The mechanisms of allergic sensitization to milk are still elusive. The major allergen Bos d 5 belongs to the lipocalin-family and thus is able to transport numerous ligands. In this study we ...investigated its ability to bind to iron-siderophore complexes and tested the immune-modulatory properties of Bos d 5 in either forms. Structural and in silico docking analysis of Bos d 5 revealed that Bos d 5 is able to bind to iron via catechol-based flavonoids (quercetin, myricetin, luteolin) that act as siderophores as confirmed by spectral-analysis and iron staining. Calculated dissociation constants of docking analyses were below 1 µM by virtual addition of iron. When incubated with human peripheral blood mononuclear cells (PBMCs), only the apo-form of Bos d 5 led to an increase of CD4+positive cells and significantly elevated IL13 and IFNγ-levels. In contrast, holo-Bos d 5 decreased numbers of CD4 expressing cells and induced apoptosis. Taken together, our data give evidence that Bos d 5 is capable of binding iron via siderophores. Moreover, our data support for the first time the notion that the form of application (apo- or holo-form) is decisive for the subsequent immune response. The apo-form promotes Th2 cells and inflammation, whereas the holo-form appears to be immunosuppressive.
The value of intraoperative extracorporeal membrane oxygenation (ECMO) in lung transplantation remains controversial. In our department, ECMO has been used routinely for intraoperatively unstable ...patients for more than 15 years. Recently, we have extended its indication to a preemptive application in almost all cases. In addition, we prolong ECMO into the early postoperative period whenever graft function does not meet certain quality criteria or in patients with primary pulmonary hypertension. The objective of this study was to review the results of this strategy.
All standard bilateral lung transplantations performed between January 2010 and June 2016 were included in this single-center, retrospective analysis. Patients were divided into 3 groups: group I—no ECMO (n = 116), group II—intraoperative ECMO (n = 343), and group III—intraoperative and prolonged postoperative ECMO (n = 123). The impact of different ECMO strategies on primary graft function, short-term outcomes, and patient survival were analyzed.
The use of intraoperative ECMO was associated with improved 1-, 3-, and 5-year survival compared with non-ECMO patients (91% vs 82%, 85% vs 76%, and 80% vs 74%; log-rank P = .041). This effect was still evident after propensity score matching of both cohorts. Despite the high number of complex patients in group III, outcome was excellent with higher survival rates than in the non-ECMO group at all time points.
Intraoperative ECMO results in superior survival when compared with transplantation without any extracorporeal support. The concept of prophylactic postoperative ECMO prolongation is associated with excellent outcomes in recipients with pulmonary hypertension and in patients with questionable graft function at the end of implantation.
In chronically damaged tissue, trefoil factor family (TFF) peptides ensure epithelial protection and restitution. In chronic kidney disease (CKD), TFF1 and TFF2 are reported to be upregulated. ...Especially in the early phase, CKD is associated with silently ongoing renal damage and inflammation. Moreover, many patients are diagnosed late during disease progression. We therefore sought to investigate the potential of TFF2 as biomarker for CKD. We followed 118 patients suffering from predialysis CKD and 23 healthy volunteers. TFF2 concentrations were measured using ELISA. Our results showed, that median TFF2 serum levels were significantly higher in patients with later CKD stages as compared to healthy controls (p < 0.001) or early stages (p < 0.001). In patients with mid CKD stages TFF2 serum levels were significantly higher than in healthy controls (p = 0.002). Patients with early or mid CKD stages had significantly higher TFF2 urine concentrations than later CKD stages (p < 0.001 and p = 0.009, respectively). Fractional TFF2 excretion differed significantly between early CKD stages and healthy controls (p = 0.01). ROC curve showed that TFF2 levels can predict different CKD stages (AUC > 0.75). In conclusion, urine and serum TFF2 levels of CKD patients show a different profile dependent on CKD stages. Whereas TFF2 urine levels continuously decreased with disease progression, TFF2 serum concentrations progressively increased from the early to later CKD stages, indicating changes in renal function and offering the potential to examine the course of CKD.
Lung transplantation for idiopathic pulmonary arterial hypertension has the highest reported postoperative mortality of all indications. Reasons lie in the complexity of treatment of these patients ...and the frequent occurrence of postoperative left ventricular failure. Transplantation on intraoperative extracorporeal membrane oxygenation support instead of cardiopulmonary bypass and even more the prolongation of extracorporeal membrane oxygenation into the postoperative period helps to overcome these problems. We reviewed our experience with this concept.
All patients undergoing bilateral lung transplantation for idiopathic pulmonary arterial hypertension on intraoperative extracorporeal membrane oxygenation with or without prophylactic extracorporeal membrane oxygenation prolongation into the postoperative period between January 2000 and December 2014 were retrospectively analysed.
Forty-one patients entered the study. Venoarterial extracorporeal membrane oxygenation support was prolonged into the postoperative period for a median of 2.5 days (range 1-40). Ninety-day, 1-, 3- and 5-year survival rates for the patient collective were 92.7%, 90.2%, 87.4% and 87.4%, respectively. When compared with 31 patients with idiopathic pulmonary arterial hypertension transplanted in the same period of time without prolongation of extracorporeal membrane oxygenation into the postoperative period, the results compared favourably (83.9%, 77.4%, 77.4%, and 77.4%; P = 0.189). Furthermore, these results are among the best results ever reported for this particularly difficult patient population.
Bilateral lung transplantation for idiopathic pulmonary arterial hypertension with intraoperative venoarterial extracorporeal membrane oxygenation support seems to provide superior outcome compared with the results reported about the use of cardiopulmonary bypass. Prophylactic prolongation of venoarterial extracorporeal membrane oxygenation into the early postoperative period provides stable postoperative conditions and seems to further improve the results.
The major cow's milk allergen Bos d 5 belongs to the lipocalin protein family, with an intramolecular pocket for hydrophobic ligands. We investigated whether Bos d 5 when loaded with the active ...vitamin A metabolite retinoic acid (RA), would elicit differential immune responses compared to the unloaded state. By in silico docking an affinity energy of -7.8 kcal/mol was calculated for RA into Bos d 5. Loading of RA to Bos d 5 could be achieved in vitro, as demonstrated by ANS displacement assay, but had no effect on serum IgE binding in tolerant or challenge-positive milk allergic children. Bioinformatic analysis revealed that RA binds to the immunodominant T-cell epitope region of Bos d 5. In accordance, Bos d 5 significantly suppressed the CD3+ CD4+ cell numbers, proliferative response and IL-10, IL-13 and IFN-γ secretion from stimulated human PBMCs only when complexed with RA. This phenomenon was neither associated with apoptosis of T-cells nor with the activation of Foxp3+ T-cells, but correlated likely with enhanced stability to lysosomal digestion due to a predicted overlap of Cathepsin S cleavage sites with the RA binding site. Taken together, proper loading of Bos d 5 with RA may suppress its immunogenicity and prevent its allergenicity.
It is hypothesized that allergens are at the borderline of self and non-self and, through as yet elusive circumstances, mount a Th2 response for allergic sensitization. The major birch pollen ...allergen Bet v 1 is considered the prototype for the PR-10 protein family causing respiratory allergy. Here, we give structural evidence that Bet v 1 is a lipocalin-like protein with a striking structural resemblance to human lipocalin 2. Lipocalin 2 is highly expressed in the lung where it exerts immunoregulatory functions dependent on being loaded with siderophore-bound iron (holo-form) or not (apo-form). We demonstrate that similar to lipocalin 2, Bet v 1 is capable of binding iron via catechol-based siderophores. Thereby, calculated Kd values of 66 nm surpassed affinities to known ligands nearly by a power of 10. Moreover, we give functional evidence of the immunomodulatory capacity of Bet v 1 being dependent on its iron-loaded state. When incubated to human immune cells, only the apo-form of Bet v 1, but not the holo-form, was able to promote Th2 cells secreting IL13. These results provide for the first time a functional understanding on the allergenicity of Bet v 1 and a basis for future allergen immunotherapies counteracting Th2 immune responses on a molecular basis.
Background: The reason of allergic sensitization to proteins like Bet v 1 is unknown.
Results: Bet v 1 binds iron via catechol-based siderophores. It can modulate human immune cells toward Th2 when not carrying iron.
Conclusion: Bet v 1 modulates immune cells toward Th2 when being devoid of iron.
Significance: We provide the functional basis under which circumstances Bet v 1 becomes an allergen.
The continuous administration of opioids in critical care patients is a common therapy for the tolerance of mechanical ventilation. Opioid choice has a crucial impact on the length of mechanical ...ventilation. Owing to its very short context-sensitive half-life, remifentanil widens the available options for sedoanalgetic strategies. Supply disruption of such established intensive care medication has been reported to worsen clinical outcomes.
This retrospective study investigated the influence of a nationwide supply shortage of remifentanil on mechanical ventilation and ventilation-associated outcomes at three perioperative intensive care units (ICUs) in a tertiary care hospital in Vienna. Two groups were followed: patients admitted to the ICU during the remifentanil shortage (July 1, 2016 to September 30, 2016) and a control group one year after the remifentanil shortage (July 1, 2017 to September 30, 2017). Included patients were adults, received mechanical ventilation for at least 6 h, were admitted less than 90 days in the respective ICU, and survived their admission.
For comparison, Poisson count regression models and logistic regression models were computed. To compensate for multiple testing, the significance level was split (0.02 for the primary and 0.006 for secondary outcome parameters). Patients in the remifentanil shortage group received significantly longer mechanical ventilation (risk ratio 2.19, 95% confidence interval 2.14-2.24, P <0.001) with significantly prolonged ICU stay (P <0.001), days with non-invasive ventilation (P <0.001), and length of hospital stay (P <0.001). No significant difference was found in the occurrence of pneumonia (P = 0.040) and sepsis (P = 0.061). A greater proportion of patients in the shortage group underwent secondary tracheostomy (P <0.001).
The remifentanil shortage caused a significant impairment of essential outcome parameters in the ICU.
Postoperative complications are still a major concern after liver resection (LR). Systemic inflammation and deregulated reactive oxygen species during major abdominal surgery may impair outcome after ...hepatectomy.
Patients undergoing LR were included in this study (n = 40). Oxidative stress (OS) was measured peri- and post-operatively as static oxidation-reduction potential markers (sORP) and antioxidant capacity ORP (cORP) by using the RedoxSYS Diagnostic system. Furthermore, Th1- and Th2-specific cytokines were assessed.
Whereas there was no significant change in systemic sORP during LR and in the early postoperative course, there was a substantial decrease of cORP immediately post-surgery, and on postoperative days 1 and 3 (p<0.001). OS response was tightly regulated, as there was a significant correlation between sORP and cORP (p<0.0001; R2:0.457). An increase of OS (sORP) after LR of more than 3 mV was predictive for severe postoperative complications (53.8% vs. 12.5; p = 0.017). There was a significantly higher IL-2 (p = 0.006) and IL-5 (p = 0.001) increase during hepatectomy in patients who developed a severe morbidity.
Antioxidant capacity remained stable during LR but dropped during the post-surgical period, suggesting a consumption of antioxidants to maintain OS within healthy range. Severe postoperative complications were associated with a pronounced inflammatory response during surgery.
We reviewed our 25-year experience in pediatric lung transplantation with the aim to identify trends and influencing factors over time.
We reviewed our prospectively maintained database and analyzed ...all patients younger than age 18 years who underwent primary lung transplantation at Medical University of Vienna between 1990 and 2015.
Eighty-six consecutive patients were enrolled with a mean age of 12.9 ± 4.1 years at primary transplantation. The most frequent indication for primary transplantation was cystic fibrosis (64.0). Bilateral double-lung transplantation was performed in 84 patients (97.7%), including lobar transplantation in 35 patients (40.7%). sixty-eight patients (79.1%) underwent transplant on venoarterial extracorporeal membrane oxygenation and 7 patients (8.1%) utilized cardiopulmonary bypass. The 30-day and in-hospital mortality was 8.1% and 17.4%, respectively, and 1-, 5-, and 10-year overall survival (OS) was 79.0%, 67.5%, and 57.1%, respectively. A significant improvement of OS was observed during the second treatment period after 2003 with a 1-, 5-, and 10-year OS of 86.0%, 73.9%, and 73.9%, respectively (P < .01). Seventeen retransplantations were performed in 14 patients. Twelve patients (85.7%) underwent 15 late elective retransplantations for chronic lung allograft dysfunction resulting in a 1- and 5-year OS of 91.7% and 80.2%, respectively. In contrast, 2 patients (14.3%) who underwent acute retransplantation for primary graft failure died during the postoperative period.
Our outcomes for pediatric lung transplantation have improved over the past 25 years and have become comparable to those for adult transplantation. Elective re-transplantations for pediatric patients were performed successfully, and strongly influenced improved long-term OS.
For a symmetry-consistent theoretical description of the ferroelectric phase of Ba2MnGe2O7 melilite compound, a precise knowledge of its crystal structure is a prerequisite. Here we report results of ...single-crystal neutron diffraction experiments on Ba2MnGe2O7 at room (300 K) and low (10 K) temperatures. The structural model based on the tetragonal space group P4̅21 m describes the Ba2MnGe2O7 symmetry both at room and low temperatures. We found reflections forbidden in the typical P4̅21 m melilite-type structure. A comparison of the experimental data collected by means of both thermal and cold neutrons with simulated multiple diffraction patterns allows us to unambiguously demonstrate that forbidden peaks originate from multiple diffraction (Renninger effect) rather than from real symmetry lowering. The precise structural parameters at 300 and 10 K are presented for the first time and compared with those of other magnetoelectric melilite-type germanates.
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