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Phosphotungstic acid (POM) was crystallized together with the neurotransmitter γ-aminobutyric acid (GABA) in acidic medium to form [(HGABA)3PW12O40], compound 1. The latter would only crystalize in the presence of dopamine, while dopamine itself did not become a part of the complex, but crystallized separately as [(Hdopamine)2HPW12O40], compound 2, as previously reported. GABA interacts with POM via hydrogen bonding between the protonated amino group and a terminal oxygen on POM and also via protonated carboxylic acid group. Based on structural information from the crystal structures of 1 and 2 together with complementary studies using other catechols we attempted to provide molecular insight into the well-known structure-directing effect of dopamine. Strong hydrogen bonding between dopamine and POM, together with formation of “dopamine dimers” in the packed structure by interactions between the aromatic rings and intermolecular hydrogen bonding might be important factors for them in directing the self-assembly of polyoxometalates into complex hierarchal structures. Interaction between dopamine and GABA in solution was investigated by diffusion ordered spectrometry (DOSY) NMR in MilliQ-water and in 0.1 M HCl.

For transscleral application of optical radiation or light to the eye, it is important to know the transmission and absorbance of the tissue layers of the eyewall. The impact of photochemical energy to the retina located directly at the point of contact with the radiation emitter must be considered as well as the absorbance in choroid and retina. Therefore, the direct transmission of ex vivo porcine eyewalls and vitreous body were measured in this study.At ex vivo porcine eyes (N=221) pressure dependent transmission measurements were performed with a pressure inducing setup. Pressure and wavelength dependent direct transmission of eyewall and vitreous body of porcine eyes were described for different applied pressures (23mmHg, 78mmHg and 132mmHg). The transmissions were investigated within the spectral range of 350-1050nm. In addition to the complete eyewall transmission measurements, the transmission of sclera, vitreous body and water was measured individually and the transmission of retina and choroid was calculated.With increasing wavelength and pressure, a significant transmission increase of the eyewall could be achieved (p0.05). At 400nm and 132mmHg the transmission raised to 0.10%. At 1050nm it increased up to a value of 12.22%. In the visible spectrum, the direct transmission was always below 3.17%. The differences in eyewall transmission of eyes with different iris colors were significant at low pressure. With increasing pressure, the effect strength decreased and the differences lost their significance.The pressure and wavelength dependent direct transmission of the eyewall and the vitreous body significantly increased with increasing pressure. This results are benefical for technical and clinical safety, research and development of illumination devices. It is necessary to know the intraocular brightness in the eye during diaphanoscopy, photocoagulation application to determine hazards.

Avoiding tidal recruitment and collapse during mechanical ventilation should reduce the risk of lung injury. Electrical impedance tomography (EIT) enables detection of tidal recruitment by measuring regional ventilation delay inhomogeneity (RVDI) during a slow inflation breath with a tidal volume (VT) of 12 mL/kg body weight (BW). Clinical applicability might be limited by such high VTs resulting in high end-inspiratory pressures (PEI) during positive end-expiratory pressure (PEEP) titration. We hypothesized that RVDI can be obtained with acceptable accuracy from reduced slow inflation VTs. In seven ventilated pigs with experimental lung injury, tidal recruitment was quantified by computed tomography at PEEP levels changed stepwise between 0 and 25 cmH2O. RVDI was measured by EIT during slow inflation VTs of 12, 9, 7.5, and 6 mL/kg BW. Linear correlation of tidal recruitment and RVDI was excellent for VTs of 12 (R2 = 0.83, p &lt, 0.001) and 9 mL/kg BW (R2 = 0.83, p &lt, 0.001) but decreased for VTs of 7.5 (R2 = 0.76, p &lt, 0.001) and 6 mL/kg BW (R2 = 0.71, p &lt, 0.001). With any reduction in slow inflation VT, PEI decreased at all PEEP levels. Receiver-Operator-Characteristic curve analyses revealed that RVDI-thresholds to predict distinct amounts of tidal recruitment differ when obtained from different slow inflation VTs. In conclusion, tidal recruitment can sufficiently be monitored by EIT-based RVDI-calculation with a slow inflation of 9 mL/kg BW.

SPIRIT checklist (2013 version). (DOCX 48 kb)

Diese Arbeit behandelt die Prozessierung verlustarmer Lichtwellenleiter für einen optischen UVC-Gassensor. Durch optische Simulationen wurde zunächst ein geeignetes Material (amorphes Quarzglas) und Design abgeleitet. Mittels Belichtung mit einem Ultrakurzpulslaser und anschließendem selektiven Nassätzen wurden die Lichtleiter aus dem Wafer strukturiert. Die resultierenden rauen Seitenwände führen zu Dämpfungen von 0,6 bis 0,8 dB/mm. Durch kurzzeitiges Aufschmelzen mit einem CO2-Laser wurden die Seitenwände geglättet, wodurch stark verbesserte Dämpfungswerte von 0,2 bis 0,3 dB/mm erreicht wurden. Mit den strukturierten und polierten Lichtleitern wurden schließlich Sensor-Prototypen aufgebaut und Gaskonzentrationen bis unterhalb von 1 ppm detektiert. Dabei wurden Standardabweichungen des Sensorsignals von unter 300 ppb (NO2) bzw. unterhalb von 100 ppb (SO2) ermittelt. Abschließende Messungen an Gasmischungen zeigten, dass Querempfindlichkeiten des Sensors gegenüber anderen Gasen aus den Absorptionsspektren abgeleitet werden und durch geschickte Wahl der LED-Emissionswellenlänge(n) kompensiert werden können. This work presents the processing of efficient waveguides for an optical UVC-gas sensor. At the beginning, a suitable material (fused silica) and an optical design was derived by optical system simulations. By irradiation with an ultra-short pulsed laser and selective wet etching, the waveguides were cut out of the silica wafers. The resulting rough sidewalls led to significant transmission losses in the range of 0.6 to 0.8 dB/mm. The rough sidewalls were polished by temporal melting of the silica surface and significantly reduced transmission losses of 0.2 to 0.3 dB/mm were achieved. Finally, the structured and polished waveguides were integrated into a sensor prototype and gas concentrations below 1 ppm were successfully detected. At the same time standard deviations of the sensor signal of less than 300 ppb (NO2) and less than 100 ppb (SO2) were determined. Measurements of gas mixtures showed that cross-sensitivities of the sensor can be derived from the respective absorption spectra of the applied gases and can be compensated by an appropriate selection of the LED emission wavelengths or calculation.

MOF score as modified by Lefering et al. [42]. (PDF 101 kb)

The need for pharmacokinetic knowledge about antibiotics directly at the site of infection, typically the interstitial space fluid (ISF) of tissues, is gaining acceptance for effective and safe treatment. One option to acquire such data is the microdialysis technique employing a catheter with a semipermeable membrane inserted directly in the ISF. A prerequisite is catheter calibration, e.g. via retrodialysis, yielding a conversion factor from measured to true ISF concentrations, termed relative recovery. This value can be influenced by various factors. The present investigation assessed the impact of three of them on relative recovery using seven drugs: (I) drug combinations/order, (II) air in the microdialysis system, (III) flow rate changes inherent when using common in vivo microdialysis pumps. All experiments were performed in a standardised in vitro microdialysis system. (I) Relative recovery of single antibiotics (linezolid, meropenem, cefazolin, metronidazole, tigecycline) was determined in microdialysis and retrodialysis settings and compared with values using either antibiotic or antibiotic+analgesic (acetaminophen and metamizole) combinations or single drugs with reversed microdialysis order. For assessing these factors for lower relative recovery values (as in in vivo), these were mimicked by increasing the flow rate for linezolid. (II) For the impact of air, linezolid relative recovery of freshly carbonated solutions was compared to degassed ones in microdialysis and retrodialysis settings. For each condition in (I) and (II), summary statistics of relative recovery were calculated and for the impact of the factors a linear mixed-effect model developed. (III) From samples taken during an automatic flush sequence (15 μL/min) of an in vivo pump and afterwards switching to the flow rate of 1 and 2 μL/min for 120 min, the time necessary for relative recovery to reach equilibrium was determined. (I) High relative recovery values (flow rate 2 μL/min: ≥84%; flow rate 5 μL/min: ≥65%) were observed for all investigated single drugs. Intra- and intercatheter variability ranged from 0.3%–11% and 3%–25%, respectively. Based on these values and on the statistical model, the impact of drug combination versus single drug as well as of reversed order was small with changes in relative recovery of smaller equal 9%. (II) Compared to degassed solutions, relative recovery in carbonated solutions was 23% and 19% lower (relative reduction) in the microdialysis and retrodialysis setting, respectively, with increased intercatheter variability (up to 37%). (III) As expected, relative recovery increased after the flush sequence and was constant 10–15 min after the switch to the typical 1 and 2 μL/min flow rate. Given the intercatheter variability, combinations and the order of drugs showed minor but clinically negligible impact on relative recovery. In contrast, air in the microdialysis catheter/system caused falsely low and inconsistent relative recovery values and must be avoided when performing a trial. Also changes in flow rate at the end of pump flush sequence impacted relative recovery. Hence, a sufficient equilibration time of 10–15 min prior to sampling should be implemented in sampling protocols. In vitro microdialysis presents a highly valuable complementary platform to clinical microdialysis studies impacting the design, sampling schedule and data analysis of such trials to gain knowledge of target-site pharmacokinetics for contributing to better informed decisions in the individual patient/special populations in future.

Objective Target-site concentrations obtained via the catheter-based minimally invasive microdialysis technique often exhibit high variability. Catheter calibration is commonly performed via retrodialysis, in which a transformation factor, termed relative recovery (RR), is determined. Leveraging RR values from a rich data set of a very large clinical microdialysis study, promised to contribute critical insight into the origin of the reportedly high target-site variability. The present work aimed (i) to quantify and explain variability in RR associated with the patient (including non-obese vs. obese) and the catheter, and (ii) to derive recommendations on the design of future clinical microdialysis studies. Methods A prospective, age- and sex-matched parallel group, single-centre trial in non-obese and obese patients (BMI=18.7-86.9 kg/m2) was performed. 1-3 RR values were obtained in the interstitial fluid of the subcutaneous fat tissue in one catheter per upper arm of 120 patients via the retrodialysis method (nRR=1008) for a panel of drugs (linezolid, meropenem, tigecycline, cefazolin, fosfomycin, piperacillin and acetaminophen). A linear mixed-effects model was developed to quantify the different types of variability in RR and to explore the association between RR and patient body size descriptors. Results Estimated RR was highest for acetaminophen (69.7%, 95%CI=65.0% to 74.3%) and lowest for piperacillin (40.4%, 95%CI=34.6% to 46.0%). The linear mixed-effects modelling analysis showed that variability associated with the patient (σ=15.9%) was the largest contributor (46.7%) to overall variability, whereas the contribution of variability linked to the catheter (σ=5.55%) was ~1/6 (16.8%). The relative contribution of residual unexplained variability (σ=12.0%, including intracatheter variability) was ~1/3 (36.4%). The limits of agreement of repeated RR determinations in a single catheter ranged from 0.694-1.64-fold (linezolid) to 0.510-3.02-fold (cefazolin). Calculated fat mass affected RR, explaining the observed lower RR in obese (ΔRRmean= -29.7% relative reduction) versus non-obese patients (p Conclusions Three recommendations for clinical microdialysis trial design were derived: 1) High interindividual variability underscored the necessity of measuring individual RR per patient. 2) The low relative contribution of intercatheter variability to overall variability indicated that measuring RR with a single catheter per patient is sufficient for reliable catheter calibration. 3) The wide limits of agreement from multiple RR in the same catheter implied an uncertainty of a factor of two in target-site drug concentration estimation necessitating to perform catheter calibration (retrodialysis sampling) multiple times per patient. To allow routine clinical use of microdialysis, research efforts should aim at further understanding and minimising the method-related variability. Optimised study designs in clinical trials will ultimately yield more informative microdialysis data and increase our understanding of this valuable sampling technique to derive target-site drug exposure.

Haut- und Weichteilinfektionen konnen zum Teil einen fulminanten Verlauf nehmen und werden dann schnell lebensbedrohlich, wenn sie nicht rechtzeitig und radikal behandelt werden. In diesem Fall stellte sich ein 44-jahriger Patient ohne Vorerkrankungen mit einer scheinbar harmlosen Bursitis olecrani und unspezifischen Allgemeinsymptomen in unserer Notfallambulanz vor. Innerhalb kurzester Zeit entwickelte sich ein absolut lebensbedrohlicher Zustand.Wir beschreiben den Verlauf wahrend des mehrwochigen Aufenthalts auf unserer Intensivstation sowie unsere Diagnosen und Therapie-Ansatze.

INTRODUCTION: Mechanical ventilation is known to activate oxidative stress and proteolytic pathways in the diaphragm. Trauma by inducing inflammation and activating proteolytic pathways may potentiate the effects of mechanical ventilation on the diaphragm. In a blunt chest trauma with concomitant injuries we tested the hypothesis that trauma via inflammation further activates the proteolytic pathways and worsens atrophy in the diaphragm. MATERIAL AND METHODS: Piglets were separated into two groups and underwent 72 h of mechanical ventilation. One group received a polytrauma (PT) by unilateral femur fracture, blunt chest trauma with lung contusion, laparotomy with standardized liver incision, and a predefined hemorrhagic shock. The second mechanically ventilated group (MV) did not receive any trauma. A non-ventilated group (Con) served as control.Diaphragmatic fiber dimensions, Western Blot analyses of proteolytic pathways, and lipid peroxidation and messenger ribonucleic acid (mRNA) levels of cytokines and nuclear factor kappa b subunit p65 were measured. RESULTS: Active Caspase-3 was significantly increased in MV (P = 0.019), and in PT (P = 0.02) compared with Con. Nuclear factor kappa b subunit p65, was upregulated in PT (P = 0.010) compared with Con. IL-6 mRNA increased significantly in PT compared with Con (P = 0.0024) but did not differ between Con and MV. CONCLUSION: Trauma and mechanical ventilation induced proteolysis and atrophy in the diaphragm, but only polytrauma induced an inflammatory response in the diaphragm. The additional traumatic inflammatory stimulus did not increase the levels of the prementioned variables. These data underline that inflammation is not a major contributor to ventilator-induced diaphragmatic dysfunction. TRIAL REGISTRY NUMBER: AZ 84-02.04.2014.A265 (Landesamt für Natur-, Umwelt- und Verbraucherschutz, LANUV NRW, Germany). ispartof: SHOCK vol:52 issue:4 pages:443-448 ispartof: location:United States status: published

The illumination of the intraocular space during pars plana vitrectomy always bears the risk of retina damage by irradiation. Conventional illumination systems consist of an external light source and an optical fiber to transfer the visible light (radiation) into the eye. Often xenon arc and halogen lamps are employed for this application with some disadvantageous properties like high phototoxicity and low efficiency. Therefore, we propose to generate the light directly within the eye by inserting a white micro LED with a diameter of 0.6 mm. The LED offers a luminous flux of 0.6 lm of white light with a blue peak @ 450 nm and a yellow peak @ 555 nm. The presented prototypes fit through a standard 23 G trocar and are the first intraocular light sources worldwide. Two different single-use approaches have already been developed: a handguided and a chandelier device. The hand-guided applicator enables a directly navigation and illumination up to a working distance of 6 mm. The chandelier device is much smaller and does not need an active navigation of the light cone. The brightness and homogeneity of the illumination of these LED devices have been successfully tested on porcine eyes. Presented measurements and calculations prove that even for high LED currents and small distances to the retina these intraocular micro LED devices expose the retina to less hazard than conventional illumination sources like fiber based xenon systems. Even under the worst circumstances application durations of 180 hours would be justifiable.

Acute and chronic respiratory failures require immediate diagnosis and preferably individualized ventilation therapy. If possible, non-invasive ventilation should be considered to avoid complications of invasive mechanical ventilation. Especially in patients with ARDS and moderate to severe cases, non-invasive ventilation may not be suitable and should not be used uncritically.Invasive mechanical ventilation parameters should be adjusted individually. In the future, additional parameters such as transpulmonary pressure, monitoring of regional ventilation using electrical impedance tomography could help to individualize ventilator settings. Problems include the lack of wide distribution of these techniques and automatic tools for data analyses are missing.So for today the best thing is to implement the current evidence consequently. This includes lung-protective ventilation with an adequate PEEP and a tidal volume between 6 and 8 ml/kg IBW and a limitation of peak pressure or driving pressure. According to this early mobilization and positioning including prone-position is important, same as a score-based sedation regime and an individualized volume therapy.Die akute oder chronische respiratorische Insuffizienz hat eine große Bedeutung sowohl in der präklinischen als auch innerklinischen Versorgung. Sie zählt zu den häufigsten Gründen für stationäre Aufnahmen. Dieser Beitrag fasst aktuelle Entwicklungen in der Diagnostik und Therapie des Krankheitsbildes zusammen. Darüber hinaus gibt er einen Ausblick, wie sich die Behandlung in den kommenden Jahren weiterentwickeln könnte.

Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) is known to play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). Several NF-κB inhibitors were shown to successfully induce apoptosis of CLL cells in vitro. Since the microenvironment is known to be crucial for the survival of CLL cells, herein, we tested whether NF-κB inhibition may still induce apoptosis in these leukemic cells in the presence of protective stromal interaction. We used the specific NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ). Microenvironmental support was mimicked by co-culturing CLL cells with bone marrow-derived stromal cell lines (HS-5 and M2-10B4). NF-κB inhibition by DHMEQ in CLL cells could be confirmed in both the monoculture and co-culture setting. In line with previous reports, NF-κB inhibition induced apoptosis in the monoculture setting by activating the intrinsic apoptotic pathway resulting in poly (ADP-ribose) polymerase (PARP)-cleavage; however, it was unable to induce apoptosis in leukemic cells co-cultured with stromal cells. Similarly, small interfering ribonucleic acid (siRNA)-mediated RELA downregulation induced apoptosis of CLL cells cultured alone, but not in the presence of supportive stromal cells. B-cell activating factor (BAFF) was identified as a microenvironmental messenger potentially protecting the leukemic cells from NF-κB inhibition-induced apoptosis. Finally, we show improved sensitivity of stroma-supported CLL cells to NF-κB inhibition when combining the NF-κB inhibitor with the SYK inhibitor R406 or the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, agents known to inhibit the stroma-leukemia crosstalk. We conclude that NF-κB inhibitors are not promising as monotherapies in CLL, but may represent attractive therapeutic partners for ibrutinib and R406.

Tigecycline, a tetracycline derivative, shows atypical plasma protein binding behavior. The unbound fraction decreases with increasing concentration at therapeutic concentrations. Moreover, uncertainty exists about the magnitude of tigecyline's protein binding in man. Unbound fractions between 2.5% and 35% have been reported in plasma from healthy volunteers, and between 25% and 100% in patients, respectively. In the present study, the protein binding of tigecycline has been investigated by ultrafiltration using different experimental conditions. Whereas temperature had only a marginal influence, the unbound fraction at 0.3/3.0 mg/L was low at pH 8.2 (9.4%/1.9%) or in unbuffered pooled plasma (6.3%/1.2%), compared with plasma buffered with HEPES to pH 7.4 (65.9%/39.7%). In experiments with phosphate buffer and EDTA, the concentration dependency was markedly attenuated or abolished, which is compatible with a cooperative binding mechanism involving divalent cations such as calcium. The unbound fraction in clinical plasma samples from patients treated with tigecycline was determined to 66.3 ± 13.7% at concentrations0.3 mg/L compared with 41.3 ± 16.0% at1 to5 mg/L. To summarize, tigecycline appears to be only moderately bound to plasma proteins as determined by ultrafiltration, when a physiological pH is maintained.

Introduction. Despite the feasibility and safety of bariatric procedures nowadays, high-risk patients with vast obesity and severe comorbidities demonstrate relatively high perioperative morbidity and mortality rates and, therefore, form a distinguished challenge for the bariatric surgeons. Methods. We retrospectively analyzed high-risk patients, who underwent bariatric surgery in University Hospital Leipzig between May 2012 and December 2016. High-risk patients were defined when (Bergeat et al., 2016) at least one of the following risk factors was met: age ≥ 70 years, body mass index (BMI) > 70 kg/m2, liver cirrhosis, end-organ failure, or immunosuppression by status after organ transplantation along with (Birkmeyer et al., 2010) at least two comorbidities associated with obesity. Our analysis included early postoperative complications. Results. A total of 25 high-risk obese patients were identified. All patients had a standardized postoperative management with a mean length of hospital stay of 4 ± 1.4 days. One patient required an operative revision due to a stapler line leak after sleeve gastrectomy. No other major postoperative complications occurred. Conclusion. Bariatric surgery for severe high-risk patients can be performed safely in high-volume centers following standardized procedures.

Conventional chandelier-endoilluminators used for pars-plana vitrectomy consist of a light-emitting tip attached to an optical fibre. The tip requires introduction into the ocular space through an incision. To achieve complete illumination of the intraocular space, the introduction of more than just one tip is sometimes necessary. An extraocular vitreoretinal LED-endoilluminator discussed in this paper represents a new approach to illuminate the intraocular space. The light source is integrated into a speculum and firmly apposed to the sclera. This approach offers the advantage of effectively illuminating the interior of the eye even though the procedure is non-invasive. Furthermore, this approach significantly reduces the risk of damage to the retina by phototoxic effects. A round white LED was used as a light source. By integrating the light source into a speculum, the LED was firmly held against the sclera. Thus, the ocular space was illuminated transsclerally. As a result, indirect uniform illumination of the complete intraocular space was achieved. The prototype was developed considering the relevant international standards. Porcine eyes were used because their properties are similar to those of human eyes. Porcine eyes could be acceptably illuminated with the selected LED. The LED-endoilluminator conforms with international standards for endoillumination. Thus, possible photochemical and thermal risks are considered and reduced to a minimum. A novel LED-endoilluminator which can be attached to a speculum was developed. The system does not need any connection to an external light source and, consequently, also avoids usage of an optical fibre. Regular and uniform illumination of the intraocular space was achieved by transmitted and scattered visible irradiation, avoiding an incision. The duration of potential light exposure, compared to existing illumination systems, can be significantly increased. This is also true when the illuminator is not directly placed over the pars-plana and the distance to the retina is reduced. Only a part of the light reaches the retina and the fraction of short wavelength becomes very small. Increased safety of the system results from now being able to increase the exposure time and reduce phototoxic stress to the retina.

Purpose: Surgical or diagnostic procedures are often accompanied by a short-term increase in intraocular pressure (IOP). A short-term increase in IOP can occur during refractive procedures, vitreoretinal surgery, transillumination, photocoagulation, or cryocoagulation. A porcine eye model was chosen (n = 89) to compile comparable study data and to de termine correlations between the force induced and the resulting intraocular pressure while excluding the effect of surgeons. Methods: The IOP was measured in the anterior chamber. IOP changes were induced by applying an external force and measured when using a cannula, trocar, and cryocoagulation (n = 32), and correlations between force and resulting IOP were assessed (n = 57). Results: A correlation was noted between the force induced and the IOP increase, which showed a linear dependency. The insertion of a 29-G cannula caused a mean ΔIOP value of 49.1 ± 2.9 mm Hg and an external force of 0.76 N, and that of a 23-G trocar 344.4 ± 5.9 mm Hg and 6.09 N, respectively. The rise in IOP during a simulated cryocoagulation reached values between 57.3 ± 14.8 mm Hg (cryoprobe tip diameter: 0.9 mm) and 130.3 ± 2.9 mm Hg (cryoprobe tip diameter: 7.0 mm). Conclusion: The values of the forces applied can be converted into the resulting IOP based on the specific action. Surgical or diagnostic procedures should, therefore, be evaluated with regard to preexisting pathologies, such as glaucoma.

Lung contusion is the most common lung injury following blunt chest trauma which, in turn, is associated with high mortality rates (Gavelli et al 2002 Eur. Radiol. 12 1273-94). Lung contusion is characterized by hemorrhage and edema with consecutively reduced compliance. Objective and Approach: In this study, unilateral lung contusion and other traumata were induced in 12 pigs by using a bolt gun machine. To investigate the pathophysiological consequences of lung contusion, information on clinical parameters was collected and monitored regularly while animals were additionally monitored with electrical impedance tomography (EIT) before trauma, and at 4, 24, 48 and 72 h after polytrauma. Main results Statistical analyses showed significant differences between the measurement time points in terms of lung compliance ([Formula: see text]) and in global EIT parameters, such as absolute global impedance (aGlobImp) ([Formula: see text]), tidal impedance variation (TIV) ([Formula: see text]) and the center of ventilation (CoV) ([Formula: see text]). Additionally, distinct analyses for the left (non-injured) and right (injured) lung were also performed. In this context, during the progress of lung contusion, significant changes were found for the injured lung in TIV ([Formula: see text]), global inhomogeneity ([Formula: see text]), regional ventilation delay ([Formula: see text]), CoV ([Formula: see text]) and in regions of non-ventilation (rNoVent) ([Formula: see text]). Furthermore, TIV and rNoVent were capable to differentiate the injured and the contralateral healthy lung at 4 and 24 h after injury (TIV: [Formula: see text] and [Formula: see text]; rNoVent: [Formula: see text] and [Formula: see text]). TIV reached a sensitivity of 82% (specificity of 100%) at 4 h and sensitivity of 82% (specificity of 82%) at 24 h after injury, in detecting lung contusion specific consequences. Significance The results indicate that EIT might be a valuable tool to detect and to monitor lung injuries including lung contusion. Most probably, EIT-derived indices could also be used to adapt ventilator settings to optimize individual lung protection.

In the past, changes of the Apparent Diffusion Coefficient in glioblastoma multiforme have been shown to be related to specific genes and described as being associated with survival. The purpose of this study was to investigate diffusion imaging parameters in combination with genome-wide expression data in order to obtain a comprehensive characterisation of the transcriptomic changes indicated by diffusion imaging parameters. Diffusion-weighted imaging, molecular and clinical data were collected prospectively in 21 patients. Before surgery, MRI diffusion metrics such as axial (AD), radial (RD), mean diffusivity (MD) and fractional anisotropy (FA) were assessed from the contrast enhancing tumour regions. Intraoperatively, tissue was sampled from the same areas using neuronavigation. Transcriptional data of the tissue samples was analysed by Weighted Gene Co-Expression Network Analysis (WGCNA) thus classifying genes into modules based on their network-based affiliations. Subsequent Gene Set Enrichment Analysis (GSEA) identified biological functions or pathways of the expression modules. Network analysis showed a strong association between FA and epithelial-to-mesenchymal-transition (EMT) pathway activation. Also, patients with high FA had a worse clinical outcome. MD correlated with neural function related genes and patients with high MD values had longer overall survival. In conclusion, FA and MD are associated with distinct molecular patterns and opposed clinical outcomes.

PLoS one 12(5), e0176069 (2017). doi:10.1371/journal.pone.0176069, Published by PLoS, Lawrence, Kan.

In their post-traumatic course, trauma patients suffering from multiple injuries have a high risk for immune dysregulation, which may contribute to post-injury complications and late mortality. Monocytes as specific effector cells of the innate immunity play a crucial role in inflammation. Using their Pattern Recognition Receptors (PRRs), notably Toll-Like Receptors (TLR), the monocytes recognize pathogens and/or pathogen-associated molecular patterns (PAMPs) and organize their clearance. TLR2 is the major receptor for particles of gram-positive bacteria, and initiates their phagocytosis. Here, we investigated the phagocytizing capability of monocytes in a long-term porcine severe trauma model (polytrauma, PT) with regard to their TLR2 expression. Polytrauma consisted of femur fracture, unilateral lung contusion, liver laceration, hemorrhagic shock with subsequent resuscitation and surgical fracture fixation. After induction of PT, peripheral blood was withdrawn before (-1 h) and directly after trauma (0 h), as well as 3.5 h, 5.5 h, 24 h and 72 h later. CD14+ monocytes were identified and the expression levels of H(S)LA-DR and TLR2 were investigated by flow cytometry. Additionally, the phagocytizing activity of monocytes by applying S. aureus particles labelled with pHrodo fluorescent reagent was also assessed by flow cytometry. Furthermore, blood samples from 10 healthy pigs were exposed to a TLR2-neutralizing antibody and subsequently to S. aureus particles. Using flow cytometry, phagocytizing activity was determined. P below 0.05 was considered significant. The number of CD14+ monocytes of all circulating leukocytes remained constant during the observational time period, while the percentage of CD14+H(S)LA-DR+ monocytes significantly decreased directly, 3.5 h and 5.5 h after trauma. The percentage of TLR2+ expressing cells out of all monocytes significantly decreased directly, 3.5 h and 5.5 h after trauma. The percentage of phagocytizing monocytes decreased immediately and remained lower during the first 3.5 h after trauma, but increased after 24 h. Antagonizing TLR2 significantly decreased the phagocytizing activity of monocytes. Both, decreased percentage of activated as well as TLR2 expressing monocytes persisted as long as the reduced phagocytosis was observed. Moreover, neutralizing TLR2 led to a reduced capability of phagocytosis as well. Therefore, we assume that reduced TLR2 expression may be responsible for the decreased phagocytizing capacity of circulating monocytes in the early post-traumatic phase.

Objectives To assess the pharmacokinetics and tissue penetration of fosfomycin in obese and non-obese surgical patients. Methods Fifteen obese patients undergoing bariatric surgery and 15 non-obese patients undergoing major intra-abdominal surgery received an intravenous single short infusion of 8 g of fosfomycin. Fosfomycin concentrations were determined by LC-MS/MS in plasma and microdialysate from subcutaneous tissue up to 8 h after dosing. The pharmacokinetic analysis was performed in plasma and interstitial fluid (ISF) by non-compartmental methods. Results Thirteen obese patients (BMI 38–50 kg/m2) and 14 non-obese patients (BMI 0–29 kg/m2) were evaluable. The pharmacokinetics of fosfomycin in obese versus non-obese patients were characterized by lower peak plasma concentrations (468 ± 139 versus 594 ± 149 mg/L, P = 0.040) and higher V (24.4 ± 6.4 versus 19.0 ± 3.1 L, P = 0.010). The differences in AUC∞ were not significant (1275 ± 477 versus 1515 ± 352 mg·h/L, P = 0.16). The peak concentrations in subcutaneous tissue were reached rapidly and declined in parallel with the plasma concentrations. The drug exposure in tissue was nearly halved in obese compared with non-obese patients (AUC∞ 1052 ± 394 versus 1929 ± 725 mg·h/L, P = 0.0010). The tissue/plasma ratio (AUCISF/AUCplasma) was 0.86 ± 0.32 versus 1.27 ± 0.34 (P = 0.0047). Conclusions Whereas the pharmacokinetics of fosfomycin in plasma of surgical patients were only marginally different between obese and non-obese patients, the drug exposure in subcutaneous tissue was significantly lower in the obese patients.

Existing light sources for intraocular illumination are often bulky and expensive and pose a risk for the patient, because light guides are inserted in the eye through incisions and if the tip of these light guides get too close to the retina, the retina can be damaged photochemically within minutes or even seconds. Therefore a new, safe and simple device for intraocular illumination is developed and evaluated for its thermal and photochemical risks to the patient. It consists of a white LED which is integrated into a pen like holder. This device is pressed against the sclera by the physician who seeks for illumination during surgery or for diagnostic purposes. The LED light is transmitted through the sclera without the need for an incision. Considering the relevant standards, the device poses no harm to the patient, and in tests with the authors’ own eyes a sufficient intraocular illumination is reached. The proposed device is quite simple but easy to handle and very gentle for the patient.

We explored the phylogenetic utility of entire plastid DNA sequences inWe used Illumina sequencing to obtain full plastid sequences of 37 accessions of 20Our phylogenetic trees of the entire data set were highly resolved, with 100% bootstrap support for most of the external and many of the internal clades, except for the clade ofOur data have allowed us to (1) produce a well-resolved plastid phylogeny of

The purpose of this study was to identify markers from perfusion, diffusion, and chemical shift imaging in glioblastomas (GBMs) and to correlate them with genetically determined and previously published patterns of structural magnetic resonance (MR) imaging. Twenty-six patients (mean age 60 years, 13 female) with GBM were investigated. Imaging consisted of native and contrast-enhanced 3D data, perfusion, diffusion, and spectroscopic imaging. In the presence of minor necrosis, cerebral blood volume (CBV) was higher (median ± SD, 2.23% ± 0.93) than in pronounced necrosis (1.02% ± 0.71), pcorr = 0.0003. CBV adjacent to peritumoral fluid-attenuated inversion recovery (FLAIR) hyperintensity was lower in edema (1.72% ± 0.31) than in infiltration (1.91% ± 0.35), pcorr = 0.039. Axial diffusivity adjacent to peritumoral FLAIR hyperintensity was lower in severe mass effect (1.08*10–3 mm2/s ± 0.08) than in mild mass effect (1.14*10–3 mm2/s ± 0.06), pcorr = 0.048. Myo-inositol was positively correlated with a marker for mitosis (Ki-67) in contrast-enhancing tumor, r = 0.5, pcorr = 0.0002. Changed CBV and axial diffusivity, even outside FLAIR hyperintensity, in adjacent normal-appearing matter can be discussed as to be related to angiogenesis pathways and to activated proliferation genes. The correlation between myo-inositol and Ki-67 might be attributed to its binding to cell surface receptors regulating tumorous proliferation of astrocytic cells.

Guidelines recommend administering antibiotics within 1 h of sepsis recognition but this recommendation remains untested by randomized trials. This trial was set up to investigate whether survival is improved by reducing the time before initiation of antimicrobial therapy by means of a multifaceted intervention in compliance with guideline recommendations. The MEDUSA study, a prospective multicenter cluster-randomized trial, was conducted from July 2011 to July 2013 in 40 German hospitals. Hospitals were randomly allocated to receive conventional continuous medical education (CME) measures (control group) or multifaceted interventions including local quality improvement teams, educational outreach, audit, feedback, and reminders. We included 4183 patients with severe sepsis or septic shock in an intention-to-treat analysis comparing the multifaceted intervention (n = 2596) with conventional CME (n = 1587). The primary outcome was 28-day mortality. The 28-day mortality was 35.1% (883 of 2596 patients) in the intervention group and 26.7% (403 of 1587 patients; p = 0.01) in the control group. The intervention was not a risk factor for mortality, since this difference was present from the beginning of the study and remained unaffected by the intervention. Median time to antimicrobial therapy was 1.5 h (interquartile range 0.1–4.9 h) in the intervention group and 2.0 h (0.4–5.9 h; p = 0.41) in the control group. The risk of death increased by 2% per hour delay of antimicrobial therapy and 1% per hour delay of source control, independent of group assignment. Delay in antimicrobial therapy and source control was associated with increased mortality but the multifaceted approach was unable to change time to antimicrobial therapy in this setting and did not affect survival.

Im Rahmen der vorliegenden Arbeit wird die Entwicklung eines Phasenfeldmodells mit gekoppeltem elasto-plastischem Model vorgestellt. Dessen Besonderheit ist es, dass im Gegensatz zu vielen der bisher veröffentlichten Ansätze die nichtlineare Kinematik und Spannungsentwicklung bei großen Deformationen berücksichtigt wird. Insbesondere bei der Simulation dynamischer Rekristallisation ist dies von Bedeutung. Da auf betrachteter Längenskala plastische Deformationen inhärent anisotrop sind, wird ein Kristallplastizitätsmodell verwendet. Dessen Implementierung in die Open-Source-Bibliothek OpenPhase wird gegen einen kommerziellen Finite-Elemente-Löser validiert und zeigt exzellente Vergleichbarkeit. Anschließend wird dynamische Rekristallisation simuliert. Das Modell zeigt seine Fähigkeit den Prozess abzubilden, die Bedeutung der korrekten Berücksichtigung finiter Deformationen sowie die Vorhersage der Temperatur- und Dehnratenabhängigkeit der makroskopischen Spannungs-Dehnungskurven.

Skin and soft tissue infections may progress rapidly and take a fatal ending unless not treated in time. A 44-year old male patient without any pre-existing conditions got hospitalized with a bursitis ofthe right olecranon and unspecific general symptoms. Within a short period of time he became critically ill due this seemingly harmless infection. We describe our approach leading to the right diagnoses and the treatment of this unexpected progress.

Scientific reports 6, 39659 (2016). doi:10.1038/srep39659, Published by Nature Publishing Group, London

The Hedgehog (HH) pathway has been identified as an important deregulated signal transduction pathway in pancreatic ductal adenocarcinoma (PDAC), a cancer type characterized by a highly metastatic phenotype. In PDAC, the canonical HH pathway activity is restricted to the stromal compartment while HH signaling in the tumor cells is reduced as a consequence of constitutive KRAS activation. Here, we report that in the tumor compartment of PDAC the HH pathway effector transcription factor GLI1 regulates epithelial differentiation. RNAi-mediated knockdown of GLI1 abolished characteristics of epithelial differentiation, increased cell motility, and synergized with TGFβ to induce an epithelial-to-mesenchymal transition (EMT). Notably, EMT conversion in PDAC cells occurred in the absence of induction of SNAIL or SLUG, two canonical inducers of EMT in many other settings. Further mechanistic analysis revealed that GLI1 directly regulated the transcription of E-cadherin, a key determinant of epithelial tissue organization. Collectively, our findings identify GLI1 as an important positive regulator of epithelial differentiation, and they offer an explanation for how decreased levels of GLI1 are likely to contribute to the highly metastatic phenotype of PDAC. Cancer Res; 72(1); 88–99. ©2011 AACR.

SummaryDuring sepsis, the balance between abundantly secreted von Wille-brand factor (VWF) and the activity of its size regulating protease ADAMTS13 is assumed to be involved in coagulation abnormalities. We aimed to establish a porcine model with haemorrhagic shock with consecutive sepsis and hypothesised that a decreased ADAMTS13-activity as well as an altered VWF multimer pattern is associated with renal failure. Animals (n=21) were subjected to haemorrhagic shock. After volume replacement, intraperitoneal Escherichia coli sepsis was induced. Blood samples were drawn at baseline, after haemorrhage and sepsis induction. Directly postmortem we examined renal tissue by JONES-silver, CD61, VWF and fibrin staining for characterisation of thrombi. Renal failure was analysed by scoring PAS-stained sections for acute tubular damage. Glomerular microthrombi were observed in six of 21 septic animals. Porcine ADAMTS13 activity declined significantly during sepsis, accompanied by a drop-off in platelet count. At 12 hours after sepsis induction, ADAMTS13 activity was significantly diminished compared to sham controls, and an elevated acute tubular damage score was associated with an increased proportion of high-molecular-weight VWF multimers. Compared to baseline the proportion of high-molecular-weight VWF multimers increased significantly in septic animals. Similar to human sepsis, diminished ADAMTS13 activity was observed in a septic porcine model associated with a shift to rather thrombogenic VWF multimers and deposition of microthrombi. Therefore, this porcine model seems to be appropriate for performing functional and therapeutic studies in sepsis-associated ADAMTS13 deficiency.

A prototype microscope built with self-reconstructing Bessel beams is shown to be able to reduce scattering artifacts as well as increase image quality and penetration depth in three-dimensional inhomogeneous opaque media.

Synthesis and liberation of adrenomedullin (ADM) are found in different tissues and endothelial cells and ADM is induced by hypoxia, oxidative stress, and pro-inflammatory cytokines [1]. The prognostic value of ADM is described in general patient populations, in medical patients and in particular recently in patients with suspected sepsis in the emergency department [2, 3]. In surgical patients, the obstacle is to differentiate between postoperative inflammation and sepsis and to assess the patients' prognosis.

The Down syndrome-associated DYRK1A kinase has been reported as a stimulator of the developmentally important Hedgehog (Hh) pathway, but cells from Down syndrome patients paradoxically display reduced Hh signalling activity. Here we find that DYRK1A stimulates GLI transcription factor activity through phosphorylation of general nuclear localization clusters. In contrast, in vivo and in vitro experiments reveal that DYRK1A kinase can also function as an inhibitor of endogenous Hh signalling by negatively regulating ABLIM proteins, the actin cytoskeleton and the transcriptional co-activator MKL1 (MAL). As a final effector of the DYRK1A-ABLIM-actin-MKL1 sequence, we identify the MKL1 interactor Jumonji domain demethylase 1A (JMJD1A) as a novel Hh pathway component stabilizing the GLI1 protein in a demethylase-independent manner. Furthermore, a Jumonji-specific small-molecule antagonist represents a novel and powerful inhibitor of Hh signal transduction by inducing GLI1 protein degradation in vitro and in vivo.