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Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis. more...

Supplemental Digital Content is available in the text., Background. Systemic exposure to high-dose corticosteroids effectively combats acute rejection after kidney transplantation, but at the cost of substantial side effects. In this study, a murine acute renal allograft rejection model was used to investigate whether liposomal-encapsulated prednisolone (LP) facilitates local exposure to enhance its therapeutic effect. Methods. Male BalbC recipients received renal allografts from male C57BL/6J donors. Recipients were injected daily with 5 mg/kg cyclosporine A and received either 10 mg/kg prednisolone (P), or LP intravenously on day 0, 3, and 6, or no additional treatment. Functional magnetic resonance imaging (fMRI) was performed on day 6 to study allograft perfusion and organs were retrieved on day 7 for further analysis. Results. Staining of polyethylene-glycol-labeled liposomes and high performance liquid chromatography analysis revealed accumulation in the LP treated allograft. LP treatment induced the expression of glucocorticoid responsive gene Fkbp5 in the allograft. Flow-cytometry of allografts revealed liposome presence in CD45+ cells, and reduced numbers of F4/80+ macrophages, and CD3+ T-lymphocytes upon LP treatment. Banff scoring showed reduced interstitial inflammation and tubulitis and fMRI analysis revealed improved allograft perfusion in LP versus NA mice. Conclusions. Liposomal delivery of prednisolone improved renal bio-availability, increased perfusion and reduced cellular infiltrate in the allograft, when compared with conventional prednisolone. Clinical studies should reveal if treatment with LP results in improved efficacy and reduced side effects in patients with renal allograft rejection. more...

Background Voltage-gated sodium channels generate action potentials in excitable cells, but they have also been attributed noncanonical roles in nonexcitable cells. We hypothesize that voltage-gated sodium channels play a functional role during extravasation of neutrophils. Methods Expression of voltage-gated sodium channels was analyzed by polymerase chain reaction. Distribution of Nav1.3 was determined by immunofluorescence and flow cytometry in mouse models of ischemic heart and kidney injury. Adhesion, transmigration, and chemotaxis of neutrophils to endothelial cells and collagen were investigated with voltage-gated sodium channel inhibitors and lidocaine in vitro. Sodium currents were examined with a whole cell patch clamp. Results Mouse and human neutrophils express multiple voltage-gated sodium channels. Only Nav1.3 was detected in neutrophils recruited to ischemic mouse heart (25 ± 7%, n = 14) and kidney (19 ± 2%, n = 6) in vivo. Endothelial adhesion of mouse neutrophils was reduced by tetrodotoxin (56 ± 9%, unselective Nav-inhibitor), ICA121431 (53 ± 10%), and Pterinotoxin-2 (55 ± 9%; preferential inhibitors of Nav1.3, n = 10). Tetrodotoxin (56 ± 19%), ICA121431 (62 ± 22%), and Pterinotoxin-2 (59 ± 22%) reduced transmigration of human neutrophils through endothelial cells, and also prevented chemotactic migration (n = 60, 3 × 20 cells). Lidocaine reduced neutrophil adhesion to 60 ± 9% (n = 10) and transmigration to 54 ± 8% (n = 9). The effect of lidocaine was not increased by ICA121431 or Pterinotoxin-2. Conclusions Nav1.3 is expressed in neutrophils in vivo; regulates attachment, transmigration, and chemotaxis in vitro; and may serve as a relevant target for antiinflammatory effects of lidocaine. more...

Renal ischemia-reperfusion injury (IRI) is a severe complication of major surgery and a risk factor for increased morbidity and mortality. Here, we investigated mechanisms that might contribute to IRI-induced progression to chronic kidney disease (CKD). Acute kidney injury (AKI) was induced by unilateral IRI for 35 min in CD1 and C57BL/6 (B6) mice. Unilateral IRI was used to overcome early mortality. Renal morphology, NGAL upregulation, and neutrophil infiltration as well as peritubular capillary density were studied by immunohistochemistry. The composition of leukocyte infiltrates in the kidney after IRI was investigated by flow cytometry. Systemic blood pressure was measured with a tail cuff, and renal perfusion was quantified by functional magnetic resonance imaging (fMRI). Mesangial matrix expansion was assessed by silver staining. Following IRI, CD1 and B6 mice developed similar morphological signs of AKI and increases in NGAL expression, but neutrophil infiltration was greater in CD1 than B6 mice. IRI induced an increase in systemic blood pressure of 20 mmHg in CD1, but not in B6 mice; and CD1 mice also had a greater loss of renal perfusion and kidney volume than B6 mice ( P < 0.05). CD1 mice developed substantial interstitial fibrosis and decreased peritubular capillary (PTC) density by day 14 while B6 mice showed only mild renal scarring and almost normal PTC. Our results show that after IRI, CD1 mice develop more inflammation, hypertension, and later mesangial matrix expansion than B6 mice do. Subsequently, CD1 animals suffer from CKD due to impaired renal perfusion and pronounced permanent loss of peritubular capillaries. more...

To evaluate Gd-EOB-DTPA-enhanced MRI for quantitative assessment of liver organ damage after hepatic ischaemia reperfusion injury (IRI) in mice. Partial hepatic IRI was induced in C57Bl/6 mice (n = 31) for 35, 45, 60 and 90 min. Gd-EOB-DTPA-enhanced MRI was performed 1 day after surgery using a 3D-FLASH sequence. A subgroup of n = 9 animals with 60 min IRI underwent follow-up with MRI and histology 7 days after IRI. The total liver volume was determined by manual segmentation of the entire liver. The volume of functional, contrast-enhanced liver parenchyma was quantified by a region growing algorithm (visual threshold) and an automated segmentation (Otsu’s method). The percentages of functional, contrast-enhanced and damaged non-enhanced parenchyma were calculated according to these volumes. MRI data was correlated with serum liver enzyme concentrations and histologically quantified organ damage using periodic acid–Schiff (PAS) staining. The percentage of functional (contrasted) liver parenchyma decreased significantly with increasing ischaemia times (control, 94.4 ± 3.3%; 35 min IRI, 89.3 ± 4.1%; 45 min IRI, 87.9 ± 3.3%; 60 min IRI, 68 ± 10.5%, p < 0.001 vs. control; 90 min IRI, 55.9 ± 11.5%, p < 0.001 vs. control). The percentage of non-contrasted liver parenchyma correlated with histologically quantified liver organ damage (r = 0.637, p < 0.01) and serum liver enzyme elevations (AST r = 0.577, p < 0.01; ALT r = 0.536, p < 0.05). Follow-up MRI visualized recovery of functional liver parenchyma (71.5 ± 8.7% vs. 84 ± 2.1%, p < 0.05), consistent with less histological organ damage on day 7. We demonstrated the feasibility of Gd-EOB-DTPA-enhanced MRI for non-invasive quantification of damaged liver parenchyma following IRI in mice. This novel methodology may refine the characterization of liver disease and could have application in future studies targeting liver organ damage. • Prolonged ischaemia times in partial liver IRI increase liver organ damage. • Gd-EOB-DTPA-enhanced MRI at hepatobiliary phase identifies damaged liver volume after hepatic IRI. • Damaged liver parenchyma quantified with MRI correlates with histological liver damage. • Hepatobiliary phase Gd-EOB-DTPA-enhanced MRI enables non-invasive assessment of recovery from liver injury. more...

Objectives IL-17A contributes to acute kidney injury and fibrosis. Therefore, we asked whether IL-17A deficiency or treatment with a IL-17A blocking antibody impacts severe renal ischaemia reperfusion injury (IRI) and the progression to chronic kidney disease (CKD). Methods IL-17A-deficient and wild-type (WT) mice underwent transient unilateral renal pedicle clamping for 45 min to induce IRI and subsequent renal fibrosis. Furthermore, a neutralizing anti-IL-17A antibody (mAb) was injected into WT mice before induction of renal IRI intravenously. On days 1, 7 and 21, inflammation, fibrosis, leukocyte infiltration and pro-inflammatory and pro-fibrotic cytokine expression were assessed in kidneys using histology, qPCR and flow cytometry. Key findings IL-17A was significantly increased after renal IRI in WT kidneys. Levels of pro-inflammatory (MCP-1) cytokine and pro-fibrotic (collagen 1α1, fibronectin) transcripts were similar in the experimental groups studied. IL-17A deficiency had no effect on renal T-cell influx or the number, inflammatory phenotype, or spatial distribution of macrophages. Similarly, administration of an IL-17A blocking antibody did not attenuate inflammation. Conclusions Despite the effects of IL-17 in other inflammation models, neither genetic IL-17A deficiency nor treatment with an IL-17A blocking antibody attenuated IRI and progression to CKD. We conclude that in severe renal IRI IL-17A is not crucially involved in disease progression. more...

Background: Ischemia reperfusion injury (IRI) plays a major role in solid organ transplantation. The length of warm ischemia time is critical for the extent of tissue damage in renal IRI. In this experimental study we hypothesized that local release of labile heme in renal tissue is triggered by the duration of warm ischemia (15 vs. 45 min IRI) and mediates complement activation, cytokine release, and inflammation. Methods: To induce IRI, renal pedicle clamping was performed in male C57BL/6 mice for short (15 min) or prolonged (45 min) time periods. Two and 24 h after experimental ischemia tissue injury labile heme levels in the kidney were determined with an apo-horseradish peroxidase assay. Moreover, renal injury, cytokines, and C5a and C3a receptor (C5aR, C3aR) expression were determined by histology, immunohistochemistry and qPCR, respectively. In addition, in vitro studies stimulating bone marrow-derived macrophages with LPS and the combination of LPS and heme were performed and cytokine expression was measured. Results: Inflammation and local tissue injury correlated with the duration of warm ischemia time. Labile heme concentrations in renal tissue were significantly higher after prolonged (45 min) as compared to short (15 min) IRI. Notably, expression of the inducible heme-degrading enzyme heme oxygenase-1 (HO-1) was up-regulated in kidneys after prolonged, but not after short IRI. C5aR, the pro-inflammatory cytokines IL-6 and TNF-alpha as well as pERK were up-regulated after prolonged, but not after short ischemia times. Consecutively, neutrophil infiltration and up-regulation of pro-fibrotic cytokines such as CTGF and PAI were more pronounced in prolonged IRI in comparison to short IRI. In vitro stimulation of macrophages with LPS revealed that IL-6 expression was enhanced in the presence of heme. Finally, administration of the heme scavenger human serum albumin (HSA) reduced the expression of pro-inflammatory cytokines, C3a receptor and improved tubular function indicated by enhanced alpha 1 microglobulin (A1M) absorption after IRI. Conclusions: Our data show that prolonged duration of warm ischemia time increased labile heme levels in the kidney, which correlates with IRI-dependent inflammation and up-regulation of anaphylatoxin receptor expression. more...

The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a &gt, 5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection. more...

PURPOSE To examine the longitudinal changes of renal perfusion due to acute and chronic renal allograft rejection by using arterial spin labeling (ASL) MRI in translational mouse models of isogenic and allogenic kidney transplantation (ktx). MATERIALS AND METHODS Acute rejection was induced by allogenic ktx of C57BL/6 (B6)-kidney grafts to BALB/c-recipients with prolonged cold ischemia (CIT) of 60 minutes (n = 13). To induce chronic rejection BALB/c-kidneys were transplanted into B6-recipients with short CIT of 30 minutes (n = 22). Isogenic grafts without rejection (n = 14 with prolonged, n = 9 with short CIT) and normal kidneys (n = 22) were used for comparison. Perfusion was measured on a 7T small-animal magnetic resonance imaging (MRI) scanner using flow-sensitive alternating inversion recovery (FAIR) ASL-sequences at day 1 and 6 (acute) or at week 3 and 6 (chronic) after surgery. Histological analyses of grafts included inflammation, vascular changes, and fibrosis. RESULTS In the acute ktx model, ASL showed perfusion impairment in isogenic and allogenic kidney grafts. Perfusion of allografts further decreased until day 6 and remained stable in isografts without rejection (allogenic ktx 62 ± 21 vs. isogenic ktx 181 ± 39 ml/min/100g, P < 0.01). In the chronic ktx model, perfusion in isografts was similar to normal kidneys over the entire observation period. Perfusion was severely reduced in allografts compared to isografts (week 3: 28 ± 7 vs. 310 ± 46 ml/min/100g, P < 0.001, week 6: 32 ± 5 vs. 367 ± 72 ml/min/100g, P < 0.001). Histological analysis revealed severe inflammation, vascular occlusion, and rejection in allografts. Chronic rejection grafts showed endothelialitis, peritubular capillaritis, interstitial fibrosis, and tubular atrophy. CONCLUSION ASL allows longitudinal assessment of renal perfusion impairment due to acute and chronic renal allograft rejection in translational mouse models. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1664-1672. more...

OBJECTIVE Case management (CM) programs are intended to improve care coordination for cancer patients. This quasi-experimental, controlled study evaluated whether such a program was effective in improving health-related quality of life and reducing the psychological distress of breast cancer patients. METHODS For the study, 126 patients with CM and 118 patients with treatment as usual (TAU) were surveyed at baseline, a 6-month follow-up and a 12-month follow-up. Comparisons of the two groups with regard to quality of life (Short Form-8, European Organization for Research and Treatment of Cancer-11; primary outcome) and psychological distress (Hospital Anxiety and Depression Scale, distress thermometer; secondary outcome) were conducted. RESULTS Univariate t-tests regarding the primary and secondary outcomes demonstrated improvements in the relevant outcomes at the 6-month and 12-month follow-ups for the intervention group as well as for the control group. An analysis of covariance revealed that the controls showed a higher level of physical quality of life at the 12-month follow-up than the other time points and no differences at 6 months after the baseline. CONCLUSIONS The tested CM model did not improve the quality of life or psychological well-being of the patients beyond treatment as usual. Possible reasons include that the treatment was already of high standards in the control group or that there are possibly different impacts than found in the literature regarding different forms of organization in CM. The need for and the tailoring of this CM model as well as the transfer of CM to other oncological indications remain to be clarified. Copyright © 2016 John Wiley & Sons, Ltd. more...

Severe ischemia reperfusion injury (IRI) results in rapid complement activation, acute kidney injury and progressive renal fibrosis. Little is known about the roles of the C5aR1 and C5aR2 complement receptors in IRI. In this study C5aR1–/– and C5aR2–/– mice were compared to the wild type in a renal IRI model leading to renal fibrosis. C5a receptor expression, kidney morphology, inflammation, and fibrosis were measured in different mouse strains one, seven and 21 days after IRI. Renal perfusion was evaluated by functional magnetic resonance imaging. Protein abundance and phosphorylation were assessed with high content antibody microarrays and Western blotting. C5aR1 and C5aR2 were increased in damaged tubuli and even more in infiltrating leukocytes after IRI in kidneys of wild-type mice. C5aR1–/– and C5aR2–/– animals developed less IRI-induced inflammation and showed better renal perfusion than wild-type mice following IRI. C5aR2–/– mice, in particular, had enhanced tubular and capillary regeneration with less renal fibrosis. Anti-inflammatory IL-10 and the survival/growth kinase AKT levels were especially high in kidneys of C5aR2–/– mice following IRI. LPS caused bone marrow–derived macrophages from C5aR2–/– mice to release IL-10 and to express the stress response enzyme heme oxygenase-1. Thus, C5aR1 and C5aR2 have overlapping actions in which the kidneys of C5aR2–/– mice regenerate better than those in C5aR1–/– mice following IRI. This is mediated, at least in part, by differential production of IL-10, heme oxygenase-1 and AKT. more...

Background Kidney transplantation (ktx) in mice is used to learn about rejection and to develop new treatment strategies. Past studies have mainly been based on histological or molecular biological methods. Imaging techniques to monitor allograft pathology have rarely been used. Methods Here we investigated mice after isogenic and allogenic ktx over time with functional MRI with diffusion-weighted imaging (DWI) and mapping of T2-relaxation time (T2-mapping) to assess graft inflammation and edema formation. To characterize graft pathology, we used PAS-staining, counted CD3-positive T-lymphocytes, analyzed leukocytes by means flow cytometry. Results DWI revealed progressive restriction of diffusion of water molecules in allogenic kidney grafts. This was paralleled by enhanced infiltration of the kidney by inflammatory cells. Changes in tissue diffusion were not seen following isogenic ktx. T2-times in renal cortex were increased after both isogenic and allogenic transplantation, consistent with tissue edema due to ischemic injury following prolonged cold ischemia time of 60 minutes. Lack of T2 increase in the inner stripe of the inner medulla in allogenic kidney grafts matched loss of tubular autofluorescence and may result from rejection-driven reductions in tubular water content due to tubular dysfunction and renal functional impairment. Conclusions Functional MRI is a valuable non-invasive technique for monitoring inflammation, tissue edema and tubular function. It permits on to differentiate between acute rejection and ischemic renal injury in a mouse model of ktx. more...

It has been shown in several species that the intestinal Na(+)-dependent glucose co-transporter 1 (SGLT1) is more abundant in the jejunum than in ileum. In contrast, the efficiency of intestinal glucose uptake rates in suckling piglets or weaned pigs is not clearly fitting with this segmental distribution. The aim of this study was to evaluate SGLT1 mediated glucose absorption in the jejunum and ileum of growing pigs (Sus scrofa) in more detail. In Ussing chambers, basal short-circuit currents were significantly more positive in the jejunum. It could be demonstrated that the electrogenic ileal glucose transport was significantly more pronounced in different breeds and occurred at 5 mmol∙L(-1) glucose 7 times faster in the ileum, although slightly higher jejunal expression of glycosylated SGLT1 was detected by Western blotting. This expression pattern was connected to significantly lower phlorizin sensitivity in the jejunum. As the more efficient ileal glucose absorption was also observable with glucose uptake studies into isolated brush-border membrane vesicles without differences in abundance and activity of the Na(+)/K(+)-ATPase in both segments, we conclude that the segmental differences in porcine glucose transport characteristics may be based on direct or indirect modulations of SGLT1 activity. more...

Objective The aim of this study was to investigate fear of disease progression (FoP) during the year following diagnosis of breast cancer and its association with general self-efficacy (SE). Methods In a prospective study, 118 breast cancer patients were recruited shortly after diagnosis disclosure (response rate: 54%) and at 1-year follow-up (follow-up rate: 90%). Participants completed self-report measures of general self-efficacy (General Self-Efficacy Scale) and fear of progression (short form of the Fear of Progression Questionnaire). Results Cross-sectional regression analysis revealed that high FoP is significantly associated with low SE, even when controlling for demographic and medical characteristics (total R² = 0.17). Having children and a relatively short time since diagnosis also significantly predicted higher FoP. Longitudinal analyses showed that FoP decreased significantly over time (p = 0.001; d = 0.25), but a significant decrease was only observed for patients with high initial FoP (p more...

Ziel der Studie: Brustkrebspatientinnen benotigen im Regelfall eine mehrfach aufeinanderfolgende und wechselnde stationare, teilstationare und ambulante Behandlung von langer Dauer. Die bedarfsgerechte Versorgung erfordert eine sektorenubergreifende Vernetzung aller an Diagnostik, Therapie, Rehabilitation und Nachsorge beteiligten multiprofessionellen Personen. Eine Methode zur Forderung der Integration des Behandlungsprozesses sowie – daraus resultierend – zur Effektivitats- und Effizienzsteigerung kann das Konzept Case Management darstellen. Voraussetzung fur eine effektive Umsetzung des Case Managements und damit Ausgangspunkt der vorliegenden Befragung ist ein gut funktionierendes Netzwerk. Im Rahmen einer Gesamtevaluation wurde vor dem Hintergrund des Innovations- und Optimierungspotenzials von Case Management einerseits sowie des Vorliegens nur weniger empirischer Daten andererseits die vorliegende Befragung von Kooperationspartnern eines transsektoralen Netzwerkes des Integrierten Versorgungsmodells „mammaNetz“ fur Frauen mit Mammakarzinom, das auf der Methode des Case Managements basiert, durchgefuhrt. Methodik: Arztliche und nichtarztliche Netzwerkpartner der Begleitstelle (N=168) wurden zu verschiedenen Aspekten der Kooperation mit jeweils unterschiedlichen Fragebogenversionen postalisch befragt. Beide Versionen enthielten ebenfalls identische Items, diese wurden miteinander verglichen. Ergebnisse: Die Rucklaufquote bei den arztlichen Netzwerkpartnern liegt bei 59% (n=35) − wobei sich ausschlieslich niedergelassene Arzte an der Befragung beteiligt haben − bei den nichtarztlichen Netzwerkpartnern bei 60% (n=66). Arztliche Netzwerkpartner beurteilen die Kooperation mit der Begleitstelle hinsichtlich des Informationsaustauschs etwas positiver (66%) als die nichtarztlichen Netzwerkpartner (59%). Arztliche Netzwerkpartner stehen signifikant haufiger in Kontakt mit der Begleitstelle und sehen signifikant haufiger Vorteile in der Zusammenarbeit fur die eigene Praxis/Einrichtung (jeweils p=0,001) als die nichtarztlichen Netzwerkpartner. Insgesamt deuten die Ergebnisse darauf hin, dass sowohl arztliche als auch nichtarztliche Netzwerkpartner die Arbeitsweise und das methodische Konzept der Begleitstelle fur sinnvoll erachten. Schlussfolgerung: Die Realisierung eines interdisziplinaren Unterstutzungsprozesses fur Patientinnen mit Mammakarzinom erfordert eine gute Zusammenarbeit von Netzwerkpartnern, Case Managerinnen und Patientinnen. Im Rahmen einer Folgeuntersuchung mit dem Ziel einer vertiefenden Prozessevaluation sollten nichtarztliche Netzwerkpartner in weitere professionsspezifische Untergruppen unterteilt werden. Daraus konnten Interventionen, die auf spezifische Berufsgruppen zugeschnitten sind, abgeleitet werden. more...

A number of previous studies have identified antigen-presenting cells (APCs) as key targets of Ebola virus (EBOV), but the role of APCs in human Ebola virus disease (EVD) is not known. We have evaluated the phenotype and kinetics of monocytes, neutrophils, and dendritic cells (DCs) in peripheral blood of patients for whom EVD was diagnosed by the European Mobile Laboratory in Guinea. Acute EVD was characterized by reduced levels of circulating nonclassical CD16(+) monocytes with a poor activation profile. In survivors, CD16(+) monocytes were activated during recovery, coincident with viral clearance, suggesting an important role of this cell subset in EVD pathophysiology. more...

Eine bedarfsgerechte sektorenubergreifende Versorgung [1] kann in Deutschland nach unseren Erfahrungen besonders schwer fur Patientinnen mit Brustkrebs sichergestellt werden, da sie langwierige und komplexe Behandlungsmasnahmen benotigen. Sie durchlaufen mehrere Therapiephasen wahrend ihrer Erkrankung und wechseln haufig zwischen den Sektoren (Fachbereiche Gynakologie, Radiologie, Pathologie, Onkologie und Psychoonkologie). Ebenso haufig ist auch sozialmedizinische bzw. sozialberaterische Expertise gefragt. Daruber hinaus sind die Patientinnen krankheits- und behandlungsbedingten Belastungen ausgesetzt (z.B. korperliche Beschwerden wie Schmerzen, Einschrankung der Leistungsfahigkeit im Alltag, existentielle Bedrohung). Diese Belastungen sind haufig mit einer eingeschrankten Lebensqualitat und psychischen Beeintrachtigung verbunden. So konnten internationale und nationale Studien zeigen, dass ein groser Teil der Frauen Angst vor dem Fortschreiten der Krankheit und dem Tod haben oder sich die Erkrankung negativ auf das Familien- und Berufsleben auswirkt [2-7]. Des Weiteren stellen die Studien Probleme im Informationsfluss und der Kommunikation zwischen den Behandlern und der Patientin sowie Defizite in der Vernetzung (gerade auch bei psychosozialen Therapiemasnahmen) fest [8-10]. Diese Versorgungsmangel zu beheben, dafur setzt sich eine Case-Management-Begleitstelle fur Frauen mit Brustkrebs ein. more...

Background & Aims Biliary atresia (BA) is a rare disease in infants, with unknown mechanisms of pathogenesis. It is characterized by hepatobiliary inflammatory, progressive destruction of the biliary system leading to liver fibrosis, and deterioration of liver function. Interleukin (IL) 17A promotes inflammatory and autoimmune processes. We studied the role of IL17A and cells that produce this cytokine in a mouse model of BA and in hepatic biopsy samples from infants with BA. Methods We obtained peripheral blood and liver tissue specimens from 20 patients with BA, collected at the time of Kasai portoenterostomy, along with liver biopsies from infants without BA (controls). The tissue samples were analyzed by reverse transcription quantitative polymerase chain reaction (PCR), in situ PCR, and flow cytometry analyses. BA was induced in balb/cAnNCrl mice by rhesus rotavirus infection; uninfected mice were used as controls. Liver tissues were collected from mice and analyzed histologically and by reverse transcriptase PCR; leukocytes were isolated, stimulated, and analyzed by flow cytometry and PCR analyses. Some mice were given 3 intraperitoneal injections of a monoclonal antibody against IL17 or an isotype antibody (control). Results Livers from rhesus rota virus−infected mice with BA had 7-fold more Il17a messenger RNA than control mice ( P = .02). γδ T cells were the exclusive source of IL17; no T-helper 17 cells were detected in livers of mice with BA. The increased number of IL17a-positive γδ T cells liver tissues of mice with BA was associated with increased levels of IL17A, IL17F, retinoid-orphan-receptor C, C-C chemokine receptor 6, and the IL23 receptor. Mice that were developing BA and given antibodies against IL17 had lower levels of liver inflammation and mean serum levels of bilirubin than mice receiving control antibodies (191 μmol/L vs 78 μmol/L, P = .002). Liver tissues from patients with BA had 4.6-fold higher levels of IL17 messenger RNA than control liver tissues ( P = .02). Conclusions In livers of mice with BA, γδ T cells produce IL17, which is required for inflammation and destruction of the biliary system. IL17 is up-regulated in liver tissues from patients with BA, compared with controls, and might serve as a therapeutic target. more...

Clays and bentonites receive increasing attention as technical buffer materials in geological barriers in order to isolate waste. Therefore, detailed knowledge of the behavior of these materials under a large variety of thermodynamical conditions is of special interest. In particular, we are interested in the varying water saturations leading to swelling and shrinking processes. Analysis of the complex material behavior of clays and bentonites requires mathematical modeling of the non-linear processes. In this paper we present a numerical model based on the finite element method (FEM) for simulation of two-phase flow in swelling porous media. The two-phase system is represented by a gas pressure ( p g )-liquid saturation ( S l ) formulation. We use the material model by Borgesson et al. (1985) [2] and Studer et al. (1984) [7] for swelling effects resulting in porosity and permeability changes. The numerical model is implemented in the context of the simulator RockFlow/RockMech, which is based on object-oriented programming techniques. As an example we consider the swelling of an X-80 bentonite during a saturation process. The simulation results are compared with data from the VEGAS-GMT test conducted by the NAGRA. more...

Background: Ischemia reperfusion injury (IRI) causes acute kidney injury (AKI) and is a relevant complication in major cardiac surgery. In addition AKI is frequent in solid organ transplantation (tx): after lung tx the incidence is 50% and after heart tx with 75% even higher. AKI increases morbidity and mortality and contributes to the progression to chronic kidney disease (CKD). During AKI the complement cascade is activated rapidly and subsequent myeloid cells infiltrate the kidney. The infiltrating cells as well as resident kidney cells express complement receptors activated by C3a and C5a. In this study, we present the distinct role of complement factors and their receptors in an IRI mouse model. Methods: Renal IRI was induced in mice deficient for C5aR, C3 and C5L2 and in wild type (WT; C57Bl/6) control mice by transient unilateral clipping of the right renal pedicle for 45 min. The renal morphology, the glomerular filtration rate (GFR), renal blood flow (RBF), expression of pro-fibrotic and pro-inflammatory markers and infiltrating leukocytes, as well as pro-inflammatory cytokines were analyzed four weeks after injury induction. Results: Renal IRI caused severe inflammation and fibrosis in addition to loss of peritubular capillaries with severley impaired renal microcirculation in WT mice. Complement deficiency reduced the tubulointerstitial fibrosis markedly. Especially, C5L2 deficient mice had less fibrosis and collagen deposition compared to WT mice. C3 deficient mice showed less tubular atrophy and fibrosis as well. Moreover, inflammatory cell infiltration was significantly decreased in all types of complement deficient mice compared to WT controls. Conclusion: C3 and also C5L2 deficiency attenuated IRI and chronic kidney disease and complement inhibition might be a promising therapeutic target to prevent early inflammation as well as later fibrosis. more...

Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD 1 . In particular, very little is known about human immune responses to Ebola virus (EBOV) 2,3 . Here, we have for the first time evaluated the physiology of the human T cell immune response in EVD patients at the time of admission at the Ebola Treatment Center (ETC) in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we have identified an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by high percentage of CD4 and CD8 T cells expressing the inhibitory molecules cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1), which was correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation despite comparable overall T cell activation. Concommittant with virus clearance, survivors mounted a robust EBOV-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology. more...