Multiparametric Functional MRI: A Tool to Uncover Subtle Changes following Allogeneic Renal Transplantation

Purpose To investigate multiparametric functional MRI to characterize acute rejection in a murine allogeneic renal transplant model and evaluate the effect of novel therapeutics. Material and Methods We performed allogeneic and syngeneic orthotopic transplantations (Balb/c to C57Bl/6 and C57Bl/6 to C57Bl/6). Allogeneic Groups (n = 5) were either treated with the anti-CCL2-Spiegelmer (mNOX-E36) in monotherapy or in combination with low doses of Ciclosporin-A (10mg/kgBW/d) for 10 days. Controls received equivalent doses of a non-functional spiegelmer (revmNOX-E36) or low dose Ciclosporin-A. Diffusion-weighted (DWI) and Dynamic-contrast-enhanced (DCE-) MRI-scans were performed using a clinical 3T-scanner. DWI analysis (b-values from 0-800 s/mm(2)) was performed mono-and biexponentially, while DCE-MRI was assessed with deconvolution analysis. Therapy effects were assessed ex vivo with histopathology, immunohistochemistry and RT-PCR. Statistical analysis was performed with unpaired t-tests and Spearman As correlation coefficient. Results DWI showed a significant diffusion restriction in allogeneic compared to syngeneic transplants (ADC: 0.63 +/- 0.08 vs. 1.29 +/- 0.12 mm(2)/s*10(3)) with decreasing diffusion restriction under therapy. DCE-MRI showed restored organ perfusion under Ciclosporin A alone and combination therapy (Plasma Flow: 43.43 +/- 12.49;38.75 +/- 7.53ml/100ml/min) compared to syngeneic controls (51.03 +/- 12.49ml/100ml/min). Ex vivo analysis showed reduced monocytic infiltrates, attenuated levels of inflammatory cytokines under mNOX-E36 monotherapy with an additive effect of low dose Ciclosporin A. There was a significant (p<0.05) negative correlation between ADC and interstitial inflammation (r = -0.73) or macrophage infiltration (r = -0.81) and between organ perfusion and intimal arteritis (r = -0.63). Conclusion Multiparametric functional MRI is suited to detect renal allograft rejection in an experimental murine model and allows to characterize effects of immunosuppressive therapy alleviating acute rejection processes in allogeneic transplantation

Cathepsin S and protease-activated receptor-2 drive alloimmunity and immune regulation in kidney allograft rejection

Alloantigen presentation is an essential process in acute allorejection. In this context, we speculated on a pathogenic role of cathepsin S (Cat-S), a cysteine protease known to promote antigenic peptide loading into MHC class II and to activate protease-activated receptor (PAR)-2 on intrarenal microvascular endothelial and tubular epithelial cells. Single-cell RNA sequencing and immunostaining of human kidney allografts confirmed Cat-S expression in intrarenal mononuclear phagocytes

Effect of Apheresis for ABO and HLA Desensitization on Anti-Measles Antibody Titers in Renal Transplantation

Desensitization strategies for ABO-incompatible renal transplants with plasma exchange (PE) or specific immunoadsorption (IA) decrease immunoglobulin levels. After recent measles outbreak and decreasing vaccination rates, we studied the impact of apheresis on anti-measles antibodies. Anti-measles antibodies were measured before desensitization, before transplantation and during followup in 12 patients with ABO incompatibility (2x PE only, 8x IA only, and 2x IA and PE) and 3 patients with donor-specific HLA antibodies (all PE). Patients received rituximab, IVIG, and standard immunosuppressive therapy. All patients had detectable anti-measles antibodies before desensitization (mean 3238 mU/l, range 560–8100). After 3–6 PE sessions, titers decreased significantly to 1710 mU/l (P < 0.05), in one patient to nondetectable values, while IA only maintained protective titers. After a median followup of 64 days, anti-measles antibodies returned to baseline in all patients. Immunity against measles was temporarily reduced by apheresis but remained detectable in most patients at time of transplantation. Desensitization maintains long-term protective immunity against measles

Antibiotic Bowel Decontamination in Gastrointestinal Surgery-A Single-Center 20 Years' Experience

Objective: Anastomotic leakage, surgical site infections, and other infectious complications are still common complications in gastrointestinal surgery. The concept of perioperative antibiotic bowel decontamination demonstrates beneficial effects in single randomized controlled trials (RCTs), but data from routine clinical use are still sparse. Our aim was to analyze the data from the routine clinical use of perioperative antibiotic bowel decontamination in gastrointestinal surgery. Methods: Based on 20 years' experience, we performed a retrospective analysis of all cases in oncologic gastrointestinal surgery with the use of antibiotic bowel decontamination in gastric, sigmoid, and rectal cancer. Clinical data and perioperative outcomes were analyzed, especially regarding anastomotic leakage, surgical site infections, and other infectious complications. Results: A total of n = 477 cases of gastrointestinal surgery in gastric cancer (n = 80), sigmoid cancer (n = 168), and rectal cancer (n = 229) using a perioperative regimen of antibiotic bowel decontamination could be included in this analysis. Overall, anastomotic leakage occurred in 4.4% (2.5% gastric cancer, 3.0% sigmoid cancer, 6.1% rectal cancer) and surgical site infections in 9.6% (6.3% gastric cancer, 9.5% sigmoid cancer, 10.9% rectal cancer). The incidence of all infectious complications was 13.6% (12.5% gastric cancer, 11.3% sigmoid cancer, 15.7% rectal cancer). Mortality was low, with an overall rate of 1.1% (1.3% gastric cancer, 1.8% sigmoid cancer, 0.4% rectal cancer). Antibiotic decontamination was completed in 98.5%. No adverse effects of antibiotic bowel decontamination could be observed. Conclusion: Overall, in this large cohort, we can report low rates of surgery-related serious morbidity and mortality when perioperative antibiotic bowel decontamination is performed. The rates are lower than other clinical reports. In our clinical experience, the use of perioperative antibiotic bowel decontamination appears to improve patient safety and surgical outcomes during gastrointestinal oncologic procedures in a routine clinical setting

Effect of Sirolimus vs. Everolimus on CMV-Infections after Kidney Transplantation — A Network Meta-Analysis

(1) Background: Following renal transplantation, infection with cytomegalovirus (CMV) is a common and feared complication. mTOR-inhibitor (mTOR-I) treatment, either alone or in combination with calcineurininhibitors (CNIs), significantly reduces the CMV incidence after organ transplantation. As of now, there is no information on which mTOR-I, sirolimus (SIR) or everolimus (ERL), has a stronger anti-CMV effect. (2) Methods: The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 1164 trials screened, of which 27 could be included (11,655 pts.). We performed a network meta-analysis to analyze the relative risk of different types of mTOR-I treatment on CMV infection 12 months after transplantation compared to CNI treatment. (3) Results: Four different types of mTOR-I treatment were analyzed in network meta-analyses—SIR mono, ERL mono, SIR with CNI, ERL with CNI. The mTOR-I treatment with the strongest anti-CMV effect compared to a regular CNI treatment was ERL in combination with a CNI (relative risk (RR) 0.27, confidence interval (CI) 0.22–0.32, p < 0.0001). The other mTOR-I therapy groups showed a slightly decreased anti-CMV efficacy (SIR monotherapy (mono): RR 0.35, CI 0.22–0.57, p < 0.001; SIR with CNI: RR 0.43, CI 0.29–0.64, p < 0.0001; ERL mono: RR 0.46, CI 0.22–0.93, p = 0.031). (4) Conclusions: The anti-CMV effect of both mTOR-Is (SRL and ERL) is highly effective, irrespective of the combination with other immunosuppressive drugs. Certain differences with respect to the potency against the CMV could be found between SRL and ERL. Data gained from this analysis seem to support that a combination of ERL and CNI has the most potent anti-CMV efficacy

Infections after kidney transplantation: A comparison of mTOR‐Is and CNIs as basic immunosuppressants. A systematic review and meta‐analysis

Background Side effects of the immunosuppressive therapy after solid organ transplantation are well known. Recently, significant benefits were shown for mTOR‐Is with respect to certain viral infections in comparison with CNIs. However, reported total incidences of infections under mTOR‐Is vs CNIs are usually not different. This raises the question to additional differences between these immunosuppressants regarding development and incidence of infections. Methods The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 954 trials screened of which 19 could be included (9861 pts.). The 1‐year incidence of infections, patient and graft survival were assessed in meta‐analyses. Results Meta‐analysis on 1‐year incidence of infections showed a significant benefit of an mTOR‐I based therapy when combined with a CNI vs CNI‐based therapy alone (OR 0.76). There was no difference between mTOR‐I w/o CNI and CNI therapy (OR 0.97). For pneumonia, a significant disadvantage was seen only for mTOR‐I monotherapy compared to CNI's (OR 2.09). The incidence of CMV infections was significantly reduced under mTOR‐I therapy (combination with CNI: OR 0.30; mTOR w/o CNI: OR: 0.46). There was no significant difference between mTOR‐I and CNI therapy with respect to patient survival (mTOR‐I w/o CNI vs CNI: OR 1.22; mTOR‐I with CNI vs CNI: OR 0.86). Graft survival was negatively affected by mTOR‐I monotherapy (OR 1.52) but not when combined with a CNI (OR 0.97). Conclusion Following renal transplantation the incidence of infections is lower when mTOR‐Is are combined with a CNI compared to a standard CNI therapy. Pneumonia occurs more often under mTOR‐I w/o CNI

The Role of Gut-Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases

BACKGROUND Hepatosteatosis is the earliest stage in the pathogenesis of nonalcoholic fatty (NAFLD) and alcoholic liver disease (ALD). As NAFLD is affecting 10-24% of the general population and approximately 70% of obese patients, it carries a large economic burden and is becoming a major reason for liver transplantation worldwide. ALD is a major cause of morbidity and mortality causing 50% of liver cirrhosis and 10% of liver cancer related death. Increasing evidence has accumulated that gut-derived factors play a crucial role in the development and progression of chronic liver diseases. METHODS A selective literature search was conducted in Medline and PubMed, using the terms \textquotedblnonalcoholic fatty liver disease,\textquotedbl \textquotedblalcoholic liver disease,\textquotedbl \textquotedbllipopolysaccharide,\textquotedbl \textquotedblgut barrier,\textquotedbl and \textquotedblmicrobiome.\textquotedbl RESULTS Gut dysbiosis and gut barrier dysfunction both contribute to chronic liver disease by abnormal regulation of the gut-liver axis. Thereby, gut-derived lipopolysaccharides (LPS) are a key factor in inducing the inflammatory response of liver tissue. The review further underlines that endotoxemia is observed in both NAFLD and ALD patients. LPS plays an important role in conducting liver damage through the LPS-TLR4 signaling pathway. Treatments targeting the gut microbiome and the gut barrier such as fecal microbiota transplantation (FMT), probiotics, prebiotics, synbiotics, and intestinal alkaline phosphatase (IAP) represent potential treatment modalities for NAFLD and ALD. CONCLUSIONS The gut-liver axis plays an important role in the development of liver disease. Treatments targeting the gut microbiome and the gut barrier have shown beneficial effects in attenuating liver inflammation and need to be further investigated

Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes account for organ injury, regeneration or atrophy

Mononuclear phagocytes (MP), i.e., monocytes, macrophages, and dendritic cells (DCs), are essential for immune homeostasis via their capacities to clear pathogens, pathogen components, and non-infectious particles. However, tissue injury-related changes in local microenvironments activate resident and infiltrating MP towards pro-inflammatory phenotypes that contribute to inflammation by secreting additional inflammatory mediators. Efficient control of injurious factors leads to a switch of MP phenotype, which changes the microenvironment towards the resolution of inflammation. In the same way, MP endorses adaptive structural responses leading to either compensatory hypertrophy of surviving cells, tissue regeneration from local tissue progenitor cells, or tissue fibrosis and atrophy. Under certain circumstances, MP contribute to the reversal of tissue fibrosis by clearance of the extracellular matrix. Here we give an update on the tissue microenvironment-related factors that, upon tissue injury, instruct resident and infiltrating MP how to support host defense and recover tissue function and integrity. We propose that MP are not intrinsically active drivers of organ injury and dysfunction but dynamic amplifiers (and biomarkers) of specific tissue microenvironments that vary across spatial and temporal contexts. Therefore, MP receptors are frequently redundant and suboptimal targets for specific therapeutic interventions compared to molecular targets upstream in adaptive humoral or cellular stress response pathways that influence tissue milieus at a contextual level

Comparison of Four Approaches to Age and Gender Recognition for Telephone Applications

This paper presents a comparative study of four different ap-proaches to automatic age and gender classification using seven classes on a telephony speech task and also compares the results with Human performance on the same data. The automatic approaches compared are based on (1) a parallel phone recognizer, derived from an automatic language identification system; (2) a system using dy-namic Bayesian networks to combine several prosodic features; (3) a system based solely on linear prediction analysis; and (4) Gaus-sian mixture models based on MFCCs for separate recognition of age and gender. On average, the parallel phone recognizer performs as well as Human listeners do, while loosing performance on short utterances. The system based on prosodic features however shows very little dependence on the length of the utterance. Index Terms — speech processing, acoustic signal analysis, speaker classification, age, gender 1