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High-dose levofloxacin was explored in a clinical trial against multidrug-resistant tuberculosis and failed to show increased efficacy. In this study, we used a murine model to explore the efficacy of a dose increase in levofloxacin monotherapy beyond the maximum dose evaluated in humans. A total of 120 4-week-old female BALB/c mice were intravenously infected with 10 6 CFU of Mycobacterium tuberculosis H37Rv wild-type (WT) or isogenic H37Rv mutants harboring GyrA A90V or D94G substitutions; the MICs were 0.25, 4, and 6 µg/mL, respectively. Levofloxacin 250 and 500 mg/kg were given every 12 h (q12h) orally for 4 weeks. Pharmacokinetic parameters were determined after five doses. These two regimens decreased lung bacillary load in mice infected with H37Rv WT but not in mice infected with the A90V and D94G mutants. Levofloxacin 250 mg/kg q12h in mice generated pharmacokinetic parameters equivalent to 1,000 mg/d in humans, whereas 500 mg/kg q12h generated a twofold greater exposure than the highest equivalent dose tested in humans (1,500 mg/d). In our dose-response model, the effective concentration at 50% (EC 50 ) produced an AUC/MIC (AUC 0-24h /MIC) ratio of 167.9 ± 27.5, and at EC 80 it was 281.2 ± 97.3. Based on this model, high-dose levofloxacin regimens above 1,000 mg/d are not expected to cause a significant increase in bactericidal activity. This study suggests no benefit of high-dose levofloxacin above 1,000 mg/d in the treatment of fluoroquinolone-susceptible or -resistant tuberculosis., Competing Interests: The authors declare no conflict of interest.

Cloxacillin and oxacillin are group M penicillins. The therapeutic monitoring of plasma concentrations of these antibiotics and those of their hydroxymethylated metabolites is of great clinical interest, especially in the choice of an adequate dosage allowing an effective treatment while limiting the occurrence of undesirable effects and the development of bacterial resistance. In this context, we conducted this work aiming at developing and validating a method allowing the determination of cloxacillin and oxacillin as well as the identification of their active metabolites in different biological matrices (CSF and plasma) using turbulent flow liquid chromatography coupled to high-resolution mass spectrometry. To do this, we carried out several optimisation tests. Subsequently, we validated our method according to the latest bioanalytical validation recommendations of the European Medicines Agency. The validation results showed that our method is specific and sensitive. We obtained good linearity in the range 0.5 to 100 µg/mL with correlation coefficients above 0.995. The lower limit of quantification was 0.5 µg/mL for each analyte. The method was found to be accurate with repeatability and reproducibility coefficients of variation below 15 %. Our method is also accurate with bias values below 15 %. Recovery values ranged from 87 % to 95 %. Finally, we were able to apply our method to the therapeutic monitoring of the analysed molecules and to identify their active metabolites. Our results suggest that LC-MS shows superiority in the therapeutic monitoring of these antibiotics due to the superiority of specificity shown by this method. This assay method can be routinely used for the daily plasma assays of patients treated with these antibiotics in the context of therapeutic monitoring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Multidrug-resistant Gram-negative bacteria-related infections have become a real public health problem and have exposed the risk of a therapeutic impasse. In recent years, many new antibiotics have been introduced to enrich the therapeutic armamentarium. Among these new molecules, some are mainly of interest for the treatment of the multidrug-resistant infections associated with Pseudomonas aeruginosa (ceftolozane/tazobactam and imipenem/relebactam); others are for carbapenem-resistant infections associated with Enterobacterales (ceftazidime/avibactam, meropenem/vaborbactam); and finally, there are others that are effective on the majority of multidrug-resistant Gram-negative bacilli (cefiderocol). Most international guidelines recommend these new antibiotics in the treatment of microbiologically documented infections. However, given the significant morbidity and mortality of these infections, particularly in the case of inadequate therapy, it is important to consider the place of these antibiotics in probabilistic treatment. Knowledge of the risk factors for multidrug-resistant Gram-negative bacilli (local ecology, prior colonization, failure of prior antibiotic therapy, and source of infection) seems necessary in order to optimize antibiotic prescriptions. In this review, we will assess these different antibiotics according to the epidemiological data.

Voriconazole is one of the most used antifungal azoles against pulmonary aspergillosis. Therapeutic drug monitoring (TDM) of the voriconazole concentration in plasma is recommended in clinical practice guidelines to prevent treatment failure and toxicity. The aim of this study was to evaluate the feasibility and utility of TDM of the voriconazole concentration in the sputum of patients treated for pulmonary aspergillosis. Fifty sputum and 31 plasma samples were analysed with high-performance tandem mass spectrometry (HPLC-MS/MS) in 24 patients included in the study. The voriconazole concentration was simultaneously assessed in the plasma and sputum in 22 samples. The correlation between the sputum and plasma levels was estimated with a univariate linear regression model, and the observed R 2 was 0.86. We determined the following equation, C sputum = 0.45 (C plasma ) + 0.21, which could predict the voriconazole concentration in plasma from sputum. TDM of the voriconazole concentration in sputum is an easy, non-invasive and accurate method with which to evaluate voriconazole exposure in patients with pulmonary aspergillosis.

Venlafaxine is the third most frequently prescribed antidepressant in France the last decade, with about 400,000 daily doses. Therapeutic drug monitoring (TDM) of this medication, by measuring the active moiety venlafaxine (V) and O-desmethylvenlafaxine (ODV), is recommended (level of recommendation 2). However, this antidepressant seems to be the one for which clinicians most often use TDM, much more frequently than escitalopram, which is more prescribed and for which TDM is also recommended. The main goal of this review is to provide an update on the TDM of venlafaxine: its therapeutic interval, its level of recommendation and the origin of its "success". From the literature does not enable to define a therapeutic interval for the active moiety V+ODV, that is to say a steady-state trough concentration allowing a clinical response without toxicity. Nevertheless, a target concentration from 100 to 400μg/L is certainly relevant for the majority of patients without any pharmacodynamic resistance ; though a greater concentration could result in an earlier response or could be required for a clinical response in a minority of patients. A patient with no clinical response despite a concentration greater than 1000μg/L should be proposed another antidepressant. Measurement of the ODV/V ratio is also a useful tool, values below 0.3 usually reflecting a slow metabolizer phenotype for cytochrome P-450 2D6, which is more at risk of adverse effects. Research for this phenotype probably explains many prescriptions for TDM., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Pharmacological and clinical data regarding cefoxitin for the treatment of ESBL-producing Enterobacteriaceae-related infections are limited. We performed a multicentric prospective cohort study to evaluate continuous/prolonged, or intermittent infusion of cefoxitin. We assessed the plasma concentration as a function of the duration of infusion and then performed a simulation of the percentage of patients who would reach the PK/PD targets, set at 100% ƒT > MIC or 100% ƒT >4 MIC . Eighty-one patients were included. All patients were treated with 6 gr./day. MICs to cefoxitin ranged from 0.5 to 64 mg/L. Sixteen (19.7%) patients were infected with strains with cefoxitin MICs ≥ 8 mg/L. In all patients infected with strains with MICs ≤ 6 mg/L, PK/PD objectives (100% ƒT > MIC ) were achieved with prolonged or continuous infusion. In contrast, when MICs were 8 mg/L only, continuous infusion was sufficient to achieve the PK/PD objectives (100% ƒT > MIC ). Extended infusion of cefoxitin is necessary for the treatment of non-UTI ESBL-related infections.

Purpose: Currently, four-dimensional (4D) cone-beam computed tomography (CBCT) requires a 3-4 min full-fan scan to ensure usable image quality. Recent advancements in sparse-view 4D-CBCT reconstruction have opened the possibility to reduce scan time and dose. The aim of this study is to provide a common framework for systematically evaluating algorithms for 4D-CBCT reconstruction from a 1-min scan. Using this framework, the AAPM-sponsored SPARE Challenge was conducted in 2018 to identify and compare state-of-the-art algorithms., Methods: A clinically realistic CBCT dataset was simulated using patient CT volumes from the 4D-Lung database. The selected patients had multiple 4D-CT sessions, where the first 4D-CT was used as the prior CT, and the rest were used as the ground truth volumes for simulating CBCT projections. A GPU-based Monte Carlo tool was used to simulate the primary, scatter, and quantum noise signals. A total of 32 CBCT scans of nine patients were generated. Additional qualitative analysis was performed on a clinical Varian and clinical Elekta dataset to validate the simulation study. Participants were blinded from the ground truth, and were given 3 months to apply their reconstruction algorithms to the projection data. The submitted reconstructions were analyzed in terms of root-mean-squared-error (RMSE) and structural similarity index (SSIM) with the ground truth within four different region-of-interests (ROI) - patient body, lungs, planning target volume (PTV), and bony anatomy. Geometric accuracy was quantified as the alignment error of the PTV., Results: Twenty teams participated in the challenge, with five teams completing the challenge. Techniques involved in the five methods included iterative optimization, motion-compensation, and deformation of the prior 4D-CT. All five methods rendered significant reduction in noise and streaking artifacts when compared to the conventional Feldkamp-Davis-Kress (FDK) algorithm. The RMS of the three-dimensional (3D) target registration error of the five methods ranged from 1.79 to 3.00 mm. Qualitative observations from the Varian and Elekta datasets mostly concur with those from the simulation dataset. Each of the methods was found to have its own strengths and weaknesses. Overall, the MA-ROOSTER method, which utilizes a 4D-CT motion model for temporal regularization, had the best and most consistent image quality and accuracy., Conclusion: The SPARE Challenge represents the first framework for systematically evaluating state-of-the-art algorithms for 4D-CBCT reconstruction from a 1-min scan. Results suggest the potential for reducing scan time and dose for 4D-CBCT. The challenge dataset and analysis framework are publicly available for benchmarking future reconstruction algorithms., (© 2019 American Association of Physicists in Medicine.)

Up to 25% of hospitalized patients in a psychiatric department exhibit troubles linked to cannabis use. Weaning patients with psychiatric disorders off drugs of abuse requires specific care to improve their clinical outcome. The present study aims to develop a predictive model of urinary excretion of creatinine-normalized cannabinoids (U CNC ) and to determine U CNC thresholds corresponding to the widely used cut-offs of 20 ng/mL and 50 ng/mL for cannabinoids. One hundred thirty-two patients with 452 urine samples were included between 2013 and 2017. Urinary cannabinoids and U CNC elimination curves were computed for each patient. Using a mono-exponential mixed effect model with 88 samples from 26 subjects exhibiting at least 3 decreasing U CNC in a row, the average calculated elimination rate constant was 0.0108 ± 0.0026 h -1 , corresponding to a mean elimination half-life of 64 ± 12 hours. The use of U CNC is of particular interest because of a high inter- and intra-individual variability of urinary creatinine concentration (from 0.06 to 3.81 mg/mL). Moreover, U CNC allows for the detection of diluted or concentrated urine specimens that may lead to false positive (FP) or false negative (FN) results. Receiver operator characteristic (ROC) curves were used to assess U CNC thresholds of 32.4 and 124.7 ng/mg that provide a strong discrimination between positive and negative samples for cannabinoids cut-offs of 20 and 50 ng/mL respectively. The developed model and the defined U CNC thresholds allowed for the accurate prediction of the time needed to reach a negative U CNC result that could be used by clinicians to optimize clinical care., (© 2019 John Wiley & Sons, Ltd.)

Stability data of toxics or drugs in gel-based or mechanical separation blood collection tubes are lacking, especially for therapeutic drug monitoring and clinical toxicology procedures. According to ISO 15189 accreditation standard, laboratories need to master the entire preanalytical process including the stability of analytes in a specific tube. Here we explored the impact of BD PST™ II and Barricor™ separator tubes on the stability of 167 therapeutic compounds and common drugs of abuse in plasma samples using LC-MS/MS. Forty drugs were significantly affected by the use of PST™ II tubes, including antidepressants (11/26), neuroleptics (9/13), cardiovascular drugs (5/26), anxiolytics and hypnotics (4/25) and some drugs of abuse (5/26). Six compounds exhibited significant reduction by the mechanical Barricor™ tubes. Ten drugs exhibited low (<85%) but non-significant recoveries due to inter-assay variability. Besides, a logP > 3.3 was determined as a cut-off value to predict a potential lack of stability in PST™ II gel tubes with an 86.4% sensitivity and a 61.4% specificity. As a consequence, determination of drugs with a logP > 3.3 should be carried out with caution in plasma samples withdrawn on PST™ II. The study showed the Barricor™ and non-gel tubes cause less drug interference and are recommended for the drugs studied., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Over the last decade, dual-energy CT scanners have gone from prototypes to clinically available machines, and spectral photon counting CT scanners are following. They require a specific reconstruction process, consisting of two steps: material decomposition and tomographic reconstruction. Image-based methods perform reconstruction, then decomposition, while projection-based methods perform decomposition first, and then reconstruction. As an alternative, 'one-step inversion' methods have been proposed, which perform decomposition and reconstruction simultaneously. Unfortunately, one-step methods are typically slower than their two-step counterparts, and in most CT applications, reconstruction time is critical. This paper therefore proposes to compare the convergence speeds of five one-step algorithms. We adapted all these algorithms to solve the same problem: spectral photon-counting CT reconstruction from five energy bins, using a three materials decomposition basis and spatial regularization. The paper compares a Bayesian method which uses non-linear conjugate gradient for minimization (Cai et al 2013 Med. Phys. 40 111916-31), three methods based on quadratic surrogates (Long and Fessler 2014 IEEE Trans. Med. Imaging 33 1614-26, Weidinger et al 2016 Int. J. Biomed. Imaging 2016 1-15, Mechlem et al 2018 IEEE Trans. Med. Imaging 37 68-80), and a primal-dual method based on MOCCA, a modified Chambolle-Pock algorithm (Barber et al 2016 Phys. Med. Biol. 61 3784). Some of these methods have been accelerated by using μ-preconditioning, i.e. by performing all internal computations not with the actual materials the object is made of, but with carefully chosen linear combinations of those. In this paper, we also evaluated the impact of three different μ-preconditioners on convergence speed. Our experiments on simulated data revealed vast differences in the number of iterations required to reach a common image quality objective: Mechlem et al (2018 IEEE Trans. Med. Imaging 37 68-80) needed ten iterations, Cai et al (2013 Med. Phys. 40 111916-31), Long and Fessler (2014 IEEE Trans. Med. Imaging 33 1614-26) and Weidinger et al (2016 Int. J. Biomed. Imaging 2016 1-15) several hundreds, and Barber et al (2016 Phys. Med. Biol. 61 3784) several thousands. We also sum up other practical aspects, like memory footprint and the need to tune extra parameters.

Four-dimensional cone-beam computed tomography (4D-CBCT) of the free-breathing thorax is a valuable tool in image-guided radiation therapy of the thorax and the upper abdomen. It allows the determination of the position of a tumor throughout the breathing cycle, while only its mean position can be extracted from three-dimensional CBCT. The classical approaches are not fully satisfactory: respiration-correlated methods allow one to accurately locate high-contrast structures in any frame, but contain strong streak artifacts unless the acquisition is significantly slowed down. Motion-compensated methods can yield streak-free, but static, reconstructions. This work proposes a 4D-CBCT method that can be seen as a trade-off between respiration-correlated and motion-compensated reconstruction. It builds upon the existing reconstruction using spatial and temporal regularization (ROOSTER) and is called motion-aware ROOSTER (MA-ROOSTER). It performs temporal regularization along curved trajectories, following the motion estimated on a prior 4D CT scan. MA-ROOSTER does not involve motion-compensated forward and back projections: the input motion is used only during temporal regularization. MA-ROOSTER is compared to ROOSTER, motion-compensated Feldkamp-Davis-Kress (MC-FDK), and two respiration-correlated methods, on CBCT acquisitions of one physical phantom and two patients. It yields streak-free reconstructions, visually similar to MC-FDK, and robust information on tumor location throughout the breathing cycle. MA-ROOSTER also allows a variation of the lung tissue density during the breathing cycle, similar to that of planning CT, which is required for quantitative post-processing.

Purpose: Reconstruction of the beating heart in 3D + time in the catheter laboratory using only the available C-arm system would improve diagnosis, guidance, device sizing, and outcome control for intracardiac interventions, e.g., electrophysiology, valvular disease treatment, structural or congenital heart disease. To obtain such a reconstruction, the patient's electrocardiogram (ECG) must be recorded during the acquisition and used in the reconstruction. In this paper, the authors present a 4D reconstruction method aiming to reconstruct the heart from a single sweep 10 s acquisition., Methods: The authors introduce the 4D RecOnstructiOn using Spatial and TEmporal Regularization (short 4D ROOSTER) method, which reconstructs all cardiac phases at once, as a 3D + time volume. The algorithm alternates between a reconstruction step based on conjugate gradient and four regularization steps: enforcing positivity, averaging along time outside a motion mask that contains the heart and vessels, 3D spatial total variation minimization, and 1D temporal total variation minimization., Results: 4D ROOSTER recovers the different temporal representations of a moving Shepp and Logan phantom, and outperforms both ECG-gated simultaneous algebraic reconstruction technique and prior image constrained compressed sensing on a clinical case. It generates 3D + time reconstructions with sharp edges which can be used, for example, to estimate the patient's left ventricular ejection fraction., Conclusions: 4D ROOSTER can be applied for human cardiac C-arm CT, and potentially in other dynamic tomography areas. It can easily be adapted to other problems as regularization is decoupled from projection and back projection.

Background: 4D cardiac computed tomography aims at reconstructing the beating heart from a series of 2D projections and the simultaneously acquired electrocardiogram. Each cardiac phase is reconstructed by exploiting the subset of projections acquired during this particular cardiac phase only. In these conditions, the Feldkamp, Davis and Kress method (FDK) generates large streak artifacts in the reconstructed volumes, hampering the medical interpretation. These artifacts can be substantially reduced by deconvolution methods., Objective: The aim of this paper is to compare two 4D cardiac CT reconstruction methods based on deconvolution, and to evaluate their practical benefits on two applications: cardiac micro CT and human cardiac C-arm CT., Methods: The first evaluated method builds upon inverse filtering. It has been proposed recently and demonstrated on 4D cardiac micro CT. The second one is an iterative deconvolution method, and turns out equivalent to an ECG-gated Iterative Filtered Back Projection (ECG-gated IFBP)., Results: Results are presented on simulated data in 2D parallel beam, 2D fan beam and 3D cone beam geometries., Conclusions: Both methods are efficient on the cardiac micro CT simulations, but insufficient to handle 4D human cardiac C-Arm CT simulations. Overall, ECG-gated IFPB largely outperforms the inverse filtering method.

Background: Carbon nanotubes (CNT) are a family of materials featuring a large range of length, diameter, numbers of walls and, quite often metallic impurities coming from the catalyst used for their synthesis. They exhibit unique physical properties, which have already led to an extensive development of CNT for numerous applications. Because of this development and the resulting potential increase of human exposure, an important body of literature has been published with the aim to evaluate the health impact of CNT. However, despite evidences of uptake and long-term persistence of CNT within macrophages and the central role of those cells in the CNT-induced pulmonary inflammatory response, a limited amount of data is available so far on the CNT fate inside macrophages. Therefore, the overall aim of our study was to investigate the fate of pristine single walled CNT (SWCNT) after their internalization by macrophages., Methods: To achieve our aim, we used a broad range of techniques that aimed at getting a comprehensive characterization of the SWCNT and their catalyst residues before and after exposure of murine macrophages: X-ray diffraction (XRD), High Resolution (HR) Transmission Electron Microscopy (TEM), High Angle Annular Dark Field-Scanning TEM (HAADF-STEM) coupled to Electron Energy Loss Spectroscopy (EELS), as well as micro-X-ray fluorescence mapping (μXRF), using synchrotron radiation., Results: We showed 1) the rapid detachment of part of the iron nanoparticles initially attached to SWCNT which appeared as free iron nanoparticles in the cytoplasm and nucleus of CNT-exposed murine macrophages, and 2) that blockade of intracellular lysosomal acidification prevented iron nanoparticles detachment from CNT bundles and protected cells from CNT downstream toxicity., Conclusions: The present results, while obtained with pristine SWCNT, could likely be extended to other catalyst-containing nanomaterials and surely open new ways in the interpretation and understanding of CNT toxicity.

With their first scanning transmission electron microscope (STEM), Albert Crewe and his collaborators have succeeded 40 years ago in bringing to reality a dream for all electron microscopists, to see individual atoms. In the derivation of Crewe's pioneering work, the present review describes various historical and present steps, involving continuous instrumental and methodological developments as well as the preparation of suitable specimens. They have lead to the identification of individual atoms by electron energy-loss spectroscopy (EELS) and to the demonstration of atom-by-atom spectroscopy. Beyond these spectacular successes which open wide fields of use, most recent technical achievements, such as the introduction of monochromators on the incident electron beam or of optical spectrometers for recording spectra (in the visible as well as in the X-ray domain), will undoubtedly lead to refine the accessible signature of single atoms and molecules., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background and Purpose: Although the ability of MRI to investigate carotid plaque composition is well established, the mechanism and the significance of plaque gadolinium (Gd) enhancement remain unknown. We evaluated clinical and histological significance of Gd enhancement of carotid plaque in patients undergoing endarterectomy for carotid stenosis., Methods: Sixty-nine patients scheduled for a carotid endarterectomy prospectively underwent a 3-T MRI. Carotid plaque enhancement was assessed on T1-weighted images performed before and 5 minutes after Gd injection. Enhancement was recorded according to its localization. Histological analysis was performed of the entire plaque and of the area with matched contrast enhancement on MR images., Results: Gd enhancement was observed in 59% patients. Three types of carotid plaques were identified depending on enhancement location (shoulder region, shoulder and fibrous cap, and central in the plaque). Fibrous cap rupture, intraplaque hemorrhage, and plaque Gd enhancement was significantly more frequent in symptomatic than in asymptomatic patients (P=0.043, P<0.0001, and P=0.034, respectively). After histological analysis, Gd enhancement was significantly associated with vulnerable plaque (American Heart Association VI, P=0.006), neovascularization (P<0.0001), macrophages (P=0.030), and loose fibrosis (P<0.0001). Prevalence of neovessels, macrophages, and loose fibrosis in the area of Gd enhancement was 97%, 87%, and 80%, respectively, and was different depending on the enhancement location in the plaque. Fibrous cap status and composition were different depending on the type of plaque., Conclusions: Gd enhancement of carotid plaque is associated with vulnerable plaque phenotypes and related to an inflammatory process.

CD4+ T cells contribute to disturbances of pancreatic microcirculation after cold and even after warm ischemia/reperfusion (I/R). The aim of this study was to investigate a possible protective role of FTY720 (fingolimod) in this setting. In an in vivo model (42 Wistar rats), ischemia of the pancreas was induced for 60 minutes under anesthesia with xylazin/ketanest. Sham-operated (SO) (I), untreated ischemic (II), and treatment group with FTY720 pre-treatment (1 mg/kg body weight i.v.) (III) were investigated. The effect of FTY720 on I/R injury was assessed by in vivo microscopy 30-90 minutes after reperfusion and by measurement of serum lipase. In the untreated ischemic group (II), capillary constriction to 85.3 ± 6.3% of SO diameters and a reduction of functional capillary density to 67% was found. After 30 minutes of reperfusion, the number of T cells in capillaries was increased (165.7%; P < .05 vs I). FTY720 pretreatment reduced this number to 54.2% of SO (P < .05 vs II). Likewise, the number of adherent leukocytes in capillaries (145.4 ± 11.2% of SO) was reduced in group III (109.3 ± 11.4%; P < .05 vs II), leading to an improvement in functional capillary density in the treatment group (98.2 ± 2% of SO; P < .05 vs II). According to improved microcirculation, lipase values were reduced in the therapy group (P < .05). In conclusion, FTY720 ameliorates the microcirculatory and biochemical manifestations of pancreatic I/R injury by preventing T-cell infiltration., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Aim: CD4(+) T cells contribute to disturbances of liver microcirculation after warm ischemia/reperfusion (I/R). The aim of this study was to investigate a possible protective role of FTY720 (Sphingosine-1 phosphate receptor agonist) in this setting., Material and Methods: In an in vivo model (42 Wistar rats), ischemia of the left liver lobe was induced for 90 min under anesthesia with xylazine/ketanest. Sham-operated untreated ischemic and treatment group with FTY720 (1 mg/kg body weight intravenous) were investigated. The effect of FTY on I/R injury was assessed by in vivo microscopy 30-90 min after reperfusion (perfusion rate, vessel diameter, leukocyte-endothelial cell interactions, T cell infiltration), by measurement of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), reverse transcription-polymerase chain reaction (RT-PCR) of interleukin (IL)-2, IL-6, IL-10, TNF-alpha, toll-like receptor 4 (TLR-4), and by histological investigation., Results: After 30 min of reperfusion, the number of T cells in sinusoids was increased four-fold. In the FTY group, the number of T cells was reduced to an half of the number of the ischemia group. Likewise, the number of adherent leukocytes in sinusoids (150.8 +/- 10.9% of s.o.) was reduced in the treatment group (117.3 +/- 12.2%; p < 0.05 vs ischemia), leading to an improvement in perfusion rate in this group (85.0 +/- 4.6% of sham group) compared to nontreated animals (57.5 +/- 10.8%; p < 0.05). According to improved microcirculation, AST/ALT values and histological tissue damage were reduced in the therapy group. RT-PCR revealed an increased expression of IL-2, IL-6, and TLR-4 in the nontreated ischemic group. This expression was clearly reduced in the treatment group., Conclusion: In conclusion, FTY720 ameliorates the microcirculatory, biochemical, and histological manifestations of hepatic I/R injury by preventing T cell infiltration. These results indicate that T cells are pivotal mediators in hepatic I/R and may have important implications early after liver transplantation and in warm ischemia.

Developments in instrumentation are essential to open new fields of science. This clearly applies to electron microscopy, where recent progress in all hardware components and in digitally assisted data acquisition and processing has radically extended the domains of application. The demonstrated breakthroughs in electron optics, such as the successful design and practical realization and the use of correctors, filters and monochromators, and the permanent progress in detector efficiency have pushed forward the performance limits, in terms of spatial resolution in imaging, as well as for energy resolution in electron energy-loss spectroscopy (EELS) and for sensitivity to the identification of single atoms. As a consequence, the objects of the nanoworld, of natural or artificial origin, can now be explored at the ultimate atomic level. The improved energy resolution in EELS, which now encompasses the near-IR/visible/UV spectral domain, also broadens the range of available information, thus providing a powerful tool for the development of nanometre-level photonics. Furthermore, spherical aberration correctors offer an enlarged gap in the objective lens to accommodate nanolaboratory-type devices, while maintaining angström-level resolution for general characterization of the nano-object under study.

X-ray fluorescence microscopy (microXRF) is applied for the first time to study macrophages exposed to unpurified and purified single-walled (SW) and multiwalled (MW) carbon nanotubes (CNT). Investigating chemical elemental distributions allows one to (i) image nanotube localization within a cell and (ii) detect chemical modification of the cell after CNT internalization. An excess of calcium is detected for cells exposed to unpurified SWCNT and MWCNT and related toxicological assays are discussed.

Energy-filtering transmission electron microscopy (EFTEM) allows the determination of elemental distributions out of a sequence of energy filtered images. Combined with electron tomography, EFTEM is a powerful tool to obtain three-dimensional chemical maps from sub-cellular structures. However, there is no existing software in the public-domain for the computation and analysis of 3D-chemical maps. Here, we present a Java-based program to compute 3D-elemental distribution. This program is available as a set of plug-ins for the public-domain Java image processing program Image J inspired by NIH Image. Its implemented algorithms have been successfully applied to the three-dimensional localization of iron granules in semi thin (200 nm) epon sections from the vent worm Riftia pachyptalia.

Objective: Aim of this study is the documentation of illness-associated costs for spouses, whose relative is suffering from a mental illness., Method: Over a period of 12 month, 117 spouses of patients who are suffering from schizophrenia, depression or anxiety disorders repeatedly filled in a standardized questionnaire about illness related expenses and financial losses., Results: 90 % of the spouses reported direct cash expenditures on behalf of the patients' illness. On average, these costs amounted to yearly expenditures of euro 1146 (range: euro 0 - 11 910). Costs did not differ significantly across types of illness and income was not found to be a significant covariate., Conclusions: Spouses reported substantial direct cash expenditures on behalf of the patients' illness. Since these expenditures varied to a large extent over the three points of measurement, repeated measurement designs seem to be a prerequisite for a reliable assessment of illness-associated costs. Since living together with a mentally ill partner is associated with an increased risk of developing a burden-related psychiatric illness for spouses themselves which may lead to double costs and double decreases in income, these aspects should be taken into consideration when planning changes in health policy.

Objective: The aim of this study was to investigate to what extent caregivers of schizophrenia patients suffer from psychiatric and psychosomatic symptoms themselves; furthermore, whether there are differences between parents and spouses., Method: 51 parents and 52 spouses of people with schizophrenia were interviewed regarding psychiatric and psychosomatic troubles using standardized questionnaires and diagnostic methods., Results: A considerably increased prevalence of depressive disorders was found compared to the level in the general population. As well as mothers and wives, caregivers of patients with severe impairments of psycho-social functioning were particularly affected. The severity of the patient's disease and the caregiver's mental problems are significant predictors of psychosomatic complaints in parents and spouses. In addition, caregivers visit physicians more frequently, in particular family doctors, psychiatrists and psychotherapists., Discussion: The results support the hypothesis that the burden carried by caregivers of severely affected schizophrenia patients increases their risk of becoming ill, which, as a consequence, leads to a greater use of medical resources. Specific offers of health care and advice on preventative measures appear to be necessary in order to preclude health impairments to caregivers as early as possible.

Objective: The aim of this study was to compare financial burden of parents and spouses, whose relative is suffering from schizophrenia. The first article (part I) draws attention to quantitative analysis., Method: 51 parents and 52 spouses filled in the questionnaire about illness related expenses and financial loss; additionally they were asked to estimate the experienced burden on a subjective dimension., Results: Direct cash expenditures on behalf of the patients' illness were reported by 63 % spouses and 69 % parents. Above all, the patient's reduced ability to work was seen as main cause for long-term loss of family income. In general economic disadvantages were not considered as burdensome., Discussion: Although most parents and spouses of schizophrenic patients experience illness related financial disadvantages, it seems that these costs were usually not defined as serious problem. For a better understanding of this finding further analysis of the subjective perspective on perceived financial burden is needed (see part II).

Objective: Part II of this study will explore more accurately, how caregivers of schizophrenic patients perceive the financial burdens of the disease., Method: 42 In-depth-interviews with parents and spouses of schizophrenic patients were analysed using a qualitative-interpretative technique., Results: When talking about their living situation, caregivers tended to keep away from the topic of financial charges; often they played down objective financial disadvantages or didn't assess them as burdensome. Considerable financial burdens were reported by parents of young patients still living in the parents' household and by spouses in families with very low income., Discussion: Financial burdens are usually superimposed by other problems of the caregivers, such as dealing with acute episodes and sorrow about the future. Thus, not only the material, but also the immaterial costs of caregivers should be taken into consideration when taking health policy decisions.

Background: According to the literature on stress and coping, the burden of caregiving to a mentally ill partner might have an impact on the mental health of the spouse., Method: As part of a study on the burden of caregiving to mentally ill family members, a structured psychiatric interview (DIA-X-M-CIDI) was conducted with spouses of patients suffering from depression, anxiety disorders, or schizophrenia (n = 151)., Results: Covarying with the partner's gender and the severity of the patient's illness a significantly increased prevalence of depressive disorders could be found., Conclusion: Psychiatric patients' partners are at a high risk of developing a depressive disorder. It appears necessary to develop special interventions for spouses reducing stress and the risk of getting depressed.

The aim of this study was to compare financial burden of spouses, whose relative suffers from schizophrenia, depression or anxiety disorder. 151 spouses filled in the questionnaire about illness related expenses and financial loss. Additionally they estimate their subjective burden according to these experienced costs. Direct cash expenditures on behalf of the patients' illness were reported by 66 % spouses. In the sampling the amount of spent money did not differ statistically, however spouses of patients with anxiety disorder emphasised experiencing financial strain and described more often subjective economic disadvantages. Although most spouses of patients with psychiatric disorders experience illness related financial disadvantages, these costs were usually not considered as serious problem or as burdensome. Based on a subjective hierarchy of burdens financial problems can be regarded as less important for spouses of patients with mental illness. Thus, not only the material, but also the immaterial costs of care giving spouses should be taken into consideration when planning health policy decisions.

Unlabelled: The German Adaptation of the Verona Service Satisfaction Scale: An Instrument for Patients' Satisfaction with Mental Health Care., Aim: Measuring effectiveness and quality of care became an important topic in psychiatry. Considering that objective criteria were not sufficient in the past, the subjective perspective gained growing interest. Client satisfaction is an important variable to evaluate psychiatric care. Patient satisfaction can influence treatment outcome as well as it determines the psychiatric system itself., Method: The Italian original version of the Verona Service Satisfaction Scale (VSSS-54) was translated and adapted to the German language. The instrument has been tested in the project "Cost-effectiveness of psychiatric service systems". The process of development, the psychometric testing and the practical application of the German version will be presented in this paper. Additional advantages and disadvantages are discussed., Results: As psychometric properties of the instrument correspond to conventional standards, they are comparable with the results of an international study. The drop out of items cannot be controlled, therefore analysing the data is difficult., Conclusion: Although the VSSS shows various methodological limitations, it is at the moment an appropriate instrument for measuring patient satisfaction in the German language.

Objective: Aims of the study are the analysis oft the structures and influence factors causing direct costs of schizophrenic diseases by means of international standardized assessment instruments., Method: Annual costs of treatment were assessed for a sample of 258 patients with the diagnosis of schizophrenia (ICD-10 F20) by means of the German version of the CSSRI. For the analysis of cost variance a regression model was computed using functional level (GAF), symptoms (BPRS 4.0), needs for care (CAN), service satisfaction (VSSS) and subjective quality of life (LQoLP) as predictors., Results: The average yearly treatment costs for the study sample were 12 726,- DM. Costs for sheltered accommodation and for psychiatric inpatient treatment were found to be the largest elements of the entire costs followed by the costs for ambulant medications. Results of the regression analysis show that illness history, the severity of symptoms and the need for care explain the greatest proportion of variance., Conclusions: The standardized instruments developed in the project enable a systematic and international comparable assessment of the costs in the treatment of schizophrenic diseases. Furthermore the instruments allow to explain 38 % of the cost variance. The impact of the severity of symptoms under statistical control of the functional impairment and the needs for care suggests that an effective reduction of symptoms could lead to savings in the entire treatment costs. However, the great influence of the illness history and, irrespective of the functional impairment, the need for care show that the possibilities for cost savings in the treatment of schizophrenia are generally low.