traditional approach to the thermal Casimir force between real metals and in favor of one of the alternative approaches. The latter assume zero contribution from the transverse electric mode at zero frequency in qualitative disagreement with unity as given by the thermal quantum field theory for ideal metals. Those authors claim that their approach is consistent with experiments as well as with thermodynamics. We demonstrate that these conclusions are incorrect. We show specifically that their results are contradicted by four recent experiments and also violate the third law of thermodynamics (the Nernst heat theorem).

Persistent activation of NF-kappa B by the tax transforming protein involves chronic phosphorylation of IkappaB kinase subunits IKKbeta and IKKgamma.

The Tax transforming protein encoded by human T-cell leukemia virus type 1 (HTLV1) persistently activates transcription factor NF-kappaB and deregulates the expression of downstream genes that mediate cell cycle entry. We recently found that Tax binds to and chronically stimulates the catalytic function of IkappaB kinase (IKK), a cellular enzyme complex that phosphorylates and inactivates the IkappaB inhibitory subunit of NF-kappaB. We now demonstrate that the IKKbeta catalytic subunit and IKKgamma regulatory subunit of IKK are chronically phosphorylated in HTLV1-infected and Tax-transfected cells. Alanine substitutions at Ser-177 and Ser-181 in the T loop of IKKbeta protect both of these IKK subunits from Tax-directed phosphorylation and prevent the induction of IkappaB kinase activity. Each of these inhibitory effects is recapitulated in Tax transfectants expressing the bacterial protein YopJ, a potent in vivo agonist of T loop phosphorylation. Moreover, ectopically expressed forms of IKKbeta that contain glutamic acid substitutions at Ser-177 and Ser-181 have the capacity to phosphorylate a recombinant IKKgamma substrate in vitro. We conclude that Tax-induced phosphorylation of IKKbeta is required for IKKbeta activation, phosphoryl group transfer to IKKgamma, and acquisition of the deregulated IKK phenotype.

Casimir force at both nonzero temperature and finite conductivity.

We find the combined effect of nonzero temperature and finite conductivity onto the Casimir force between real metals. Configurations of two parallel plates and a sphere (lens) above a plate are considered. Perturbation theory in two parameters (the relative temperature and the relative penetration depth of zero-point oscillations into the metal) is developed. Perturbative results are compared with computations. Recent improper computations based on the Lifshitz formula for the temperature Casimir force are discussed.

Targeting sigma receptor-binding benzamides as in vivo diagnostic and therapeutic agents for human prostate tumors.

Sigma receptors are known to be expressed in a variety of human tumor cells, including breast, neural, and melanoma tumors. A very high density (1.0-1.5 million receptors/cell) of sigma receptors was also reported in a human androgen-dependent prostate tumor cell line (LNCaP). In this study, we show that a very high density of sigma receptors is also expressed in an androgen-independent human prostate tumor cell line (DU-145). Pharmacological binding studies using the sigma-1-selective ligand [3H](+)-pentazocine showed a high-affinity binding (Kd = 5.80 nM, Bmax = 1800 fmol/mg protein). Similarly, binding studies with [3H]1,3-di-o-tolylguanidine in the presence of dextrallorphan also showed a high-affinity binding (Kd = 15.71 nM, Bmax = 1930 fmol/mg protein). Radioiodinated benzamide N-[2-(1'-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide ([125I]PIMBA) was also shown to bind DU-145 cells in a dose-dependent manner. Three different radioiodinated benzamides, [125I]PIMBA, 4-[125I]iodo-N-[2-(1'-piperidinyl)ethyl]benzamide, and 2-[125I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide, were screened for their potential to image human prostate tumors in nude mice bearing human prostate cells (DU-145) xenografts. All three compounds showed a fast clearance from the blood pool and a high uptake and retention in the tumor. Therapeutic potential of nonradioactive PIMBA was studied using in vitro colonogenic assays. A dose-dependent inhibition of cell colony formation was found in two different human prostate cells. These results demonstrate the potential use of sigma receptor binding ligands in non-invasive diagnostic imaging of prostate cancer and its treatment.

Synthesis, in vitro pharmacologic characterization, and preclinical evaluation of N-[2-(1'-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide (P[125I]MBA) for imaging breast cancer.

The goal of this study was to investigate the potential use of a radioiodinated benzamide, N-[2-(1'-piperidinyl)ethyl]-3-iodo[125I]-4-methoxybenzamide (P[125I]MBA), a sigma receptor binding radioligand for imaging breast cancer. The chemical and radiochemical syntheses of PIMBA are described. The pharmacological evaluation of PIMBA was carried out for sigma-1 and sigma-2 receptor sites. The in vivo pharmacokinetics of the radioiodinated benzamide were determined in rats and comparison of P[125I]MBA with Tc-99m sestamibi were made in a rat mammary tumor model. Sigma-1 affinity (Ki) for PIMBA in guinea pig brain membranes using [3H](+)pentazocine was found to be 11.82 +/- 0.68 nM, whereas sigma-2 affinity in rat liver using [3H]DTG (1,3-o-di-tolylguanidine) was 206 +/- 11 nM. Sites in guinea pig brain membranes labeled by P[125I]MBA showed high affinity for haloperidol, (+)-pentazocine, BD1008, and PIMBA (Ki = 4.87 +/- 1.49, 8.81 +/- 1.97, 0.057 +/- 0.005, 46.9 +/- 1.8 nM, respectively). Competition binding studies were carried out in human ductal breast carcinoma cells (T47D). A dose-dependent inhibition of specific binding was observed with several sigma ligands. Ki values for the inhibition of P[125I]MBA binding in T47D cells for haloperidol, N-[2-(1'-piperidinyl)]ethyl]4-iodobenzamide (IPAB), N-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), and PIMBA were found to be 1.30 +/- 0.07, 13 +/- 1.5, 5.19 +/- 2.3, 1.06 +/- 0.5 nM, respectively. The in vitro binding data in guinea pig brain membranes and breast cancer cells confirmed binding to sigma sites. The saturation binding of P[125I]MBA in T47D cells as studied by Scatchard analysis showed saturable binding, with a Kd = 94 +/- 7 nM and a Bmax = 2035 +/- 305 fmol/mg of proteins. Biodistribution studies in Sprague-Dawley rats showed a rapid clearance of P[125I]MBA from the normal organs. The potential of PIMBA in imaging breast cancer was evaluated in Lewis rats bearing syngeneic RMT breast cancers, a cancer that closely mimics human breast cancer histology. At 1 h postinjection, tumor uptake for P[125I]MBA and Tc-99m sestamibi were found to be 0.35 +/- 0.01 and 0.32 +/- 0.01% injected dose/organ (%ID/g), respectively. The %ID/g for liver, kidneys, and heart were 2, 11, and 20 times lower, respectively, for P[125I]MBA as compared with Tc-sestamibi. Slightly higher uptake of P[125I]MBA in tumors (than Tc-sestamibi) and a low nontarget organ uptake warrants further studies of this and other sigma receptor ligands for their use as breast cancer imaging agents.

High-Temperature In Situ Straining Experiments in the High-Voltage Electron Microscope.

: Design rules are described here for high-temperature straining stages for transmission electron microscopy. Temperatures above 1000 degreesC can be attained by electron bombardment of the specimen grips. Thermal equilibrium can be reached in a short time by carrying off the heat by water cooling. Some applications of this stage are described. Ferroelastic deformation was observed at 1150 degreesC in t' and partially stabilized zirconia, which changes the microstructure for successive dislocation plasticity. In the oxide-dispersion-strengthened alloy INCOLOY MA 956, dislocations are impeded by oxide particles and move smoothly between the particles. At high temperatures, both the resting and traveling times control the average dislocation velocity. In MoSi2 single crystals of a soft orientation, dislocations with 1/2<111> Burgers vectors are created in localized sources and move on {110} planes in a viscous manner. The dislocations in Al-Pd-Mn single quasicrystals are oriented in preferred crystallographic directions and move in a viscous way as well. On the basis of in situ observations, conclusions are drawn for interpreting macroscopic deformation behavior at high temperatures.

Substituted halogenated arylsulfonamides: a new class of sigma receptor binding tumor imaging agents.

The discovery of a series of novel halogenated arylsulfonamides (HAS) as new sigma receptor binding tumor imaging agents is described. Several substituted halogenated sulfonamides have been prepared and characterized. Target compounds were examined for their affinity for sigma1 and sigma2 receptor subtypes using guinea pig brain membranes and rat liver membranes, respectively. A number of substituted halogenated sulfonamides displayed subnanomolar affinities for sigma1 sites and low nanomolar affinities for sigma2 subtype receptors. A limited structure-activity relationship study of this chemical series is discussed. The radioiodination (I-125) of one congener member (4-[125I]iodo-N-[2-(1'-piperidinyl)ethyl]benzenesulfonamide, 4-[125I]IPBS) was accomplished in high yields. The in vitro competition binding studies of 4-[125I]IPBS in guinea pig brain membranes with sigma receptor binding ligands confirmed its sigma pharmacology. The rank order of potency was BD1008 (N-[2-(3, 4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) > 4-IPBS > haloperidol > (+)-pentazocine > DTG (1, 3-di-o-tolylguanidine) > (-)-pentazocine. The inhibition constants (IC50) were 0.70, 1.46, 6.28, 10.4, 87.2, and 152 nM, respectively, and are consistent with labeling of sigma1 receptors. The tumor imaging potential of 4-[125I]IPBS was studied in C57 black mice bearing B16 melanoma xenograft. A high tumor uptake of 4-[125I]IPBS was observed (7.40% ID/g) at 1 h postinjection. The wash out of activity from the tumor was slow at 6 h postinjection (7.22% ID/g). The tumor also had the highest amount of radioactivity (1.54% ID/g) at 24 h postinjection. These results demonstrate that radiohalogenated benzenesulfonamides could be a potentially useful class of compounds in nuclear oncologic scintigraphy.

99mTc-labeled sigma-receptor-binding complex: synthesis, characterization, and specific binding to human ductal breast carcinoma (T47D) cells.

sigma-Receptors have recently been shown to be expressed in a variety of human tumor cells. In an attempt to prepare 99mTc chelates that would bind to sigma-receptors and be useful for imaging sigma-receptor-positive tumors, we have synthesized and characterized a bisaminothiol (BAT) chelate appended with a sigma-receptor pharmacophore. The synthesis of target ligand VII was accomplished in three steps starting from bicyclic imidazolidino[1,2-d]dithiazapine. The labeling of the BAT ligand with 99mTc was carried out in high yields (> 80%) using stannous tartarate as a reducing agent, resulting in the target sigma-receptor-binding chelate [99mTc]BAT-EN6, III. Similarly, 99gTc chelate with ligand VII was prepared from ammonium pertechnetate by reduction with stannous tartarate. 99nTc-radiolabeled chelate was purified by reversed phase HPLC, and cell binding with human breast ductal carcinoma (T47D) was performed. A high degree of specific binding (90-97%) was obtained when sigma-receptor ligands such as halogenated phenylethylenediamines were used to determine nonspecific binding. A modest affinity dose-dependent inhibition of binding was found with BD1008, I, and 4-IPEMP, II (IC50 = 47 +/- 2 and 59 +/- 5 nM, respectively), known sigma-ligands. No specific binding was found with [99mTc]BAT, VIII [without appended sigma-pharmacophore (N-alkyl-substituted ethylenediamine)], showing that biological activity resulted from the pendent pharmacophore. 99gTc complex was found to be a potent inhibitor (Ki = 42.7 +/- 8.5 nM) of [3H]DTG binding in guinea pig brain membranes. Scatchard analysis of [99mTc]BAT-EN6 (spiked with [99gTc]BAT-EN6) binding in T47D breast cancer cells showed a saturable binding, with a Kd of 43.5 +/- 14.7 nM and a Bmax of 3121 +/- 130 fmol/(mg of protein). A biodistribution study of [99mTc]BAT-EN6 chelates in Sprague Dawley rats showed hepatic clearance, as expected. A blocking study at 4 h postinjection using 2 mumol of BD1008 with [99mTc]BAT-EN6 showed a significant decrease of radiopharmaceutical in liver (15.32 vs 22.31% ID/organ) and kidney (1.01 vs 2.21% ID/ organ), organs known to possess high concentrations of sigma-receptors. These results imply that [99mTc]BAT-EN6 binds with high affinity to sigma-receptors expressed in human breast tumor cells, and it may be useful for imaging breast cancer.

[Ultrasonic studies in reptiles]. / Ultraschalluntersuchung bei Reptilien.

Ultrasonography in reptiles is a safe, noninvasive repeatable diagnostic imagine method. Size, volume and inner structure of organs can easily be determined. Based on 460 ultrasonographic examinations in 8 species of terrapins, 12 species of snakes and 22 species of lizard normal appearance of heart, gonads, fat bodies, kidneys, bladder and gastrointestinal tract are described. Pathological findings are explained in details using examples.

[Orthopedic treatment of regular dorsal and dorsolumbar hyperkyphosis. New principles of active correction]. / Traitement orthopédique des hypercyphoses dorsales et dorso-lombaires régulières. Nouveaux principes de correction active.

The orthopaedic treatment of hyper-kyphosis should not be unique. If the principles of treatment are different in relation with the thoracic or thoraco-lumbar localisation of the apex of the deformity, it is necessary to distinguish for the middle thoracic curve two types of patients: these in whom the kyphosis and the lordosis are balanced (the cast must diminish the lumbar lordosis and the imbalanced posterior types with a great kyphotic curve and a short compensatory lordosis which is important not to be diminish by the treatment. The principles of plaster casting are described in the two types; emphasizing on the unlucky aspect of the sternal support in the middle thoracic kyphosis and in the necessity of the thoracic modification if we wish to obtain a good result. The active expiratory reeducation is capital before and during the treatment.