Posttraumatic stress symptoms after solid-organ transplantation: preoperative risk factors and the impact on health-related quality of life and life satisfaction

Background: Solid-organ transplantations (SOT) are usually life-saving high-tech medical procedures. The transplantation itself and the intensive care unit stay could be traumatic stressors triggering posttraumatic stress symptoms (PTSS). Our retrospective follow-up study aimed to explore preoperative risk factors of PTSS in a cohort of SOT recipients, and we investigated how PTSS are associated with health-related quality of life (HRQOL) and life satisfaction. Methods: 126 SOT recipients were enrolled in this investigation. Psychiatric examination of all SOT candidates based on the Transplant Evaluation Rating Scale was carried out before SOT, and after SOT, recipients completed the PTSS-10, the SF-36 and the FLZ. Results: After the surgical intervention 19 (15.1\%) SOT recipients had clinical significant PTSS. Preoperative risk factors for developing postoperative PTSS were: 1.) preexisting psychiatric morbidity, 2.) history of retransplantation, 3.) chronic benzodiazepine consumption, 4.) age, and 5.) type of transplantation. SOT-related PTSS were associated with maximal decrements in HRQOL and life satisfaction. The following HRQOL and life satisfaction domains were affected: Physical Functioning, Role Physical, Pain, General Health, Vitality, Social Functioning, Role Emotional, Mental Health, Occupation/Work and Character/Own Skills. Conclusion: SOT recipients may face a major risk of transplantation-and treatment-related PTSS and the development of impairments to HRQOL and life satisfaction

Overall mental distress and health-related quality of life after solid-organ transplantation: results from a retrospective follow-up study

Background: Our retrospective follow-up study aimed to explore the degree of overall mental distress in a cohort of solid-organ transplantation (SOT) recipients after liver, heart or lung transplantation. Furthermore, we investigated how overall mental distress is linked to health-related quality of life. Methods: 123 SOT patients treated during the study period were enrolled in this investigation at a mean of 24.6 months (SD=11.6) after transplantation. Before transplantation, the Transplant Evaluation Rating Scale (TERS) was used to classify the level of adjustment in psychosocial functioning among transplantation candidates. After transplantation, recipients completed a research battery, which included the SCL-90-R, and the SF-36. Results: 39 (31.7\%) transplantation recipients had clinically significant overall mental distress as measured on the Global Severity Index of the SCL-90-R. Obsessive-compulsive symptoms (92.3\%), somatization symptoms (87.2\%), anxiety symptoms (84.6\%), depression symptoms (82.1\%) and phobic anxiety symptoms (69.2\%) were a frequent finding. Transplantation recipients with overall mental distress had significant lower levels of adjustment in psychosocial functioning before transaplantation than those without overall mental distress as measured in the TERS. Transplantation-related overall mental distress symptomatology was associated with maximal decrements in health-related quality of life. Conclusion: Transplantation recipients may face major transplantation-and treatment-related overall mental distress and impairments to their health-related quality of life. Further, overall mental distress is a high-risk factor in intensifying impairments to patients' overall quality of life

Assessment of trimethylamine-N-oxide at the blood-cerebrospinal fluid barrier

Recently, the microbiome-derived trimethylamine-N-oxide (TMAO) was shown to be present in human cerebrospinal fluid (CSF). However, data on the potential of TMAO crossing the blood-CSF barrier are still lacking. This retrospective study aimed at investigating possible associations between the CSF/serum albumin (QALB) and TMAO (QTMAO) quotient and evaluating QTMAO values in individuals with and without blood-CSF barrier dysfunction. A total of 290 patients, who underwent diagnostic lumbar puncture with QALB and QTMAO determination, were evaluated. Serum and CSF TMAO measurements were performed on a tandem mass spectrometry SCIEX QTRAP 4500 (Applied Biosystems, Framingham, MA, USA) coupled with an Agilent 1260 Infinity HPLC system (Agilent Technologies Santa Clara, CA, USA). Serum and CSF albumin were measured on the Atellica® NEPH 630 system (Siemens Healthineers, Erlangen, Germany). CSF TMAO levels were positively correlated with serum TMAO levels (ρ = 0.709, p < 0.001). The QALB was significantly associated with the QTMAO (ß-coefficient = 0.312; p < 0.001). A total of 117 patients with blood-CSF barrier dysfunction had significantly higher median (Q1 – Q3) QTMAO values (4.7 (2.8 – 7.5) vs. 3.8 (2.5 – 5.7) x 10-1, p = 0.002) compared to 173 individuals with normal blood-CSF barrier function. CSF and serum TMAO concentrations were significantly associated in 290 CSF/serum pairs from lumbar punctures of clinical routine. QALB showed a relevant influence on QTMAO. Present results indicate that TMAO may cross the blood-CSF barrier

Long time blood-transfusion trend in a European general hospital

Reports about long-time transfusion trends in Austrian hospitals are rare. In our hospital, we implemented an algorithm of preoperative anemia management as part of a patient blood management (PBM) program in October 2011. Anemic individuals with elective surgery underwent an adequate preoperative anemia classification and treatment with erythropoietin and intravenous iron. The aim of this study was to assess red blood cell (RBC), platelet and plasma transfusions before and after implementation of an anemia management program in a general hospital in Austria. This retrospective study evaluated a 12-year trend (2006 – 2017) of RBC, platelet and plasma transfusions in an Austrian general hospital comprising a 6-year period before (2006 – 2011) and a 6-year period after (2012 – 2017) the implementation of an algorithm-guided anemia management. From overall 49,142 transfused RBC units between 2006 - 2017, 22,745 units were transfused in the post-implementation period compared to 26,397 units before PBM initiation (-13.8 %). The plasma unit use decreased also distinctly (787 vs. 1065 units, - 26.1 %) in the period after PBM implementation, whereas a slight decrease of platelet concentration use (807 vs. 843 units, - 4.3 %) was observed, only. This study demonstrates a 12-year pattern of blood use in an Austrian hospital with a distinct decreasing trend of transfused RBC and plasma units during this period. The implementation of PBM activities decreased the need of blood utilization at our institution. Further initiatives are needed to continue this trend in the next years

Interleukin-6 is associated with tryptophan metabolism and signs of depression in individuals with carbohydrate malabsorption

The aim of the present study was to investigate possible associations between interleukin-6 (IL-6), interferon-gamma (INF-γ), tumor necrosis factor-alpha (TNF-α), lactoferrin and lipopolysaccharide binding protein (LBP) with TRP metabolism and signs of depression in a large cohort of outpatients referred for carbohydrate malabsorption testing. Serum concentrations of IL-6, INF-γ, TNF-α, lactoferrin, LBP, tryptophan (TRP), kynurenine (KYN) and kynuric acid were determined in 250 adults referred for lactose and fructose malabsorption testing. All participants filled out the Beck Depression Inventory (BDI). Serum IL-6 levels were positively correlated with the BDI score (p = 0.001, ρ = 0.205) and indicators of TRP metabolism (KYN/TRP ratio, KYN) (P-values 13 showed significantly higher IL-6 serum levels (1.7 [1.0 – 2.8] vs. 1.1 [0.8 – 1.7] pg/mL, p < 0.001) compared to 115 individuals with a BDI score ≤ 13. LBP showed a positive correlation with the KYN/TRP ratio (p = 0.005, ρ = 0.177). IL-6 and LBP were associated with indicators of TRP metabolism. IL-6 was found to be linked to signs of depression. Individuals with the presence of depressive symptoms showed higher serum IL-6 levels compared to individuals without depressive symptoms

The site of allergen expression in hematopoietic cells determines the degree and quality of tolerance induced through molecular chimerism

The transplantation of allergens (e.g. Phl p 5 or Bet v 1) expressed on BM cells as membrane-anchored full-length proteins leads to permanent tolerance at the T-cell, B-cell, and effector-cell levels. Since the exposure of complete allergens bears the risk of inducing anaphylaxis, we investigated here whether expression of Phl p 5 in the cytoplasm (rather than on the cell surface) is sufficient for tolerance induction. Transplantation of BALB/c BM retrovirally transduced to express Phl p 5 in the cytoplasm led to stable and durable molecular chimerism in syngeneic recipients (∼20% chimerism at 6 months). Chimeras showed allergen-specific T-cell hyporesponsiveness. Further, Phl p 5-specific TH1-dependent humoral responses were tolerized in several chimeras. Surprisingly, Phl p 5-specific IgE and IgG1 levels were significantly reduced but still detectable in sera of chimeric mice, indicating incomplete B-cell tolerance. No Phl p 5-specific sIgM developed in cytoplasmic chimeras, which is in marked contrast to mice transplanted with BM expressing membrane-anchored Phl p 5. Thus, the expression site of the allergen substantially influences the degree and quality of tolerance achieved with molecular chimerism in IgE-mediated allergy

Cell Therapy for Prophylactic Tolerance in Immunoglobulin E-mediated Allergy

AbstractBackgroundTherapeutic strategies for the prophylaxis of IgE-mediated allergy remain an unmet medical need. Cell therapy is an emerging approach with high potential for preventing and treating immunological diseases.We aimed to develop a cell-based therapy inducing permanent allergen-specific immunological tolerance for preventing IgE-mediated allergy.MethodsWild-type mice were treated with allergen-expressing bone marrow cells under a short course of tolerogenic immunosuppression (mTOR inhibition and costimulation blockade). Bone marrow was retrieved from a novel transgenic mouse ubiquitously expressing the major grass pollen allergen Phl p 5 as a membrane-anchored protein (BALB/c-Tg[Phlp5-GFP], here mPhl p 5). After transplantation recipients were IgE-sensitized at multiple time points with Phl p 5 and control allergen.ResultsMice treated with mPhl p 5 bone marrow did not develop Phl p 5-specific IgE (or other isotypes) despite repeated administration of the allergen, while mounting and maintaining a strong humoral response towards the control allergen. Notably, Phl p 5-specific T cell responses and allergic airway inflammation were also completely prevented. Interestingly allergen-specific B cell tolerance was maintained independent of Treg functions indicating deletional tolerance as underlying mechanism.ConclusionThis proof-of-concept study demonstrates that allergen-specific immunological tolerance preventing occurrence of allergy can be established through a cell-based therapy employing allergen-expressing leukocytes

Allograft rejection is associated with development of functional IgE specific for donor MHC antigens.

BACKGROUND: Donor-specific antibodies of the IgG isotype are measured routinely for diagnostic purposes in renal transplant recipients and are associated with antibody-mediated rejection and long-term graft loss. OBJECTIVE: This study aimed to investigate whether MHC-specific antibodies of the IgE isotype are induced during allograft rejection. METHODS: Anti-MHC/HLA IgE levels were measured in sera of mice grafted with skin or heart transplants from various donor strains and in sera of kidney transplant patients with high levels of HLA IgG. Mediator release was triggered in vitro by stimulating basophils that were coated with murine or human IgE-positive serum, respectively, with specific recombinant MHC/HLA antigens. Kidney tissue samples obtained from organ donors were analyzed by using flow cytometry for cells expressing the high-affinity receptor for IgE (FcεRI). RESULTS: Donor MHC class I- and MHC class II-specific IgE was found on acute rejection of skin and heart grafts in several murine strain combinations, as well as during chronic antibody-mediated heart graft rejection. Anti-HLA IgE, including donor HLA class I and II specificities, was identified in a group of sensitized transplant recipients. Murine and human anti-MHC/HLA IgE triggered mediator release in coated basophils on stimulation with specific MHC/HLA antigens. HLA-specific IgE was not linked to atopy, and allergen-specific IgE present in allergic patients did not cross-react with HLA antigens. FcεRI+ cells were found in the human renal cortex and medulla and provide targets for HLA-specific IgE. CONCLUSION: These results demonstrate that MHC/HLA-specific IgE develops during an alloresponse and is functional in mediating effector mechanisms

Challenges in microbial ecology: building predictive understanding of community function and dynamics.

The importance of microbial communities (MCs) cannot be overstated. MCs underpin the biogeochemical cycles of the earth's soil, oceans and the atmosphere, and perform ecosystem functions that impact plants, animals and humans. Yet our ability to predict and manage the function of these highly complex, dynamically changing communities is limited. Building predictive models that link MC composition to function is a key emerging challenge in microbial ecology. Here, we argue that addressing this challenge requires close coordination of experimental data collection and method development with mathematical model building. We discuss specific examples where model-experiment integration has already resulted in important insights into MC function and structure. We also highlight key research questions that still demand better integration of experiments and models. We argue that such integration is needed to achieve significant progress in our understanding of MC dynamics and function, and we make specific practical suggestions as to how this could be achieved