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The ventral tegmental area (VTA) is involved in adaptive reward and motivation processing and is composed of dopamine (DA) and GABA neurons. Defining the elements regulating activity and synaptic plasticity of these cells is critical to understanding mechanisms of reward and addiction. While endocannabinoids (eCBs) that potentially contribute to addiction are known to be involved in synaptic plasticity mechanisms in the VTA, where they are produced is poorly understood. In this study, DA and GABAergic cells were identified using electrophysiology, cellular markers, and a transgenic mouse model that specifically labels GABA cells. Using single-cell RT-qPCR and immunohistochemistry, we investigated mRNA and proteins involved in eCB signaling such as diacylglycerol lipase α, N-acyl-phosphatidylethanolamine-specific phospholipase D, and 12-lipoxygenase, as well as type I metabotropic glutamate receptors (mGluRs). Our results demonstrate the first molecular evidence of colocalization of eCB biosynthetic enzyme and type I mGluR mRNA in VTA neurons. Further, these data reveal higher expression of mGluR1 in DA neurons, suggesting potential differences in eCB synthesis between DA and GABA neurons. These data collectively suggest that VTA GABAergic and DAergic cells have the potential to produce various eCBs implicated in altering neuronal activity or plasticity in adaptive motivational reward or addiction.

In molecular imaging, multimodal imaging agents can provide complementary information, for improving the accuracy of disease diagnosis or enhancing patient management. In particular, optical/nuclear imaging may find important preclinical and clinical applications. To simplify the preparation of dual-labeled imaging agents, we prepared versatile monomolecular multimodal imaging probe (MOMIP) platforms containing both a fluorescent dye (BODIPY) and a metal chelator (polyazamacrocycle). One of the MOMIP was conjugated to a cyclopeptide (i.e., octreotide) and radiolabeled with (111) In. In vitro and in vivo studies of the resulting bioconjugate were conducted, highlighting the potential of these BODIPY-based bimodal probes. This work also confirmed that the biovector and/or the bimodal probes must be chosen carefully, due to the impact of the MOMIP on the overall properties of the resulting imaging agent., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We present a method to control the interfacial tension of a liquid alloy of gallium via electrochemical deposition (or removal) of the oxide layer on its surface. In sharp contrast with conventional surfactants, this method provides unprecedented lowering of surface tension (∼ 500 mJ/m(2) to near zero) using very low voltage, and the change is completely reversible. This dramatic change in the interfacial tension enables a variety of electrohydrodynamic phenomena. The ability to manipulate the interfacial properties of the metal promises rich opportunities in shape-reconfigurable metallic components in electronic, electromagnetic, and microfluidic devices without the use of toxic mercury. This work suggests that the wetting properties of surface oxides--which are ubiquitous on most metals and semiconductors--are intrinsic "surfactants." The inherent asymmetric nature of the surface coupled with the ability to actively manipulate its energetics is expected to have important applications in electrohydrodynamics, composites, and melt processing of oxide-forming materials.

The Cherenkov radiation (CR) from [(18)F]-FDG, [(177)Lu]-LuCl3 and [(90)Y]-YCl3 was detected and CR energy transfer (CRET) to several fluorophores was examined. Subsequent fluorescence emission was found to be a function of the position of absorption bands with respect to the CR peak, energy of emitted particles, radionuclide/fluorophore loading, and fluorophore brightness. A variant of the best fluorophore with a built-in radionuclide was synthesized to achieve inter- and intra-molecular CRET.

Objectives: The composite radial forearm flap is a surgical option in the reconstruction of large traumatic or oncologic orofacial defects. Nevertheless, it has been criticized for its poor bone transport faculties that would make this flap insufficient in large osseous mandibular reconstructions, or for oral prosthetic rehabilitation with dental implants. What is more, the morbidity of the donor site has often been pointed. The aim of this radioanatomic study was to revisit the vascularization of the composite radial forearm flap, focusing on the bone stick., Methods: A radioanatomic study was performed on seven upper limbs taken from fresh cadavers. First, the vessels were washed with a 40°C solution of potassium acetate. Then an intra-arterial injection of a mixture of lead oxide and agar-agar was performed. 3D-CT-scan examinations of the anatomical pieces were performed. In a second step, the flaps were harvested and analyzed with a Microscan examination (NanoSPECT-CT Bioscan(®), voxel 220 microns). Collateral branches of the radial artery to the bone and the skin were counted and classified., Results: One radial diaphyseal artery was present in all the cases. The nutrient foramen took place at the anteromedial aspect of the diaphysis, between 45 and 65 % of the length of the bone. A dense anastomotic periosteal network was highlightened, supplied by one to four musculoperiosteal branches, and one to six fascio-periosteal arteries arising from the radial artery. A total of mean five osseous branches, and 12 cutaneous branches have been observed., Conclusions: The results of the present preclinical study suggested that a 16-cm bone stick could be harvested with an optimal vascular safety, without consideration for the morbidity at the donor site. The original approach in this study, relating anatomy to the preclinical imaging, allowed a precise visualization of the microvascularization of the soft and hard tissues. It opened a field of innovative research in plastic and reconstructive surgery., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

We examined copper (Cu) absorption, distribution and toxicity and the role of a silicon (Si) supplementation in the bamboo Phyllostachys fastuosa. Bamboos were maintained in hydroponics for 4 months and submitted to two different Cu (1.5 and 100 μm Cu(2+)) and Si (0 and 1.1 mM) concentrations. Cu and Si partitioning and Cu speciation were investigated by chemical analysis, microscopic and spectroscopic techniques. Copper was present as Cu(I) and Cu(II) depending on plant parts. Bamboo mainly coped with high Cu exposure by: (i) high Cu sequestration in the root (ii) Cu(II) binding to amino and carboxyl ligands in roots, and (iii) Cu(I) complexation with both organic and inorganic sulfur ligands in stems and leaves. Silicon supplementation decreased the visible damage induced by high Cu exposure and modified Cu speciation in the leaves where a higher proportion of Cu was present as inorganic Cu(I)S compounds, which may be less toxic., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Lipopolysaccharides (LPS) or endotoxins are amphipathic, pro-inflammatory components of the outer membrane of Gram-negative bacteria. In the host, LPS can trigger a systemic inflammatory response syndrome. To bring insight into in vivo tissue distribution and cellular uptake of LPS, dual labeling was performed with a bimodal molecular probe designed for fluorescence and nuclear imaging. LPS were labeled with DOTA-Bodipy-NCS, and pro-inflammatory properties were controlled after each labeling step. LPS were then radiolabeled with (111)In and subsequently injected intravenously into wild-type, C57B16 mice, and their in vivo behavior was followed by single photon emission computed tomography coupled with X-ray computed tomography (SPECT-CT) and fluorescence microscopy. Time course of liver uptake of radiolabeled LPS ((111)In-DOTA-Bodipy-LPS) was visualized over a 24-h period in the whole animal by SPECT-CT. In complementary histological analyses with fluorescent microscopy, the bulk of injected (111)In-DOTA-Bodipy-LPS was found to localize early within the liver. Serum kinetics of unlabeled and DOTA-Bodipy-labeled LPS in mouse plasma were similar as ascertained by direct quantitation of β-hydroxymyristate, and DOTA-Bodipy-LPS was found to retain the potent, pro-inflammatory property of the unlabeled molecule as assessed by serum cytokine assays. It is concluded that the dual labeling process, involving the formation of covalent bonds between a DOTA-Bodipy-NCS probe and LPS molecules is relevant for imaging and kinetic analysis of LPS biodistribution, both in vivo and ex vivo. Data of the present study come in direct and visual support of a lipopolysaccharide transport through which pro-inflammatory LPS can be transported from the periphery to the liver for detoxification. The (111)In-DOTA-Bodipy-LPS probe arises here as a relevant tool to identify key components of LPS detoxification in vivo.

The objective of this study was to investigate the role of the CeO2 nanoparticle (NP) surface charge and the presence of natural organic matter (NOM) in determining bioavailability and toxicity to the model soil organism Caenorhabditis elegans. We synthesized CeO2-NPs functionalized with positively charged, negatively charged, and neutral coatings. The positively charged CeO2-NPs were significantly more toxic to C. elegans and bioaccumulated to a greater extent than the neutral and negatively charged CeO2-NPs. Surface charge also affected the oxidation state of Ce in C. elegans tissues after uptake. Greater reduction of Ce from Ce (IV) to Ce (III) was found in C. elegans, when exposed to the neutral and negatively charged relative to positively charged CeO2-NPs. The addition of humic acid (HA) to the exposure media significantly decreased the toxicity of CeO2-NPs, and the ratio of CeO2-NPs to HA influenced Ce bioaccumulation. When the concentration of HA was higher than the CeO2-NP concentration, Ce bioaccumulation decreased. These results suggest that the nature of the pristine coatings as a determinant of hazard may be greatly reduced once CeO2-NPs enter the environment and are coated with NOM.

Purpose: Micro-CT is considered to be a powerful tool to investigate various models of disease on anesthetized animals. In longitudinal studies, the radiation dose delivered by the micro-CT to the same animal is a major concern as it could potentially induce spurious effects in experimental results. Optically stimulated luminescence dosimeters (OSLDs) are a relatively new kind of detector used in radiation dosimetry for medical applications. The aim of this work was to assess the dose delivered by the CT component of a micro-SPECT (single-photon emission computed tomography)∕CT camera during a typical whole-body mouse study, using commercially available OSLDs based on Al2O3:C crystals., Methods: CTDI (computed tomography dose index) was measured in micro-CT with a properly calibrated pencil ionization chamber using a rat-like phantom (60 mm in diameter) and a mouse-like phantom (30 mm in diameter). OSLDs were checked for reproducibility and linearity in the range of doses delivered by the micro-CT. Dose measurements obtained with OSLDs were compared to those of the ionization chamber to correct for the radiation quality dependence of OSLDs in the low-kV range. Doses to tissue were then investigated in phantoms and cadavers. A 30 mm diameter phantom, specifically designed to insert OSLDs, was used to assess radiation dose over a typical whole-body mouse imaging study. Eighteen healthy female BALB∕c mice weighing 27.1 ± 0.8 g (1 SD) were euthanized for small animal measurements. OLSDs were placed externally or implanted internally in nine different locations by an experienced animal technician. Five commonly used micro-CT protocols were investigated., Results: CTDI measurements were between 78.0 ± 2.1 and 110.7 ± 3.0 mGy for the rat-like phantom and between 169.3 ± 4.6 and 203.6 ± 5.5 mGy for the mouse-like phantom. On average, the displayed CTDI at the operator console was underestimated by 1.19 for the rat-like phantom and 2.36 for the mouse-like phantom. OSLDs exhibited a reproducibility of 2.4% and good linearity was found between 60 and 450 mGy. The energy scaling factor was calculated to be between 1.80 ± 0.16 and 1.86 ± 0.16, depending on protocol used. In phantoms, mean doses to tissue over a whole-body CT examination were ranging from 186.4 ± 7.6 to 234.9 ± 7.1 mGy. In mice, mean doses to tissue in the mouse trunk (thorax, abdomen, pelvis, and flanks) were between 213.0 ± 17.0 and 251.2 ± 13.4 mGy. Skin doses (3 OSLDs) were much higher with average doses between 350.6 ± 25.3 and 432.5 ± 34.1 mGy. The dose delivered during a topogram was found to be below 10 mGy. Use of the multimouse bed of the system gave a significantly 20%-40% lower dose per animal (p < 0.05)., Conclusions: Absorbed doses in micro-CT were found to be relatively high. In micro-SPECT∕CT imaging, the micro-CT unit is mainly used to produce a localization frame. As a result, users should pay attention to adjustable CT parameters so as to minimize the radiation dose and avoid any adverse radiation effects which may interfere with biological parameters studied.

Due to its high growth rate and biomass production, bamboo has recently been proven to be useful in wastewater treatment. Bamboo accumulates high silicon (Si) levels in its tissues, which may improve its development and tolerance to metal toxicity. This study investigates the effect of Si supplementation on bamboo growth and copper (Cu) sensitivity. An 8-month hydroponic culture of bamboo Gigantocloa sp. "Malay Dwarf " was performed. The bamboo plants were first submitted to a range of Si supplementation (0-1.5 mM). After 6 months, a potentially toxic Cu concentration of 1.5 μM Cu(2+) was added. Contrary to many studies on other plants, bamboo growth did not depend on Si levels even though it absorbed Si up to 218 mg g(-1) in leaves. The absorption of Cu by bamboo plants was not altered by the Si supplementation; Cu accumulated mainly in roots (131 mg kg(-1)), but was also found in leaves (16.6 mg kg(-1)) and stems (9.8 mg kg(-1)). Copper addition did not induce any toxicity symptoms. The different Cu and Si absorption mechanisms may partially explain why Si did not influence Cu repartition and concentration in bamboo. Given the high biomass and its absorption capacity, bamboo could potentially tolerate and accumulate high Cu concentrations making this plant useful for wastewater treatment.

Dysregulation in patterns of alternative RNA splicing in cancer cells is emerging as a significant factor in cancer pathophysiology. In this study, we investigated the little known alternative splice isoform survivin-3B (S-3B) that is overexpressed in a tumor-specific manner. Ectopic overexpression of S-3B drove tumorigenesis by facilitating immune escape in a manner associated with resistance to immune cell toxicity. This resistance was mediated by interaction of S-3B with procaspase-8, inhibiting death-inducing signaling complex formation in response to Fas/Fas ligand interaction. We found that S-3B overexpression also mediated resistance to cancer chemotherapy, in this case through interactions with procaspase-6. S-3B binding to procaspase-6 inhibited its activation despite mitochondrial depolarization and caspase-3 activation. When combined with chemotherapy, S-3B targeting in vivo elicited a nearly eradication of tumors. Mechanistic investigations identified a previously unrecognized 7-amino acid region as responsible for the procancerous properties of survivin proteins. Taken together, our results defined S-3B as an important functional actor in tumor formation and treatment resistance., (©2013 AACR.)

Four experiments investigated the effects on speech intelligibility of reverberation, sound source locations, and amplitude modulation of the interferers. Speech reception thresholds (SRTs) were measured using headphones and stimuli that simulated real-room listening, considering one or two interferers which were stationary or speech-modulated noises. In experiment 1, SRTs for modulated noises showed little variation with increasing interferer reverberation. Reverberation might have increased masking by filling in the modulated noise gaps, but simultaneously changed the noise spectra making them less effective maskers. In experiment 2, SRTs were lower when measured using a unique one-voice modulated interferer rather than a different interferer for each target sentence, suggesting that listeners could take advantage of the predictability of the interferer gaps. In experiment 3, increasing speech reverberation did not significantly affect the difference of SRTs measured with stationary and modulated noises, indicating that the ability to exploit noise modulations was still useful for temporally smeared speech. In experiment 4, spatial unmasking remained constant when applying modulations to the interferers, suggesting an independence of the abilities to exploit these modulations and the spatial separation of sources. Finally, a model predicting binaural intelligibility for modulated noises was developed and provided a good fit to the experimental data.

Reported outbreaks of Vibrio parahaemolyticus have increased worldwide, particularly in regions of high seafood consumption. In Mozambique, seafood constitutes an important food resource and diarrheal diseases are common among its inhabitants. Edible clams were collected in Maputo Bay during both the dry and rainy seasons, with the results showing the number of viable counts of vibrios in clams to peak during the latter. Vibrio parahaemolyticus was the predominant species identified among the isolated strains. Although only one of 109 total strains carried the tdh virulence gene, 69% of isolates showed evidence of hemolytic capacity when subjected to a functional test. Similar virulence patterns and biochemical properties were found in strains isolated from Indian and Swedish marine waters. Antibiotic resistance was, however, more pronounced in strains isolated from these latter two environments., (© 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

Sex determination is known to be male heterogametic in the rainbow trout, Oncorhynchus mykiss; however, scattered observations that deviate from this rather strict genetic control have been reported. Here, we provide a detailed morphological and histological characterization of the gonadal differentiation and development (from 43 days postfertilization to 11 months of age) in an all-female (XX) population with a genetically governed masculinization phenotype. In comparison with control males and females, the gonadal differentiation in these animals was characterized by many perturbations, including significantly fewer germ cells. This decrease in germ cells was confirmed by the significantly decreased expression of 2 germ cell maker genes (vasa and sycp3) in the masculinized XX populations as compared with the control females and control males. Although only a proportion of the total adult population was partially or fully masculinized, this early differentiating phenotype affected nearly all the sampled animals. This suggests that the adult masculinization phenotype is the consequence of an early functional imbalance in ovarian differentiation in the entire population. We hypothesize that the lower number of germ cells that we observed in this population could be one cause of their masculinization., (Copyright © 2013 S. Karger AG, Basel.)

Purpose: The aim of our work is to evaluate the added diagnostic value of respiratory gated (4-D) positron emission tomography/computed tomography (PET/CT) in lung lesion detection/characterization in a large patient population of a multicentre retrospective study., Methods: The data of 155 patients (89 men, 66 women, mean age 63.9 ± 11.1 years) from 5 European centres and submitted to standard (3-D) and 4-D PET/CT were retrospectively analysed. Overall, 206 lung lesions were considered for the analysis (mean ± SD lesions dimension 14.7 ± 11.8 mm). Maximum standardized uptake values (SUV(max)) and lesion detectability were assessed for both 3-D and 4-D PET/CT studies; 3-D and 4-D PET/CT findings were compared to clinical follow-up as standard reference., Results: Mean ± SD 3-D and 4-D SUV(max) values were 5.2 ± 5.1 and 6.8 ± 6.1 (p < 0.0001), respectively, with an average percentage increase of 30.8 %. In 3-D PET/CT, 86 of 206 (41.7 %) lesions were considered positive, 70 of 206 (34 %) negative and 50 of 206 (24.3 %) equivocal, while in 4-D PET/CT 117 of 206 (56.8 %) lesions were defined as positive, 80 of 206 (38.8 %) negative and 9 of 206 (4.4 %) equivocal. In 34 of 50 (68 %) 3-D equivocal lesions follow-up data were available and the presence of malignancy was confirmed in 21 of 34 (61.8 %) lesions, while in 13 of 34 (38.2 %) was excluded. In 31 of these 34 controlled lesions, 20 of 34 (58.8 %) and 11 of 34 (32.4 %) were correctly classified by 4-D PET/CT as positive and negative, respectively; 3 of 34 (8.8 %) remained equivocal. With equivocal lesions classified as positive, the overall accuracy of 3-D and 4-D was 85.7 and 92.8 %, respectively, while the same figures were 80.5 and 94.2 % when equivocal lesions were classified as negative., Conclusion: The respiratory gated PET/CT technique is a valuable clinical tool in diagnosing lung lesions, improving quantification and confidence in reporting, reducing 3-D undetermined findings and increasing the overall accuracy in lung lesion detection and characterization.

Improved bifunctional chelating agents (BFC) are required for indium-111 radiolabeling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific agents. 2,2',2"-(10-(2,6-Dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTAGA-anhydride) was evaluated for mAb conjugation and labeling with indium-111. The DOTA analogue was synthesized and conjugated to trastuzumab-which targets the HER2/neu receptor-in mild conditions (PBS pH 7.4, 25 °C, 30 min) and gave a mean degree of conjugation of 2.6 macrocycle per antibody. Labeling of this immunoconjugate with indium-111 was performed in 75% yield after 1 h at 37 °C, and the proportion of (111)In-DOTAGA-trastuzumab reached 97% after purification. The affinity of DOTAGA-trastuzumab was 5.5 ± 0.6 nM as evaluated by in vitro saturation assays using HCC1954 breast cancer cell line. SPECT/CT imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumors were clearly visualized on SPECT images at 24, 48, and 72 h postinjection. The tumor uptake of [(111)In-DOTAGA]-trastuzumab reached 65%ID/g 72 h postinjection. These results show that the DOTAGA BFC appears to be a valuable tool for biologics conjugation.

During the summer of 2006, several wound infections - of which three were fatal - caused by Vibrio cholerae were reported from patients who had been exposed to water from the Baltic Sea. Before these reports, we initiated a sampling project investigating the occurrence of potential human pathogenic V. cholerae, Vibrio vulnificus and Vibrio parahaemolyticus in The Sound between Sweden and Denmark. The Blue mussel (Mytilus edulis) was used as an indicator to follow the occurrence of vibrios over time. Molecular analyses showed high frequencies of the most potent human pathogenic Vibrio spp.; 53% of mussel samples were positive for V. cholerae (although none were positive for the cholera toxin gene), 63% for V. vulnificus and 79% for V. parahaemolyticus (of which 47% were tdh(+) and/or trh(+)). Viable vibrios were also isolated from the mussel meat and screened for virulence by PCR. The mortality of eukaryotic cells when exposed to bacteria was tested in vivo, with results showing that the Vibrio strains, independent of species and origin, were harmful to the cells. Despite severe infections and several deaths, no report on potential human pathogenic vibrios in this area had been published before this study., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

Vibrio abundance generally displays seasonal patterns. In temperate coastal areas, temperature and salinity influence Vibrio growth, whereas in tropical areas this pattern is not obvious. The present study assessed the dynamics of Vibrio in the Arabian Sea, 1-2 km off Mangalore on the south-west coast of India, during temporally separated periods. The two sampling periods were signified by oligotrophic conditions, and stable temperatures and salinity. Vibrio abundance was estimated by culture-independent techniques in relation to phytoplankton community composition and environmental variables. The results showed that the Vibrio density during December 2007 was 10- to 100-fold higher compared with the February-March 2008 period. High Vibrio abundance in December coincided with a diatom-dominated phytoplankton assemblage. A partial least squares (PLS) regression model indicated that diatom biomass was the primary predictor variable. Low nutrient levels suggested high water column turnover rate, which bacteria compensated for by using organic molecules leaking from phytoplankton. The abundance of potential Vibrio predators was low during both sampling periods; therefore it is suggested that resource supply from primary producers is more important than top-down control by predators., (© 2011 Society for Applied Microbiology and Blackwell Publishing Ltd.)

Ventral tegmental area (VTA) GABA neurons appear to be critical substrates underlying the acute and chronic effects of ethanol on dopamine (DA) neurotransmission in the mesocorticolimbic system implicated in alcohol reward. The aim of this study was to examine the role of midbrain connexin-36 (Cx36) gap junctions (GJs) in ethanol intoxication and consumption. Using behavioral, molecular, and electrophysiological methods, we compared the effects of ethanol in mature Cx36 knockout (KO) mice and age-matched wild-type (WT) controls. Compared to WT mice, Cx36 KO mice exhibited significantly more ethanol-induced motor impairment in the open field test, but less disruption in motor coordination in the rotarod paradigm. Cx36 KO mice, and WT mice treated with the Cx36 antagonist mefloquine (MFQ), consumed significantly less ethanol than their WT controls in the drink-in-the-dark procedure. The firing rate of VTA GABA neurons in WT mice was inhibited by ethanol with an IC₅₀ of 0.25 g/kg, while VTA GABA neurons in KO mice were significantly less sensitive to ethanol. Dopamine neuron GABA-mediated sIPSC frequency was reduced by ethanol (30 mM) in WT mice, but not affected in KO mice. Cx36 KO mice evinced a significant up-regulation in DAT and D2 receptors in the VTA, as assessed by quantitative RT-PCR. These findings demonstrate the behavioral relevance of Cx36 GJ-mediated electrical coupling between GABA neurons in mature animals, and suggest that loss of coupling between VTA GABA neurons results in disinhibition of DA neurons, a hyper-DAergic state and lowered hedonic valence for ethanol consumption., (Copyright © 2010 Wiley-Liss, Inc.)

An equine fetlock joint pendulum test was studied and the influence of post mortem time and intra-articular lipid solvent on the viscous frictional response examined. Fresh equine digits (group 1, n=6 controls; group 2, n=6 lipid solvent) were mounted on a pendulum tribometer. Assuming that pendular joint damping could be modelled by a harmonic oscillator fluid damping (HOFD), damping time (τ), viscous damping coefficient (c) and friction coefficient (μ) were monitored for 5h under experimental conditions (400N; 20°C). In all experiments, pendular joint damping was found to follow an exponential decay function (R(2)=0.99714), which confirmed that joint damping was fluid. The evolution of τ, c and μ was found to be significantly (P<0.05) different in the two groups, with a decrease in τ and an increase in c and μ that was faster and more prominent in digits from group 2. It was concluded that pendular joint damping could be modelled by a HOFD model. The influence of post mortem time on results suggested that, ideally, joint mechanical properties should only be tested on fresh cadavers at the same post mortem time. Moreover, the addition of lipid solvent was found to be responsible for upper viscous friction parameters and for a reduced damping time, which suggested that articular lubricating ability was compromised. This equine pendulum test could be used to test the efficacy of various bio-lubricant treatments., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: Asymmetric dimethylarginine (ADMA) is an endogenous modulator of endothelial function and oxidative stress, and increased levels of this molecule have been reported in some metabolic disorders and cardiovascular diseases. The aim of this work was to analyze the time course of dimethylarginine compounds and oxidative stress levels and the relationship between these and cardiovascular function in fructose-hypertensive rats., Methods and Results: 90 male Sprague-Dawley rats were randomized into 2 groups, fed for 3 months with standard (C) chow supplemented or not with fructose (F, 60%). After sacrifice at different weeks (W), the aorta and plasma were harvested to assess the vascular and biochemical parameters. Our work showed that the plasma levels of ADMA in the fructose-fed rats increased after 2 weeks of the diet (1.6 ± 0.3 μM vs. 1.2 ± 0.3 μM, p < 0.05) with no changes in plasma levels of either SDMA or L-arginine and after an increase in glycemia. Levels of vascular oxidative stress, estimated in aortic segments using an oxidative fluorescence technique, were higher in the F group (W2: 1.14 ± 0.2% vs. 0.33 ± 0.02%, p < 0.01). An increase in expression levels of nitrotyrosine (3-fold) and iNOS (2-fold) were noted in the fructose-fed rats. After 1 month, this was associated with a significant increase in NAD(P)H oxidase activity. Concerning vascular function, a 15% decrease in maximal endothelium-dependent relaxation was found in the aorta of the F group. Our work showed that the presence of exogenous L-MMA, an inhibitor of NO synthase, was associated with a significant reduction in endothelium-dependent relaxation in isolated aorta rings of the C group; this effect was not observed in the vessels of fructose-fed rats., Conclusion: Our findings suggest that the elevated levels of ADMA observed could in part be secondary to the early development of oxidative stress associated with the development of hypertension., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Aims: There is conflicting evidence regarding the relationship between hypercholesterolemia and oxidative stress in vessels. To test the potential relationship, a mouse model of hypercholesterolemia was used., Methods: Low density lipoprotein receptor-deficient (LDLR(-/-)) and control (C57Bl/6) mice were fed a normal or (1.25%) high-cholesterol (HC) diet for 8 weeks, and the incidence of this chronic diet was evaluated on the degree of vascular oxidative stress and vascular structure (collagen content and lipid infiltration expressed in arbitrary units: AU=%/mm(2))., Results: Animals treated with the HC diet presented an increase in lipid infiltration (0.35±0.13 vs. 1.7±0.18 control and 1.04±0.16 vs. 1.84±0.23 LDLR(-/-), AU p<0.05) associated with higher collagen content (control: 2.13±0.40 vs. 3.46±0.36 and LDLR(-/-): 2.37±0.36 vs. 3.79±0.60; AU p<0.05 red Sirius staining). Interestingly, ROS production in the aorta was only increased in the LDLR(-/-) +cholesterol group (0.17±0.04 and 0.16±0.05 in the control groups, 0.14±0.02 vs. 0.34±0.06 in the LDLR(-/-) groups, p<0.05). C57Bl/6 and LDLR(-/-) mice presented altered vascular structure associated with the rich cholesterol diet, which was not necessarily associated with increased oxidative stress., Conclusion: These findings highlight the complex interrelation between oxidative stress and lipid metabolism in the circulatory tract., (Copyright © 2011 S. Karger AG, Basel.)

Aims: Despite the results of recent randomised studies, the systematic use of aspiration techniques in ST-elevation myocardial infarction has not been included in the new guidelines. To date, there have been very few bench tests of the different systems and the aim of our study was to test two catheters on different models of arteries with thrombi at six and 12 hours., Methods and Results: The test apparatus consisted of 3 mm diameter glass tubes of 150 mm in length. The thrombi were left for either six or 12 hours and ten models of tubes were used: straight, with a single bend and with two bends. Two types of catheters were tested: the Export® aspiration catheter (EAC) and the Proxis® embolic protection system (PES). The main assessment criterion was total thrombectomy. Total thrombectomy was achieved in only 55.3% of the tests and no difference appeared between the two systems. Total thrombectomy was achieved more frequently with 6-hour thrombi than with 12-hour thrombi for the two techniques, 62.5% vs. 42.5% (p = 0.018) and 67.5% vs. 48.7% (p = 0.025) for EAC and PES catheter, respectively. In contrast, total thrombectomy was more frequent in straight tubes and in tubes with a single bend than in tubes with double bends, respectively for EAC (64% vs. 44.8%, p = 0.028) and for PES (85.9% vs. 35.4%, p < 0.001)., Conclusions: The use of thrombectomy in the invasive management of acute coronary syndromes is growing. Our work on a "laboratory bench" reveals important technical differences. In consequence, in clinical practice, we speculate that the catheter system must be chosen according to both the artery anatomy and the delay between chest pain and PCI.

Reasons for Performing Study: Whereas the effect of heel configuration on the tension of the suspensory apparatus is well documented in the literature, there are few reports of joint contact force components in the equine distal forelimb., Objectives: To improve understanding of the effect of heel configuration on equine digit joint loading, a sensitivity analysis was performed to compare the effect of a raised heel on joint contact force components in the coffin and fetlock joints during the stance phase of the trot., Materials and Methods: Four Warmblood horses were used. An inverse dynamic analysis was carried out using kinematic and kinetic data. Taking into account the tendon wrapping forces (WF) around the sesamoid bones in the calculations, the joint contact forces (CF) were estimated for the coffin and fetlock joints during the trot stance phase (4 m/s). To test the sensitivity of the results to heel configuration changes, calculations were performed repeatedly for different heel configurations (raised by 0, 6 and 12°). A one-way ANOVA with repeated measures was used to test the effect of heel configuration (at the 3 levels) (α = 0.05; P < 0.05; post hoc testing: Bonferroni)., Results: For heel configurations raised from 0-12°: whereas the tension of the deep digital flexor tendon decreased and the tension of the superficial digital flexor tendon increased, for the coffin joint the peak WF (1.4 ± 0.25 bwt; 1.2 ± 0.2 bwt; 0.95 ± 0.1 bwt) and the peak CF (2.45 ± 0.25 bwt; 2.2 ± 0.2 bwt; 2 ± 0.1 bwt) decreased significantly (P < 0.05). For the fetlock joint, the peak WF (3.8 ± 0.7 bwt; 4.1 ± 0.3 bwt; 4.4 ± 0.25 bwt) and the peak CF (4.35 ± 0.7 bwt; 4.7 ± 0.35 bwt; 5 ± 0.3 bwt) increased, but not significantly., Conclusion: This analysis suggests that the coffin joint loading and fetlock joint loading are strongly connected. The heel configuration may influence both coffin joint and fetlock joint contact force components., (© 2010 EVJ Ltd.)

Background: Sarcoidosis is a multisystem granulomatous disease of unknown aetiology, which most often involves the lungs and lymphatic system. Cutaneous involvement is found in approximately 25% of cases of sarcoid. Most previous studies of cutaneous sarcoidosis have been drawn from populations with defined pulmonary disease, so may represent a population with more systemic involvement., Objective: We describe a cohort of patients with cutaneous sarcoid seen in a dermatology department., Methods: Case records were reviewed for patients with a histopathological diagnosis of noncaseating sarcoidal granuloma on skin biopsy, taken between 1996 and 2005., Results: In total, 34 patient records were analysed; 21 patients were found to have extracutaneous systemic sarcoid and 10 patients had sarcoid localized to the skin. Patients with lupus pernio and with ulcerated sarcoid lesions all had extracutaneous disease. No other cutaneous features, including the extent of cutaneous disease, were found to be predictive of systemic involvement., Conclusions: All patients presenting to a dermatology department with cutaneous sarcoidal granulomas require investigation for systemic sarcoid. Our data suggest that approximately 30% of patients seen in a dermatology clinic with cutaneous sarcoidal granulomas will have disease apparently limited to the skin.

This study describes an equine joint friction test using a cartilage-on-cartilage arrangement and investigates the influence of age and load on the frictional response. Osteochondral plugs were extracted from equine shoulder joints (2-5 years, n=12; 10-14 years, n=15), and mounted in a pin-on-disc tribometer. The frictional response was then measured under constant conditions (2N; 20 degrees C; 5 mm/s), and with increasing load (2N, 5N, 10N). In all experiments, the friction coefficient of young cartilage was significantly (P<0.001) smaller than obtained from old cartilage, while the application of a greater load resulted in a significant (P<0.001) decrease in friction coefficient only in old cartilage. It was concluded that cartilage ageing was responsible for an increase in friction coefficient under these experimental conditions. Moreover, where young cartilage lubrication remained stable, cartilage ageing may have been responsible for lubrication regime change. The cartilage-on-cartilage model could be used to better understand lubrication regime disturbances in healthy and diseased equine joints, and to test the efficacy of various bio-lubricant treatments., (Copyright (c) 2008 Elsevier Ltd. All rights reserved.)

Background: Conflicting evidence is reported about the beneficial effects of post-conditioning (Post-C) in pathologic conditions. A pathologic mouse model of hypercholesterolemia was used. The study examined the effect of Post-Con cardiac recovery after the ischemia-reperfusion sequence and the effect of Post-Con on low-density lipoprotein receptor-deficient (LDLR(-/-)) mice and control animals., Methods: LDLR(-/-) and C57bl/6 mice were fed for 8 weeks with a high-cholesterol (1.25%) or normal diet. The hearts were isolated and perfused on a working heart apparatus. The hearts underwent 20 minutes of global total ischemia, followed by 36 minutes of reperfusion. Post-Con was applied at the onset of reperfusion with three 10-second cycles of ischemia-reperfusion. Tissue injury was evaluated (triphenyl-tetrazolium chloride staining), and superoxide anion production was assessed (dihydroethidium)., Results: Post-ischemia recovery was very low in the control and LDLR(-/-) groups, and Post-C induced an increase in functional recovery (p < 0.05). The high-cholesterol groups showed better cardiac recovery, but Post-C did not accentuate this improvement. Post-C was associated with a significant reduction in tissue injury and superoxide production in LDLR(-/-) and C57bl/6 (p < 0.05), but these effects were not observed in animals fed the high-cholesterol diet., Conclusions: Our results demonstrated that control and LDLR(-/-) mice may be protected by Post-C, and an 8-week high-cholesterol diet led to improved recovery of the myocardium after the ischemia-reperfusion sequence in both series. However, the endogenous protective mechanism of Post-C appears to be lost in the presence of hypercholesterolemia.

Restenosis after the implantation of a drug-eluting stent or after vascular irradiation therapy shares similar physiopathological mechanisms. No experimental data are currently available on vascular wall behavior after external irradiation on arteries stented with sirolimus-eluting stents (SES). Ten New Zealand white rabbits received a 0.5% cholesterol-enriched chow for 1 month. Bilateral iliac artery stent implantation was then performed with an SES (Cypher; Cordis Corp). The animals were randomized into either an irradiated group (I, 2 Gy external x-ray irradiation, n = 5) or a control group (C, n = 5). The cholesterol-enriched chow was continued for 1 additional month after stent implantation. The stented arteries were harvested for histological analyses. The number and the percentage of incompletely apposed stents struts (IASS) were significantly higher in irradiated versus control group (3.05 +/- 0.46 vs. 1.57 +/- 0.27 IASS, P < 0.01, and 28.44% +/- 3.97% vs. 15.2% +/- 2.46% of IASS, P < 0.01, respectively). The mean neointimal thickness behind the IASS was also higher in the irradiated group (I: 28.3 +/- 2.5 microm vs. C: 18.2 +/- 2.3 microm, P < 0.01). Re-endothelialization was lower in irradiated group (I: 44.6% +/- 17.5% vs. C: 75.2% +/- 5.7%, P < 0.01). The present study revealed that low-dose external irradiation increased incomplete stent apposition and reduced re-endothelialization of SES. These results underscore the potential deleterious cumulative side effects of these 2 procedures to prevent restenosis.

Background: Severe plaque psoriasis in childhood has a significant morbidity and can warrant the use of systemic agents, although there are no published clinical trials in this group., Objectives: We report a series of 13 children with severe plaque psoriasis treated with low-dose once-weekly methotrexate., Methods: We reviewed the notes of all 13 children treated with low-dose methotrexate at Birmingham Children's Hospital., Results: Of the 13 patients reviewed, 11 responded with clearance of psoriasis, leaving small residual plaques. Five patients are currently maintained on methotrexate. Three patients needed two courses of methotrexate and one needed three courses, with treatment-free intervals of between 9 and 22 months. One patient stopped treatment due to rises in the results of liver function tests (LFTs) at 6 weeks, and one patient stopped the second course of methotrexate after two doses because of slightly raised baseline LFT results. There were no other adverse events., Conclusions: We propose that when carefully monitored, methotrexate can be a safe and efficacious treatment option for severe psoriasis in children as well as in adults. Obesity may be a relative contraindication, as associated nonalcoholic fatty liver disease is likely to increase hepatotoxicity.

To evaluate the mechanisms and the impact of the angiotensin-converting enzyme inhibitor perindopril (P) in a model of doxorubicin (D)-induced cardiotoxicity, male Wistar rats received D (1 mg/kg/d, IP for 10 days), P (2 mg/kg/d by gavage from day 1 to day 18), D (for 10 days) + P (for 18 days) or saline. D decreased systolic blood pressure and body and heart weights. Left ventricular diastolic diameter was increased by D (P < 0.01), but it was not attenuated by P. D decreased plasma vitamin C (P < 0.05) and increased the ascorbyl radical/vitamin C ratio (P < 0.01). This ratio was attenuated by P. No difference was found among groups in cardiac troponin I, brain natriuretic peptide concentrations, and tissue oxidative stress (OS). Myocardial MCP-1 expression was higher in the D group. Cardiac kinin receptor (B1R and B2R) expression was not affected by D, yet binding sites for B2R and B1R were increased in D+P and P groups, respectively (P < 0.05). In conclusion, D induced cardiac functional alterations, inflammation and plasma OS whereas tissue OS, and cardiac kinin receptors expression were not modified. P did not improve cardiac performance, but it modulated kinin receptor expression and enhanced antioxidant defense.

Background: There is at present a tragic lack of organs available for transplantation. This has led to the harvesting of hearts from older donors. Unfortunately, hearts from such donors are much more sensitive to ischemic insult. Models such as "Senescence Accelerated Mouse" Prone 8 (SAM-P8) can help understand this sensitivity. New cardioprotective techniques such as postconditioning (PostC) could be of interest in this context. We studied (1) senescence in vessels and hearts and (2) the ability of the senescent heart to adapt to an ischemia-reperfusion (I/R) sequence in the context of PostC., Methods: Isolated working mouse hearts (8 months) were subjected to total ischemia, followed by 36 min of reperfusion; PostC was performed in the first minutes of reperfusion as three 10-sec sequences of I/R. Superoxide anion (O2.-) production was evaluated on heart and aorta cryosections with the dihydroethidium staining method. The collagen content in aortas was quantified., Results: The aortas of SAM-P8 mice showed a higher production of O2.- and a higher collagen content than did those of SAM-R1 mice (P<0.05). During reperfusion, SAM-P8 hearts showed the worst recovery of cardiac output. PostC significantly reduced reperfusion dysfunction (P<0.05) and was associated with a reduction in heart O2.- staining., Conclusions: These results indicate that SAM-P8 presents a high degree of cardiovascular oxidative stress and a higher susceptibility to I/R injury, which confirms the senescence of the cardiovascular system in these animals. However, they remain sensitive to cardioprotection afforded by in vitro PostC.

Background: Methotrexate is frequently used in dermatology practice and is potentially toxic. Prescribing and monitoring strategies have evolved over time and many areas of practice remain controversial and without firm evidence base., Objectives: To document current U.K. prescribing and monitoring practice and to identify variations in practice., Methods: A postal questionnaire was sent, in a single mailshot, in January 2004 to the entire consultant membership (n = 531) of the British Association of Dermatologists., Results: We received a response rate of 71%. The majority of respondents prescribed for small numbers of patients and 81% reported using a patient information sheet. Almost all monitored full blood count, liver function tests and urea, electrolytes and creatinine, and 71% measured aminoterminal peptide of type III procollagen levels. We identified a wide range of practice in the use of liver biopsy. In terms of adverse events, 12% reported experience of patients developing irreversible liver damage (severity not defined). Forty-nine deaths were reported, of which 18 were due to myelosuppression, six to possible pulmonary fibrosis, two to liver failure in the absence of reported alcohol consumption and four as a consequence of liver biopsy., Conclusions: We have documented wide variations in methotrexate prescribing and monitoring practice. We compare reported practice with current guidelines and highlight the importance of monitoring for myelosuppression.

We report an activating fibroblast growth factor receptor 3 (FGFR3) mutation (R248C) occurring in a verrucous epidermal naevus, and not found in other tissues, in a girl with mild facial dysmorphism. We demonstrate the presence of the mutation in keratinocytes cultured from the naevus and we speculate that a low level of the mutation in other tissues may account for her facial dysmorphism. The possibility that the mutation is present in other tissues implies a possible risk to her future offspring.

Objective: Hypercholesterolemia (HC) has been associated with impairment of vascular and myocardial functions. As HC could generate an alteration in the oxidative status, we studied the effects of a 1-month cholesterol diet on cardiovascular oxidative stress., Methods and Results: New Zealand rabbits received cholesterol (1%) or normal chow for 1 month. At 30 days, superoxide anion levels, assessed by ESR spectroscopy, NAD(P)H oxidase (NOX) activity, and dihydroethidium (DHE) staining of aortas were higher in the cholesterol-fed (CF) group compared with control (respectively, 4.0 +/- 0.6 Arbitrary Units/mg (AU/mg) vs. 2.6 +/- 0.3, p < 0.05; 4231 +/- 433 vs. 2931 +/- 373 AU/mg, p<0.05; 21.4 +/- 1.2 vs. 12.9 +/- 1.7% fluorescence/mm2, p < 0.001). NOX gp91 phox and p67 phox expression in the aortas were higher in the CF group vs. control (1.5 +/- 0.2 vs. 0.5 +/- 0.2, p < 0.001; 0.9 +/- 0.2 vs. 0.3 +/- 0.2, p<0.05). The endothelium-dependent relaxation evaluated on the iliac arteries was higher in control than in the CF group (64.8 +/- 10.1 vs. 13.1 +/- 3.70%, p<0.001). The cardiac diastolic pressure estimated on isolated hearts was higher in the CF group than in control (21.1 +/- 4.1 vs. 10.3 +/- 1.4 mmHg, p<0.05) after 60 min of ischemia., Conclusions: Hypercholesterolemia induced increased levels of superoxide in the aortas and a higher expression of NOX subunits, associated with altered vasorelaxation. The increased diastolic pressure observed in hearts, consistent with a post-ischemic contractile dysfunction might be mediated by the production of superoxide.

The aim of our study was to explore some potential pleïotropic effects of atorvastatin, after stenting in the iliac arteries of normocholesterolemic rabbits. On day 0, 27 rabbits underwent stent implantation and were randomized into either the control group (standard chow, CTRL, n = 15) or the atorvastatin group (10 mg/kg/d per os, Ator, n = 12). On day 30, the stented arteries were harvested for histomorphometry and neointimal analysis [macrophages, matrix metalloproteinases (MMP-2), tissue inhibitor of metalloproteinase-2, vascular smooth muscle cells, and collagen]. Atorvastatin did not induce significant histomorphometric and inflammatory modifications but reduced neointimal expression of MMP-2 with no modification of tissue inhibitor of metalloproteinase-2, and also induced higher neointimal collagen content (Ator vs. CTRL: MMP-2: 0.05 +/- 0.03 vs. 0.70 +/- 0.20, P < 0.01; collagen: 17.0+/-0.7%/mm vs. 12.0 +/- 1.2%/mm(2) P < 0.01). Atorvastatin treatment also induced a significant decrease in neointimal vascular smooth muscle cells and cellular density (respectively: 2.0 +/- 0.2 vs. 1.4 +/- 0.2, P < 0.05; 5406 +/- 241 nuclei/mm(2) vs. 4402 +/- 163 nuclei/mm(2), P < 0.001). Our study provides new insights into the field of MMP response to stenting and the effects of statin therapy, which could have important implications in the field of in-stent restenosis.

Thrombus removal by aspiration is one of the adjunctive techniques used to avoid embolization during PCI for acute myocardial infarction. Numerous devices are now available, but little is known about the mechanical rationale used in comparing them. The aim of the present study was to determine parameters to obtain optimal thrombus aspiration (TA). Heparin- and antiplatelet-free blood samples were aspirated into 3 mm diameter standardized glass tubes to create a 30 mm long thrombus. Thrombus formation took place at room temperature over a period of 6 or 12 hr. Various catheters were tested using a variable vacuum device: three with right-angle distal tip (0.038'', 0.067'', and 0.070'') and one with a beveled distal (length of the beveled, 0.054''; inner diameter catheter, 0.040''). The single endpoint was complete thrombus aspiration. A total of 103 TAs were presented for the four catheters. For 6- or 12-hr-old thrombus for a given catheter, there was no significant difference in vacuum pressure required to succeed TA (P = 0.47). For 6- or 12-hr-old thrombus, the larger the contact area is, the lower the pressure needed to aspirate the thrombus. Moreover, a beveled distal tip length (0.054'') does not make it possible to succeed TA at a lower pressure. The main factor for successful TA for thrombi > or = 6 hr is inner diameter and not immediate thrombus contact area., (2006 Wiley-Liss, Inc.)

The aim of this study was to appreciate consequences of rosuvastatin administration on hemodynamic function, vascular oxidative stress and ischemia/reperfusion disorders in normotensive and hypertensive rats. At 10 weeks of age, spontaneously hypertensive rats (SHR, n=20) and normotensive Wistar Kyoto male rats (WKY, n=20) were divided into four groups and given, either vehicle or 10 mg/kg/day of rosuvastatin by gavage for 3 weeks. Systolic blood pressure was assessed every week. At the end of these treatments, vascular NADPH oxidase activity was evaluated by chemiluminescence (lucigenin 0.5 microM). Hearts were isolated and perfused according to the Langendorff method and were subjected to 30 min of global ischemia. Reactive oxygen species (ROS) produced during reperfusion were quantified by electron spin resonance (ESR) spectroscopy using a spin probe (CP-H, 1 mM). After one week of treatment, rosuvastatin reduced the arterial pressure in SHR rats (180.3 +/- 2.1, SHR vs 169.7 +/- 2.3 mmHg, SHR+rosuvastatin; p < 0.01), without lowering plasma cholesterol levels; these effects were not observed in WKY. NADPH activity was 25% higher in control SHR rat aortas compared to control WKY, and was reduced by rosuvastatin in SHR rats. In isolated rat hearts subjected to ischemia/reperfusion sequences, there was a deterioration in functional parameters in control SHR compared to control WKY hearts. Rosuvastatin decreased post-ischemic contracture in WKY hearts by 50% (41.5 +/- 7.5, WKY control vs 18.4 +/- 4.6 mmHg, WKY+rosuvastatin; p < 0.01) and increased left ventricular developed pressure. This beneficial effect was accompanied by a decrease in ROS detected by ESR during reperfusion (312.5 +/- 45.3, WKY control; vs 219.3 +/- 22.9 AUC/mL, WKY+rosuvastatin; p < 0.05). In conclusion, these results are in accordance with the hypothesis that oxidative stress plays a crucial role in the pathogenesis of cardiovascular diseases including hypertension, and demonstrate the beneficial effects of rosuvastatin.

We report on a measurement of the parity-violating asymmetry in the scattering of longitudinally polarized electrons on unpolarized protons at a Q2 of 0.230 (GeV/c)(2) and a scattering angle of theta (e) = 30 degrees - 40 degrees. Using a large acceptance fast PbF2 calorimeter with a solid angle of delta omega = 0.62 sr, the A4 experiment is the first parity violation experiment to count individual scattering events. The measured asymmetry is A(phys)=(-5.44+/-0.54(stat)+/-0.26(sys))x10(-6). The standard model expectation assuming no strangeness contributions to the vector form factors is A(0) = (-6.30+/-0.43) x 10(-6). The difference is a direct measurement of the strangeness contribution to the vector form factors of the proton. The extracted value is G(s)(E) + 0.225G(s)(M) = 0.039+/-0.034 or F(s)(1) + 0.130F(s)(2) = 0.032+/-0.028.

We present the results of a search for point sources of high-energy neutrinos in the northern hemisphere using AMANDA-II data collected in the year 2000. Included are flux limits on several active-galactic-nuclei blazars, microquasars, magnetars, and other candidate neutrino sources. A search for excesses above a random background of cosmic-ray-induced atmospheric neutrinos and misreconstructed downgoing cosmic-ray muons reveals no statistically significant neutrino point sources. We show that AMANDA-II has achieved the sensitivity required to probe known TeV gamma-ray sources such as the blazar Markarian 501 in its 1997 flaring state at a level where neutrino and gamma-ray fluxes are equal.

Methods and Results: 101 patients hospitalized for acute non-ST-elevation myocardial infarction (NSTEMI) were included in the study. Median N-terminal fragment of the brain natriuretic peptide (BNP) prohormone (Nt-proBNP) plasma level was 136 (40-335) pmol/l. Patients with increasing levels of troponin I [from low (0.1-10 ng/ml), intermediate (10-40 ng/ml) to high (> or =40 ng/ml) levels] had significantly increased levels of Nt-proBNP (p < 0.05). High-risk patients classified by a high PURSUIT score (i.e. supramedian) had significantly increased Nt-proBNP levels compared to patients with low scores (p < 0.001). Moreover, patients with in-hospital events (death, recurrent MI or clinical heart failure: 27%) had significantly increased median levels of Nt-proBNP compared to event-free patients (184 vs. 105 pmol/l, p = 0.02)., Conclusion: Our data in an unselected population of NSTEMI patients indicate that high levels of circulating Nt-proBNP levels are associated with an increased risk of early cardiovascular events., (Copyright 2004 S. Karger AG, Basel)

It was shown in 1999 thalidomide could induce a therapeutic response in patients with refractory multiple myeloma. Between March 2000 and January 2002, we treated 21 patients with refractory multiple myeloma with thalidomide (Thalidomide) at initial dose of 400 mg a day. Response rate (Intergroupe Francophone du Myélome criteria) was 33 percent and median progression-free survival estimated to 15 months. All patients suffered from drowsiness and constipation requiring lowest doses. Five patients developed a sensitive neuropathy. Eight refractory patients were treated by a combination of their prior maximally tolerated dose of thalidomide and monthly dexamethasone (Soludécadron) alone (n = 4) or associated to cyclophosphamide (Endoxan) and étoposide (Etopophos) (n = 4). Six patients on 8 were responders. Our results suggest that the combination thalidomide/dexamethasone should be compared to thalidomide alone in a prospective, randomized study in patients with refractory multiple myeloma.

Bacteria remain an important cause of infection in bone marrow transplants. To examine shifts in the etiology and susceptibility of bacterial isolates from transplants, we reviewed the incidence and susceptibility of blood isolates during a 7-year period. The infection rate fell dramatically during this time. Gram-positive organisms were isolated more often than gram-negative organisms, but the trend is reversing. Streptococci surpassed staphylococci for 5 years as the leading pathogen. Increasing resistance to penicillin, ciprofloxacin, and imipenem was noted in Streptococcus species. With the exception of type 1 beta-lactamase-producing bacteria and Pseudomonas aeruginosa, gram-negative isolates remained overall susceptible to ceftazidime. Increased antibiotic prophylaxis coincided with the reduction in percentage of infected patients and increase in resistance to beta-lactam antibiotics. Mortality attributed to bacteremia was low except for infections caused by P. aeruginosa and the Enterobacter, Serratia, Citrobacter group. There was no mortality attributable to gram-positive organisms such as Staphylococcus aureus and viridans streptococci.

Non- Candida albicans species have emerged as important bloodstream pathogens. They tend to have decreased susceptibility to antifungal agents in vitro and cause infections associated with high morbidity and mortality. Fluconazole resistance can emerge in any Candida spp., but is most commonly seen with Candida krusei, for which resistance is universal, and with Candida glabrata. Amphotericin B resistance has also been increasingly reported, most notably in isolates of Candida lusitaniae and Candida guilliermondii. Efforts are underway to correlate in-vitro antifungal susceptibility of individual Candida isolates with response to therapy of patients with candidemia. Future advances in this field might allow physicians to identify Candida isolates resistant to specific antifungal agents and thereby tailor therapy of candidemia. Copyright 1999 Harcourt Publishers Ltd.

Navicular bones from the four limbs of 95 horses, classified in 9 categories, were studied. The effects of age on navicular bone morphometry and histomorphometry were estimated, after adjustment of the data to even out the effects of front and rear limbs, morphometrical type, sex, weight, and size. All the external measurements of the navicular bone decreased significantly with increasing age. From the histomorphometrical data, cortical bone volume decreased with age in most horses, whereas cancellous bone volume and, in particular, the marrow spaces increased. The increase in the cancellous bone volume could have resulted from tunnelling of the internal part of the cortex, which converted it progressively into a porous trabecular-like structure. Trabecular bone volume also decreased with age and the trabecular lattice changed dramatically to become disconnected in aged horses. These observations corresponded closely to those reported for ageing of the skeletal system in humans. However, in sporting horses, the navicular cortical bone volume increased with age and the cancellous bone volume decreased. Exercise appeared to have decreased bone resorption and increased bone formation at the endocortical junction. The cancellous bone architecture was also improved. in that the trabecular lattice and trabecular bone volume remained unchanged in aged sporting horses. Our findings confirmed that exercise may be good practice to prevent age-related bone loss.

Navicular bones from the 4 limbs of 95 horses, classified in 9 categories, were studied. The anatomical bases were established for the morphometry of the navicular bone and its variations according to the category of horse, after corrections were made for front or rear limb, sex, weight, size and age. In ponies, navicular bone measurements were smallest for light ponies and regularly increased with body size, but in horses, navicular bone dimensions were smallest for the athletic halfbred, intermediate for draft horse, thoroughbreds and sedentary halfbreds and largest for heavy halfbreds. The athletic halfbred thus showed reduced bone dimensions when compared with other horse types. Navicular bones from 61 horses were studied histomorphometrically. Light horses and ponies possessed larger amounts of cancellous bone and less cortical bone. Draft horses and heavy ponies showed marked thickening of cortical bone with minimum intracortical porosity, and a decrease in marrow spaces associated with more trabecular bone. Two distinct zones were observed for the flexor surface cortex: an external zone composed mainly of poorly remodelled lamellar bone, disposed in a distoproximal oblique direction, and an internal zone composed mainly of secondary bone, with a lateromedial direction for haversian canals. Flexor cortex external zone tended to be smaller for heavy ponies than for the light ponies. It was the opposite for horses, with the largest amount of external zone registered for draft horses. In athletic horses, we observed an increase in the amount of cortical bone at the expense of cancellous bone which could be the result of reduced resorption and increased formation at the corticoendosteal junction. Cancellous bone was reduced for the athletic horses but the number of trabeculae and their specific surfaces were larger. Increased bone formation and reduced resorption could also account for these differences.