Tezepelumab decreases airway epithelial IL-33 and T2-inflammation in response to viral stimulation in patients with asthma.

BACKGROUND: Respiratory virus infections are main triggers of asthma exacerbations. Tezepelumab, an anti-TSLP mAb, reduces exacerbations in patients with asthma, but the effect of blocking TSLP on host epithelial resistance and tolerance to virus infection is not known. AIM: To examine effects of blocking TSLP in patients with asthma on host resistance (IFNß, IFNλ, and viral load) and on the airway epithelial inflammatory response to viral challenge. METHODS: Bronchoalveolar lavage fluid (BALF, n = 39) and bronchial epithelial cells (BECs) were obtained from patients with uncontrolled asthma before and after 12 weeks of tezepelumab treatment (n = 13) or placebo (n = 13). BECs were cultured in vitro and exposed to the viral infection mimic poly(I:C) or infected by rhinovirus (RV). Alarmins, T2- and pro-inflammatory cytokines, IFNß IFNλ, and viral load were analyzed by RT-qPCR and multiplex ELISA before and after stimulation. RESULTS: IL-33 expression in unstimulated BECs and IL-33 protein levels in BALF were reduced after 12 weeks of tezepelumab. Further, IL-33 gene and protein levels decreased in BECs challenged with poly(I:C) after tezepelumab whereas TSLP gene expression remained unaffected. Poly(I:C)-induced IL-4, IL-13, and IL-17A release from BECs was also reduced with tezepelumab whereas IFNß and IFNλ expression and viral load were unchanged. CONCLUSION: Blocking TSLP with tezepelumab in vivo in asthma reduced the airway epithelial inflammatory response including IL-33 and T2 cytokines to viral challenge without affecting anti-viral host resistance. Our results suggest that blocking TSLP stabilizes the bronchial epithelial immune response to respiratory viruses.

Engineering osteogenic microenvironments by combination of multilayers from collagen type I and chondroitin sulfate with novel cationic liposomes.

Cationic liposomes composed of a novel lipid (N-{6-amino-1-[N-(9Z) -octadec9-enylamino] -1-oxohexan-(2S) -2-yl} -N'- {2- [N, N-bis(2-aminoethyl) amino] ethyl} -2-hexadecylpropandiamide) (OO4) and dioleoylphosphatidylethanolamine (DOPE) possess high amounts of amino groups and are promising systems for lipofection. Moreover, these cationic liposomes can also be used as a polycationic entity in multilayer formation using layer-by-layer technique (LbL), which is a method to fabricate surface coatings by alternating adsorption of polyanions and polycations. Since liposomes are suitable for endocytosis by or fusion with cells, controlled release of their cargo on site is possible. Here, a polyelectrolyte multilayer (PEM) system was designed of chondroitin sulfate (CS) and collagen type I (Col I) by LbL technique with OO4/DOPE liposomes embedded in the terminal layers to create an osteogenic microenvironment. Both, the composition of PEM and cargo of the liposomes were used to promote osteogenic differentiation of C2C12 myoblasts as in vitro model. The internalization of cargo-loaded liposomes from the PEM into C2C12 cells was studied using lipophilic (Rhodamine-DOPE conjugate) and hydrophilic (Texas Red-labeled dextran) model compounds. Besides, the use of Col I and CS should mimic the extracellular matrix of bone for future applications such as bone replacement therapies. Physicochemical studies of PEM were done to characterize the layer growth, thickness, and topography. The adhesion of myoblast cells was also evaluated whereby the benefit of a cover layer of CS and finally Col I above the liposome layer was demonstrated. As proof of concept, OO4/DOPE liposomes were loaded with dexamethasone, a compound that can induce osteogenic differentiation. A successful induction of osteogenic differentiation of C2C12 cells with the novel designed liposome-loaded PEM system was shown. These findings indicate that designed OH4/DOPE loaded PEMs have a high potential to be used as drug delivery or transfection system for implant coating in the field of bone regeneration and other applications.

[Intrahepatic cholangiocarcinoma : Results after 84 resections]. / Das intrahepatische Cholangiokarzinom : Ergebnisse nach 84 Resektionen.

BACKGROUND: The incidence of intrahepatic cholangiocarcinoma (ICC) is increasing worldwide. Surgical resection is the only curative treatment option. AIM OF THE STUDY: This study analyzed the prognostic factors after resection of ICC. MATERIAL AND METHODS: A total of 84 patients were surgically treated under potentially curative intent. Perihilar and distal cholangiocarcinomas were excluded. The 5­year survival was analyzed with respect to tumor stage (TNM), number of lesions, complete surgical resection (R0), peritoneal carcinosis and postoperative complications. RESULTS: The 5­year survival was 27% and 77% of patients underwent R0 resections. In the univariate analysis a T stage >2, an N+ situation or an R+ resection as well as peritoneal and multilocular intrahepatic spread were associated with a poorer prognosis. Postoperative complications also negatively influenced survival. On multivariate analysis the absence of peritoneal spread, node-negative tumor stages, singular hepatic lesions and a low T stage as well as the absence of complications were associated with improved survival. DISCUSSION: The prognosis of ICC is poor even after successful surgical resection. Well-known tumor characteristics such as TNM are relevant prognostic factors. Surgical resection is accompanied by postoperative complications (most frequently biliary), which negatively influence survival. Adjuvant strategies are urgently needed to improve long-term survival even after complete surgical resection.

House dust mite impairs antiviral response in asthma exacerbation models through its effects on TLR3.

BACKGROUND: Impaired antiviral interferon expression may be involved in asthma exacerbations commonly caused by rhinovirus infections. Allergy is a known risk factor for viral-induced asthma exacerbation, but little is known whether allergens may affect interferon responses. OBJECTIVE: Our hypothesis is that house dust mite (HDM) impairs viral stimulus-induced antiviral signalling. METHODS: Experimental asthma exacerbations were produced in vitro in human bronchial epithelial cells (HBECs) and in mice using sequential challenges with HDM and a viral infection mimic, Poly(I:C). We examined rhinovirus pattern recognition receptors (PRRs) signalling pathways and potential mechanisms of impaired interferon response. RESULTS: HBECs and mice exposed to HDM prior to Poly(I:C) exhibited a reduced antiviral response compared to Poly(I:C) alone, including reduced IFN-ß, IFN-λ, TLR3, RIG-I, MDA5, IRF-3 and IRF-7. Heat inactivation of HDM partially restored the TLR3-induced interferon response in vitro and in vivo. Our HBEC-data further showed that HDM directly affects TLR3 signalling by targeting the receptor glycosylation level. CONCLUSIONS: Direct effects of allergens such as HDM on PRRs can present as potential mechanism for defective antiviral airway responses. Accordingly, therapeutic measures targeting inhibitory effects of allergens on antiviral PRRs may find use as a strategy to boost antiviral response and ameliorate exacerbations in asthmatic patients.

Allergens produce serine proteases-dependent distinct release of metabolite DAMPs in human bronchial epithelial cells.

BACKGROUND: The respiratory epithelium is a major site for disease interaction with inhaled allergens. Additional to IgE-dependent effects, allergens contain proteases that may stimulate human bronchial epithelial cells (HBECs) through protease-activated receptors, causing the release of mediators important in driving Th2-mediated immune responses. OBJECTIVE: We aimed to investigate whether different allergens induce metabolite DAMPs such as ATP and uric acid (UA) release in HBECs. METHODS: HBECs (BEAS-2B cell line) were exposed to different allergen extracts; house dust mite (HDM), Alternaria alternata, Artemisia vulgaris and Betula pendula and UA, ATP, IL-8 and IL-33 release were measured. Allergen extracts were heat-inactivated or pre-incubated with serine (AEBSF) or cysteine (E64) protease inhibitors to study the involvement of protease activity in ATP, UA and IL-8 release. HDM-induced release of UA was studied in a mouse model of allergic inflammation. RESULTS: All allergens caused dose-dependent rapid release of ATP and IL-8, but only HDM induced UA release from HBECs. HDM also caused release of UA in vivo in our mouse model of allergic inflammation. ATP release by all 4 allergen extracts was significantly reduced by heat-inactivation and by serine protease inhibitors. Similarly, the HDM-induced UA release was also abrogated by heat-inactivation of HDM extract and dependent on serine proteases. Furthermore, allergen-induced IL-8 mRNA expression was inhibited by serine protease inhibitors. CONCLUSIONS AND CLINICAL RELEVANCE: ATP was released by all 4 allergens in HBECs supporting the role of ATP involvement in asthma pathology. However, HDM stands out by its capacity to cause UA release, which is of interest in view of the proposed role of UA in early initiation of allergic asthma. Although serine proteases may be involved in the activity of all the studied allergens, further work is warranted to explain the differences between HDM and the other 3 allergens regarding the effects on UA release.

[Prewarming according to the AWMF S3 guidelines on preventing inadvertant perioperative hypothermia 2014 : Retrospective analysis of 7786 patients]. / Vorwärmung entsprechend der "S3 Leitlinie Vermeidung von unbeabsichtigter perioperativer Hypothermie 2014" : Retrospektive Analyse von 7786 Patienten.

BACKGROUND: Inadvertent perioperative hypothermia, which is defined as a core body temperature of less than 36.0 °C, can have serious consequences in surgery patients. These include cardiac complications, increased blood loss, wound infections and postoperative shivering; therefore, the scientific evidence that inadvertent perioperative hypothermia should be avoided is undisputed and several national guidelines have been published summarizing the scientific evidence and recommending specific procedures. The German AWMF guidelines were the first to emphasize the importance of prewarming for surgery patients to avoid inadvertant perioperative hypothermia; however, in contrast to intraoperative warming, prewarming is so far not sufficiently implemented in clinical practice in many hospitals. Furthermore, a recent study has questioned the effectiveness of prewarming. OBJECTIVE: The aim of this retrospective investigation was to evaluate the hypothermia rates that can be achieved when prewarming in the anesthesia induction room is introduced into the clinical practice and performed in addition to intraoperative warming. MATERIAL AND METHODS: The ethics committee of the Medical Faculty of the Martin Luther University Halle Wittenberg gave approval for data storage and retrospective data analysis from the anesthesia database. According to the existing local standard operating procedure, prewarming with forced air was performed in addition to intraoperative warming in the anesthesia induction room in 3899 patients receiving general anesthesia with a duration of 30 min or longer from January 2015 to December 2016. The results were compared with a control group of 3887 patients from July 2012 to August 2014 who received intraoperative warming but were not subjected to prewarming. Tracheal intubation was carried out in all patients and temperature measurements after the induction of anesthesia were performed using esophageal, urinary catheter or intra-arterial temperature probes. RESULTS: The mean duration of prewarming was 25 min in the treatment group. Patients subjected to prewarming showed an intraoperative hypothermia rate of 15.8% and a postoperative hypothermia rate of 5.1%. Patients without prewarming showed an intraoperative hypothermia rate of 30.4% and a postoperative hypothermia rate of 12.4%. This means a 52% reduction of the intraoperative hypothermia rate and a 41% reduction of the postoperative hypothermia rate for patients who received prewarmimg (p < 0.0001). Multivariate logistic regression revealed that the lack of prewarming was independently associated with intraoperative hypothermia with an odds ratio of 2.5 (95% confidence interval CI 2.250-2.841; p < 0.0001) and postoperative hypothermia with an odds ratio of 2.8 (95% CI 2.316-3.277; p < 0.0001). CONCLUSION: Prewarming, as recommended in the AWMF guidelines, resulted in a significant and clinically relevant reduction in the incidence of inadvertent perioperative hypothermia; therefore, prewarming can still be regarded as an effective method to avoid perioperative hypothermia. Hypothermia rates of 15.8% intraoperatively and 5.1% postoperatively can be achieved in clinical practice, when prewarming is performed in addition to intraoperative warming in the anesthesia induction room directly before the start of surgical procedures.

[Implementation of a thermal management concept to prevent perioperative hypothermia : Results of a 6­month period in clinical practice]. / Umsetzung eines Wärmemanagementkonzeptes zur Vermeidung von perioperativer Hypothermie : Ergebnisse eines Sechsmonatszeitraums in der klinischen Praxis.

BACKGROUND: Perioperative hypothermia is defined as a core temperature below 36 °C. The literature shows that perioperative hypothermia is a frequent but potentially preventable complication of the surgical process. The risk of experiencing perioperative hypothermia is inherent for all anesthetized patients, independent of the type of surgery. Unless preventative measures are taken, perioperative hypothermia occurs in 50 to 70 % of all surgical patients. In Germany and Austria the guideline "Preventing inadvertent perioperative hypothermia" has been published. In Wolfsburg we started already in 2012 with a standard operating procedure to prevent perioperative hypothermia in all surgical patients. In two clinical departments we established an additional prewarming-protocol starting prior to induction of anaesthesia on the normal ward on the day of surgery. MATERIAL AND METHODS: For a period of 6 months we analyzed all temperature data of patients having undergone surgery, beginning before the start of general anaesthesia until the end of the operation. RESULTS: In total 3228 patients were enrolled into the study. Prewarming was performed in 1329 patients. In 1902 patients active warming was limited to the intraoperative period. The total rate of hypothermia in all patients was 32.6 %, whereas the rate of hypothermia at the end of the operation was 19.3 %. In the group of patients without prewarming the overall rate was 39.1 vs. 25 % at the end of the operation. In the groups of patients with prewarming the total rates of hypothermia were 25.2 and 24.7 % overall and 14.4 and 12.5 % at the end of the operation. In multifactorial regression it could be shown that patients without prewarming had a 1.8-fold increased risk of perioperative hypothermia compared to patients with intraoperative warming only. CONCLUSION: We conclude that temperature management is a challenge in the clinical situation, and that it is difficult to achieve rates of hypothermia close to zero. The addition of prewarming was very effective in improving the results in our patients.

A setup for synchrotron-radiation-induced total reflection X-ray fluorescence and X-ray absorption near-edge structure recently commissioned at BESSY II BAMline.

An automatic sample changer chamber for total reflection X-ray fluorescence (TXRF) and X-ray absorption near-edge structure (XANES) analysis in TXRF geometry was successfully set up at the BAMline at BESSY II. TXRF and TXRF-XANES are valuable tools for elemental determination and speciation, especially where sample amounts are limited (<1 mg) and concentrations are low (ng ml(-1) to µg ml(-1)). TXRF requires a well defined geometry regarding the reflecting surface of a sample carrier and the synchrotron beam. The newly installed chamber allows for reliable sample positioning, remote sample changing and evacuation of the fluorescence beam path. The chamber was successfully used showing accurate determination of elemental amounts in the certified reference material NIST water 1640. Low limits of detection of less than 100 fg absolute (10 pg ml(-1)) for Ni were found. TXRF-XANES on different Re species was applied. An unknown species of Re was found to be Re in the +7 oxidation state.

A Jones matrix formalism for simulating three-dimensional polarized light imaging of brain tissue.

The neuroimaging technique three-dimensional polarized light imaging (3D-PLI) provides a high-resolution reconstruction of nerve fibres in human post-mortem brains. The orientations of the fibres are derived from birefringence measurements of histological brain sections assuming that the nerve fibres­consisting of an axon and a surrounding myelin sheath­are uniaxial birefringent and that the measured optic axis is oriented in the direction of the nerve fibres (macroscopic model). Although experimental studies support this assumption, the molecular structure of the myelin sheath suggests that the birefringence of a nerve fibre can be described more precisely by multiple optic axes oriented radially around the fibre axis (microscopic model). In this paper, we compare the use of the macroscopic and the microscopic model for simulating 3D-PLI by means of the Jones matrix formalism. The simulations show that the macroscopic model ensures a reliable estimation of the fibre orientations as long as the polarimeter does not resolve structures smaller than the diameter of single fibres. In the case of fibre bundles, polarimeters with even higher resolutions can be used without losing reliability. When taking the myelin density into account, the derived fibre orientations are considerably improved.

Liver fluke-infested graft used for living-donor liver transplantation: case report and review of the literature.

Clonorchiasis is a cholangiopathy caused by foodborne trematode parasites, also known as liver flukes. Clonorchiasis is endemic in a wide geographical area extending from Eastern Europe to Southeast Asia. Infested hosts may remain asymptomatic for decades and consequently their liver can become available as a graft. To date, 20 liver transplantations with liver fluke-infested grafts have been reported in the literature. All of them occurred in Asian countries. We, here, report the first case to our knowledge in the Western world of living-donor liver transplantation (LDLT) with an Opisthorchis felineus-infested graft, and present a review of the literature. A 6-month-old girl with decompensated secondary biliary cirrhosis underwent an LDLT with a left lateral graft infested with O. felineus. After prompt diagnosis and adequate therapy, both donor and recipient had an uneventful postoperative course and long-term follow-up. Liver grafts infested with liver flukes do not pose a contraindication to liver donation from deceased or living donors, provided that a correct diagnosis and treatment are performed in a timely fashion.

Depression storage capacities of different ideal pavements as quantified by a terrestrial laser scanning-based method.

Rainfall partition on paved urban surfaces is governed to a great extent by depression storage. This is especially the case for small rainfall events, which are often ignored in urban hydrology. If storage, infiltration and evaporation (important for urban heat island mitigation), rather than storm water run-off, are of interest, high-resolution simulations with exact values for depression storage capacities are required. Terrestrial laser scanners deliver fast, high-resolution surveys of pavement surface morphology. The depression storage capacity can be quantified from 3D points by generating digital elevation models and applying cut-and-fill algorithms in a geographic information system. The method was validated using a test model. It was possible to quantify depressions with a depth of at least 1.4 × 10(-3) m and a surface of at least 15 × 10(-6) m(2) with an uncertainty below 30%. Applying this method, the depression storage capacities for 11 ideal, typical pavement designs were found to vary from 0.07 to 1.4 mm. Realistic urban pavements must also be surveyed, as cracks and puddles from their use history can have a major impact on the depression storage capacities and thus on infiltration, evaporation and, finally, the annual run-off.

Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder.

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Apparent rate constant mapping using hyperpolarized [1-(13)C]pyruvate.

Hyperpolarization of [1-13C]pyruvate in solution allows real-time measurement of uptake and metabolism using MR spectroscopic methods. After injection and perfusion, pyruvate is taken up by the cells and enzymatically metabolized into downstream metabolites such as lactate, alanine, and bicarbonate. In this work, we present comprehensive methods for the quantification and interpretation of hyperpolarized 13C metabolite signals. First, a time-domain spectral fitting method is described for the decomposition of FID signals into their metabolic constituents. For this purpose, the required chemical shift frequencies are automatically estimated using a matching pursuit algorithm. Second, a time-discretized formulation of the two-site exchange kinetic model is used to quantify metabolite signal dynamics by two characteristic rate constants in the form of (i) an apparent build-up rate (quantifying the build-up of downstream metabolites from the pyruvate substrate) and (ii) an effective decay rate (summarizing signal depletion due to repetitive excitation, T1-relaxation and backward conversion). The presented spectral and kinetic quantification were experimentally verified in vitro and in vivo using hyperpolarized [1-13C]pyruvate. Using temporally resolved IDEAL spiral CSI, spatially resolved apparent rate constant maps are also extracted. In comparison to single metabolite images, apparent build-up rate constant maps provide improved contrast by emphasizing metabolically active tissues (e.g. tumors) and suppression of high perfusion regions with low conversion (e.g. blood vessels). Apparent build-up rate constant mapping provides a novel quantitative image contrast for the characterization of metabolic activity. Its possible implementation as a quantitative standard will be subject to further studies.

Nuclear deformation and neutron excess as competing effects for dipole strength in the pygmy region.

The electromagnetic dipole strength below the neutron-separation energy has been studied for the xenon isotopes with mass numbers A=124, 128, 132, and 134 in nuclear resonance fluorescence experiments using the γELBE bremsstrahlung facility at Helmholtz-Zentrum Dresden-Rossendorf and the HIγS facility at Triangle Universities Nuclear Laboratory Durham. The systematic study gained new information about the influence of the neutron excess as well as of nuclear deformation on the strength in the region of the pygmy dipole resonance. The results are compared with those obtained for the chain of molybdenum isotopes and with predictions of a random-phase approximation in a deformed basis. It turned out that the effect of nuclear deformation plays a minor role compared with the one caused by neutron excess. A global parametrization of the strength in terms of neutron and proton numbers allowed us to derive a formula capable of predicting the summed E1 strengths in the pygmy region for a wide mass range of nuclides.

Microporous calcium phosphate ceramics as tissue engineering scaffolds for the repair of osteochondral defects: Histological results.

Treatment of defects in joint cartilage aims to re-establish normal joint function. In vitro experiments have shown that the application of synthetic scaffolds is a promising alternative to existing therapeutic options. A sheep study was conducted to test the suitability of microporous pure ß-tricalcium phosphate (TCP) ceramics as tissue engineering scaffolds for the repair of osteochondral defects. Cylindrical plugs of microporous ß-TCP (diameter: 7mm; length: 25mm; porosity: 43.5±2.4%; pore diameter: ~5µm) with interconnecting pores were used. Scaffolds were seeded with autologous chondrocytes in vitro and cultured for 4weeks. A drill hole (diameter 7mm) was placed in both medial femoral condyles of sheep. For the left knee the defect was filled with a TCP plug and for the right knee the defect was left empty. After 6, 12, 26 and 52weeks, seven animals from each group were killed and studied. The samples were examined employing histological, histomorphometric and immunohistological methods as well as various imaging techniques (X-ray, microcomputer tomography and scanning electron microscopy). After explantation the cartilage defects were first assessed macroscopically. There were no signs of infection or inflammation. Histological grading scales were used for assessment of bony integration and cartilage repair. An increasing degradation (81% after 52weeks) of the ceramic with concomitant bone formation was observed. The original structure of cancellous bone was almost completely restored. After 26 and 52weeks, collagen II-positive hyaline cartilage was detected in several samples. New subchondral bone had formed. The formation of cartilage began at the outer edge and proceeded to the middle. According to the O'Driscoll score, values corresponding to healthy cartilage were not reached after 1year. Integration of the newly formed cartilage tissue into the surrounding native cartilage was found. The formation of biomechanical stable cartilage began at the edge and progressed towards the centre of the defect. After 1year this process was still not completed. Microporous ß-TCP scaffolds seeded with chondrocytes are suitable for the treatment of osteochondral defects.

Postoperative versus definitive chemoradiation in early-stage anal cancer. Results of a matched-pair analysis.

BACKGROUND AND PURPOSE: The goal of the present study was to comparatively assess the results of definitive chemoradiation (CRT) with or without previous macroscopically complete resection in patients with early-stage node-negative (T1-2 N0) anal carcinoma. PATIENTS AND METHODS: A total of 20 patients with T1-2 N0 anal carcinoma who received radiotherapy (RT) with or without chemotherapy following incidental R0/1 tumor resection (S/CRT group) were selected. These were matched to 20 comparable patients who underwent definitive chemoradiation without previous surgery (CRT group). Major objectives of this analysis were treatment outcomes in terms of locoregional tumor control (LRC), overall survival (OS), colostomy-free survival, and toxicity. RESULTS: Patients treated postoperatively received significantly lower RT doses (median 54.0 Gy vs. 59.7 Gy; p < 0.001) and less frequently concomitant chemotherapy than those treated definitely. The 5-year LRC and 5-year OS rates were 97.5% and 90.0%, respectively, without significant differences between the S/CRT and the CRT groups. The distribution of acute and late toxicities was comparable, and the 5-year colostomy-free survival was 95% in both groups. CONCLUSION: This matched-pair comparison of incidental R0/1 resection plus dose-reduced CRT with standard definitive CRT of early-stage anal cancer shows similar treatment results. Thus, dose-reduced RT with or without chemotherapy may be considered in R0/1 resected patients with T1-2 N0 anal carcinoma.

Effects of pyruvate dose on in vivo metabolism and quantification of hyperpolarized ¹³C spectra.

Real-time in vivo measurements of metabolites are performed by signal enhancement of [1-(13)C]pyruvate using dynamic nuclear polarization, rapid dissolution and intravenous injection, acquisition of free induction decay signals and subsequent quantification of spectra. The commonly injected dose of hyperpolarized pyruvate is larger than typical tracer doses, with measurement before complete dilution of the injected bolus. Pyruvate is in exchange with its downstream metabolites lactate, alanine and bicarbonate. A transient exposure to high pyruvate blood concentrations may cause the saturation of cellular uptake and metabolic conversion. The goal of this study was to examine the effects of a [1-(13)C]pyruvate bolus on metabolic conversion in vivo. Spectra were quantified by three different methods: frequency-domain fitting with LCModel, time-domain fitting with AMARES and simple linear least-squares fitting in the time domain. Since the simple linear least-squares approach showed bleeding artifacts and LCModel produced noisier time signals. AMARES performed best in the quantification of in vivo hyperpolarized pyruvate spectra. We examined pyruvate doses of 0.1-0.4 mmol/kg (body mass) in male Wistar rats by acquiring slice-selective free induction decay signals in slices dominated by heart, liver and kidney tissue. Dose effects were noted in all cases, except for alanine in the cardiac slice below the dose of 0.2 mmol/kg. Our results indicate unlimited cellular uptake of pyruvate up to this dose and limited enzymatic activity of lactate dehydrogenase. In the cardiac slice above 0.2 mmol/kg and in liver and kidney slices, reflect limited cellular uptake or enzymatic activity, or a combination of both effects. The results indicate that the dose of pyruvate must be recognized as an important determinant for metabolic tissue kinetics, and saturation effects must be taken into account for the quantitative interpretation of the observed results.

[Development of an emergency room algorithm for treatment of multiple trauma. Wolfsburg model]. / Entwicklung eines Schockraumalgorithmus für die Polytraumaversorgung. "Wolfsburger Modell."

Within the framework of restructuring for the certification to a regional trauma centre of the DGU (German Society for Casualty Surgery), a uniform algorithm for multiple trauma was developed in the medical centre of Wolfsburg. The Wolfsburg multiple trauma algorithm is based on ATLS (advanced trauma life support) with integration of FAST (focused assessment with sonography for trauma), as well as the white paper of the DGU and regional-specific features. Thus structural, instrumental, organizational and personnel conditions were created to improve the care of multiply traumatized patients even further. The conditions for transition to a regional trauma centre of the DGU were confirmed by a successful audit.