Angiotensin II type 1 receptor antibodies in childhood kidney transplantation

Angiotensin II type 1 receptor antibodies (AT1 RAb) have emerged as non-HLA Ab present in patients with acute AMR and risk of graft loss. Furthermore, AT1 RAb have been shown to increase angiotensin II sensitivity which may play a role in the development of CVD and hypertension. Data on AT1 RAb in stable transplant recipients are lacking. The aim of this study was to analyze the levels of AT1 RAb in a cohort of stable patients after kidney transplantation (tx) in childhood. A cross-sectional study of 30 children (median age 14, range 3-19 yr, median time since tx five yr) and 28 adults who were transplanted in childhood (median age 26, range 20-40 yr, median time since tx 18 yr) transplanted between 1993-2006 and 1983-2002, respectively, was performed. Healthy controls were 51 healthy children (5-8 yr) and 199 healthy donors (median age 56.5 yr, range 42-83 yr). Plasma AT1 RAb were analyzed by immunoassay. Median total AT1 RAb IgG concentration was significantly higher in the pediatric-tx group as compared to the adult-tx group (40.0 and 10.95 U/mL, p < 0.0001). For both groups, the tx group showed higher levels: the pediatric-tx group vs. control group (40.0 vs. 13.3 U/mL, p = 0.0006) and the adult-tx group vs. adult control group (10.95 vs. 6.5 U/mL, p < 0.0001). Age was the strongest indicator of high levels of AT1 RAb IgG (p = 0.0003). AT1 RAb total IgG levels are significantly higher in a stable pediatric-tx cohort as compared to adult-tx patients and healthy controls of comparable age groups. The relevance of our findings in relation to age, time since tx, previous or future rejection, and CVD risk merits future studies

Beaver Research in the Uvs Nuur Region

In 1985, 1988, and 2002 Castor fiber birulai was introduced to the Tes Gol of the Uvs Nuur basin in North-western Mongolia. The beavers migrated through the Republic of Tyva and settled in the middle part of Tes Gol near the Tyvinian-Mongolian border. About 10 colonies were recorded in this region in 2002. Strict protection of Castor fiber birulai has to be ensured in Mongolia and the Republic of Tyva in future

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

Bacterial migration through punctured surgical gloves under real surgical conditions

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to confirm recent results from a previous study focussing on the development of a method to measure the bacterial translocation through puncture holes in surgical gloves under real surgical conditions.</p> <p>Methods</p> <p>An established method was applied to detect bacterial migration from the operating site through the punctured glove. Biogel™ double-gloving surgical gloves were used during visceral surgeries over a 6-month period. A modified Gaschen-bag method was used to retrieve organisms from the inner glove, and thus-obtained bacteria were compared with micro-organisms detected by an intra-operative swab.</p> <p>Results</p> <p>In 20 consecutive procedures, 194 gloves (98 outer gloves, 96 inner gloves) were examined. The rate of micro-perforations of the outer surgical glove was 10% with a median wearing time of 100 minutes (range: 20-175 minutes). Perforations occurred in 81% on the non-dominant hand, with the index finger most frequently (25%) punctured. In six cases, bacterial migration could be demonstrated microbiologically. In 5% (5/98) of outer gloves and in 1% (1/96) of the inner gloves, bacterial migration through micro-perforations was observed. For gloves with detected micro-perforations (n = 10 outer layers), the calculated migration was 50% (n = 5). The minimum wearing time was 62 minutes, with a calculated median wearing time of 71 minutes.</p> <p>Conclusions</p> <p>This study confirms previous results that bacterial migration through unnoticed micro-perforations in surgical gloves does occur under real practical surgical conditions. Undetected perforation of surgical gloves occurs frequently. Bacterial migration from the patient through micro-perforations on the hand of surgeons was confirmed, limiting the protective barrier function of gloves if worn over longer periods.</p

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

In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability.</p> <p>Methods</p> <p>6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA.</p> <p>Results</p> <p>MRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm³+/-243 mm³) with MRI (mean 918 mm³+/-193 mm³) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm²+/-22.8 mm²versus 32.6 mm²+/-22.6 mm²(histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm³+/-56.7 mm³after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium-DTPA. All imaging experiments could be done repeatedly to comply with the 3R-principle thus reducing the number of experimental animals.</p> <p>Conclusions</p> <p>This model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and physicians to further improve translational research and therapies of pancreatic cancer.</p