Matrix metalloproteinase 13 modulates intestinal epithelial barrier integrity in inflammatory diseases by activating TNF

Several pathological processes, such as sepsis and inflammatory bowel disease (IBD), are associated with impairment of intestinal epithelial barrier. Here, we investigated the role of matrix metalloproteinase MMP13 in these diseases. We observed that MMP13(-/-) mice display a strong protection in LPS- and caecal ligation and puncture-induced sepsis. We could attribute this protection to reduced LPS-induced goblet cell depletion, endoplasmic reticulum stress, permeability and tight junction destabilization in the gut of MMP13(-/-) mice compared to MMP13(+/+) mice. Both in vitro and in vivo, we found that MMP13 is able to cleave pro-TNF into bioactive TNF. By LC-MS/MS, we identified three MMP13 cleavage sites, which proves that MMP13 is an alternative TNF sheddase next to the TNF converting enzyme TACE. Similarly, we found that the same mechanism was responsible for the observed protection of the MMP13(-/-) mice in a mouse model of DSS-induced colitis. We identified MMP13 as an important mediator in sepsis and IBD via the shedding of TNF. Hence, we propose MMP13 as a novel drug target for diseases in which damage to the gut is essential

A holistic review of the medical school admission process: examining correlates of academic underperformance

Background: Despite medical school admission committees’ best efforts, a handful of seemingly capable students invariably struggle during their first year of study. Yet, even as entrance criteria continue to broaden beyond cognitive qualifications, attention inevitably reverts back to such factors when seeking to understand these phenomena. Using a host of applicant, admission, and post-admission variables, the purpose of this inductive study, then, was to identify a constellation of student characteristics that, taken collectively, would be predictive of students at-risk of underperforming during the first year of medical school. In it, we hypothesize that a wider range of factors than previously recognized could conceivably play roles in understanding why students experience academic problems early in the medical educational continuum. Methods: The study sample consisted of the five most recent matriculant cohorts from a large, southeastern medical school (n=537). Independent variables reflected: 1) the personal demographics of applicants (e.g., age, gender); 2) academic criteria (e.g., undergraduate grade point averages [GPA], medical college admission test); 3) selection processes (e.g., entrance track, interview scores, committee votes); and 4) other indicators of personality and professionalism (e.g., Mayer-Salovey-Caruso Emotional Intelligence Test™ emotional intelligence scores, NEO PI-R™ personality profiles, and appearances before the Professional Code Committee [PCC]). The dependent variable, first-year underperformance, was defined as ANY action (repeat, conditionally advance, or dismiss) by the college's Student Progress and Promotions Committee (SPPC) in response to predefined academic criteria. This study protocol was approved by the local medical institutional review board (IRB). Results: Of the 537 students comprising the study sample, 61 (11.4%) met the specified criterion for academic underperformance. Significantly increased academic risks were identified among students who 1) had lower mean undergraduate science GPAs (OR=0.24, p=0.001); 2) entered medical school via an accelerated BS/MD track (OR=16.15, p=0.002); 3) were 31 years of age or older (OR=14.76, p=0.005); and 4) were non-unanimous admission committee admits (OR=0.53, p=0.042). Two dimensions of the NEO PI-R™ personality inventory, openness (+) and conscientiousness (−), were modestly but significantly correlated with academic underperformance. Only for the latter, however, were mean scores found to differ significantly between academic performers and underperformers. Finally, appearing before the college's PCC (OR=4.21, p=0.056) fell just short of statistical significance. Conclusions: Our review of various correlates across the matriculation process highlights the heterogeneity of factors underlying students’ underperformance during the first year of medical school and challenges medical educators to understand the complexity of predicting who, among admitted matriculants, may be at future academic risk

Breakdown of Mucin as Barrier to Digestive Enzymes in the Ischemic Rat Small Intestine

Loss of integrity of the epithelial/mucosal barrier in the small intestine has been associated with different pathologies that originate and/or develop in the gastrointestinal tract. We showed recently that mucin, the main protein in the mucus layer, is disrupted during early periods of intestinal ischemia. This event is accompanied by entry of pancreatic digestive enzymes into the intestinal wall. We hypothesize that the mucin-containing mucus layer is the main barrier preventing digestive enzymes from contacting the epithelium. Mucin breakdown may render the epithelium accessible to pancreatic enzymes, causing its disruption and increased permeability. The objective of this study was to investigate the role of mucin as a protection for epithelial integrity and function. A rat model of 30 min splanchnic arterial occlusion (SAO) was used to study the degradation of two mucin isoforms (mucin 2 and 13) and two epithelial membrane proteins (E-cadherin and toll-like receptor 4, TLR4). In addition, the role of digestive enzymes in mucin breakdown was assessed in this model by luminal inhibition with acarbose, tranexamic acid, or nafamostat mesilate. Furthermore, the protective effect of the mucin layer against trypsin-mediated disruption of the intestinal epithelium was studied in vitro. Rats after SAO showed degradation of mucin 2 and fragmentation of mucin 13, which was not prevented by protease inhibition. Mucin breakdown was accompanied by increased intestinal permeability to FITC-dextran as well as degradation of E-cadherin and TLR4. Addition of mucin to intestinal epithelial cells in vitro protected against trypsin-mediated degradation of E-cadherin and TLR4 and reduced permeability of FITC-dextran across the monolayer. These results indicate that mucin plays an important role in the preservation of the mucosal barrier and that ischemia but not digestive enzymes disturbs mucin integrity, while digestive enzymes actively mediate epithelial cell disruption

Fixed Dystonia in Complex Regional Pain Syndrome: a Descriptive and Computational Modeling Approach

Background: Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. Involvement of dysfunctional GABAergic interneurons has been suggested, however the mechanisms that underpin fixed dystonia are still unknown. We hypothesized that dystonia could be the result of aberrant proprioceptive reflex strengths of position, velocity or force feedback. Methods: We systematically characterized the pattern of dystonia in 85 CRPS-patients with dystonia according to the posture held at each joint of the affected limb. We compared the patterns with a neuromuscular computer model simulating aberrations of proprioceptive reflexes. The computer model consists of an antagonistic muscle pair with explicit contributions of the musculotendinous system and reflex pathways originating from muscle spindles and Golgi tendon organs, with time delays reflective of neural latencies. Three scenarios were simulated with the model: (i) increased reflex sensitivity (increased sensitivity of the agonistic and antagonistic reflex loops); (ii) imbalanced reflex sensitivity (increased sensitivity of the agonistic reflex loop); (iii) imbalanced reflex offset (an offset to the reflex output of the agonistic proprioceptors). Results: For the arm, fixed postures were present in 123 arms of 77 patients. The dominant pattern involved flexion of the fingers (116/123), the wrists (41/123) and elbows (38/123). For the leg, fixed postures were present in 114 legs of 77 patients. The dominant pattern was plantar flexion of the toes (55/114 legs), plantar flexion and inversion of the ankle (73/114) and flexion of the knee (55/114). Only the computer simulations of imbalanced reflex sensitivity to muscle force from Golgi tendon organs caused patterns that closely resembled the observed patient characteristics. In parallel experiments using robot manipulators we have shown that patients with dystonia were less able to adapt their force feedback strength. Conclusions: Findings derived from a neuromuscular model suggest that aberrant force feedback regulation from Golgi tendon organs involving an inhibitory interneuron may underpin the typical fixed flexion postures in CRPS patients with dystonia.Biomechanical EngineeringMechanical, Maritime and Materials Engineerin

Circulating microparticles: square the circle

Background: The present review summarizes current knowledge about microparticles (MPs) and provides a systematic overview of last 20 years of research on circulating MPs, with particular focus on their clinical relevance. Results: MPs are a heterogeneous population of cell-derived vesicles, with sizes ranging between 50 and 1000 nm. MPs are capable of transferring peptides, proteins, lipid components, microRNA, mRNA, and DNA from one cell to another without direct cell-to-cell contact. Growing evidence suggests that MPs present in peripheral blood and body fluids contribute to the development and progression of cancer, and are of pathophysiological relevance for autoimmune, inflammatory, infectious, cardiovascular, hematological, and other diseases. MPs have large diagnostic potential as biomarkers; however, due to current technological limitations in purification of MPs and an absence of standardized methods of MP detection, challenges remain in validating the potential of MPs as a non-invasive and early diagnostic platform. Conclusions: Improvements in the effective deciphering of MP molecular signatures will be critical not only for diagnostics, but also for the evaluation of treatment regimens and predicting disease outcomes

Dienstleistungscontrolling und -performance in Gesundheitsorganisationen : begleitende Erfolgsmessung im Rahmen von Lean-Prozessoptimierungen

Gesundheitsdienstleister sind mit steigendem Kostendruck konfrontiert. Diesem Kostendruck kann durch eine Analyse und Optimierung bestehender Prozesse begegnet werden. Viele Leistungserbringer haben dabei das Konzept des Lean Managements als Methode ihrer Wahl bestimmt und bereits mit der Optimierung einzelner Bereiche begonnen. Entscheidungsträger wünschen sich eine Erfolgsquantifizierung solcher Optimierungsprojekte, um die investierten Ressourcen zu rechtfertigen. Leider zeigt der aktuelle Stand der Forschung, dass der Einfluss von Lean Management bei Gesundheitsdienstleistern auf Prozess- und Finanzkennzahlen kaum untersucht ist. Um diese Forschungslücke zu schließen erläutert der Beitrag, wie das Lean Management in einem Krankenhaus mittels Kennzahlen gezielt validiert werden kann. Er beschreibt das Vorgehen bei der Konzeptualisierung und Durchführung einer begleitenden Evaluation im Rahmen einer Prozessoptimierung, wobei ein Fokus auf der Erstellung eines Kennzahlen-Cockpits sowie verschiedenen Erhebungsmethoden liegt