Publications by authors named "Harry van Goor"

520 Publications

Immediate versus Postponed Intervention for Infected Necrotizing Pancreatitis.

N Engl J Med 2021 10;385(15):1372-1381

From the Departments of Gastroenterology and Hepatology (L.B., P.F., R.P.V.), Surgery (S.M.D., J.G., M.A.B., M.F.G.F., M.G.B.), Radiology (M.P.M.K., K.P.L.), and Epidemiology and Data Science (M.G.W.D.), Amsterdam UMC, University of Amsterdam, and the Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam (M.A.J.M.J.), Amsterdam Gastroenterology Endocrinology Metabolism, and the Department of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis (J.M.J.), Amsterdam, the Departments of Research and Development (L.B., S.M.D., N.D.L.H., H.C.T.), Gastroenterology and Hepatology (R.C.V.), Radiology (T.L.B., K.P.L.), and Surgery (H.C.T., H.C.S.), St. Antonius Hospital, Nieuwegein, the Department of Surgery, Maastricht University Medical Center, Maastricht (S.A.W.B., C.H.C.D., M.P.), the Departments of Gastroenterology and Hepatology (M.J.B., J.-W.P.), and Surgery (C.H.J.E.), Erasmus MC University Medical Center, and the Department of Gastroenterology and Hepatology, Maasstad Hospital (M.H.), Rotterdam, the Departments of Radiology (V.C.C.), and Gastroenterology and Hepatology (T.E.H.R.), Jeroen Bosch Hospital, Den Bosch, the Department of Surgery, Gelre Hospitals, Apeldoorn (P.D.), the Department of Surgery, Radboud University Medical Center, Nijmegen (H.G., M.W.J.S.), the Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen (J.W.H.), the Department of Surgery, Medical Center Leeuwarden, Leeuwarden (E.R.M.), the Department of Surgery, Leiden University Medical Center, Leiden (J.S.D.M.), the Department of Surgery, University Medical Center Utrecht, Utrecht (I.Q.M., H.C.S.), the Departments of Surgery (V.B.N.), and Gastroenterology and Hepatology (A.C.P.), Isala Clinics, Zwolle, the Department of Gastroenterology and Hepatology, Reinier de Graaf Gasthuis, Delft (R.Q.), the Department of Gastroenterology and Hepatology, Meander Medical Center, Amersfoort (M.P.S.), the Department of Gastroenterology and Hepatology, Amphia Hospital, Breda (T.C.S.), the Department of Gastroenterology and Hepatology, Maxima Medical Center, Veldhoven (J.W.A.S.), the Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede (N.G.V.), the Department of Gastroenterology and Hepatology, Albert Schweitzer Hospital, Dordrecht (W.V.), and the Department of Gastroenterology and Hepatology, Hospital Gelderse Vallei, Ede (B.J.W.) - all in the Netherlands.

Background: Infected necrotizing pancreatitis is a potentially lethal disease that is treated with the use of a step-up approach, with catheter drainage often delayed until the infected necrosis is encapsulated. Whether outcomes could be improved by earlier catheter drainage is unknown.

Methods: We conducted a multicenter, randomized superiority trial involving patients with infected necrotizing pancreatitis, in which we compared immediate drainage within 24 hours after randomization once infected necrosis was diagnosed with drainage that was postponed until the stage of walled-off necrosis was reached. The primary end point was the score on the Comprehensive Complication Index, which incorporates all complications over the course of 6 months of follow-up.

Results: A total of 104 patients were randomly assigned to immediate drainage (55 patients) or postponed drainage (49 patients). The mean score on the Comprehensive Complication Index (scores range from 0 to 100, with higher scores indicating more severe complications) was 57 in the immediate-drainage group and 58 in the postponed-drainage group (mean difference, -1; 95% confidence interval [CI], -12 to 10; P = 0.90). Mortality was 13% in the immediate-drainage group and 10% in the postponed-drainage group (relative risk, 1.25; 95% CI, 0.42 to 3.68). The mean number of interventions (catheter drainage and necrosectomy) was 4.4 in the immediate-drainage group and 2.6 in the postponed-drainage group (mean difference, 1.8; 95% CI, 0.6 to 3.0). In the postponed-drainage group, 19 patients (39%) were treated conservatively with antibiotics and did not require drainage; 17 of these patients survived. The incidence of adverse events was similar in the two groups.

Conclusions: This trial did not show the superiority of immediate drainage over postponed drainage with regard to complications in patients with infected necrotizing pancreatitis. Patients randomly assigned to the postponed-drainage strategy received fewer invasive interventions. (Funded by Fonds NutsOhra and Amsterdam UMC; POINTER ISRCTN Registry number, ISRCTN33682933.).
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http://dx.doi.org/10.1056/NEJMoa2100826DOI Listing
October 2021

Oxidative stress biomarkers in fetal growth restriction with and without preeclampsia.

Placenta 2021 Sep 20;115:87-96. Epub 2021 Sep 20.

Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Introduction: Oxidative stress as observed in fetal growth restriction (FGR) and preeclampsia (PE) can be identified by decreased levels of systemic free thiols (FT) and increased levels of plasma ischemia-modified albumin (IMA), which may serve as biomarkers in maternal blood for pregnancy complications. We evaluate the performance of oxidative stress-associated potential biomarkers for FGR and PE, and their relationship with clinical characteristics.

Methods: A prospective clinical pilot study was performed in healthy controls and women with pregnancies complicated by severe FGR with or without PE. Blood samples were taken directly after inclusion and analyzed for FT; IMA; soluble FMS-like tyrosine kinase-1 (sFlt-1); placenta growth factor (PlGF); and biomarkers like leptin and soluble receptors for advanced glycation end products (sRAGE). Placentas were examined microscopically. Descriptive statistics and receiver operating characteristics statistics were performed.

Results: Mothers with both severe FGR and PE had significantly reduced FT levels (p < 0.001) and PlGF levels (p < 0.001), and increased levels of plasma IMA (p < 0.05), sFlt (p < 0.001), leptin (p < 0.05) and sRAGE (p < 0.01) compared to women with FGR only. Systemic FT levels were significantly inversely associated with blood pressure (p < 0.01) and plasma IMA (p < 0.001), leptin (p = 0.01) and sRAGE (p < 0.001). Systemic FT and leptin showed significant discriminative ability to differentiate mothers with both FGR and PE from mothers with uncomplicated pregnancies or pregnancies complicated by FGR only.

Discussion: There is a significant discriminative capacity of FT, IMA, leptin and sRAGE that harbor potential as biomarkers of pregnancies complicated by combined FGR and PE.
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http://dx.doi.org/10.1016/j.placenta.2021.09.013DOI Listing
September 2021

The Effect of Lifestyle Intervention on Systemic Oxidative Stress in Women with Obesity and Infertility: A Post-Hoc Analysis of a Randomized Controlled Trial.

J Clin Med 2021 Sep 18;10(18). Epub 2021 Sep 18.

Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

We aimed to study whether lifestyle intervention could reduce systemic oxidative stress (OS) and the association between OS and cardiometabolic outcomes in women with obesity and infertility. From 2009 to 2012, infertile women with a BMI ≥ 29 kg/m were randomly assigned to a six-month lifestyle intervention followed by infertility treatment ( = 289) or to prompt infertility treatment ( = 285). Fasting serum free thiols (FT) concentrations were determined by colorimetry at baseline, at three and six months after randomization. Generalized estimating equations and restricted cubic spline regressions were used to estimate mean differences in serum FT levels between groups and to explore associations between serum FT levels and cardiometabolic outcomes. Baseline serum FT levels did not differ between the two groups ( = 203 in the intervention group vs = 226 in the control group, 222.1 ± 48.0 µM vs 229.9 ± 47.8 µM, = 0.09). Body weight decreased by 3.70 kg in the intervention group compared with the control group at six months (95% confidence interval [CI]: -7.61 to 0.21, = 0.06). No differences in serum FT levels were observed between groups at either three months ( = 142 vs = 150, mean differences: -1.03 µM, 95% CI: -8.37 to 6.32, = 0.78) or six months ( = 104 vs = 96, mean differences: 2.19 µM, 95% CI: -5.90 to 10.28, = 0.60). In a pooled analysis of all available measurements, triglycerides (crude B: 5.29, 95% CI: 1.08 to 9.50, = 0.01), insulin (crude B: 0.62, 95% CI: 0.26 to 0.98, = 0.001), and homeostasis model assessment of insulin resistance (crude B: 2.50, 95% CI: 1.16 to 3.38, < 0.001) were positively associated with serum FT levels. High-sensitivity C-reactive protein (hs-CRP) was negatively associated with serum FT levels (crude B: -0.60, 95% CI: -1.11 to -0.10, = 0.02). The change in hs-CRP during the lifestyle intervention was strongly and inversely associated with serum FT levels (crude B: -0.41, 95% CI: -0.70 to -0.13, = 0.005). No significant deviations from linear associations were observed between serum FT and hs-CRP. We do not observe an improvement in systemic OS in women with obesity and infertility with modest weight loss. There were potential associations between OS and biomarkers of cardiometabolic health. Trial registration: This trial was registered on 16 November 2008 at the Dutch trial register (NTR1530).
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http://dx.doi.org/10.3390/jcm10184243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467169PMC
September 2021

Aggravation of fibrin deposition and microthrombus formation within the graft during kidney transplantation.

Sci Rep 2021 Sep 23;11(1):18937. Epub 2021 Sep 23.

Department of Surgery, University Medical Center Groningen, University of Groningen, P.O. Box 30 001, 9700 RB, Groningen, The Netherlands.

In kidney transplantation, microthrombi and fibrin deposition may lead to local perfusion disorders and subsequently poor initial graft function. Microthrombi are often regarded as donor-derived. However, the incidence, time of development, and potential difference between living donor kidneys (LDK) and deceased donor kidneys(DDK), remains unclear. Two open-needle biopsies, taken at preimplantation and after reperfusion, were obtained from 17 LDK and 28 DDK transplanted between 2005 and 2008. Paraffin-embedded sections were immunohistochemically stained with anti-fibrinogen antibody. Fibrin deposition intensity in peritubular capillaries(PTC) and glomeruli was categorized as negative, weak, moderate or strong and the number of microthrombi/mm was quantified. Reperfusion biopsies showed more fibrin deposition (20% to 100% moderate/strong, p < 0.001) and more microthrombi/mm (0.97 ± 1.12 vs. 0.28 ± 0.53, p < 0.01) than preimplantation biopsies. In addition, more microthrombi/mm (0.38 ± 0.61 vs. 0.09 ± 0.22, p = 0.02) and stronger fibrin intensity in glomeruli (28% vs. 0%, p < 0.01) and PTC (14% vs. 0%, p = 0.02) were observed in preimplantation DDK than LDK biopsies. After reperfusion, microthrombi/mm were comparable (p = 0.23) for LDK (0.09 ± 0.22 to 0.76 ± 0.49, p = 0.03) and DDK (0.38 ± 0.61 to 0.90 ± 1.11, p = 0.07). Upon reperfusion, there is an aggravation of microthrombus formation and fibrin deposition within the graft. The prominent increase of microthrombi in LDK indicates that they are not merely donor-derived.
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http://dx.doi.org/10.1038/s41598-021-97629-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460629PMC
September 2021

Trends in risk factors of anastomotic leakage after colorectal cancer surgery (2011-2019): A Dutch population-based study.

Colorectal Dis 2021 Sep 18. Epub 2021 Sep 18.

Radboud Institute for Health Sciences, Department of Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands.

Aim: Anastomotic leakage (AL) after colon cancer (CC) and rectal cancer (RC) surgery often requires reintervention. Prevalence and morbidity may change over time with evolutions in treatment strategies and changes in patient characteristics. This nationwide study aimed to evaluate changes in the incidence, risk factors and mortality from AL during the past nine years.

Methods: Data of CC and RC resections with primary anastomosis were extracted from the Dutch Colorectal Audit (2011-2019). AL was registered if requiring reintervention. Three consecutive cohorts were compared using logistic regression analysis.

Results: Incidence of AL after CC surgery decreased from 6.6% in 2011-2013 to 4.8% in 2017-2019 and increased from 8.6% to 11.9% after RC surgery. In 2011-2013, male sex, ASA ≥3, (y)pT3-4, neoadjuvant therapy, emergency surgery and multivisceral resection were identified as risk factors for AL after CC surgery. In 2017-2019, only male sex and ASA ≥3 were risk factors for AL. For RC patients, male sex and neoadjuvant therapy were a risk factor for AL in 2011-2013. In 2017-2019, transanal approach was also a risk factor for AL. Postoperative mortality rate after AL was 12% (CC) and 2% (RC) in 2017-2019, without significant changes over time.

Conclusion: Contradictory trends in incidence and mortality for AL were observed among CC and RC surgery with changing risk factors over the past 9 years. High mortality after AL is only observed after CC surgery and remains unchanged. Continued efforts should be made to improve early detection and treatment of AL for these patients.
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http://dx.doi.org/10.1111/codi.15911DOI Listing
September 2021

New polyoxazoline loaded patches for hemostasis in experimental liver resection.

J Biomed Mater Res B Appl Biomater 2021 Sep 18. Epub 2021 Sep 18.

Department of Surgery, RadboudUMC, Nijmegen, The Netherlands.

A new cost-effective NHS functionalized polyoxazoline (POx) loaded polymer with strong hemostatic properties has been developed. In this study, we investigate POx loaded hemostatic patches regarding hemostatic efficacy, local inflammatory reaction and wound-healing, as compared to the non-POx treated blanks and commercially available hemostatic products. Hundred and ten rats divided into 11 groups of 10 animals underwent partial liver lobe resection. Eight groups received experimental patches, two groups commercially available hemostatic patches (TachoSil® and Veriset™, positive controls), one group with gauzes (negative control). Each animal received twice a patch with a size 1.5 × 2.5 cm, on each partially resected lobe. Primary endpoint was time to hemostasis (TTH). The rats were sacrificed at different time points (1, 3, or 7 days) to measure local inflammatory response and early wound healing. Of the POx loaded patches, GFC NHS-POx (TTH 20.4 s, p = .019) and GFC-NHS-POx1.5 (TTH 0.0 s, p = .003) showed significantly faster TTH compared to TachoSil® (TTH 95.4 s), and were comparable to Veriset™ (TTH 17.0 s). Three patches, GFC-NHS-POx 1.5 (TTH 0.0 s, p = .016), ORC NHS-POx:NU-POx (TTH 91.4 s, p = .033), and ORC-PLGA NHS-POx:NU-POx (TTH 105.6 s, p = .04) had a lower TTH compared to their own blank carrier (TTH 74.9, 157.8, and 195.7 s, respectively). With regard to biocompatibility, all POx loaded patches showed results comparable to TachoSil® and Veriset™. NHS-POx-loaded hemostatic patch demonstrate fast and effective hemostasis, comparable or better than commercially available hemostatic patches, with similar early biocompatibility.
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http://dx.doi.org/10.1002/jbm.b.34938DOI Listing
September 2021

Rationale and Design of the Groningen Intervention Study for the Preservation of Cardiac Function with Sodium Thiosulfate after ST-segment Elevation Myocardial Infarction (GIPS-IV) Trial.

Am Heart J 2021 Sep 14. Epub 2021 Sep 14.

University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, 9713 GZ, the Netherlands; Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, 3584 CX, the Netherlands.

Rationale: Ischemia and subsequent reperfusion cause myocardial injury in patients presenting with ST-segment elevation myocardial infarction (STEMI). Hydrogen sulfide (HS) reduces "ischemia-reperfusion injury" in various experimental animal models, but has not been evaluated in humans. This trial will examine the efficacy and safety of the HS-donor sodium thiosulfate (STS) in patients presenting with a STEMI.

Study Design: The Groningen Intervention study for the Preservation of cardiac function with STS after STEMI (GIPS-IV) trial (NCT02899364) is a double-blind, randomized, placebo-controlled, multicenter trial, which will enroll 380 patients with a first STEMI. Patients receive STS 12.5 gram intravenously or matching placebo in addition to standard care immediately at arrival at the catheterization laboratory after providing consent. A second dose is administered 6 hours later at the coronary care unit. The primary endpoint is myocardial infarct size as quantified by cardiac magnetic resonance imaging 4 months after randomization. Secondary endpoints include the effect of STS on peak CK-MB during admission and left ventricular ejection fraction and NT-proBNP levels at 4 months follow-up. Patients will be followed-up for 2 years to assess clinical endpoints.

Conclusions: The GIPS-IV trial is the first study to determine the effect of a HS-donor on myocardial infarct size in patients presenting with STEMI.
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http://dx.doi.org/10.1016/j.ahj.2021.08.012DOI Listing
September 2021

A pandemic recap: lessons we have learned.

World J Emerg Surg 2021 09 10;16(1):46. Epub 2021 Sep 10.

Division of Trauma, Emergency Surgery, and Surgical Critical Care, LAC+USC Medical Center, Los Angeles, USA.

On January 2020, the WHO Director General declared that the outbreak constitutes a Public Health Emergency of International Concern. The world has faced a worldwide spread crisis and is still dealing with it. The present paper represents a white paper concerning the tough lessons we have learned from the COVID-19 pandemic. Thus, an international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making. With the present paper, international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making.
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http://dx.doi.org/10.1186/s13017-021-00393-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430288PMC
September 2021

Exposome and foetoplacental vascular dysfunction in gestational diabetes mellitus.

Mol Aspects Med 2021 Sep 2:101019. Epub 2021 Sep 2.

Cellular and Molecular Physiology Laboratory (CMPL), Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville, E-41012, Spain; Medical School (Faculty of Medicine), Sao Paulo State University (UNESP), Brazil; University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston, QLD 4029, Queensland, Australia; Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen (UMCG), 9713GZ, Groningen, the Netherlands. Electronic address:

A balanced communication between the mother, placenta and foetus is crucial to reach a successful pregnancy. Several windows of exposure to environmental toxins are present during pregnancy. When the women metabolic status is affected by a disease or environmental toxin, the foetus is impacted and may result in altered development and growth. Gestational diabetes mellitus (GDM) is a disease of pregnancy characterised by abnormal glucose metabolism affecting the mother and foetus. This disease of pregnancy associates with postnatal consequences for the child and the mother. The whole endogenous and exogenous environmental factors is defined as the exposome. Endogenous insults conform to the endo-exposome, and disruptors contained in the immediate environment are the ecto-exposome. Some components of the endo-exposome, such as Selenium, vitamins D and B, adenosine, and a high-fat diet, and ecto-exposome, such as the heavy metals Arsenic, Mercury, Lead and Copper, and per- and polyfluoroakyl substances, result in adverse pregnancies, including an elevated risk of GDM or gestational diabesity. The impact of the exposome on the human placenta's vascular physiology and function in GDM and gestational diabesity is reviewed.
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http://dx.doi.org/10.1016/j.mam.2021.101019DOI Listing
September 2021

Impact of Red Blood Cells on Function and Metabolism of Porcine Deceased Donor Kidneys During Normothermic Machine Perfusion.

Transplantation 2021 Aug 27. Epub 2021 Aug 27.

Department of Surgery, University Medical Center Groningen, University of Groningen, The Netherlands Department of Critical Care, University Medical Center Groningen, University of Groningen, The Netherlands Department of Pathology, University Medical Center Groningen, University of Groningen, The Netherlands Department of Surgery, Nuffield Department of Surgical Science, University of Oxford, United Kingdom IRTOMIT, INSERM U1082, Faculté de Médecine et de Pharmacie, Université de Poitiers, France Department for Surgical Research/General Surgery, University Hospital Essen, Germany.

Normothermic machine perfusion (NMP) protocols using blood-based solutions are commonly used in the assessment of kidneys prior to transplantation. This procedure is nevertheless limited by blood availability and warrants the search for alternatives. We compared a blood-based solution to a serum-like preservation solution (Aqix) enriched with colloids, with and without red blood cells (RBC). Porcine kidneys retrieved from an abattoir were subjected to 30 min of warm ischemia, followed by 3h of hypothermic oxygenated machine perfusion at 4°C. Subsequently, kidneys (n = 6 per group) were evaluated with NMP for 4h with 5 different solutions: Diluted blood, Aqix with bovine serum albumin (BSA) +/- RBC's; or Aqix with Dextran 40 +/- RBC's. Throughout NMP, markers of renal function and tubular metabolism were favorable in RBC's groups. Addition of RBC's resulted in a 4- to 6-fold higher oxygen consumption rates. Controls had significantly higher ATP levels post-NMP, exhibited decreased production of oxidative stress markers, and had the highest creatinine clearance. In conclusion, this study shows that addition of RBC's during NMP reduced renal injury, improved function, and was associated with increased renal metabolism. Although the RBC-BSA-supplemented Aqix solution was also able to support metabolism and renal function, a blood-based perfusion solution remains superior.
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http://dx.doi.org/10.1097/TP.0000000000003940DOI Listing
August 2021

Elevated plasma free thiols are associated with early and one-year graft function in renal transplant recipients.

PLoS One 2021 11;16(8):e0255930. Epub 2021 Aug 11.

Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.

Background: Reduced free thiols in plasma are indicative of oxidative stress, which is an important contributor to ischaemia-reperfusion injury (IRI) in kidney transplantation leading to kidney damage and possibly delayed graft function (DGF). In a post-hoc, exploratory analysis of the randomised controlled CONTEXT trial, we investigated whether higher (i.e. less oxidised) plasma levels of free thiols as a biomarker of reduced oxidative stress are associated with a better initial graft function or a higher GFR.

Methods: Free thiol levels were measured in plasma at baseline, 30 and 90 minutes after reperfusion of the kidney as well as at Day 1, Day 5 and twelve months after kidney transplantation in 217 patients from the CONTEXT study. Free thiol levels were compared to the kidney graft function measured as the estimated time to a 50% reduction in plasma creatinine (tCr50), the risk of DGF and measured GFR (mGFR) at Day 5 and twelve months after transplantation.

Results: Higher levels of free thiols at Day 1 and Day 5 are associated with higher mGFR at Day 5 (p<0.001, r2adj. = 0.16; p<0.001, r2adj. = 0.25), as well as with mGFR at twelve months (p<0.001, r2adj. = 0.20; p<0.001, r2adj. = 0.16). However, plasma levels of free thiols at 30 minutes and 90 minutes, but not Day 1, were significantly higher among patients experiencing DGF.

Conclusion: Higher levels of plasma free thiols at Day 1 and Day 5, which are reflective of lower levels of oxidative stress, are associated with better early and late graft function in recipients of a kidney graft from deceased donors.

Trial Registration: ClinicalTrials.gov Identifier: NCT01395719.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255930PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357095PMC
August 2021

The Role of Gasotransmitters in Gut Peptide Actions.

Front Pharmacol 2021 20;12:720703. Epub 2021 Jul 20.

Departement of Endocrinology, University Medical Center Groningen, Groningen, Netherlands.

Although gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (HS) receive a bad connotation; in low concentrations these play a major governing role in local and systemic blood flow, stomach acid release, smooth muscles relaxations, anti-inflammatory behavior, protective effect and more. Many of these physiological processes are upstream regulated by gut peptides, for instance gastrin, cholecystokinin, secretin, motilin, ghrelin, glucagon-like peptide 1 and 2. The relationship between gasotransmitters and gut hormones is poorly understood. In this review, we discuss the role of NO, CO and HS on gut peptide release and functioning, and whether manipulation by gasotransmitter substrates or specific blockers leads to physiological alterations.
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http://dx.doi.org/10.3389/fphar.2021.720703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329365PMC
July 2021

Synthetic Peptides That Antagonize the Angiotensin-Converting Enzyme-2 (ACE-2) Interaction with SARS-CoV-2 Receptor Binding Spike Protein.

J Med Chem 2021 Jul 30. Epub 2021 Jul 30.

XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands.

The SARS-CoV-2 viral spike protein S receptor-binding domain (S-RBD) binds ACE2 on host cells to initiate molecular events, resulting in intracellular release of the viral genome. Therefore, antagonists of this interaction could allow a modality for therapeutic intervention. Peptides can inhibit the S-RBD:ACE2 interaction by interacting with the protein-protein interface. In this study, protein contact atlas data and molecular dynamics simulations were used to locate interaction hotspots on the secondary structure elements α1, α2, α3, β3, and β4 of ACE2. We designed a library of discontinuous peptides based upon a combination of the hotspot interactions, which were synthesized and screened in a bioluminescence-based assay. The peptides demonstrated high efficacy in antagonizing the SARS-CoV-2 S-RBD:ACE2 interaction and were validated by microscale thermophoresis which demonstrated strong binding affinity (∼10 nM) of these peptides to S-RBD. We anticipate that such discontinuous peptides may hold the potential for an efficient therapeutic treatment for COVID-19.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353989PMC
July 2021

Clinical implications of vitamin B as redox-active cofactor.

Trends Mol Med 2021 Oct 23;27(10):931-934. Epub 2021 Jul 23.

Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

Vitamin B is a redox-active compound containing a cobalt atom that cycles between oxidation states. Superoxide scavenging induces its oxidation, disabling activation of the enzymes methionine synthase and methylmalonyl-CoA mutase, disrupting gene expression and energy production. High-dosed vitamin B may be clinically used to reduce oxidative stress and preserve cofactor functions.
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http://dx.doi.org/10.1016/j.molmed.2021.07.002DOI Listing
October 2021

Correction: Continuous Monitoring of Vital Signs Using Wearable Devices on the General Ward: Pilot Study.

JMIR Mhealth Uhealth 2021 Jul 16;9(7):e31899. Epub 2021 Jul 16.

Radboud University Medical Center, Radboud REshape Innovation Center, Nijmegen, Netherlands.

[This corrects the article DOI: 10.2196/mhealth.7208.].
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http://dx.doi.org/10.2196/31899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325082PMC
July 2021

Diagnosis and management of small bowel obstruction in virgin abdomen: a WSES position paper.

World J Emerg Surg 2021 07 3;16(1):36. Epub 2021 Jul 3.

Department of Surgery, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Background: Small bowel obstruction (SBO) is a common surgical emergency, causing high morbidity and healthcare costs. The majority of SBOs are caused by adhesions that result from previous surgeries. Bowel obstruction, however, also occurs in patients without previous operation or known pathology, a so called virgin abdomen. It is unknown if small bowel obstruction in the virgin abdomen (SBO-VA) can be managed according to the same principles as other cases of small bowel obstruction. The aim of this position paper is to evaluate the available evidence on etiology and management of small bowel obstruction in the virgin abdomen.

Methods: This is a narrative review with scoping aspects. Clinical topics covered in this review include epidemiology and etiology of SBO-VA, diagnosis and imaging, initial assessment, the role of surgical management in SBO-VA, and the role of non-operative management in SBO-VA.

Results: Our scoping search revealed seven original studies reporting original patient data related to SBO-VA. All the included studies are retrospective cohorts, with populations ranging between 44 and 103 patients with SBO-VA. Adhesions were found to be the cause of the obstruction in approximately half of the reported cases of SBO-VA. A relatively high number of cases of SBO-VA were managed surgically with studies reporting 39-83%. However, in cases where a trial of non-operative management was started, this was generally successful.

Conclusion: The data available suggest that etiology and treatment results for patients with SBO-VA are largely comparable to the results in patients with SBO after previous abdominal surgery. We therefore propose that patients with a virgin abdomen could be treated according to existing guidelines for SBO and adhesive small bowel obstruction.
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http://dx.doi.org/10.1186/s13017-021-00379-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254282PMC
July 2021

Mildly Increased Renin Expression in the Absence of Kidney Injury in the Murine Transverse Aortic Constriction Model.

Front Pharmacol 2021 15;12:614656. Epub 2021 Jun 15.

Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.

Cardiorenal syndrome type 2 is characterized by kidney failure as a consequence of heart failure that affects >50% of heart failure patients. Murine transverse aortic constriction (TAC) is a heart failure model, where pressure overload is induced on the heart without any systemic hypertension or its consequences. Whether renal function is altered in this model is debated, and if so, at which time post-TAC renal dysfunction starts to contribute to worsening of cardiac function. We therefore studied the effects of progressive heart failure development on kidney function in the absence of chronically elevated systemic blood pressure and renal perfusion pressure. C57BL/6J mice (N = 129) were exposed to TAC using a minimally invasive technique and followed from 3 to 70 days post-TAC. Cardiac function was determined with 3D ultrasound and showed a gradual decrease in stroke volume over time. Renal renin expression and plasma renin concentration increased with progressive heart failure, suggesting hypoperfusion of the kidney. In addition, plasma urea concentration, a surrogate marker for renal dysfunction, was increased post-TAC. However, no structural abnormalities in the kidney, nor albuminuria were present at any time-point post-TAC. Progressive heart failure is associated with increased renin expression, but only mildly affected renal function without inducing structural injury. In combination, these data suggest that heart failure alone does not contribute to kidney dysfunction in mice.
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http://dx.doi.org/10.3389/fphar.2021.614656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239225PMC
June 2021

Algorithms for Prediction of Clinical Deterioration on the General Wards: A Scoping Review.

J Hosp Med 2021 10;16(10):612-619

Radboud University Medical Center, Department of Internal Medicine, Nijmegen, The Netherlands.

Objective: The primary objective of this scoping review was to identify and describe state-of-the-art models that use vital sign monitoring to predict clinical deterioration on the general ward. The secondary objective was to identify facilitators, barriers, and effects of implementing these models.

Data Sources: PubMed, Embase, and CINAHL databases until November 2020.

Study Selection: We selected studies that compared vital signs-based automated real-time predictive algorithms to current track-and-trace protocols in regard to the outcome of clinical deterioration in a general ward population.

Data Extraction: Study characteristics, predictive characteristics and barriers, facilitators, and effects.

Results: We identified 1741 publications, 21 of which were included in our review. Two of the these were clinical trials, 2 were prospective observational studies, and the remaining 17 were retrospective studies. All of the studies focused on hospitalized adult patients. The reported area under the receiver operating characteristic curves ranged between 0.65 and 0.95 for the outcome of clinical deterioration. Positive predictive value and sensitivity ranged between 0.223 and 0.773 and from 7.2% to 84.0%, respectively. Input variables differed widely, and predicted endpoints were inconsistently defined. We identified 57 facilitators and 48 barriers to the implementation of these models. We found 68 reported effects, 57 of which were positive.

Conclusion: Predictive algorithms can detect clinical deterioration on the general ward earlier and more accurately than conventional protocols, which in one recent study led to lower mortality. Consensus is needed on input variables, predictive time horizons, and definitions of endpoints to better facilitate comparative research.
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http://dx.doi.org/10.12788/jhm.3630DOI Listing
October 2021

Speed versus damage: using selective feedback to modulate laparoscopic simulator performance.

BMC Med Educ 2021 Jun 29;21(1):361. Epub 2021 Jun 29.

Department of Surgery, Radboud University Medical Center, Geert Grooteplein zuid 10, Nijmegen, 6525 GA, Gelderland, The Netherlands.

Background: Adaptive training is an approach in which training variables change with the needs and traits of individual trainees. It has potential to mitigate the effect of personality traits such as impulsiveness on surgical performance. Selective performance feedback is one way to implement adaptive training. This paper investigates whether selective feedback can direct performance of trainees of either high- or low impulsiveness.

Methods: A total of 83 inexperienced medical students of known impulsiveness performed a four-session laparoscopic training course on a Virtual Reality Simulator. They performed two identical series of tasks every session. During one series of tasks they received performance feedback on duration and during the other series they received feedback on damage. Performance parameters (duration and damage) were compared between the two series of tasks to assess whether selective performance feedback can be used to steer emphasis in performance. To assess the effectiveness of selective feedback for people of high- or low impulsiveness, the difference in performance between the two series for both duration and damage was also assessed.

Results: Participants were faster when given performance feedback for speed for all exercises in all sessions (average z-value = - 4.14, all p values < .05). Also, they performed better on damage control when given performance feedback for damage in all tasks and during all sessions except for one (average z-value = - 4.19, all but one p value < .05). Impulsiveness did not impact the effectiveness of selective feedback.

Conclusion: Selective feedback on either duration or damage can be used to improve performance for the variable that the trainee receives feedback on. Trainee impulsiveness did not modulate this effect. Selective feedback can be used to steer training focus in adaptive training systems and can mitigate the negative effects of impulsiveness on damage control.
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http://dx.doi.org/10.1186/s12909-021-02789-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243418PMC
June 2021

Wearable Patch Heart Rate Variability Is an Early Marker of Systemic Inflammation During Experimental Human Endotoxemia.

Shock 2021 10;56(4):537-543

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.

Introduction: Early diagnosis and treatment can reduce the risk of organ failure and mortality in systemic inflammatory conditions. Heart rate variability (HRV) has potential for early identification of the onset of systemic inflammation, as it may detect changes in sympathetic nervous system activity resulting from the developing inflammatory response before clinical signs appear. With the use of new methodologies, we investigated the onset and kinetics of HRV changes as well as several inflammatory parameters and symptoms during experimental human endotoxemia, a model of systemic inflammation in humans in vivo.

Patients And Methods: Healthy volunteers were intravenously administered LPS (n = 15) or placebo (n = 15). HRV was determined using a wireless wearable device, and parameters low to high frequency (LF:HF) ratio, root mean square of the successive differences (RMSSD), and standard deviation of normal-to-normal R-R intervals (SDNN)were calculated through 1-min-rolling 6-min windows. Plasma cytokine levels and flu-like symptoms and vital signs were serially assessed.

Results: The increase in LF:HF ratio, reflecting sympathetic predominance, was more pronounced in the LPS group compared to the placebo group, with the difference becoming statistically significant 65 min following LPS administration (1.63 [1.42-1.83] vs. 1.28 [1.11-1.44], P = 0.005). Significant between-group differences in RMSSD and SDNN were observed from 127 to 140 min post-LPS administration onwards, respectively. Plasma cytokine levels showed significant between-group differences staring 60 min post-LPS. For symptom score, heart rate, temperature, and diastolic blood pressure, significant differences compared with the placebo group were observed at 90, 118, 120, and 124 min post-LPS, respectively.

Conclusion: In a controlled human model of systemic inflammation, elevations in the LF:HF ratio followed very shortly after elevations in plasma cytokine levels and preceded onset of flu-like symptoms and alterations in vital signs. HRV may represent a promising non-invasive tool for early detection of a developing systemic inflammatory response.
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http://dx.doi.org/10.1097/SHK.0000000000001827DOI Listing
October 2021

Do Simulated Hospital Admissions Reflect Reality? A Qualitative Study of Volunteer Well-Being During a 24-Hr Simulated Hospitalization.

HERD 2021 Jun 9:19375867211020682. Epub 2021 Jun 9.

Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands.

Objectives: This study aims to delineate if and how healthy volunteers admitted to simulated care can aid in understanding real well-being experiences of in-hospital surgical patients.

Background: Scientific research is necessary to understand the mediating effect of healthcare design on patient outcomes. Studies with patients are, however, difficult to conduct as they require substantial funding, time, and research capacity, and recovering patients are often not willing or able to participate. If studies conducted with volunteers provide similar findings, such studies might serve as fruitful alternatives for future research.

Method: A multimethod study was conducted between July 2017 and December 2017 with 17 volunteers who underwent a 24-hr simulated inpatient postsurgical care protocol. Data on value experiences, norms, and design requirements for an optimal healing environment were collected via diaries and semi-structured value-oriented interviews, focused on the values of spatial comfort, privacy, autonomy, sensory comfort, safety and security, and social comfort. Volunteers' outcomes were compared to prior literature on similar patients' outcomes.

Results: Volunteers seem to experience their healing environment similarly to patients with regard to the values of spatial comfort, privacy, autonomy, sensory comfort, and social comfort related to contact with personnel and relatives. Less valuable insights were gained on the values of safety and security, and social comfort related to interaction with other patients, most probably due to the study design and because the participants did not truly experience a diseased bodily state.

Conclusion: Simulated hospital admissions with volunteers provide a satisfactory alternative for studying real patient outcomes.
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http://dx.doi.org/10.1177/19375867211020682DOI Listing
June 2021

Donor Heart Preservation with Hydrogen Sulfide: A Systematic Review and Meta-Analysis.

Int J Mol Sci 2021 May 27;22(11). Epub 2021 May 27.

University Medical Centre Groningen, Department of Cardiothoracic Surgery, University of Groningen, 9700 RB Groningen, The Netherlands.

Preclinical studies have shown that postconditioning with hydrogen sulfide (HS) exerts cardioprotective effects against myocardial ischemia-reperfusion injury (IRI). The aim of this study was to appraise the current evidence of the cardioprotective effects of HS against IRI in order to explore the future implementation of HS in clinical cardiac transplantation. The current literature on HS postconditioning in the setting of global myocardial ischemia was systematically reviewed and analyzed, performing meta-analyses. A literature search of the electronic databases Medline, Embase and Cinahl identified 1835 studies that were subjected to our pre-defined inclusion criteria. Sixteen studies were considered eligible for inclusion. Postconditioning with HS showed significant robust effects with regard to limiting infarct size (standardized mean difference (SMD) = -4.12, 95% CI [-5.53--2.71], < 0.00001). Furthermore, HS postconditioning consistently resulted in a significantly lower release of cardiac injury markers, lower levels of oxidative stress and improved cardiac function. Postconditioning with slow-releasing HS donors offers a valuable opportunity for novel therapies within cardiac preservation for transplantation. Before clinical implication, studies evaluating the long-term effects of HS treatment and effects of HS treatment in large animal studies are warranted.
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http://dx.doi.org/10.3390/ijms22115737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198118PMC
May 2021

Real-time visualization of renal microperfusion using laser speckle contrast imaging.

J Biomed Opt 2021 05;26(5)

Medical Centre Leeuwarden, Department of Intensive Care, Leeuwarden, The Netherlands.

Significance: Intraoperative parameters of renal cortical microperfusion (RCM) have been associated with postoperative ischemia/reperfusion injury. Laser speckle contrast imaging (LSCI) could provide valuable information in this regard with the advantage over the current standard of care of being a non-contact and full-field imaging technique.

Aim: Our study aims to validate the use of LSCI for the visualization of RCM on ex vivo perfused human-sized porcine kidneys in various models of hemodynamic changes.

Approach: A comparison was made between three renal perfusion measures: LSCI, the total arterial renal blood flow (RBF), and sidestream dark-field (SDF) imaging in different settings of ischemia/reperfusion.

Results: LSCI showed a good correlation with RBF for the reperfusion experiment (0.94  ±  0.02; p  <  0.0001) and short- and long-lasting local ischemia (0.90  ±  0.03; p  <  0.0001 and 0.81  ±  0.08; p  <  0.0001, respectively). The correlation decreased for low flow situations due to RBF redistribution. The correlation between LSCI and SDF (0.81  ±  0.10; p  <  0.0001) showed superiority over RBF (0.54  ±  0.22; p  <  0.0001).

Conclusions: LSCI is capable of imaging RCM with high spatial and temporal resolutions. It can instantaneously detect local perfusion deficits, which is not possible with the current standard of care. Further development of LSCI in transplant surgery could help with clinical decision making.
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http://dx.doi.org/10.1117/1.JBO.26.5.056004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140613PMC
May 2021

Prolonged ex-vivo normothermic kidney perfusion: The impact of perfusate composition.

PLoS One 2021 18;16(5):e0251595. Epub 2021 May 18.

Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Normothermic machine perfusion (NMP) of donor kidneys provides the opportunity for improved graft preservation and objective pre-transplant ex-vivo organ assessment. Currently, a multitude of perfusion solutions exist for renal NMP. This study aimed to evaluate four different perfusion solutions side-by-side and determine the influence of different perfusate compositions on measured renal perfusion parameters. Porcine kidneys and blood were obtained from a slaughterhouse. Kidneys underwent NMP at 37°C for 7 hours, with 4 different perfusion solutions (n = 5 per group). Group 1 consisted of red blood cells (RBCs) and a perfusion solution based on Williams' Medium E. Group 2 consisted of RBCs, albumin and a balanced electrolyte composition. Group 3 contained RBCs and a medium based on a British clinical NMP solution. Group 4 contained RBCs and a medium used in 24-hour perfusion experiments. NMP flow patterns for solutions 1 and 2 were similar, solutions 3 and 4 showed lower but more stable flow rates. Thiobarbituric acid reactive substances were significantly higher in solution 1 and 4 compared to the other groups. Levels of injury marker N-acetyl-β-D glucosaminidase were significantly lower in solution 2 in comparison with solution 3 and 4. This study illustrates that the perfusate composition during NMP significantly impacts the measured perfusion and injury parameters and thus affects the interpretation of potential viability markers. Further research is required to investigate the individual influences of principal perfusate components to determine the most optimal conditions during NMP and eventually develop universal organ assessment criteria.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251595PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130974PMC
October 2021

Gestational diabesity and foetoplacental vascular dysfunction.

Acta Physiol (Oxf) 2021 08 13;232(4):e13671. Epub 2021 May 13.

Cellular and Molecular Physiology Laboratory, Department of Obstetrics, Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Gestational diabetes mellitus (GDM) shows a deficiency in the metabolism of D-glucose and other nutrients, thereby negatively affecting the foetoplacental vascular endothelium. Maternal hyperglycaemia and hyperinsulinemia play an important role in the aetiology of GDM. A combination of these and other factors predisposes women to developing GDM with pre-pregnancy normal weight, viz. classic GDM. However, women with GDM and prepregnancy obesity (gestational diabesity, GDty) or overweight (GDMow) show a different metabolic status than women with classic GDM. GDty and GDMow are associated with altered l-arginine/nitric oxide and insulin/adenosine axis signalling in the human foetoplacental microvascular and macrovascular endothelium. These alterations differ from those observed in classic GDM. Here, we have reviewed the consequences of GDty and GDMow in the modulation of foetoplacental endothelial cell function, highlighting studies describing the modulation of intracellular pH homeostasis and the potential implications of NO generation and adenosine signalling in GDty-associated foetal vascular insulin resistance. Moreover, with an increase in the rate of obesity in women of childbearing age worldwide, the prevalence of GDty is expected to increase in the next decades. Therefore, we emphasize that women with GDty and GDMow should be characterized with a different metabolic state from that of women with classic GDM to develop a more specific therapeutic approach for protecting the mother and foetus.
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http://dx.doi.org/10.1111/apha.13671DOI Listing
August 2021

Cardiac Protection by Oral Sodium Thiosulfate in a Rat Model of L-NNA-Induced Heart Disease.

Front Pharmacol 2021 15;12:650968. Epub 2021 Apr 15.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands.

Hypertension contributes to cardiac damage and remodeling. Despite the availability of renin-angiotensin system inhibitors and other antihypertensive therapies, some patients still develop heart failure. Novel therapeutic approaches are required that are effective and without major adverse effects. Sodium Thiosulfate (STS), a reversible oxidation product of hydrogen sulfide (HS), is a promising pharmacological entity with vasodilator and anti-oxidant potential that is clinically approved for the treatment of calciphylaxis and cyanide poisoning. We hypothesized that Sodium Thiosulfate improves cardiac disease in an experimental hypertension model and sought to investigate its cardioprotective effects by direct comparison to the ACE-inhibitor lisinopril, alone and in combination, using a rat model of chronic nitric oxide (NO) deficiency. Systemic nitric oxide production was inhibited in Sprague Dawley rats by administering N-ω-nitro-l-arginine (L-NNA) with the food for three weeks, leading to progressive hypertension, cardiac dysfunction and remodeling. We observed that STS, orally administered the drinking water, ameliorated L-NNA-induced heart disease. Treatment with STS for two weeks ameliorated hypertension and improved systolic function, left ventricular hypertrophy, cardiac fibrosis and oxidative stress, without causing metabolic acidosis as is sometimes observed following parenteral administration of this drug. STS and lisinopril had similar protective effects that were not additive when combined. Our findings indicate that oral intervention with a HS donor such as STS has cardioprotective properties without noticeable side effects.
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http://dx.doi.org/10.3389/fphar.2021.650968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082682PMC
April 2021

A systematic review and meta-analyses on animal models used in bone adhesive research.

J Orthop Res 2021 Apr 19. Epub 2021 Apr 19.

Department of Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands.

Currently, steel implants are used for osteosynthesis of (comminuted) fractures and intra-articular bone defects. These osteosyntheses can sometimes be complicated procedures and can have several drawbacks including stress shielding of the bone. A bone glue might be a safe and effective alternative to current materials. Despite numerous animal studies on bone adhesives, no such material is clinically applied yet. We have conducted a systematic review to summarize the evidence in experimental animal models used in research on bone adhesive materials for trauma and orthopedic surgery. Additionally, we analysed the efficacy of the different bone adhesives for different experimental designs. A heterogeneity in experimental parameters including animal species, defect types, and control measurements resulted in a wide variety in experimental models. In addition, no standard outcome measurements could be identified. Meta-analysis on bone regeneration between adhesive treatment and nonadhesive treatment showed a high heterogeneity and no statistically significant overall effect (M: -0.71, 95% confidence interval [CI]: -1.63-0.21, p = 0.13). Besides, currently there is not enough evidence to draw conclusions based on the effectiveness of the individual types of adhesives or experimental models. A positive statistically significant effect was found for the adhesive treatment in comparison with conventional osteosynthesis materials (M: 2.49, 95% CI: 1.20-3.79, p = 0.0002). To enhance progression in bone adhesive research and provide valuable evidence for clinical application, more standard experimental parameters and a higher reporting quality in animal studies are needed. Statement of Clinical Significance: Current materials restoring anatomical alignments of bones have several drawbacks. A (biodegradable) adhesive for fixating bone defects can be a treatment breakthrough. Although numerous bone adhesives have been researched, most seemed to fail at the preclinical stage. An overview in this field is missing. This systematic review highlights the relevant parameters for design of experimental bone adhesive studies. It demonstrates evidence regarding benefit of bone adhesives but also that the quality of reporting and the risk of bias in studies need to be improved. The results will aid in designing better quality animal studies for bone adhesive research with higher translational value.
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http://dx.doi.org/10.1002/jor.25057DOI Listing
April 2021

Spatiotemporal regulation of hydrogen sulfide signaling in the kidney.

Redox Biol 2021 07 2;43:101961. Epub 2021 Apr 2.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Hydrogen sulfide (HS) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, HS is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. HS-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, HS is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of HS are not precisely understood. HS modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, HS affects cellular function by modulating protein activity via post-translational protein modification: a process termed persulfidation. Persulfidation modulates protein activity, protein localization and protein-protein interactions. Additionally, acute kidney injury (AKI) due to mitochondrial dysfunction, which occurs during hypoxia or ischemia-reperfusion (IR), is attenuated by HS. HS enhances ATP production, prevents damage due to free radicals and regulates endoplasmic reticulum stress during IR. In this review, we discuss current insights in the (sub)cellular regulation of HS anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal HS levels. Together, HS is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of HS not only expands fundamental insight in the regulation of functional effects mediated by HS, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury.
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http://dx.doi.org/10.1016/j.redox.2021.101961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065217PMC
July 2021

Fighting Oxidative Stress with Sulfur: Hydrogen Sulfide in the Renal and Cardiovascular Systems.

Antioxidants (Basel) 2021 Mar 2;10(3). Epub 2021 Mar 2.

Department of Nephrology & Hypertension, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.

Hydrogen sulfide (HS) is an essential gaseous signaling molecule. Research on its role in physiological and pathophysiological processes has greatly expanded. Endogenous enzymatic production through the transsulfuration and cysteine catabolism pathways can occur in the kidneys and blood vessels. Furthermore, non-enzymatic pathways are present throughout the body. In the renal and cardiovascular system, HS plays an important role in maintaining the redox status at safe levels by promoting scavenging of reactive oxygen species (ROS). HS also modifies cysteine residues on key signaling molecules such as keap1/Nrf2, NFκB, and HIF-1α, thereby promoting anti-oxidant mechanisms. Depletion of HS is implicated in many age-related and cardiorenal diseases, all having oxidative stress as a major contributor. Current research suggests potential for HS-based therapies, however, therapeutic interventions have been limited to studies in animal models. Beyond HS use as direct treatment, it could improve procedures such as transplantation, stem cell therapy, and the safety and efficacy of drugs including NSAIDs and ACE inhibitors. All in all, HS is a prime subject for further research with potential for clinical use.
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http://dx.doi.org/10.3390/antiox10030373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998720PMC
March 2021

Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate - PCSK9 Interaction.

J Am Soc Nephrol 2021 06 23;32(6):1371-1388. Epub 2021 Mar 23.

Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Background: Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol.

Methods: Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats.

Results: Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all <0.05), which were most apparent in hypertensive MWF-CKD rats. Hepatic PCSK9 expression increased in both CKD groups (<0.05), with unusual sinusoidal localization, which was not seen in 22-week-old rats. Heparan sulfate (HS) disaccharide analysis, staining with anti-HS mAbs, and mRNA expression of HS polymerase exostosin-1 (), revealed elongated HS chains in both CKD groups. Solid-phase competition assays showed that the PCSK9 interaction with heparin-albumin (HS-proteoglycan analogue) was critically dependent on polysaccharide chain length. VLDL binding to HS from CKD livers was reduced (<0.05). Proteinuria and plasma creatinine strongly associated with plasma cholesterol, PCSK9, and HS changes.

Conclusions: Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.
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http://dx.doi.org/10.1681/ASN.2020091376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259657PMC
June 2021
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