A Potential Association between Ribonuclease 1 Dynamics in the Blood and the Outcome in COVID-19 Patients.

The COVID-19 pandemic caused by the new SARS-CoV-2 coronavirus is the most recent and well-known outbreak of a coronavirus. RNase 1 is a small endogenous antimicrobial polypeptide that possesses antiviral activity against viral diseases. In this study, we investigated a potential association between ribonuclease 1 and the outcome in COVID-19 patients and the impact of increased and decreased RNase 1 levels serum during the course of the disease. Therefore, two patient populations, Cohort A (n = 35) and B (n = 80), were subclassified into two groups, in which the RNase 1 concentration increased or decreased from time point one to time point two. We show that the RNase 1 serum levels significantly increased in the increasing group of both cohorts (p = 0.0171; p < 0.0001). We detect that patients in the increasing group who died had significantly higher RNase 1 serum levels at both time points in Cohort A (p = 0.0170; p = 0.0393) and Cohort B (p = 0.0253; p = 0.0034) than patients who survived. Additionally, we measured a significant correlation of RNase 1 serum levels with serum creatinine as well as creatinine clearance in the increasing and decreasing group at both time points of Cohort A. Based on these results, there is now good evidence that RNase 1 may play a role in renal dysfunction associated with ICU COVID-19 patients and that increasing RNase 1 serum level may be a potential biomarker to predict outcome in COVID-19 patients.

Standardized pharmacological management of delirium after on-pump cardiac surgery reduces ICU stay and ventilation in a retrospective pre-post study.

Cardiac surgery patients not only undergo a highly invasive procedure but are at risk for a diversity of postoperative complications. Up to 53% of these patients suffer from postoperative delirium (POD). This severe and common adverse event increases mortality and prolonged mechanical ventilation and extends the intensive care unit stay. The objective of this study was to test the hypothesis that standardized pharmacological management of delirium (SPMD) may reduce the length of stay in the intensive care unit (ICU), duration of postoperative mechanical ventilation, and the incidence of postoperative complications such as pneumonia or bloodstream infections in on-pump cardiac surgery ICU patients. In this retrospective, single-center observational cohort study, 247 patients were examined between May 2018 to June 2020, who underwent on-pump cardiac surgery, suffered from POD, and received pharmacological POD treatment. 125 were treated before and 122 after SPMD implementation in the ICU. The primary endpoint was a composite outcome, including the length of ICU stay, postoperative mechanical ventilation time, and ICU survival rate. The secondary endpoints were complications including postoperative pneumonia and bloodstream infections. Although the ICU survival rate was not significantly different between both groups, the length of ICU stay (control group: 23 ± 27 days; SPMD group: 16 ± 16 days; p = 0.024) and the duration of mechanical ventilation were significantly reduced in the SPMD-cohort (control group: 230 ± 395 h; SPMD group: 128 ± 268 h; p = 0.022). Concordantly, the pneumonic risk was reduced after SPMD introduction (control group: 44.0%; SPMD group: 27.9%; p = 0.012) as well as the incidence for bloodstream infections (control group: 19.2%; SPMD group: 6.6%; p = 0.004). Standardized pharmacological management of postoperative delirium in on-pump cardiac surgery ICU patients reduced the length of ICU stay and duration of mechanical ventilation significantly, leading to a decrease in pneumonic complications and bloodstream infections.

Tissue Engineering of Vascular Grafts: A Case Report From Bench to Bedside and Back.

For over 25 years, our group has used regenerative medicine strategies to develop improved biomaterials for use in congenital heart surgery. Among other applications, we developed a tissue-engineered vascular graft (TEVG) by seeding tubular biodegradable polymeric scaffolds with autologous bone marrow-derived mononuclear cells. Results of our first-in-human study demonstrated feasibility as the TEVG transformed into a living vascular graft having an ability to grow, making it the first engineered graft with growth potential. Yet, outcomes of this first Food and Drug Administration-approved clinical trial evaluating safety revealed a prohibitively high incidence of early TEVG stenosis, preventing the widespread use of this promising technology. Mechanistic studies in mouse models provided important insight into the development of stenosis and enabled advanced computational models. Computational simulations suggested both a novel inflammation-driven, mechano-mediated process of in vivo TEVG development and an unexpected natural history, including spontaneous reversal of the stenosis. Based on these in vivo and in silico discoveries, we have been able to rationally design strategies for inhibiting TEVG stenosis that have been validated in preclinical large animal studies and translated to the clinic via a new Food and Drug Administration-approved clinical trial. This progress would not have been possible without the multidisciplinary approach, ranging from small to large animal models and computational simulations. This same process is expected to lead to further advances in scaffold design, and thus next generation TEVGs.

In-hospital mortality and organ failure after open and endovascular thoraco-abdominal aortic surgery can be predicted by increased levels of circulating dipeptidyl peptidase 3.

OBJECTIVES: Endovascular and open thoraco-abdominal aortic aneurysm (TAAA) repair is associated with specific complications. Circulating dipeptidyl peptidase 3 (cDPP3) is a novel biomarker that shows a strong association with organ failure which has not been assessed in surgical settings. Therefore, the objective of this study was to assess the prognostic capabilities of cDPP3 for predicting patient survival and organ failure following open and endovascular TAAA repair. METHODS: Thirty-three patients undergoing TAAA repair were assessed in this prospective observational single-centre study. cDPP3 levels were serially measured perioperatively until 72 h after admission to the intensive care unit (ICU). In-hospital mortality and any organ failure were the clinical end points. RESULTS: Postoperative organ failure was detected in 17 patients (51.5%), and 6 patients died after surgery (18.2%). At 12 h after admission to the ICU, cDPP3 levels were significantly increased in patients who died or developed organ failure (P < 0.001). cDPP3 levels after surgery demonstrated a remarkable predictive accuracy for in-hospital mortality [12 h area under the receiver operating characteristic curve (AUC): 0.907 (P < 0.001), 24 h AUC: 0.815 (P = 0.016), 48 h AUC: 0.914 (P = 0.003)] and the development of organ failure [12 h AUC: 0.882 (P < 0.001), 24 h AUC: 0.850 (P < 0.001), 48 h AUC: 0.846 (P < 0.001)]. Additionally, a significant correlation between cDPP3, the sequential organ failure assessment score and procalcitonin, C-reactive protein and interleukin-6 levels (P < 0.001, P < 0.001, P = 0.011, P = 0.007, respectively) based on all available measurements and time points was observed. CONCLUSIONS: The present findings highlight the role of cDPP3 as an early, highly specific postoperative biomarker for prediction of in-hospital mortality and organ failure after TAAA repair.

Lethal (2) giant discs (Lgd)/CC2D1 is required for the full activity of the ESCRT machinery.

BACKGROUND: A major task of the endosomal sorting complex required for transport (ESCRT) machinery is the pinching off of cargo-loaded intraluminal vesicles (ILVs) into the lumen of maturing endosomes (MEs), which is essential for the complete degradation of transmembrane proteins in the lysosome. The ESCRT machinery is also required for the termination of signalling through activated signalling receptors, as it separates their intracellular domains from the cytosol. At the heart of the machinery lies the ESCRT-III complex, which is required for an increasing number of processes where membrane regions are abscised away from the cytosol. The core of ESCRT-III, comprising four members of the CHMP protein family, organises the assembly of a homopolymer of CHMP4, Shrub in Drosophila, that is essential for abscission. We and others identified the tumour-suppressor lethal (2) giant discs (Lgd)/CC2D1 as a physical interactor of Shrub/CHMP4 in Drosophila and mammals, respectively. RESULTS: Here, we show that the loss of function of lgd constitutes a state of reduced activity of Shrub/CHMP4/ESCRT-III. This hypomorphic shrub mutant situation causes a slight decrease in the rate of ILV formation that appears to result in incomplete incorporation of Notch into ILVs. We found that the forced incorporation in ILVs of lgd mutant MEs suppresses the uncontrolled and ligand-independent activation of Notch. Moreover, the analysis of Su(dx) lgd double mutants clarifies their relationship and suggests that they are not operating in a linear pathway. We could show that, despite prolonged lifetime, the MEs of lgd mutants have a similar ILV density as wild-type but less than rab7 mutant MEs, suggesting the rate in lgd mutants is slightly reduced. The analysis of the MEs of wild-type and mutant cells in the electron microscope revealed that the ESCRT-containing electron-dense microdomains of ILV formation at the limiting membrane are elongated, indicating a change in ESCRT activity. Since lgd mutants can be rescued to normal adult flies if extra copies of shrub (or its mammalian ortholog CHMP4B) are added into the genome, we conclude that the net activity of Shrub is reduced upon loss of lgd function. Finally, we show that, in solution, CHMP4B/Shrub exists in two conformations. LGD1/Lgd binding does not affect the conformational state of Shrub, suggesting that Lgd is not a chaperone for Shrub/CHMP4B. CONCLUSION: Our results suggest that Lgd is required for the full activity of Shrub/ESCRT-III. In its absence, the activity of the ESCRT machinery is reduced. This reduction causes the escape of a fraction of cargo, among it Notch, from incorporation into ILVs, which in turn leads to an activation of this fraction of Notch after fusion of the ME with the lysosome. Our results highlight the importance of the incorporation of Notch into ILV not only to assure complete degradation, but also to avoid uncontrolled activation of the pathway.

PET/MRI and genetic intrapatient heterogeneity in head and neck cancers.

PURPOSE: The relation between functional imaging and intrapatient genetic heterogeneity remains poorly understood. The aim of our study was to investigate spatial sampling and functional imaging by FDG-PET/MRI to describe intrapatient tumour heterogeneity. METHODS: Six patients with oropharyngeal cancer were included in this pilot study. Two tumour samples per patient were taken and sequenced by next-generation sequencing covering 327 genes relevant in head and neck cancer. Corresponding regions were delineated on pretherapeutic FDG-PET/MRI images to extract apparent diffusion coefficients and standardized uptake values. RESULTS: Samples were collected within the primary tumour (n = 3), within the primary tumour and the involved lymph node (n = 2) as well as within two independent primary tumours (n = 1). Genetic heterogeneity of the primary tumours was limited and most driver gene mutations were found ubiquitously. Slightly increasing heterogeneity was found between primary tumours and lymph node metastases. One private predicted driver mutation within a primary tumour and one in a lymph node were found. However, the two independent primary tumours did not show any shared mutations in spite of a clinically suspected field cancerosis. No conclusive correlation between genetic heterogeneity and heterogeneity of PET/MRI-derived parameters was observed. CONCLUSION: Our limited data suggest that single sampling might be sufficient in some patients with oropharyngeal cancer. However, few driver mutations might be missed and, if feasible, spatial sampling should be considered. In two independent primary tumours, both lesions should be sequenced. Our data with a limited number of patients do not support the concept that multiparametric PET/MRI features are useful to guide biopsies for genetic tumour characterization.

In vitro comparison of the hemocompatibility of two centrifugal left ventricular assist devices.

OBJECTIVES: Shear stress from left ventricular assist devices induces von Willebrand factor degradation and platelet dysfunction, leading to nonsurgical bleeding. We characterized the hemostatic changes induced by 2 centrifugal left ventricular assist devices, the HeartMate 3 (Abbott Inc, Chicago, Ill) and the EVAHEART (Evaheart Inc, Houston, Tex), for comparison. METHODS: Whole blood from 8 healthy volunteers was used ex vivo. Blood from the same donor was used for 6 hours of circulation in a miniature mock-loop system consisting of 2 identical extracorporeal circuits to compare the following experimental settings: (1) optimal revolutions per minute (rpm) for the HeartMate 3 (n = 4; 5000 rpm) and the EVAHEART (n = 4; 2500 rpm) and (2) equal rpm (3000 rpm for the HeartMate 3 and EVAHEART, n = 4 vs n = 4). For both settings, blood flow was adjusted to 1 mock-loop filling volume per minute (HeartMate 3 = 82 mL/min, EVAHEART = 100 mL/min). A panel of coagulation markers was analyzed to investigate hemostatic changes. RESULTS: The free plasma hemoglobin concentration was significantly lower in the EVAHEART compared with the HeartMate 3 after 6 hours of mock-loop circulation under both settings (optimal: 37 ± 31 vs 503 ± 173 mg/dL, P < .0001; equal: 27 ± 4 vs 139 ± 135 mg/dL, P = .024). Loss of von Willebrand factor high-molecular-weight multimers occurred in both left ventricular assist devices and settings, but the von Willebrand factor:activity/von Willebrand factor:antigen ratio after 6 hours was significantly lower in optimal settings for the HeartMate 3 (P = .009). The thrombin-antithrombin complex level was significantly lower with the EVAHEART for both settings (P < .0001). CONCLUSIONS: The EVAHEART left ventricular assist device caused less hemolysis, resulted in lower coagulation activation, and provided better preservation of von Willebrand factor functional activity compared with the HeartMate 3 device. These findings prove that left ventricular assist device design plays a major role in minimizing blood damage during left ventricular assist device support.

Effect of Long-Term Polytrauma on Ventilator-Induced Diaphragmatic Dysfunction in a Piglet Model.

INTRODUCTION: Mechanical ventilation is known to activate oxidative stress and proteolytic pathways in the diaphragm. Trauma by inducing inflammation and activating proteolytic pathways may potentiate the effects of mechanical ventilation on the diaphragm. In a blunt chest trauma with concomitant injuries we tested the hypothesis that trauma via inflammation further activates the proteolytic pathways and worsens atrophy in the diaphragm. MATERIAL AND METHODS: Piglets were separated into two groups and underwent 72 h of mechanical ventilation. One group received a polytrauma (PT) by unilateral femur fracture, blunt chest trauma with lung contusion, laparotomy with standardized liver incision, and a predefined hemorrhagic shock. The second mechanically ventilated group (MV) did not receive any trauma. A non-ventilated group (Con) served as control.Diaphragmatic fiber dimensions, Western Blot analyses of proteolytic pathways, and lipid peroxidation and messenger ribonucleic acid (mRNA) levels of cytokines and nuclear factor kappa b subunit p65 were measured. RESULTS: Active Caspase-3 was significantly increased in MV (P = 0.019), and in PT (P = 0.02) compared with Con. Nuclear factor kappa b subunit p65, was upregulated in PT (P = 0.010) compared with Con. IL-6 mRNA increased significantly in PT compared with Con (P = 0.0024) but did not differ between Con and MV. CONCLUSION: Trauma and mechanical ventilation induced proteolysis and atrophy in the diaphragm, but only polytrauma induced an inflammatory response in the diaphragm. The additional traumatic inflammatory stimulus did not increase the levels of the prementioned variables. These data underline that inflammation is not a major contributor to ventilator-induced diaphragmatic dysfunction. TRIAL REGISTRY NUMBER: AZ 84-02.04.2014.A265 (Landesamt für Natur-, Umwelt- und Verbraucherschutz, LANUV NRW, Germany).

Oxidation-Reduction Potential in Patients undergoing Transcatheter or Surgical Aortic Valve Replacement.

BACKGROUND: Aortic valve stenosis has gained increasingly more importance due to its high prevalence in elderly people. More than two decades ago, transcatheter aortic valve replacement emerged for patients who were denied surgery, and its noninferiority has been demonstrated in numerous studies. Oxidative stress has generated great interest because of its sensitivity to cell damage and the possibility of offering early hints of clinical outcomes. The aim of the present study was to investigate whether there is a significant difference between transcatheter (TAVR) or surgical aortic valve replacement (SAVR) in terms of the changes in oxidation-reduction potential (ORP) and antioxidant capacity. Therefore, we investigated perioperative oxidative stress levels and their influence on clinical outcomes. METHODS: A total of 72 patients (50% TAVR versus 50% SAVR) were included in the present study. Static oxidation-reduction potential (sORP) and antioxidant capacity were measured using the RedoxSys™ Diagnostic System (Luoxis Diagnostics, USA) in serum samples drawn before and after surgery, as well as on the first postoperative day. In addition, clinical data were obtained to evaluate the clinical outcome of each case. RESULTS: TAVR patients had higher preoperative sORP levels compared to the SAVR patients and more severe comorbidities. Unlike the TAVR cohort, patients in the SAVR group showed a significant difference in sORP from the pre- to postoperative levels. Capacity demonstrated higher preoperative levels in the SAVR cohort and also a greater difference postoperatively compared to the TAVR cohort. Regression analysis revealed a significant correlation between pre- and postoperative capacity levels (r = -0.9931, p < 0.0001), providing a method of predicting postoperative capacity levels by knowing the preoperative levels. According to the multivariable analysis, both sORP and antioxidant capacity are dependent on time point, baseline value, and type of surgery, with the largest variations observed for time effect and surgery method. CONCLUSION: A high preoperative sORP level correlated to more severe illness in the TAVR patients. As the TAVR patients did not show significant differences in their preoperative levels, we assume that there was a smaller production of oxidative agents during TAVR due to the less invasive nature of the procedure. Baseline values and development of antioxidant capacity values strengthen this hypothesis. The significant correlation of pre- and postoperative capacity levels might allow high risk patients to be detected more easily and might provide more adequate and individualized therapy preoperatively. This trial is registered with clinicaltrials.gov, identifier: NCT 02488876.

Life-course immunization as a gateway to health.

INTRODUCTION: Extending the benefits of vaccination against infectious diseases from childhood throughout the entire life-span is becoming an increasingly urgent priority in view of the world's aging population, emergence and reemergence of infectious diseases, and the necessity to invest more on prevention versus cure in global healthcare. Areas covered: This perspective discusses how life-course immunization could benefit human health at all stages of life. To achieve this, the current vaccination paradigm should be changed and all stakeholders have a role to play. Expert commentary: To enhance immunization confidence in the population, it is essential that stakeholders eliminate complacency toward infectious diseases, improve vaccination convenience, remove barriers among different healthcare specialties, and address prevention as a single entity. They must also consider societal and cultural mindsets by understanding and including public viewpoints. A new "4Cs' model encompassing convenience, confidence, complacency, and cultural acceptance is proposed to convert 'vaccine availability' to 'vaccination acceptance' throughout life. Life-course vaccination should become the new social norm of a healthy life-style, along with a healthy diet, adequate physical exercise, and not smoking. We are 'all in' to make life-course immunization a gateway for all people to lead longer, healthier lives.

Retrospective Analysis of Air Handling by Contemporary Oxygenators in the Setting of Cardiac Surgery.

PURPOSE: Cardiac surgery with the use of extracorporeal circulation is associated with a significant risk for gaseous microemboli (GME) despite excellent surgical techniques and highest operative standards. GME are associated with postoperative neurocognitive dysfunction and negative clinical outcome. This study determines whether oxygenator design has influence on perioperative outcome after cardiac surgery. METHODS: Three different oxygenator models with integrated arterial filter (HiliteAF 7000, Fusion Affinity, and Synthesis) were retrospectively evaluated in 55 patients undergoing elective cardiac surgery with the use of extracorporeal circulation. The two-channel ultrasound bubble counter BCC200 was used to detect GME in real time. RESULTS: All three oxygenators differ in terms of structural specifications and have different rates of number and volume GME reduction. The Fusion Affinity had the lowest arterial GME volume (1.81 µL ± 0.23 µL), which was statistically significant compared to the Synthesis (3.37 µL ± 0.71 µL, p = 0.014). However, the Synthesis had lower absolute numbers at the venous GME count (31771 µL ± 6579 µL) versus the Fusion Affinity (49304 µL ± 8196 µL). However, with regard to clinical outcome after cardiac surgery (duration of invasive and non-invasive mechanical ventilation, incidence of delirium, stroke, acute renal failure, or new myocardial infarction), we found no differences between groups. CONCLUSION: Despite significant differences in the design specifications, all oxygenators eliminated relevant GME volumes safely.

Heating capabilities of small fluid warming systems.

BACKGROUND: Perioperative temperature management is fundamental to ensure normothermia in patients. Fluid warmers, which have become smaller in size over the past few years, can help to maintain a stable body temperature. Potentially, the reduction of the size may influence the heating performance. METHODS: Therefore, we tested the effectiveness of enFlow®, Fluido compact® and Thermosens® fluid warmers by measuring the inlet and outlet temperature for room-tempered and ice-cooled saline at flow rates of 25, 50, 75 and 100 ml/min. RESULTS: At all examined flow rates, the tested heating devices warmed up room-tempered saline effectively. The enFlow® provided the significantly (p < 0.05) highest outlet temperature throughout all tested flow rates in comparison to the other devices. When ice-cooled saline was used, the enFlow® maintained a stable outlet temperature > 38 °C at all tested flow rates. The Fluido compact® ensured this only at flow rates of 25 and 50 ml/min, while the Thermosens® provided these conditions at flow rates of 25, 50 and 75 ml/min. CONCLUSIONS: The heating capability for room-tempered saline was effective in all tested devices, but with ice-cooled saline enFlow® is superior at high flow rates. At low flow rates the heating capabilities of enFlow®, Fluido compact® and Thermosens® are comparable.

Volatile anesthetics versus propofol in the cardiac surgical setting of remote ischemic preconditioning: a secondary analysis of a Cochrane Systematic Review.

INTRODUCTION: So far, the concept of remote ischemic preconditioning (RIPC) failed its translation from experimental to clinical studies. In addition to our Cochrane Systematic Review, we systematically assessed the use of the intravenous anesthetic propofol, as a potential confounding factor. EVIDENCE ACQUISITION: We searched CENTRAL, MEDLINE, Embase and Web of Science. We included randomized controlled trials comparing RIPC with no RIPC in adult patients scheduled for coronary artery bypass graft surgery (with or without valve surgery) receiving either exclusively propofol or exclusively volatile anesthetics. Two authors independently assessed methodological quality and extracted data. We report odds ratios (ORs) with 95% confidence intervals as our summary statistics are based on random-effects models. EVIDENCE SYNTHESIS: We included 14 studies involving 4060 participants. We found no difference in treatment effect between the propofol and volatile anesthetic groups when RIPC or no RIPC is applied on a composite endpoint (all-cause mortality, non-fatal myocardial infarction and/or any new stroke), all-cause mortality, non-fatal myocardial infarction, stroke, or length of stay on ICU. On cardiac markers, RIPC did show a treatment effect on cardiac troponin T measured as AUC 72 hours (SMD -0.80, CI -1.34, -0.25) in the propofol group. However, these findings have to be interpreted with great caution, to date only a very limited number of patients received volatile anesthetics in RIPC trials (minimum N.=15, maximum N.=232). CONCLUSIONS: Present data do not permit a final assessment regarding the role of volatile or intravenous anesthetics as a possible confounding factor in RIPC trials.

Acceleration sensors in abdominal wall position as a non-invasive approach to detect early breathing alterations induced by intolerance of increased airway resistance.

BACKGROUND: Early detection of respiratory overload is crucial to mechanically ventilated patients, especially during phases of spontaneous breathing. Although a diversity of methods and indices has been established, there is no highly specific approach to predict respiratory failure. This study aimed to evaluate acceleration sensors in abdominal and thoracic wall positions to detect alterations in breathing excursions in a setting of gradual increasing airway resistance. METHODS: Twenty-nine healthy volunteers were committed to a standardized protocol of a two-minutes step-down spontaneous breathing on a 5 mm, 4 mm and then 3 mm orally placed endotracheal tube. Accelerator sensors in thoracic and abdominal wall position monitored breathing excursions. 15 participants passed the breathing protocol ("completed" group), 14 individuals cancelled the protocol due to subjective intolerance to the increasing airway resistance ("abandoned" group). RESULTS: Gradual increased respiratory workload led to a significant decrease of acceleration in abdominal wall position in the "abandoned" group compared to the "completed" group (p < 0.001), while these gradual accelerating changes were not observed in thoracic wall position (p = 0.484). Thoracic acceleration sensors did not detect any time- and group-specific changes (p = 0.746). CONCLUSIONS: The abdominal wall position of the acceleration sensors may be a non-invasive, economical and practical approach to detect early breathing alterations prior to respiratory failure. TRIAL REGISTRATION: EK 309-15; by the Ethics Committee of the Faculty of Medicine, RWTH Aachen, Aachen, Germany. Retrospectively registered 28th of December 2015.

Abundance and turnover of GLP-1 producing L-cells in ileal mucosa are not different in patients with and without type 2 diabetes.

INTRODUCTION: The gastrointestinal hormone GLP-1 is released from enteroendocrine L-cells and augments postprandial insulin secretion. In patients with type 2 diabetes, the incretin effect is markedly diminished. It is unclear, whether this is due to a reduction in the abundance of L-cells in the intestine. METHODS: Ileal tissue samples from 10 patients with and 10 patients without diabetes that underwent surgery for the removal of colon tumors were included. Tissue sections were stained for GLP-1, Ki67, TUNEL and chromogranin A. RESULTS: The number of L-cells was not different between patients with and without diabetes in either crypts (1.81±0.21% vs. 1.49±0.24%, respectively; p=0.31) or villi (1.07±0.16% vs. 0.83±0.10%, respectively; p=0.23). L-cell number was higher in crypts than in villi (p<0.0001). L-cell replication was detected rarely and not different between the groups. L-cell apoptosis was similar in patients with and without diabetes in both crypts (7.84±2.77% vs. 8.65±3.77%, p=0.85) and villi (4.48±2.89% vs. 8.62±4.64%, p=0.42). Chromogranin A staining was found in a subset of L-cells only. CONCLUSIONS: Intestinal L-cell density is higher in crypts than in villi. Chromogranin A is not a prerequisite for GLP-1 production. L-cell density and turnover are not different between patients with and without diabetes. Thus, alterations in the number of GLP-1 producing cells do not explain the reduced incretin effect in patients with type 2 diabetes.

Xenon triggers pro-inflammatory effects and suppresses the anti-inflammatory response compared to sevoflurane in patients undergoing cardiac surgery.

INTRODUCTION: Cardiac surgery encompasses various stimuli that trigger pro-inflammatory mediators, reactive oxygen species and mobilization of leucocytes. The aim of this study was to evaluate the effect of xenon on the inflammatory response during cardiac surgery. METHODS: This randomized trial enrolled 30 patients who underwent elective on-pump coronary-artery bypass grafting in balanced anaesthesia of either xenon or sevoflurane. For this secondary analysis, blood samples were drawn prior to the operation, intra-operatively and on the first post-operative day to measure the pro- and anti-inflammatory cytokines interleukin-6 (IL-6), interleukin-8/C-X-C motif ligand 8 (IL-8/CXCL8), and interleukin-10 (IL-10). Chemokines such as C-X-C motif ligand 12/ stromal cell-derived factor-1α (CXCL12/SDF-1α) and macrophage migration inhibitory factor (MIF) were measured to characterize xenon's perioperative inflammatory profile and its impact on migration of peripheral blood mononuclear cells (PBMC). RESULTS: Xenon enhanced the postoperative increase of IL-6 compared to sevoflurane (Xenon: 90.7 versus sevoflurane: 33.7 pg/ml; p = 0.035) and attenuated the increase of IL-10 (Xenon: 127.9 versus sevoflurane: 548.3 pg/ml; p = 0.028). Both groups demonstrated a comparable intraoperative increase of oxidative stress (intra-OP: p = 0.29; post-OP: p = 0.65). While both groups showed an intraoperative increase of the cardioprotective mediators MIF and CXCL12/SDF-1α, only MIF levels decreased in the xenon group on the first postoperative day (50.0 ng/ml compared to 23.3 ng/ml; p = 0.012), whereas it remained elevated after sevoflurane anaesthesia (58.3 ng/ml to 53.6 ng/ml). Effects of patients' serum on chemotactic migration of peripheral mononuclear blood cells taken from healthy volunteers indicated a tendency towards enhanced migration after sevoflurane anaesthesia (p = 0.07). CONCLUSIONS: Compared to sevoflurane, balanced xenon anaesthesia triggers pro-inflammatory effects and suppresses the anti-inflammatory response in cardiac surgery patients even though the clinical significance remains unknown. TRIAL REGISTRATION: This clinical trial was approved by the European Medicines Agency (EudraCT-number: 2010-023942-63) and at ClinicalTrials.gov ( NCT01285271 ; first received: January 24, 2011).

Sevoflurane exposure prevents diaphragmatic oxidative stress during mechanical ventilation but reduces force and affects protein metabolism even during spontaneous breathing in a rat model.

BACKGROUND: Ventilator-induced diaphragmatic dysfunction is associated with the generation of oxidative stress, enhanced proteolysis, autophagy and reduced protein synthesis in the diaphragm. Sevoflurane is a common operating room anesthetic and can be used in the intensive care medicine as well. Besides its anesthetic properties, its use in cardiac ischemia-reperfusion models can maintain protein synthesis and inhibit generation of reactive oxygen species, if used at the beginning of heart surgery. This study has been performed on the hypothesis that sevoflurane might protect against ventilator-induced diaphragmatic dysfunction by preventing the production of oxidative stress. METHODS: Four-month-old, male Sprague-Dawley rats sedated with sevoflurane (minimal alveolar concentration = 1) were either mechanically ventilated (MV) for 12 hours (n = 8) or allowed to breathe spontaneously (SB) for 12 hours (n = 8). An acutely anesthetized group was used as a control (Con) group (n = 8). After euthanization, diaphragmatic contractile properties, fiber cross-sectional areas, proteolysis (calpain-1 and caspase-3), and oxidative stress (lipid peroxidation, protein oxidation) were examined. After testing for normality, 1-way or 2-way analysis of variance with the Dunnett post hoc test was used to test for significance. RESULTS: The diaphragm contractile force was similarly reduced at all stimulation frequencies in the SB and MV groups compared with controls. Markers of oxidative stress and fiber cross-sectional areas were unaltered between Con and SB/MV, respectively. The calcium-dependent proteases (calpain-1 and caspase-3) were enhanced in the MV group. The p-AKT/AKT ratio and p-FoxO1/FoxO1 ratio were significantly and similarly reduced after sevoflurane exposure in the SB and MV group compared with Con group. CONCLUSIONS: Exposure to sevoflurane did not induce oxidative stress. It led to reduction in diaphragmatic force. In the MV group, sevoflurane led to the activation of atrophy signaling pathways. These findings are of particular importance for clinical utilization in intensive care units and question its use, especially during the phases of SB.

A multi-country study of intussusception in children under 2 years of age in Latin America: analysis of prospective surveillance data.

BACKGROUND: Intussusception (IS) is a form of acute intestinal obstruction that occurs mainly in infants and is usually of unknown cause. An association between IS and the first licensed rotavirus vaccine, a reassortant-tetravalent, rhesus-based rotavirus vaccine (RRV-TV), led to the withdrawal of the vaccine. New rotavirus vaccines have now been developed and extensively studied for their potential association with IS. This study aimed to describe the epidemiology and to estimate the incidence of IS in Latin American infants prior to new vaccine introduction. METHODS: Children under 2 years of age representing potential IS cases were enrolled in 16 centers in 11 Latin American countries from January 2003 to May 2005. IS cases were classified as definite, probable, possible or suspected as stated on the Brighton Collaboration Working Group guidelines. RESULTS: From 517 potential cases identified, 476 (92%) cases were classified as definite, 21 probable, 10 possible and 10 suspected for intussusception. Among the 476 definite IS cases, the median age at presentation was 6.4 months with 89% of cases aged <1 year. The male to female ratio was 1.5:1. The incidence of definite IS per 100,000 subject-years ranged from 1.9 in Brazil to 62.4 in Argentina for children <2 years of age, and from 3.8 in Brazil to 105.3 in Argentina for children aged <1 year. Median hospital stay was 4 days with a high prevalence of surgery as the primary treatment (65%). Most cases (88%) made a complete recovery, but 13 (3%) died. No clear seasonal pattern of IS cases emerged. CONCLUSIONS: This study describes the epidemiology and estimates the incidence of IS in Latin American infants prior to the introduction of new rotavirus vaccines. The incidence of IS was found to vary between different countries, as observed in previous studies. TRIAL REGISTRATION: Clinical study identifier 999910/204 (SERO-EPI-IS-204).

Selecting a mix of prevention strategies against cervical cancer for maximum efficiency with an optimization program.

BACKGROUND: Screening and vaccination against human papillomavirus (HPV) can protect against cervical cancer. Neither alone can provide 100% protection. Consequently it raises the important question about the most efficient combination of screening at specified time intervals and vaccination to prevent cervical cancer. OBJECTIVE: Our objective was to identify the mix of cervical cancer prevention strategies (screening and/or vaccination against HPV) that achieves maximum reduction in cancer cases within a fixed budget. METHODS: We assessed the optimal mix of strategies for the prevention of cervical cancer using an optimization program. The evaluation used two models. One was a Markov cohort model used as the evaluation model to estimate the costs and outcomes of 52 different prevention strategies. The other was an optimization model in which the results of each prevention strategy of the previous model were entered as input data. The latter model determined the combination of the different prevention options to minimize cervical cancer under budget, screening coverage and vaccination coverage constraints. We applied the model in two countries with different healthcare organizations, epidemiology, screening practices, resource settings and treatment costs: the UK and Brazil. 100,000 women aged 12 years and above across the whole population over a 1-year period at steady state were included. The intervention was papanicolaou (Pap) smear screening programmes and/or vaccination against HPV with the bivalent HPV 16/18 vaccine (Cervarix® [Cervarix is a registered trademark of the GlaxoSmithKline group of companies]). The main outcome measures were optimal distribution of the population between different interventions (screening, vaccination, screening plus vaccination and no screening or vaccination) with the resulting number of cervical cancer and associated costs. RESULTS: In the base-case analysis (= same budget as today), the optimal prevention strategy would be, after introducing vaccination with a coverage rate of 80% in girls aged 12 years and retaining screening coverage at pre-vaccination levels (65% in the UK, 50% in Brazil), to increase the screening interval to 6 years (from 3) in the UK and to 5 years (from 3) in Brazil. This would result in a reduction of cervical cancer by 41% in the UK and by 54% in Brazil from pre-vaccination levels with no budget increase. Sensitivity analysis shows that vaccination alone at 80% coverage with no screening would achieve a cervical cancer reduction rate of 20% in the UK and 43% in Brazil compared with the pre-vaccination situation with a budget reduction of 30% and 14%, respectively. In both countries, the sharp reduction in cervical cancer is seen when the vaccine coverage rate exceeds the maximum screening coverage rate, or when screening coverage rate exceeds the maximum vaccine coverage rate, while maintaining the budget. As with any model, there are limitations to the value of predictions depending upon the assumptions made in each model. CONCLUSIONS: Spending the same budget that was used for screening and treatment of cervical cancer in the pre-vaccination era, results of the optimization program show that it would be possible to substantially reduce the number of cases by implementing an optimal combination of HPV vaccination (80% coverage) and screening at pre-vaccination coverage (65% UK, 50% Brazil) while extending the screening interval to every 6 years in the UK and 5 years in Brazil.

Long-term recovery of ß-cell function after partial pancreatectomy in humans.

Glucose homeostasis is significantly altered immediately after partial pancreatectomy. The present study examined the long-term consequences of a hemipancreatectomy in 10 patients with chronic pancreatitis and 10 patients with benign pancreatic and extrapancreatic tumors. A 240-minute oral glucose challenge was performed before and shortly after pancreatic surgery, as well as after a follow-up of 3.1 ± 0.5 years. Plasma concentrations of glucose, insulin, and C-peptide were determined; and indices of insulin sensitivity and insulin secretion were calculated. In both groups of patients, fasting and postchallenge glucose concentrations were significantly altered immediately after surgery, but returned to preoperative levels at the time of follow-up (P < .0001). Postchallenge insulin and C-peptide concentrations were reduced immediately after surgery (P < .0001), but were partly normalized at the time of follow-up (P < .0001). These changes were not accompanied by improvements in insulin sensitivity (Matsuda index). However, the oral disposition index revealed a significant recovery of ß-cell function at the time of follow-up (P < .05). These findings demonstrate a capacity for recovery of glucose control after partial pancreatectomy and suggest that ß-cell function can improve significantly over time even in adult humans.