Postoperative Immune Suppression in Visceral Surgery: Characterisation of an Intestinal Mouse Model

Background: Postoperatively acquired immune dysfunction is associated with a higher mortality rate in case of septic complications. As details of this severe clinical problem are still unknown, animal models are essential to characterise the mechanisms involved. Methods: Mice were laparotomised and the small intestine was pressed smoothly in antegrade direction. For extension of trauma, the intestine was manipulated three times consecutively. Following this, the ex vivo cytokine release of splenocytes was determined. The degree of surgical trauma was analysed by detection of HMGB1 and IL-6 in serum and by neutrophil staining in the muscularis mucosae. Results: We adapted the previously described animal model of intestinal manipulation to provide a model of surgically induced immune dysfunction. Following intestinal manipulation, the mice showed elevated serum levels of HMGB1 and IL-6 and increased infiltration of granulocytes into the muscularis mucosae. Ex vivo cytokine release by splenocytes was suppressed in the postoperative period. The degree of suppression correlated with the extent of surgical trauma. Conclusions: In this study, we describe a surgically induced immune dysfunction animal model, in which a significant surgical trauma is followed by an immune dysfunction. This model may be ideal for the characterisation of the postoperative immune dysfunction syndrome

Surgical Trauma and Postoperative Immune Dysfunction

Background: In postoperative sepsis, mortality is increased due to the surgically induced immune dysfunction. Further causes of this traumatic effect on the immune system include burn injuries and polytrauma, as well as endogenous traumata like stroke. Several animal models have been defined to analyse the characteristics of trauma-induced immune suppression. This article will correlate our results from animal studies and clinical observations with the recent literature on postoperative immune suppression. Methods: The previously described model of surgically induced immune dysfunction (SID) was performed in mice by laparotomy and manipulation of the small intestine in the antegrade direction. Blood samples were collected 6 and 72 h following SID to analyse the white blood cell count and corticosterone levels. To assess the postoperative immune status in humans, we analysed expression of HLA-DR on monocytes of 118 patients by flow cytometry prior to and 24, 48 and 72 h after surgery. Results: The postoperative immune suppression in our SID model is characterised by lymphocytopenia and significantly increased corticosterone levels in mice dependent on the degree of surgical trauma. This is comparable to the postoperative situation in humans: major and especially long-lasting surgery results in a significantly reduced expression of HLA-DR on circulating monocytes. Previous studies describe a similar situation following burn injury and endogenous trauma, i.e. stroke. Conclusions: We suggest the completion of our previously published sepsis classification due to the immune status at the onset of sepsis: type A as the spontaneously acquired sepsis and type B as sepsis in trauma-induced pre-existing immune suppression

Cold atmospheric pressure plasma for treatment of chronic wounds: drug or medical device?

Objective: The use of cold atmospheric pressure plasma (CAPP) as a new therapeutic option to aid the healing of chronic wounds appears promising. Currently, uncertainty exists regarding their classification as medical device or medical drug. Because the classification of CAPP has medical, legal, and economic consequences as well as implications for the level of preclinical and clinical testing, the correct classification is not an academic exercise, but an ethical need. Method: A multidisciplinary team of physicians, surgeons, pharmacists, physicists and lawyers has analysed the physical and technical characteristics as well as legal conditions of the biological action of CAPP. Results: It was concluded that the mode of action of the locally generated CAPP, with its main active components being different radicals, is pharmacological and not physical in nature. Conclusion: Depending on the intended use, CAPP should be classified as a drug, which is generated by use of a medical device directly at the point of therapeutic application

A retrospective of the GREGOR solar telescope in scientific literature

In this review, we look back upon the literature, which had the GREGOR solar telescope project as its subject including science cases, telescope subsystems, and post-focus instruments. The articles date back to the year 2000, when the initial concepts for a new solar telescope on Tenerife were first presented at scientific meetings. This comprehensive bibliography contains literature until the year 2012, i.e., the final stages of commissioning and science verification. Taking stock of the various publications in peer-reviewed journals and conference proceedings also provides the "historical" context for the reference articles in this special issue of Astronomische Nachrichten/Astronomical Notes.Comment: 6 pages, 2 color figures, this is the pre-peer reviewed version of Denker et al. 2012, Astron. Nachr. 333, 81

A large-scale experiment to evaluate control of invasive muskrats

The muskrat (Ondatra zibethicus) is an invasive species in Europe. The extensive waterways of the Netherlands provide ideal habitat for muskrats, and a large population established itself after arrival in 1941. A control program was put into effect immediately because muskrat burrowing can compromise the integrity of dikes and, hence, poses a significant public safety risk. The current (2015) annual catch of approximately 89,000 individuals is equivalent to approximately 0.30 muskrats/km of waterway, well above the national objective in spite of decades of effort. The control program is expensive (€35 M annually) and contested by animal rights groups. These factors created the need for a careful evaluation of the full range of control possibilities, from ‘no control’ to ‘extermination.’ As part of this, we experimentally evaluated the validity of a previously published correlation (based on historical data) between catch and effort. We raised or lowered removal effort (2013–2016) in a stratified random sample of 117 5-km × 5-km ‘atlas squares’ from the national grid. We found that catch-per-unit effort (CPUE) decreased after effort was increased, and rose after effort was decreased, by amounts slightly greater than expected based on the correlational data, though confidence intervals enclose zero. As anticipated, CPUE varied consistently and strongly between seasons. The biggest (and unanticipated) effects were those of the catch in the preceding 3 years (‘history’), and surrounding area (‘neighborhood’). Our experiment confirms estimates of intensity of control required to lower muskrat populations. These results will help with more effective allocation of control effort, and better-informed evaluation of the economic costs of various control options

Compensatory upregulation of anti-beta-adrenergic receptor antibody levels might prevent heart failure presentation in pediatric myocarditis

BACKGROUND: Myocarditis can be associated with severe heart failure and is caused by different inflammatory and autoimmune responses. The aim of this study was to describe the immunological response in children with myocarditis by analyzing anti-beta-adrenergic receptor antibodies (anti-β-AR Abs). METHODS: Sera of children who were hospitalized with biopsy-proven myocarditis were prospectively collected between April 2017 and March 2019. Anti-β1-AR Ab, anti-β2-AR Ab, and anti-β3-AR Ab were quantified by a CE-certified ELISA kit. According to normal values for immunoglobulin G (IgG), three age groups, 5–17 years, were defined. Children without inflammatory cardiac pathology and no heart failure signs were served as a control group. RESULTS: We compared 22 patients with biopsy-proven myocarditis and 28 controls. The median age (interquartile range) of the myocarditis group (MYC) was 12.1 (2.7–16.4) years, 13 men, left ventricular ejection fraction (LVEF) 51% and for control group, the median age was 5.0 (3.0–6.8) years, nine men, LVEF 64%. Myocarditis patients in the age group >5–17 years showed significantly higher anti-β3-AR Ab levels as compared to controls (p = 0.014). Lower anti-β2-AR Ab and anti-β3-AR Ab levels were significantly correlated with higher left ventricular diameters in myocarditis patients. The event-free survival using a combined endpoint (mechanical circulatory support [MCS], transplantation, and/or death) was significantly lower in myocarditis patients with antibody levels below the median as compared to myocarditis patients with antibody levels ≥ the median. CONCLUSION: Anti-β-AR Ab levels are increased in children with myocarditis and >5 years of age. These antibodies might be upregulated compensatory to prevent further cardiac deterioration. A worse event-free survival in patients with lower anti-β-AR Ab levels might be a therapeutic target for immunoglobulin substitution

Receptor autoantibodies: Associations with cardiac markers, histology, and function in human non-ischaemic heart failure

AIMS: A causal link between non-ischaemic heart failure (HF) and humoral autoimmunity against G-protein-coupled receptors (GPCR) remains unclear except for Chagas' cardiomyopathy. Uncertainty arises from ambiguous reports on incidences of GPCR autoantibodies, spurious correlations of autoantibody levels with disease activity, and lack of standardization and validation of measuring procedures for putatively cardio-pathogenic GPCR autoantibodies. Here, we use validated and certified immune assays presenting native receptors as binding targets. We compared candidate GPCR autoantibody species between HF patients and healthy controls and tested associations of serum autoantibody levels with serological, haemodynamic, metabolic, and functional parameters in HF. METHODS: Ninety-five non-ischaemic HF patients undergoing transcatheter endomyocardial biopsy and 60 healthy controls were included. GPCR autoantibodies were determined in serum by IgG binding to native receptors or a cyclic peptide (for ß1AR autoantibodies). In patients, cardiac function, volumes, and myocardial structural properties were assessed by cardiac magnetic resonance imaging; right heart catheterization served for determination of cardiac haemodynamics; endomyocardial biopsies were used for histological assessment of cardiomyopathy and determination of cardiac mitochondrial oxidative function by high-resolution respirometry. RESULTS: Autoantibodies against ß(1) adrenergic (ß(1) AR), M5-muscarinic (M5AR), and angiotensin II type 2 receptors (AT2R) were increased in HF (all P < 0.001). Autoantibodies against a(1) -adrenergic (a(1) AR) and angiotensin II type 1 receptors (AT1R) were decreased in HF (all P < 0.001). Correlation of alterations of GPCR autoantibodies with markers of cardiac or systemic inflammation or cardiac damage, haemodynamics, myocardial histology, or left ventricular inflammation (judged by T2 mapping) were weak, even when corrected for total IgG. ß(1) AR autoantibodies were related inversely to markers of left ventricular fibrosis indicated by T1 mapping (r = -0.362, P < 0.05) and global longitudinal strain (r = -0.323, P < 0.05). AT2R autoantibodies were associated with improved myocardial mitochondrial coupling as measured by high-resolution respirometry in myocardial biopsies (r = -0.352, P < 0.05). In insulin-resistant HF patients, AT2R autoantibodies were decreased (r = -.240, P < 0.05), and AT1R autoantibodies were increased (r = 0.212, P < 0.05). CONCLUSIONS: GPCR autoantibodies are markedly altered in HF. However, they are correlated poorly or even inversely to haemodynamic, metabolic, and functional markers of disease severity, myocardial histology, and myocardial mitochondrial efficiency. These observations do not hint towards a specific cardio-pathogenic role of GPCR autoantibodies and suggest that further investigations are required before specific therapies directed at GPCR autoantibodies can be clinically tested in non-ischaemic HF

How Market-Based Water Allocation Can Improve Water Use Efficiency in the Aral Sea Basin?

Increasing water demand due to population growth, irrigation expansion, industrial development, and the need for ecosystem improvements under mounting investment costs for developing new water sources calls for the efficient, equitable and sustainable management of water resources. This is particularly essential in the Aral Sea Basin (ASB) where ineffective institutions are the primary reason of intersectoral and inter-state water sharing conflicts and lack of sufficient investments for improving water use efficiency. This study examined market-based water allocation as an alternative option to the traditional administrative allocation to deal with water scarcity issues in the ASB. Potential economic gains of tradable water use rights were analyzed based on a newly constructed integrated hydro-economic river basin management model. The analysis differentiates between inter- catchment and intra-catchment water trading. The former does not consider any restrictions on water trading whereas the latter is based on the assumption that water trading is more likely to happen between neighboring water users located within the same catchment area. The analyses show that compared to fixed water allocation, inter-catchment water trading can improve basin-wide benefits by US$373 and US$ 476 million depending on water availability. Similarly, additional gains of US$259 to US$ 339 million are estimated under intra-catchment water trading depending on relative water availability. Trading gains are higher under drier conditions. However, water trading carries a series of transaction costs. We find that transaction costs exceeding US$0.05 per m3 of water traded wipe out the economic potential for water trading. Enforcement of the rule of law, infrastructural improvements, participation of representatives of all water stakeholders in decision making processes, and friendly relationships among the riparian countries are suggested as means for reducing transaction costs of water trading contracts

Rapid induction of autoantibodies during ARDS and septic shock

<p>Abstract</p> <p>Background</p> <p>Little is known about the induction of humoral responses directed against human autoantigens during acute inflammation. We utilized a highly sensitive antibody profiling technology to study autoantibodies in patients with acute respiratory distress syndrome (ARDS) and severe sepsis, conditions characterized by intensive immune activation leading to multiple organ dysfunction.</p> <p>Methods</p> <p>Using Luciferase Immunoprecipitation Systems (LIPS), a cohort of control, ARDS and sepsis patients were tested for antibodies to a panel of autoantigens. Autoantibody titers greater than the mean plus 3 SD of the 24 control samples were used to identify seropositive samples. Available longitudinal samples from different seropositive ARDS and sepsis patient samples, starting from within the first two days after admission to the intensive care, were then analyzed for changes in autoantibody over time.</p> <p>Results</p> <p>From screening patient plasma, 57% of ARDS and 46% of septic patients without ARDS demonstrated at least one statistically significant elevated autoantibody compared to the controls. Frequent high titer antibodies were detected against a spectrum of autoantigens including potassium channel regulator, gastric ATPase, glutamic decarboxylase-65 and several cytokines. Analysis of serial samples revealed that several seropositive patients had low autoantibodies at early time points that often rose precipitously and peaked between days 7-14. Further, the use of therapeutic doses of corticosteroids did not diminish the rise in autoantibody titers. In some cases, the patient autoantibody titers remained elevated through the last serum sample collected.</p> <p>Conclusion</p> <p>The rapid induction of autoantibodies in ARDS and severe sepsis suggests that ongoing systemic inflammation and associated tissue destruction mediate the break in tolerance against these self proteins.</p