Author: "A Klinke" / Topic: medicine.medical_specialty - Searchworks@Jio Institute Digital Library Search Results

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1. Significance of myeloperoxidase plasma levels as a predictor for cardiac resynchronization therapy response

Author: Thorben Ravekes, Jonas Wörmann, Daniel Steven, Tobias Plenge, Martin Mollenhauer, Volker Rudolph, Arian Sultan, Jakob Lüker, A Klinke, Jan-Hendrik van den Bruck, Stephan Baldus, Jordi Heijman, Cardiologie, and RS: Carim - H01 Clinical atrial fibrillation
Subjects: Male, medicine.medical_specialty, Non-response, medicine.medical_treatment, Cardiac resynchronization therapy, 030204 cardiovascular system & hematology, Nyha class, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, Natriuretic Peptide, Brain, medicine, Humans, cardiovascular diseases, Aged, Peroxidase, Heart Failure, Inflammation, Original Paper, Ejection fraction, response, biology, business.industry, General Medicine, Plasma levels, Brain natriuretic peptide, medicine.disease, Peptide Fragments, Pathophysiology, myeloperoxidase, BRAIN NATRIURETIC PEPTIDE, Myeloperoxidase, Heart failure, cardiovascular system, biology.protein, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers, 030217 neurology & neurosurgery, circulatory and respiratory physiology
Abstract: Objectives This study aimed to determine if changes in myeloperoxidase (MPO) levels correlate with response to cardiac resynchronization therapy (CRT) and the potential role of MPO as a predictor of response to CRT. Background CRT is a well-established treatment option in chronic heart failure (CHF) with 50–80% of patients benefiting. Inflammation and oxidative stress play a key role in CHF pathophysiology. Previous studies have demonstrated increased levels of MPO in CHF patients, but the correlation with CRT response remains incompletely understood. Methods Fifty-three patients underwent CRT implantation. During follow-up, patients were divided into two groups, responders and non-responders to CRT, based on improved physical capacity and NYHA classification. Levels of MPO and NT-pro-brain-natriuretic-peptide (NT-proBNP) were determined prior to implantation, 30 and 90 days after. Physical capacity, including a 6-min walking-test, NYHA class, and LVEF were evaluated at baseline and during follow-up. Results Thirty-four patients (64%) responded to CRT, showing improved physical capacity and LVEF. All responders revealed a significant decrease of MPO levels (503.8 ng/ml vs. 188.4 ng/ml; p p = 0.672) during follow-up. At baseline, physical capacity and NYHA class, as well as MPO levels differed significantly between both groups (p p = 0.005) and physical capacity (Spearman’s rho: − 0.335; p = 0.042). Conclusions Response to CRT and course of MPO levels correlate significantly. MPO levels differ between responders and non-responders prior to CRT, which may indicate an additional value of MPO as a predictor for CRT response. Further randomized studies are required to confirm our data in larger patient cohorts.
Published: 2021
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2. Effects of insular involvement on functional outcome after intracerebral hemorrhage

Author: Alexander Storch, Kezia Meyer, Matthias Wittstock, Annette Grossmann, Uwe Walter, and Jan Klinke
Subjects: medicine.medical_specialty, Insular cortex, Modified Rankin Scale, Internal medicine, Odds Ratio, medicine, Humans, Hospital Mortality, Prospective Studies, cardiovascular diseases, Cerebral Hemorrhage, Intracerebral hemorrhage, medicine.diagnostic_test, business.industry, Mortality rate, Atrial fibrillation, General Medicine, Odds ratio, medicine.disease, nervous system diseases, Stroke, Intraventricular hemorrhage, nervous system, Neurology, Cardiology, Neurology (clinical), business, Electrocardiography
Abstract: OBJECTIVE Ischemic stroke, as well as intracerebral hemorrhage (ICH), involving the insular cortex tends to be more severe. The impact of insular involvement on outcome of ICH remains enigmatic. METHODS We analyzed 159 patients with supratentorial ICH. Depending on insular involvement the patients were classified into two groups (ICHnon-insular vs. ICHinsular ). Volume and symptom severity of ICH were assessed. Electrocardiography, chest X-ray, and laboratory examinations including myocardial enzymes and inflammatory markers were made. In-hospital death and outcome at discharge from hospital were assessed on the modified Rankin scale (mRS). RESULTS The main finding was an association of insular involvement of ICH with worse short-term outcome as measured by mRS (common odds ratio: 4.08 (95% CI: 2.09-7.92); p
Published: 2021
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3. Emerging therapies for right ventricular dysfunction and failure

Author: Duncan J. Stewart, L. Christian Napp, Jason G.E. Zelt, Volker Rudolph, Torben Schubert, Ekaterina Legchenko, Georg Hansmann, Anna Klinke, Marion Müller, Tsukasa Shimauchi, Alexander M.K. Rothman, and Sébastien Bonnet
Subjects: Denervation, medicine.medical_specialty, Angiogenesis, business.industry, Context (language use), Inflammation, 030204 cardiovascular system & hematology, Review Article on Right Ventricular Dysfunction, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Internal medicine, medicine.artery, microRNA, Circulatory system, Pulmonary artery, medicine, Cardiology, Progenitor cell, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Abstract: Therapeutic options for right ventricular (RV) dysfunction and failure are strongly limited. Right heart failure (RHF) has been mostly addressed in the context of pulmonary arterial hypertension (PAH), where it is not possible to discern pulmonary vascular- and RV-directed effects of therapeutic approaches. In part, opposing pathomechanisms in RV and pulmonary vasculature, i.e., regarding apoptosis, angiogenesis and proliferation, complicate addressing RHF in PAH. Therapy effective for left heart failure is not applicable to RHF, e.g., inhibition of adrenoceptor signaling and of the renin-angiotensin system had no or only limited success. A number of experimental studies employing animal models for PAH or RV dysfunction or failure have identified beneficial effects of novel pharmacological agents, with most promising results obtained with modulators of metabolism and reactive oxygen species or inflammation, respectively. In addition, established PAH agents, in particular phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators, may directly address RV integrity. Promising results are furthermore derived with microRNA (miRNA) and long non-coding RNA (lncRNA) blocking or mimetic strategies, which can target microvascular rarefaction, inflammation, metabolism or fibrotic and hypertrophic remodeling in the dysfunctional RV. Likewise, pre-clinical data demonstrate that cell-based therapies using stem or progenitor cells have beneficial effects on the RV, mainly by improving the microvascular system, however clinical success will largely depend on delivery routes. A particular option for PAH is targeted denervation of the pulmonary vasculature, given the sympathetic overdrive in PAH patients. Finally, acute and durable mechanical circulatory support are available for the right heart, which however has been tested mostly in RHF with concomitant left heart disease. Here, we aim to review current pharmacological, RNA- and cell-based therapeutic options and their potential to directly target the RV and to review available data for pulmonary artery denervation and mechanical circulatory support.
Published: 2020
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4. Long-term safety and efficacy of Eculizumab in Aquaporin-4 IgG-positive NMOSD

Author: Wingerchuk, D.M., Fujihara, K., Palace, J., Berthele, A., Levy, M., Kim, H.J., Nakashima, I., Oreja-Guevara, C., Wang, K.-C., Miller, L., Shang, S., Sabatella, G., Yountz, M., Pittock, S.J., Villa, A., Garcea, O., Manin, A., Melamud, L., Aguirre, F., Fernandez, V., Munoz, D.J., Amor, J., Bocchiardo, C., Obregon, C.D.D., Laffue, A., Paez, M.F., Perez, R.M., Rocchi, V., Teijeiro, L., De Virgiliis, M., Cordoba, M., Ingolotti, M., Lupinacci, A., Ballario, C., Chiesa, A., Gomez, H., Mainella, C., Lattini, H., Barnett, M., Barton, J., Beadnall, H., Garber, J., Hardy, T., Pollard, J., Trewin, B., Shuey, N., Bryson, A., French, A., Laing, J., Law, L.Y., Plummer, C., Sanders, L., Sedal, L., Winkel, A., Neal, A., Habek, M., Adamec, I., Barun, B., Crnosija, L., Gabelic, T., Pitha, J., Nytrova, P., Novakova, I., Tyblova, M., Krasulova, E., Pavlickova, J., Petersen, T., Rasmussen, P., Stilund, M., Svendsen, K., Diem, R., Platten, M., Berberich, A., Jaschonek, H., Wildemann, B., Biberacher, V.M., Brinkhoff, K., Golkowski, D., Kowarik, M., Lehmann-Horn, K., Pongratz, V., Zettl, U., Klinke, J., Loebermann, M., Meister, S., Rimmele, F., Winkelmann, A., Lau, A.Y.L., Au, L.W.C., Fan, S.Y.F., Ip, V.H.L., Ma, S.H., Ma, K.Y.K., Mok, C.T.V., Patti, F., Messina, S., Proietto, M., Filla, A., Morra, V.B., Costabile, T., Nozzolillo, A., Sacc, Sacca, Tackley, George, and MATUR, ZELİHA
Subjects: 0301 basic medicine, medicine.medical_specialty, Neuromyelitis optica, business.industry, Maintenance dose, Eculizumab, Placebo, Interim analysis, medicine.disease, Confidence interval, ddc, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Aquaporin 4, Neurology, Internal medicine, Medicine, Neurology (clinical), Adverse effect, business, Research Articles, 030217 neurology & neurosurgery, Research Article, medicine.drug
Abstract: Objective\udDuring PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open-label extension (OLE; NCT02003144) evaluating eculizumab's long-term safety and efficacy.\ud\udMethods\udPatients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.\ud\udResults\udAcross PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient-years (PY). Treatment-related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab-treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse-free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab-treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use.\ud\udInterpretation\udThis analysis demonstrates that eculizumab's long-term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long-term eculizumab treatment to reduce relapse risk in patients with AQP4-IgG+ NMOSD. ANN NEUROL 2021;89:1088–1098
Published: 2021

5. Stamp2 Protects From Maladaptive Structural Remodeling and Systolic Dysfunction in Post-Ischemic Hearts by Attenuating Neutrophil Activation

Author: Martin Mollenhauer, Senai Bokredenghel, Simon Geißen, Anna Klinke, Tobias Morstadt, Merve Torun, Sabrina Strauch, Wibke Schumacher, Martina Maass, Jürgen Konradi, Vera B. M. Peters, Eva Berghausen, Marius Vantler, Stephan Rosenkranz, Dennis Mehrkens, Simon Braumann, Felix Nettersheim, Alexander Hof, Sakine Simsekyilmaz, Holger Winkels, Volker Rudolph, Stephan Baldus, Matti Adam, and Henrik ten Freyhaus
Subjects: Male, medicine.medical_specialty, polymorphonuclear neutrophils (PMN), Cardiac fibrosis, Neutrophils, p38 mitogen-activated protein kinases, Immunology, Ischemia, Myocardial Infarction, Inflammation, Myocardial Reperfusion Injury, p38 Mitogen-Activated Protein Kinases, Neutrophil Activation, Proinflammatory cytokine, Mice, Internal medicine, Immunology and Allergy, Medicine, Animals, Protein kinase A, Peroxidase, Original Research, left ventricular dysfunction, Steap4, biology, business.industry, Macrophages, Myocardium, Transdifferentiation, NF-kappa B, Membrane Proteins, Heart, RC581-607, ischemia and reperfusion damage, medicine.disease, Mice, Inbred C57BL, six-transmembrane protein of prostate 2, Stamp2, Endocrinology, inflammation, Myeloperoxidase, biology.protein, medicine.symptom, Immunologic diseases. Allergy, business, Cardiomyopathies, Signal Transduction
Abstract: The six-transmembrane protein of prostate 2 (Stamp2) acts as an anti-inflammatory protein in macrophages by protecting from overt inflammatory signaling and Stamp2 deficiency accelerates atherosclerosis in mice. Herein, we describe an unexpected role of Stamp2 in polymorphonuclear neutrophils (PMN) and characterize Stamp2’s protective effects in myocardial ischemic injury. In a murine model of ischemia and reperfusion (I/R), echocardiography and histological analyses revealed a pronounced impairment of cardiac function in hearts of Stamp2-deficient- (Stamp2-/-) mice as compared to wild-type (WT) animals. This difference was driven by aggravated cardiac fibrosis, as augmented fibroblast-to-myofibroblast transdifferentiation was observed which was mediated by activation of the redox-sensitive p38 mitogen-activated protein kinase (p38 MAPK). Furthermore, we observed increased production of reactive oxygen species (ROS) in Stamp2-/- hearts after I/R, which is the likely cause for p38 MAPK activation. Although myocardial macrophage numbers were not affected by Stamp2 deficiency after I/R, augmented myocardial infiltration by polymorphonuclear neutrophils (PMN) was observed, which coincided with enhanced myeloperoxidase (MPO) plasma levels. Primary PMN isolated from Stamp2-/- animals exhibited a proinflammatory phenotype characterized by enhanced nuclear factor (NF)-κB activity and MPO secretion. To prove the critical role of PMN for the observed phenotype after I/R, antibody-mediated PMN depletion was performed in Stamp2-/- mice which reduced deterioration of LV function and adverse structural remodeling to WT levels. These data indicate a novel role of Stamp2 as an anti-inflammatory regulator of PMN and fibroblast-to-myofibroblast transdifferentiation in myocardial I/R injury.
Published: 2021

6. Nitro-oleic acid reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome

Author: Alexander Hof, Richard J. Nies, Felix Sebastian Nettersheim, Anna Klinke, Matti Adam, Simon Braumann, Volker Rudolph, Martin Mollenhauer, Bruce A. Freeman, Holger Winkels, Dennis Mehrkens, Senai Bokredenghel, Simon Geißen, Julian Lemties, and Stephan Baldus
Subjects: Marfan syndrome, Pathology, medicine.medical_specialty, Physiology, Fibrillin-1, Aortic Diseases, Oleic Acids, Thoracic aortic aneurysm, Marfan Syndrome, Aortic aneurysm, Mice, Physiology (medical), medicine.artery, medicine, Animals, Aortic rupture, Aorta, biology, Aortic Aneurysm, Thoracic, business.industry, Transforming growth factor beta, medicine.disease, Nitro Compounds, Angiotensin II, Aortic Aneurysm, Elastin, Disease Models, Animal, biology.protein, Matrix Metalloproteinase 2, Cardiology and Cardiovascular Medicine, business
Abstract: Aims Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular-signal regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS. Methods and results Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for four weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+mice challenged with Angiotensin II. Conclusion NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition. Translational perspective Thoracic aortic aneurysm formation is the major life-threatening complication of Marfan syndrome, a relatively common genetic connective tissue disorder. Although various potential therapeutic targets have been identified, specific pharmacological treatment options are still unavailable. In this study, we demonstrate that Nitro-oleic acid reduces ascending aortic elastin fragmentation, apoptosis, and fibrotic remodelling in Marfan syndrome through inhibition of extracellular-signal regulated kinases 1/2, Smad2 as well as nuclear factor kappa B overactivation and thereby mitigates aneurysm formation. Thus, Nitro-oleic acid, which has been developed as an oral compound, emerges as a potential treatment option for Marfan-related aortic disease.
Published: 2021

7. Cardiac and Inflammatory Necrotizing Enterocolitis in Newborns Are Not the Same Entity

Author: Hansjörg Schäfer, Michael Boettcher, Hanna Wiskemann, Deirdre Vincent, Michaela Klinke, Laia Pagerols Raluy, Konrad Reinshagen, and Benjamin Bay
Subjects: medicine.medical_specialty, neutrophil extracellular traps, Neutropenia, Gastroenterology, Pediatrics, Sepsis, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, Medicine, 030212 general & internal medicine, Prospective cohort study, Original Research, necrotizing enterocolitis, biology, business.industry, lcsh:RJ1-570, NEC, lcsh:Pediatrics, NETs, Neutrophil extracellular traps, medicine.disease, neonates, Neutrophilia, digestive system diseases, Neutrophil elastase, cardiology, Pediatrics, Perinatology and Child Health, Necrotizing enterocolitis, biology.protein, medicine.symptom, business
Abstract: Background: Necrotizing enterocolitis (NEC) is an often-fatal neonatal disease involving intestinal hyperinflammation leading to necrosis. Despite ongoing research, (1) conflicting results and (2) comorbidities of NEC patients make early NEC detection challenging and may complicate therapy development. Most research suggests that NEC pathogenesis is multifactorial, involving a combination of (1) gut prematurity; (2) abnormal bacterial colonization; and (3) ischemia-reperfusion (I/R) injury. As neutrophil extracellular traps (NETs) partially mediate I/R injury and drive inflammation in NEC, we hypothesized that NETs contribute to NEC development; particularly in cardiac patients.Methods: A retrospective analysis of baseline characteristics, clinical signs, laboratory parameters, and imaging was conducted for surgically verified NEC cases over 10 years. Patients were stratified into two groups: (1) prior medically or surgically treated cardiac disease (cardiac NEC) and (2) no cardiac comorbidities (inflammatory NEC). Additionally, histology was reassessed for neutrophil activation and NETs formation.Results: A total of 110 patients (cNEC 43/110 vs. iNEC 67/110) were included in the study, with cNEC neonates being significantly older than iNEC neonates (p = 0.005). While no significant differences were found regarding clinical signs and imaging, laboratory parameters revealed that cNEC patients have significantly increased leucocyte (p = 0.024) and neutrophil (p < 0.001) counts. Both groups also differed in pH value (p = 0.011). Regarding histology: a non-significant increase in staining of myeloperoxidase within the cNEC group could be found in comparison to iNEC samples. Neutrophil elastase (p = 0.012) and citrullinated histone H3 stained (p = 0.041) slides showed a significant markup for neonates diagnosed with cNEC in comparison to neonates with iNEC.Conclusion: The study shows that many standardized methods for diagnosing NEC are rather unspecific. However, differing leucocyte and neutrophil concentrations for iNEC and cNEC may indicate a different pathogenesis and may aid in diagnosis. As we propose that iNEC is grounded rather in sepsis and neutropenia, while cNEC primarily involves I/R injuries, which involves neutrophilia and NETs formation, it is plausible that I/R injury due to interventions for cardiac comorbidities results in pronounced neutrophil activation followed by a hyperinflammation reaction and NEC. However, prospective studies are necessary to validate these findings and to determine the accuracy of the potential diagnostic parameters.
Published: 2021

8. The BAL-Score Almost Perfectly Predicts Testicular Torsion in Children: A Two-Center Cohort Study

Author: Tarik Ghadban, Michaela Klinke, Jochen Herrmann, Carl-Martin Junge, Julia Elrod, Michael Boettcher, Carolin Stiel, Konrad Reinshagen, and Julia Wenskus
Subjects: Infertility, medicine.medical_specialty, Pediatrics, Nausea, 030232 urology & nephrology, Acute scrotum, hydatide torsion, clinical, 03 medical and health sciences, 0302 clinical medicine, Pediatric surgery, medicine, Testicular torsion, epidydimitis, Original Research, Cremasteric reflex, business.industry, lcsh:RJ1-570, scrotal edema, lcsh:Pediatrics, prediction score, medicine.disease, testicular torsion, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Vomiting, acute scrotum, medicine.symptom, business, Cohort study
Abstract: Introduction: Testicular torsion (TT) is a common emergency that warrants immediate exploration to prevent infertility or testicular loss. To improve diagnostic reliability, various scoring systems have been published. The aim of this study was to evaluate and validate different testicular torsion scores in a large cohort of children with acute scrotum.Methods: Retrospective analysis of all male children that were admitted for acute scrotum at the Pediatric Surgery Department of the Altonaer Kinderkrankenhaus and University medical Center Hamburg-Eppendorf from 01/2013 to 03/2019. Two testicular torsion scores (Boettcher Alert Score, Testicular Workup for Ischemia and Suspected Torsion Score) were applied to all data sets. Furthermore, an artificial intelligence (AI)-based score was developed and compared to the two current scores.Results: In total, 460 boys were included in the study. Of those, 48 (10.4%) had TT. Children with TT suffered most often from short duration of pain, nausea and vomiting, high riding testicle and absent cremasteric reflex. The BALS and the AI-based score had excellent predictive values and all patients with TT would have been detected.Conclusion: The BAL and the AI score show excellent predictive capabilities and may be used to identify all cases of TT in a pediatric population. The scores are easy to apply. As the BALS was slightly better, we advocate to use this score but to validate our findings in prospective multicenter studies.
Published: 2020
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9. The Modified Heidelberg and the AI Appendicitis Score Are Superior to Current Scores in Predicting Appendicitis in Children: A Two-Center Cohort Study

Author: Konrad Reinshagen, Michael Boettcher, Jochen Herrmann, Carl-Martin Junge, Tarik Ghadban, Carolin Stiel, Michaela Klinke, and Julia Elrod
Subjects: appendicitis, medicine.medical_specialty, Abdominal pain, diagnosis, business.industry, lcsh:RJ1-570, lcsh:Pediatrics, Emergency department, medicine.disease, Pediatrics, Appendicitis, scores, children, predicition, Alvarado score, Internal medicine, Pediatrics, Perinatology and Child Health, Pediatric surgery, Medicine, medicine.symptom, business, Prospective cohort study, Original Research, Abdominal surgery, Cohort study
Abstract: Background: Acute appendicitis represents the most frequent reason for abdominal surgery in children. Since diagnosis can be challenging various scoring systems have been published. The aim of this study was to evaluate and validate (and improve) different appendicitis scores in a very large cohort of children with abdominal pain. Methods: Retrospective analysis of all children that have been hospitalized due to suspected appendicitis at the Pediatric Surgery Department of the Altonaer Children's Hospital and University Medical Center Hamburg-Eppendorf from 01/2018 until 11/2019. Four different appendicitis scores (Heidelberg Appendicitis Score, Alvarado Score, Pediatric Appendicitis Score and Tzanakis Score) were applied to all data sets. Furthermore, the best score was improved and artificial intelligence (AI) was applied and compare the current scores. Results: In 23 months, 463 patients were included in the study. Of those 348 (75.2%) were operated for suspected appendicitis and in 336 (96.6%) patients the diagnosis was confirmed histopathologically. The best predictors of appendicitis (simple and perforated) were rebound tenderness, cough/hopping tenderness, ultrasound, and laboratory results. After modifying the HAS, it provided excellent results for simple (PPV 95.0%, NPV 70.0%) and very good for perforated appendicitis (PPV 34.4%, NPV 93.8%), outperforming all other appendicitis score. Discussion: The modified HAS and the AI score show excellent predictive capabilities and may be used to identify most cases of appendicitis and more important to rule out perforated appendicitis. The new scores outperform all other scores and are simple to apply. The modified HAS comprises five features that can all be assessed in the emergency department as opposed to current scores that are relatively complex to utilize in a clinical setting as they include of up to eight features with various weighting factors. In conclusion, the modified HAS and the AI score may be used to identify children with appendicitis, yet prospective studies to validate our findings in a large mutli-center cohorts are needed.
Published: 2020
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10. Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial

Author: Jacqueline Palace, Dean M. Wingerchuk, Kazuo Fujihara, Achim Berthele, Celia Oreja-Guevara, Ho Jin Kim, Ichiro Nakashima, Michael Levy, Murat Terzi, Natalia Totolyan, Shanthi Viswanathan, Kai-Chen Wang, Amy Pace, Marcus Yountz, Larisa Miller, Róisín Armstrong, Sean Pittock, Daniel Julio Muñoz, Jorge David Amor, Carolina Bocchiardo, Julieta Iourno Danielle, Alfredo Laffue, Carolina Daniela Diaz Obregon, Maria Fernanda Paez, Roberto Martin Perez, Viviana Ana Maria Rocchi, Loreley Deborah Teijeiro, Jesica Gómez, Andres Maria Villa, Florencia Aguirre, Victoria Carla Fernández, Ramon F. Goicoechea, Luciana Melamud, Ana Stillman, Mariana de Virgiliis, Fatima Pagani Cassara, Marta Cordoba, Maria Teresa Gutierrez, Mariana Ingolotti, Natalia Larripa, Anahi Lupinacci, Josefina Arroyo, Alejandra Romano, Mariana Foa Torres, Carlos Héctor Ballario, Ana Elisa Chiesa, Hernán Gustavo Gómez, Hernán Gabriel Lattini, Carolina Natalia Mainella, Gisel Edith Bolner, María Soledad Eschoyez, Simon Andrew Broadley, Saman Heshmat, Arman Sabet, Andrew Swayne, Susan Freeman, Sofia Jimenez Sanchez, Neil Shuey, Linda Dalic, Ann French, Guru Kuma, Joshua Laing, Lai Yin Law, Jennifer MacIntyre, Andrew Neal, Christopher Plummer, Prashanth Ramachandran, Leslie Sedal, Ian Wilson, Antony Winkel, Wenwen Zhang, Tina Chen, Rani Watts, Michael Barnett, Joshua Barton, Heidi Beadnall, Justin Garber, Todd Andrew Hardy, Benjamin Trewin, Marinda Taha, Deleni Walters, Federico Arturo Silva Sieger, Nhora Patricia Ruiz Alfonso, Anna Maria Pinzon Camacho, Alexander Pabón Moreno, Jorge Armando Castellanos Prad, Adriana Paola Duarte Rueda, Tatiana Castillo, Karol Melissa Castillo Gonzalez, Martha Yolanda Moreno Pico, Judith Castill, Mario Habek, Ivan Adamec, Barbara Barun, Luka Crnosija, Tereza Gabelic, Petra Nytrova, Eva Krasulova, Jana Pavlickova, Michaela Tyblova, Jana Zubkova, Thor Petersen, Gro Helen Dale, Peter Vestergaard Rasmussen, Morten Stilund, Kristina Bacher Svendsen, Vivi Brandt, Nicolas Collongues, Marie-Celine Fleury, Laurent Kremer, Sandrine Bendele, Valérie Neff, Ricarda Diem, Michael Platten, Anne Berberich, Jonabelle Jansen, Hannah Jaschoneck, Brigitte Wildemann, Ursula Aures, Tanja Brandenburger, Tanja Haut, Maria-Lourdes Treceno Fernández, Lilian Aly, Kirsten Brinkhoff, Dorothea Buck, Daniel Golkowski, Mirjam Hermisson, Muna-Miriam Hoshi, Miriam Kaminski, Markus Christian Kowarik, Helena Kronsbein, Klaus Lehmann-Horn, Viola Maria Pongratz, Andreas Schweiker, Lisa-Ann Leddy, Silvia Mueller, Kim Obergfell, Marion Wanka, Uwe Klaus Zettl, Jan Klinke, Micha Loebermann, Stefanie Meister, Florian Rimmele, Alexander Winkelmann, Ina Schroeder, Alexander Yuk-Lun Lau, Lisa Wing-Chi Au, Florence Sin-Ying Fan, Vincent Hing-Lung Ip, Karen Ka-Yan Ma, Sze-Ho Ma, Vincent Chung-Tong Mok, Cheryl Chung-Kwan Au, Pauline Wing-Lam Kwan, Francesco Patti, Andrea Salvatore Caramma, Clara Grazia Chisari, Salvatore Lo Fermo, Silvia Messina, Maria Projetto, Cinzia Caserta, Alessandro Filla, Teresa Costabile, Chiara Pane, Francesco Sacca, Angela Marsili, Giorgia Puorro, Roberto Bergamaschi, Eliana Berra, Giulia Mallucci, Cinzia Fattore, Claudio Gasperini, Simonetta Galgani, Shalom Haggiag, Serena Ruggieri, Claudio Vento, Esmeralda Maria Quartuccio, Carlo Pozzilli, Valeria Teresa Barletta, Giovanna Borriello, Laura De Giglio, Fabiana Marinelli, Miriam Tasillo, Alessandra Amadori, Mariano Fischetti, Flavia Gurreri, Masahiro Mori, Hiroki Masuda, Ryohei Ohtani, Yukari Sekiguchi, Tomohiko Uchida, Akiyuki Uzawa, Hiromi Ito, Emi Kabasawa, Yoko Kaneko, Takuya Matsushita, Dai Matsuse, Hiroyuki Murai, Shintaro Hayashi, Katsuhisa Masak, Hidenori Ogata, Koji Shinoda, Taira Uehara, Mitsuru Watanabe, Hiroo Yamaguchi, Ryo Yamasaki, Tomomi Yonekawa, Maki Jingu, Makiko Nagano, Yumiko Nakamura, Yoshiko Sano, Manabu Araki, Youwei Lin, Madoka Mori, Yohei Mukai, Terunori Sano, Wakiro Sato, Naoya Gogun, Yuriko Maeda, Asami Nishimoto, Sachiko Tsukamoto, Ritsuko Yanagi, Takahiko Saida, Shinichi Nakamura, Tetsuya Nasu, Kyoko Saida, Yuko Shikata, Yoshimi Kodani, Megumi Saeki, Yukako Sawada, Hiroo Yoshikawa, Takashi Kimura, Masamitsu Nishi, Shun Sakamoto, Shinichiro Ukon, Shohei Watanabe, Saori Ebisuya, Nami Kimura, Manami Matsuura, Yukie Morisaki, Yoshiko Muroi, Kuniko Onishi, Ikuko Oshima, Yuki Washino, Tomomi Yamashita, Tatsuro Misu, Kimihiko Kaneko, Masaaki Kato, Hiroshi Kuroda, Kazuhiro Kurosawa, Shuhei Nishiyama, Hirohiko Ono, Yoshiki Takai, Keiko Abe, Hitomi Hoshi, Mari Jinushi, Azusa Oyama, Motonari Sakuma, Yuko Sawada, Satoru Ishibashi, Takanori Yokota, Yoichiro Nishida, Kokoro Ozaki, Nobuo Sanjo, Nozomu Sato, Fuki Denno, Haruko Hiraki, Yumi Matsubara, Takashi Kanda, Masaaki Abe, Masaya Honda, Motoharu Kawai, Michiaki Koga, Toshihiko Maeda, Junichi Ogasawara, Masatoshi Omoto, Yasuteru Sano, Ryota Sato, Fumitaka Shimizu, Hideki Arima, Sachie Fukui, Yoshiko Ishikawa, Tomoko Koyama, Shigemi Shimose, Hirokazu Shinozaki, Masanori Watanabe, Sachi Yasuda, Chieko Yoshiwaka, Suffian Adenan, Mohd Azman M Aris, Ahmad Shahir bin Mawardi, Muhammad Al Hafiz Adnan, Nanthini Munusamy, Siti Nur Omaira Razali, Punitha Somasundram, Jae Won Hyun, In Hye Jeong, Su-Hyun Kim, Hyun-June Shin, Ji Sung Yoo, HyunMin Jang, AeRan Joung, Byung-Jo Kim, Seol-Hee Baek, Jung Bin Kim, Yoo Hwan Kim, Yong Seo Koo, Chan Nyoung Lee, Hung Youl Seok, Jinhee Hwang, Sung Min Kim, So Hyun Ahn, Kyomin Choi, Seok-Jin Choi, Jun-Soon Kim, Young Nam Kwon, Je-Young Shin, Hyeonju Kwon, Byoung Joon Kim, Eun Bin Cho, Hye-Jin Cho, Misong Choi, DongSun Kim, Ju Hyeon Kim, SeungJu Ki, Hye Lim Lee, Kwang-Ho Lee, Ju-Hong Min, Ji-Hyung Park, Jinmyoung Seok, Eunhwa Choi, Sang Ae Park, Seung Min Kim, Ha-Neul Jeong, Bong Jeongbin, Jin Woo Jung, Seung Woo Kim, Yool-hee Kim, Hyung Seok Lee, Ha Young Shin, Yeon Jung, Min Jung Kim, Nou Ri Lee, MiJu Shin, Farit A Khabirov, Lyudmila Averyanova, Natalya Babicheva, Eugenii Granatov, Sergey Kazarov, Timur Khaybullin, Alexander Rogozhin, Dmitry V Pokhabov, Vladislav Abramov, Anastasia Amelina, Yulia Nesteroca, Tatyana Bozhenkina, Aleksey N Boyko, Elena G Demyan, Inessa Khoroshilova, Mikhail Melnikov, Ekaterina V Popova, Svetlana N Sharanova, Sergey G Shchur, Denis V Sazonov, Larisa Babenko, Elena Bayandina, Asya Yarmoschuk, Victor A Baliazin, Elena Baliazina, Elena Budaeva, Irina Chernikova, Zoya Goncharova, Vladimir Krasnov, Marina Myatleva, Olga V. Rodionova, Iuliana Samulyzhko, Alla A. Timofeeva, Sabas Boyero Duran, Maria Mar Mendibe Bilbao, Irene Diaz Cuervo, Jose Maria Losada Domingo, Amaia Gonzalez Eizaguirre, Jose Eulalio Barcena Llona, Roberto Valverde Moyano, Carmen Bahamonde, Fernando Sanchez Lopez, Raquel Pinar Morales, Eduardo Agüera Morales, Carmen Bahamonde Roman, Juan Jose Ochoa Sepulveda, Maria del Carmen Blanco Valero, Nazaret Pelaez Viña, Cristina Conde Gavilan, Ana Maria Jover Sanchez, Sara Vila Bedmar, Nuria Gonzalez Garcia, Aida Orviz Garcia, Ines Gonzalez-Suarez, Elena Miñano Guillamon, Miguel Kawiorski, Elena Guerra Schulz, Alba Garcia Alonso, Francisco Jesus Lopez Perez, Marta Palacios Sarmiento, Guillermo Izquierdo Ayuso, Guillermo Navarro Mascarell, Cristina Paramo Camino, Asuncion Varas Garcia, Yaiza Montserrat Mendoza, Veronica Ines Vargas Muñoz, Patricia Torres Tonda, Ching-Piao Tsai, Jiu-Haw Yin, Mei-Jung Chen, Shan-Ni Li, Fei-Ti Wang, Suwat Srisuwannanukorn, Thanatat Boonmongkol, Duangporn Borisutbuathip, Duangkamol Singwicha, Krittika Siritanan, Chidchanoke Thearapati, Kwanmuang Sornda, Metha Apiwattanakul, Saharat Aungsumart, Narupat Suanprasert, Kaona Suksuchano, Nittaya Parkinsee, Kongkiat Kulkantrakorn, Praween Lolekha, Artit Potigumjon, Puchit Sukphulloprat, Dararat Suksasunee, Chankawee Komaratat, Sunattana Luangtong, Arkhom Arayawichanont, Phanpaphon Konpan, Nathapol Riablershirun, Thaddao Wiroteurairuang, Panadda Jantaweesirirat, Aslı Kurne, Irem Erkent, Ebru Bekircan Kurt, Ezgi Saylam, Yagmur Caliskan, Gulsah Orsel, Yahya Celik, Canan Celebi, Aslan Tekatas, Tugce Banbal, Gulsen Akman Demir, Burcu Altunrende, Zeliha Matur, Baris Topcular, Tules Elmas, Aysenur Gulo, Selin Ozdemir, Cansu Ozkoklesen, Mahinur Ozturk, Mertkan Yanik, Elif Yildirim, Melih Tutuncu, Ayse Altintas, Abdulsamet Cam, Ayse Deniz Elmali, Sabahattin Saip, Aksel Siva, Uygur Tanrıverdi, Ugur Uygunoglu, Sinem Caliskan, Pinar Gulo, Esra Kozig, Sakine Sakiz, Ihsan Sukru Sengun, Egemen Idiman, Rahmi Tumay Ala, Duygu Arslan, Utku Bulut, Yasemin Karakaptan, Derya Kaya, Zaur Mehdiyev, Bengu Balkan, Berfu Kuku, Mujgan Ozhun, Celal Tuga, Muzeyyen Ugur, Husnu Efendi, Sena Destan Bunul, Hakan Cavus, Yunus Emre Gorke, Ayse Kutlu, Seda Ozturk, Cansu Egilmez Sarikaya, Gulsah Becerikli, Cansu Semiz, Ozlem Tun, Sehriban Ayer, Musa Kazim Onar, Mehlika Berra Ozberk, Sedat Sen, Tugce Kirbas Cavdar, Adife Veske, Cavit Boz, Didem Altiparmak, Cigdem Ozen Aydin, Sibel Gazioglu, Duygu Bekircan, Anu Jacob, Heike Arndt, Liene Elsone, Shahd Hassan Mahmoud Hamid, Daniel Hugh Whittam, Martin Wilson, Imelda O'Brien, Maria Isabel da Silva Leite, Pedro Maria Rodriguez Cruz, Damian Robert Jenkins, George Tackley, Ana Cavey, Rosie Everett, Joy Hodder, Abigail Koelewyn, Ellen Mowry, Walter Royal, Robert Shin, Christopher Bever, Daniel Harrison, Horea Rus, Wei Zheng, Karen Callison, Kerry Naunton, Benjamin M Frishberg, Andrew M Blumenfeld, Andrew Inocelda, Kalyani Korabathina, Michael Lobatz, Melissa M Mortin, Irene J Oh, Jay H Rosenberg, Mark Sadoff, Gregory A Sahagian, Anchi Wang, Yasmin Camberos, Guadalupe Sanchez, Estela Soto, Jacqueline A Nicholas, Aaron Boster, Geoffrey Eubank, Katy Groezinger, Meghan Lauf, Annette F Okai, Rashedul Hasan, Chaouki Khoury, Victoria Stokes, Stacey Clardy, Melissa Cortez, John Greenlee, John Rose, Mateo Paz Soldan, Amanda Emett, Lawanda Esquibel, Lilly Fagatele, Ka-Ho Wong, James C Stevens, Thomas M Banas, Marlene C Bultemeyer, Andrea Haller, Natalie Manalo, Keri Aeschliman, Debi Kocks, Michael Racke, Aaron Lee Boster, Michelle Bowman, Jaime Imitola, Yasushi Kisanuki, Misty Green, Stephanie Scarberry, Sharon G Lynch, Heather S Anderson, Gary S Gronseth, Nancy E Hammond, Yasir N Jassam, Manoj K Mittal, Muhammed M Nashatizadeh, Nicholas Levine, Lisa Schmidt, Jill Sibley, Vonda Whitley, James Winkley, Timothy Coleman, Gregory Cooper, Stephanie Sheffield, Keri Turner, Dana Galloway, Robert S Tillett, Geeta A Ganesh, Brian M Plato, Tad D Seifert, Diana Godwin, Deborah Lockridge, Kottil W Rammohan, William A Sheremata, Silvia Delgado, Jose Gonzalez, Alexis Lizarraga, Janice Maldonado, Melissa Ortega, Leticia Tornes, Yanet Babcock, Osmara Cailam, Yesica Campos, Irlisse Couvertier, Bettina Daneri, Jeremy Deni, Jeffrey Hernandez, Tatiana Jaramillo, Tenita Morris, Daniel Nobel, Anjelis Oliveira, Reshma Richardson, Gloria Rodriguez, Ana Romero, Carlos Sandova, Ruta Sawant, Lissett Tueros, Eric S Zetka, Chao Zheng, Daniel H Jacobs, Constance Easterling, Jennifer Fairbank, Revathi Iyengar, Mark Klafter, Justin Lindquist, Ahmed H Sadek, Elizabeth Carmona Toro, Navin Verma, Brigith Patino Castro, Nadia Sukhraj-Singh, Joseph Berger, Eric Williamson, Salim Chahin, Dina Jacobs, Clyde Markowitz, Jessica Dobbins, Lauren Mace, Maria Martin, Ashley Pinckney, Amber Roberts, Islam Zaydan, Galen W Mitchell, Rock A Heyman, Ryan L Orie, Valerie R Suski, Kerry Oddis, Darlene Punjack, Eoin Flanagan, Avi Gadoth, Andrew McKeon, W Oliver Tobin, Anastasia Zekeridou, Katie Dunlay, Jessica Sagen, Jonathan L Carter, Bachir Estephan, Brent P Goodman, Charlene R Hoffman Snyder, Andrea Francone, Irene Galasky, Martha Thomas, Pavle Repovic, James Bowen, Angeli Mayadev, Peiqing Qian, Yuriko Courtney, Lauren Lennox, Robert Thomas Naismith, Anne Haney Cross, Emily Evans, Erin E Longbrake, Megan E Orchard, Gregory F Wu, Linda Heinrich, Susan Sommers, Faria Amjad, Erika Mitchell, Carlos Mora, Bethany Schreiber, Carlo Tornatore, Alexis Carlson, Sacha McCarthy, and Alexandria Oliver
Subjects: Adult, medicine.medical_specialty, Population, Placebo, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Complement inhibitor, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, education, Aquaporin 4, education.field_of_study, Neuromyelitis optica, business.industry, Neuromyelitis Optica, General Medicine, Eculizumab, medicine.disease, Comorbidity, ddc, Neurology, Concomitant, Rituximab, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).
Published: 2020

11. Markers of neutrophil activation and extracellular traps formation are predictive of appendicitis in mice and humans: a pilot study

Author: Michael Boettcher, Nariman Mokhaberi, Michaela Klinke, Birgit Appl, Melina Esser, Julian Trah, Konrad Reinshagen, Julia Wenskus, Stefan Klohs, Laia Pagerols Raluy, and Madgalena Trochimiuk
Subjects: 0301 basic medicine, Male, Neutrophils, Pilot Projects, Gastroenterology, Extracellular Traps, Neutrophil Activation, Histones, Mice, 0302 clinical medicine, Gastrointestinal models, Child, Multidisciplinary, biology, Appendix, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Myeloperoxidase, Neutrophil elastase, Medicine, Female, medicine.symptom, Cell-Free Nucleic Acids, medicine.medical_specialty, Science, Peritonitis, Inflammation, Paediatric research, Article, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Animals, Humans, Peroxidase, business.industry, Case-control study, medicine.disease, Appendicitis, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Case-Control Studies, biology.protein, Citrullination, Ligation, business, Leukocyte Elastase, Biomarkers
Abstract: Appendicitis is one of the most frequent emergencies in pediatric surgery, yet current biomarkers for diagnosis are unspecific and have low predictive values. As neutrophils and extracellular traps (ETs) are an essential component of the immune defense against bacterial infections, and appendicitis is considered an inflammation reaction of the appendix, we hypothesized that neutrophil activation and NET formation play an essential role in appendicitis development and maintenance. Therefore, this pilot study aimed to establish a murine model of appendicitis and to evaluate ETs markers to diagnose appendicitis in mice and humans. The study used 20 (12 appendicitis- and 8 controls) 6-week old mice which underwent advanced appendicitis induction using a modified caecal ligation puncture procedure. During the study, cell-free DNA, neutrophil elastase (NE), myeloperoxidase (MPO), and citrullinated Histone H3 (H3cit) were assessed. Additionally, samples of 5 children with histologically confirmed appendicitis and 5 matched controls with catarrhal appendicitis, were examined for the same biomarkers. Moreover, NE, MPO, and H3cit were assessed histologically via immunofluorescence in mice and humans. All mice in the appendicitis group developed an advanced form of appendicitis with focal peritonitis. In mice and humans with appendicitis, markers of neutrophil activation and ETs formation (especially cfDNA, NE and H3cit) were significantly elevated in blood and tissue compared to controls. Ultimately, biomarkers correlated extremely well with tissue expression and thus disease severity. It appears that neutrophil activation and possibly NETs contribute to appendicitis development and biomarkers of neutrophil activation and ET formation reflect disease severity and thus could be used as biomarkers for appendicitis. However, large prospective clinical studies are needed to confirm our findings.
Published: 2020

12. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial

Author: Sora Ludwig, Melissa Deans, Stacey Lacerte, Catherine Young, Kellie E. Murphy, J. Johanna Sanchez, Peter Subrt, David Thompson, Kayla Schutt, George Carson, Bernard Zinman, Thomas Ransom, Melanie Robinson, Minnie Parsons, Shirley Beauchamp, Darlene Baxendale, Afshan Zahedi, Richard Phillips, Natasha Garfield, Paul Karanicolas, Jason Kong, Adriana Breen, Agnieszka Barts, Vincent Wong, Elizabeth Asztalos, Jon Barrett, Heather Belanger, Bonnie Stone-Hope, Josee Champagne, Julie Lambert, Myriam Bouchard, Michele Mahone, Sharon Thompson, Carolyn Oldford, David McIntyre, Dynika St Omer, Raquel Dias, Martin D'Amours, Josephine Laurie, Leila MacBean, Nashwah Taha, Veronica Gale, Wayne Andrews, Heidi Virtanen, Judy Brandt, Heidi Hirsimaki, Mauricio Marin, Gail Klein, Heather Clark, Bernadette Rowe, Joel Ray, Julie Lee, Mark McLean, Siobhan Tobin, Anne-Marie Powell, Janine Malcolm, Paul J. Karanicolas, Claire Gougeon, Leanne De Souza, Elaine O'Shea, Cathy Robb, Marci Turner, Jill Newstead-Angel, Sharon Young, Joan Crane, Leslie Berndl, Simona Meier, Valérie-Ève Julien, Maureen Mattick, Lorraine L. Lipscombe, Simon Tian, Lisa Vizza, Karen Coles, Ken Lim, Razita Singh, Abhay Lodha, George Tomlinson, Shari Segal, Marie-Christine Dubé, Barbara Cleave, Colette Favreau, Howard Berger, Florence Weber, Shital Gandhi, Carol Fergusson, Anthony Armson, Sarah Kwong, Margaret Watson, Michele Strom, George I Fantus, Steve Chalifoux, Ilana Halperin, Anne E. Cook, J Johanna Sanchez, Jillian Coolen, Marnie Nerdal-Bussell, Cheryl Verhesen, Debbie Fong, Marie-Josee Bedard, Susan Hendon, Allison Sigmund, Sara Meltzer, Madalena Neculau, Renee Kludas, Annie Castonguay, Jennifer M. Yamamoto, Bekki Cavallaro, Rshmi Khurana, Effie Viguiliouk, Camille Lambert, Helen R. Murphy, Cora Fanning, Grace Lee, Robyn L. Houlden, Laurie Slater, Eileen K. Hutton, Lorraine Cauchi, Janet Slaunwhite, Prem Lata, Lois E. Donovan, Debbie McGuire, Carolyn Bergan, Aarthi Kamath, Louise Bastien, Sarah Capes, Kathryn Mangoff, Rohit Rajagopal, Anne Tremellen, David Miller, Sophie Perreault, Louise Rheaume, Sherri Pockett, Sophie Leblanc, Christyne Allen, Wenjun Nie, Amira El-Messidi, Edmond A. Ryan, Denice S Feig, Christine Orr, Vinolia ArthurHayward, H. David McIntyre, Ariane Godbout, Denice S. Feig, Jennifer Sloan, Heather Rylance, Simon Yu Tian, Hamish Russell, Sylvie Daigle, Suzanne Williams, Diane Donat, Krista Rideout, Vivian Zhou, Carol Joyce, Krystyna Szwiega, Allan Karovitch, Marie-Claude Bourbonniere, Helen Barrett, Amir Hanna, Tina Kader, Claudia Bishop, I. George Fantus, Ruth McManus, Stephanie Cooper, Jennifer Klinke, Bi Lan Wo, Keitha McMurray, Brenda Galway, S. John Weisnagel, Erin Keely, Jodie Nema, Joyce Mitchell, Hélène Long, Frances Maguire, Alice Cheng, Munira Sultana, Melin Peng, Jane Fox, Evelyne Rey, Francina Carr, Galina Smushkin, Tammy McNab, Maria Wolfs, Helen G. Liley, and David Simmons
Subjects: Adult, Blood Glucose, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Placebo-controlled study, 030209 endocrinology & metabolism, Type 2 diabetes, Placebo, law.invention, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Endocrinology, Randomized controlled trial, Double-Blind Method, law, Pregnancy, Diabetes mellitus, Internal medicine, Internal Medicine, Medicine, Humans, Hypoglycemic Agents, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Glycated Hemoglobin, business.industry, Pregnancy Outcome, International Agencies, Middle Aged, medicine.disease, Metformin, Diabetes Mellitus, Type 2, Female, business, Biomarkers, medicine.drug, Follow-Up Studies
Abstract: Summary Background Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. Methods In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI ( ClinicalTrials.gov , NCT01353391 . Findings Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [–10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference −0·2 [–0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference −0·4 [95% CI −0·5 to −0·2]; p Interpretation We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy. Funding Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.
Published: 2020

13. High incidence of maternal vitamin B12 deficiency detected by newborn screening: first results from a study for the evaluation of 26 additional target disorders for the German newborn screening panel

Author: Glynis Klinke, Jürgen G. Okun, Georg F. Hoffmann, Patrik Feyh, Gwendolyn Gramer, Junmin Fang-Hoffmann, and Péter Monostori
Subjects: Vitamin, Newborn screening, Pediatrics, medicine.medical_specialty, biology, business.industry, Citrullinemia, medicine.disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Methylenetetrahydrofolate reductase, Pediatrics, Perinatology and Child Health, Pediatric surgery, biology.protein, Medicine, 030212 general & internal medicine, High incidence, business, Prospective cohort study, 030217 neurology & neurosurgery, Maternal vitamin
Abstract: Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel. Since August 2016, a prospective study evaluating 26 additional target disorders (25 metabolic disorders and vitamin B12-deficiency) in addition to the German screening panel is performed at the Newborn Screening Center Heidelberg. First-tier results from tandem-MS screening are complemented by second-tier strategies for 15 of the additional target disorders. NBS results of seven patients diagnosed symptomatically with one of the additional target disorders by selective screening since August 2016 are retrospectively evaluated. Over a 13-month period, 68,418 children participated in the study. Second-tier analyses were performed in 5.4% of samples. Only 59 (0.1%) of study participants had abnormal screening results for one of the additional target disorders. Target disorders from the study panel were confirmed in 12 children: 1 3-hydroxy-3-methylglutaryl coenzyme A (CoA)-lyase deficiency, 1 citrullinemia type I, 1 multiple acyl-CoA dehydrogenase-deficiency, 1 methylenetetrahydrofolate reductase-deficiency, and 8 children with maternal vitamin B12-deficiency. In addition, six of seven patients diagnosed symptomatically outside the study with one of the target disorders would have been identified by the study strategy in their NBS sample. Within 13 months, the study “Newborn Screening 2020” identified additional 12 children with treatable conditions while only marginally increasing the recall rate by 0.1%. Maternal vitamin B12-deficiency was the most frequent finding. Even more children could benefit from screening for the additional target disorders by extending the NBS panel for Germany and/or other countries.
Published: 2018
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14. Dunkelziffer nicht-akzidenteller thermischer Verletzungen im Kindesalter – Kinderschutzstrategien zur Reduktion

Author: Claudia Maria Schmidt, Michael Boettcher, Michaela Klinke, Laura C. Tegtmeyer, Ingo Koenigs, and Konrad Reinshagen
Subjects: Gynecology, Child abuse, medicine.medical_specialty, Injury control, Accident prevention, business.industry, Poison control, 030208 emergency & critical care medicine, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Pediatrics, Perinatology and Child Health, medicine, business
Abstract: Zusammenfassung Hintergrund Thermische Verletzungen stellen eine relevante Unfallursache im Kindesalter dar und sind häufig mit langen Krankenhausaufenthalten und schwerwiegenden physischen und psychischen Beeinträchtigungen der Patienten sowie oftmals lebenslangen Folgen verbunden. Verbrühungen, insbesondere im Kleinkindalter, sind die häufigste Form thermischer Verletzungen. Neben akzidentellen Unfallhergängen spielen nicht-akzidentelle Verletzungen eine wesentliche Rolle. Diese von akzidentellen Verletzungen zu unterscheiden, ist von höchster Wichtigkeit und stellt eine enorme Herausforderung für Ärzte, Pflegende und Mitarbeiter psychosozialer Dienste dar. Methode In dieser multizentrischen Registerstudie wurden thermische Kindeswohlgefährdungen in Deutschland über einen Zeitraum von 10 Jahren analysiert. Ergebnisse Es wurden Daten von 13.353 pädiatrischen Patienten mit thermischen Verletzungen aus 32 Krankenhäusern der Jahre 2006 bis 2015 in Deutschland erhoben. Entsprechend den Ergebnissen dieser Studie erscheint die Anzahl nicht-akzidenteller thermischer Verletzungen mit 0,5% in Deutschland im Vergleich zu internationalen Erhebungen, die von durchschnittlich 10% berichten, deutlich unterrepräsentiert. Diskussion Es ist naheliegend, dass sich hinter dieser Differenz eine nicht unerhebliche Dunkelziffer verbirgt und wir folglich in Deutschland einen relevanten Anteil nicht-akzidenteller thermischer Verletzungen übersehen. Ziel dieser Arbeit ist die Vermittlung eines Bewusstseins und die Sensibilisierung für nicht-akzidentelle thermische Verletzungen im Kindesalter. Darüber hinaus wird eine Strategie zur Erhöhung der Detektionsrate und Reduktion der Dunkelziffer definiert. Schlussfolgerung Zukünftig ist eine umfassendere Datenerhebung notwendig, um nicht-akzidentelle thermische Verletzungen im Kindesalter realitätsnah abzubilden. Dies wird mit dem neu konzeptionierten Verbrennungsregister der Deutschen Gesellschaft für Verbrennungsmedizin (DGV) und des Arbeitskreises „Das schwerbrandverletzte Kind“ umgesetzt.
Published: 2017
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15. Nitro-oleic acid regulates growth factor-induced differentiation of bone marrow-derived macrophages

Author: Michaela Pekarova, Gabriela Ambrozova, Adolf Koudelka, Ondrej Vasicek, Steven R. Woodcock, Tanja K. Rudolph, Hana Verescakova, Tomas Perecko, Anna Klinke, Lukáš Kubala, and Bruce A. Freeman
Subjects: 0301 basic medicine, MAPK/ERK pathway, medicine.medical_specialty, MAP Kinase Signaling System, medicine.medical_treatment, Bone Marrow Cells, Inflammation, Biology, Nitric Oxide, Biochemistry, Article, Mice, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, Colony-Stimulating Factors, Downregulation and upregulation, Physiology (medical), Internal medicine, STAT5 Transcription Factor, medicine, Animals, Macrophage, Extracellular Signal-Regulated MAP Kinases, 030102 biochemistry & molecular biology, Macrophages, Growth factor, Cell Differentiation, Cell biology, Gene Expression Regulation, Neoplastic, RAW 264.7 Cells, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, STAT protein, Bone marrow, medicine.symptom, Signal transduction, Oleic Acid
Abstract: Many diseases accompanied by chronic inflammation are connected with dysregulated activation of macrophage subpopulations. Recently, we reported that nitro-fatty acids (NO2-FAs), products of metabolic and inflammatory reactions of nitric oxide and nitrite, modulate macrophage and other immune cell functions. Bone marrow cell suspensions were isolated from mice and supplemented with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with NO2-OA for different times. RAW 264.7 macrophages were used for short-term (1–5 min) experiments. We discovered that NO2-OA reduces cell numbers, cell colony formation, and proliferation of macrophages differentiated with colony-stimulating factors (CSFs), all in the absence of toxicity. In a case of GM-CSF-induced bone marrow-derived macrophages (BMMs), NO2-OA acts via downregulation of signal transducer and activator of transcription 5 (STAT5) and extracellular signal-regulated kinase (ERK) activation. In the case of M-CSF-induced BMMs, NO2-OA decreases activation of M-CSFR and activation of related PI3K and ERK. Additionally, NO2-OA also attenuates activation of BMMs. In aggregate, we demonstrate that NO2-OA regulates the process of macrophage differentiation and that NO2-FAs represent a promising therapeutic tool in the treatment of inflammatory pathologies linked with increased accumulation of macrophages in inflamed tissues.
Published: 2017
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16. Abstract NS9: Screening for Spatial Neglect in a Ward-based Environment Within Two Weeks From Stroke Onset: Preliminary Results of a Pilot Study

Author: Vaidas Matijošaitis, Marianne E. Klinke, and Haukur Hjaltason
Subjects: Advanced and Specialized Nursing, medicine.medical_specialty, Rehabilitation, business.industry, medicine.medical_treatment, media_common.quotation_subject, medicine.disease, Neglect, Stroke onset, Physical medicine and rehabilitation, medicine, In patient, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Stroke, media_common
Abstract: Background and purpose: Spatial neglect (SN) occurs frequently in patients with stroke, resulting in worse recovery. Without screening, the presence of SN may remain undetected and prevent initiation of alleviating strategies. There is limited evidence available to suggest bedside identification of SN in the subacute phase following stroke. Thus we set out to identify effective screening tests for SN. Method: The following index tests were used; (a) six conventional subtests of The Behavioural Inattention test (BIT), (b) an additional figure copying test, (c) a newly developed neglect experience questionnaire, and (d) an additional component added to the National Institute of Health Stroke Scale (NIHSS). The Catherine Bergego Scale (CBS) functioned as a reference frame to ascertain the presence of SN. Results: Consecutive stroke patients (N=125) were included from the Neurological Department of Landspitali University Hospital in Iceland, within two weeks following stroke. Of those 30 patients had SN. If all subtests of the BIT were administered, approximately 35% of stroke patients without SN would be incorrectly identified with the disorder. Statistically more patients without SN were identified as having SN if ≥ three tests of the BIT was administered (p=0.002). If patients did not, at stroke onset, comprehend why they had to go to the hospital, this was correlated to the presence of SN. The star cancellation and figure copying were the most sensitive paper-and pen tests to identify SN. Inclusion of an additional item to NIHSS correctly identified SN in 86% instances. Conclusion: Results contests the common belief that use of more tests increase identification of SN. Rather we found that the use a large test battery decreases sensitivity in the subacute phase following stroke. A short question about patients’ experiences of stroke onset and adding a novel item to the NIHSS provided new pragmatic ways of identifying SN. Results have been used to inform a larger cross-country study between Iceland and Lithuania, where psychometric properties of screening strategies are being further validated.
Published: 2020
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17. An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer

Author: Qing Wang, Yan Wu, David J. Klinke, and Zhijun Wang
Subjects: 0301 basic medicine, Oncology, Cancer Research, Colorectal cancer, medicine.medical_treatment, Mice, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Adenoviral vector, 0303 health sciences, Liver Neoplasms, Impulsive ordinary differential equation, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Interleukin-12, 3. Good health, Oxaliplatin, Treatment Outcome, 030220 oncology & carcinogenesis, Interleukin 12, Colorectal Neoplasms, Algorithms, Research Article, medicine.drug, medicine.medical_specialty, Combination therapy, Antineoplastic Agents, lcsh:RC254-282, Viral vector, 03 medical and health sciences, Immune system, Therapeutic index, Cell Line, Tumor, Internal medicine, Genetics, medicine, Animals, Humans, 030304 developmental biology, Chemotherapy, business.industry, Stability analysis, Models, Theoretical, medicine.disease, Xenograft Model Antitumor Assays, Disease Models, Animal, 030104 developmental biology, Mathematical modeling, business, CD8
Abstract: Background Combining anti-cancer therapies with orthogonal modes of action, such as direct cytotoxicity and immunostimulatory, hold promise for expanding clinical benefit to patients with metastatic disease. For instance, a chemotherapy agent Oxaliplatin (OXP) in combination with Interleukin-12 (IL-12) can eliminate pre-existing liver metastatic colorectal cancer and protect from relapse in a murine model. However, the underlying dynamics associated with the targeted biology and the combinatorial space consisting of possible dosage and timing of each therapy present challenges for optimizing treatment regimens. To address some of these challenges, we developed a predictive simulation platform for optimizing dose and timing of the combination therapy involving Mifepristone-induced IL-12 and chemotherapy agent OXP. Methods A multi-scale mathematical model comprised of impulsive ordinary differential equations was developed to describe the interaction between the immune system and tumor cells in response to the combined IL-12 and OXP therapy. An ensemble of model parameters were calibrated to published experimental data using a genetic algorithm and used to represent three different phenotypes: responders, partial-responders, and non-responders. Results The multi-scale model captures tumor growth patterns of the three phenotypic responses observed in mice in response to the combination therapy against a tumor re-challenge and was used to explore the impacts of changing the dose and timing of the mixed immune-chemotherapy on tumor growth subjected to a tumor re-challenge in mice. An increased ratio of CD8 + T effectors to regulatory T cells during and after treatment was key to improve tumor control in the responder cohort. Sensitivity analysis indicates that combined OXP and IL-12 therapy worked more efficiently in responders by increased priming of T cells, enhanced CD8 + T cell-mediated killing, and functional inhibition of regulatory T cells. In a virtual cohort that mimics non-responders and partial-responders, simulations show that an increased dose of OXP alone would improve the response. In addition, enhanced IL-12 expression alone or an increased number of treatment cycles of the mixed immune-chemotherapy can barely improve tumor control for non-responders and partial responders. Conclusions Overall, this study illustrates how mechanistic models can be used for in silico screening of the optimal therapeutic dose and timing in combined cancer treatment strategies.
Published: 2020
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18. Moving from stigmatization toward competent interdisciplinary care of patients with functional neurological disorders: focus group interviews

Author: Aldís Hauksdóttir, Haukur Hjaltason, Marianne E. Klinke, GuĐbjörg Thóra Andrésdóttir, Helga Jónsdóttir, and Thórdís Edda Hjartardóttir
Subjects: 030506 rehabilitation, medicine.medical_specialty, Attitude of Health Personnel, Health Personnel, education, Stigma (botany), Clinical knowledge, 03 medical and health sciences, 0302 clinical medicine, Health care, medicine, Humans, Psychiatry, Conversion disorder, Qualitative Research, Stereotyping, Inpatient care, business.industry, Rehabilitation, Focus Groups, medicine.disease, Focus group, Nervous System Diseases, 0305 other medical science, business, 030217 neurology & neurosurgery
Abstract: To explore facilitating and inhibiting factors in the inpatient care of patients with functional neurological disorders as experienced by interdisciplinary teams of healthcare professionals.Qualitative focus group interviews were conducted with 18 healthcare professionals of various professions. Data were analyzed using qualitative content analysis with inductive coding of data.Two main categories were formulated: (a) Giving the diagnosis to patients - a moment of fragility and opportunities, and (b) Organization of care - ensuring the continuity and protecting patients' self-image. One overarching theme tied the two categories together: Establishing coherence in the inpatient trajectory - moving from stigmatization toward competent care. Coherence and steadiness in care was a prerequisite for transparency in goalsetting and for designating the responsibilities of individual healthcare professionals. Stigma and having clinical experience and knowledge of functional neurological disorders, as two counter-factors, influenced the extent to which this was achieved. Examples of facilitating factors for enhancing competent care were documentation of symptoms, effective ways of passing on clinical information, education, professional dialog, and organizational support.To nurture competent care, guidelines, structured educational initiatives and other supportive actions should be promoted. We provide ideas for the next logical steps for clinical practice and research.IMPLICATIONS FOR REHABILITATIONClose collaboration between interdisciplinary healthcare professionals plays an important role for reaching optimal results in the rehabilitation of inpatients with functional neurological disorder.There is currently limited knowledge regarding the facilitating and inhibiting features encountered by interdisciplinary healthcare professionals in the provision of care for patients with a functional neurological disorder.The findings show that a working environment that endorses a skillful culture of practice and which facilitates actions to reduce problems that hamper effective teamwork needs to be promoted.Solutions that help to solve many obstacles encountered by the team of healthcare professionals in the care provision of patients with functional neurological disorders include open dialog regarding symptoms, diagnosis and treatment, effective ways of documenting and reporting symptoms, and availability of guidelines and supporting educational material.
Published: 2019

19. S1 guidelines on the diagnosis and treatment of scabies – short version

Author: Regina Fölster-Holst, Sabine Klinke-Rehbein, Bernhardt Sachs, Bertram Geisel, Hermann Feldmeier, Cord Sunderkötter, Sandra Philipp, Julia C. Stingl, Johanna Stoevesandt, Henning Hamm, and Alexander Nast
Subjects: Insecticides, medicine.medical_specialty, Toluidines, Administration, Topical, Population, Administration, Oral, Dermoscopy, Dermatology, Crotamiton, Drug Administration Schedule, Diagnosis, Differential, Scabies, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Ivermectin, Germany, parasitic diseases, Mite, medicine, Humans, 030212 general & internal medicine, education, Permethrin, Skin, education.field_of_study, integumentary system, biology, business.industry, Pruritus, Risk of infection, Outbreak, Guideline, biology.organism_classification, Treatment Outcome, Practice Guidelines as Topic, business, medicine.drug
Abstract: The goals of this German guideline are the improvement of diagnosis and therapy of scabies, the implementation of a coordinated action in outbreaks of scabies, and the control of this infestation in large migration or refugee flows.Sarcoptes scabiei var. hominis is transmitted by direct skin-to-skin contact of sufficient duration. The infectivity of female mites when removed from patients does not exceed 48 hours at room temperature (21°C) and relative humidity of 40-80%. The risk of infection rises proportionally to the number of mites on the skin and is particularly high in crusted scabies. As elderly persons tend to develop crusted scabies due to disease- or medication-related immunosuppression, there is an increased risk for outbreaks of scabies at nursing homes and extended-care facilities. The guideline contains detailed recommendations for management of such outbreaks. In refugees the prevalence of scabies is higher than in the general population in Germany, but the risk for outbreaks is not high. Scabies infestation should be considered when a recent onset of itching is associated with eczema and presence of burrows or comma-like papules at predilection sites. It is confirmed by dermatoscopic detection of mites or by microscopic identification of mites, mite eggs or fecal matter (scybala) from skin scrapings.The treatment of choice for common scabies is topical permethrin 5% cream applied for 8-12 hours. Permethrin can be considered for off-label use also in infants of less than 3 months of age and pregnant women. For this group crotamiton is another option, which, besides benzyl benzoate, presents a good second line therapy for the other indications. Indications for oral ivermectin, which has just been licensed in Germany, include patients with immunosuppression, severe dermatitis, and low adherence.Crusted scabies is preferentially treated by a combination of topical permethrin and oral ivermectin. Affected patients should be isolated, and all contact persons should be treated. The guideline contains lists for additional measures, including possible treatment of contact persons, clothes, linen and other possibly infested articles.
Published: 2016
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20. P4551Myeloperoxidase activity aggravates aortic wall remodeling and participates in aneurysm development in Marfan Syndrome

Author: Dennis Mehrkens, M Kochen, Martin Mollenhauer, G Sengle, Volker Rudolph, Matti Adam, Stephan Baldus, J K Dohr, A Silva, and Anna Klinke
Subjects: 0301 basic medicine, Marfan syndrome, medicine.medical_specialty, business.industry, medicine.disease, Aortic wall, 03 medical and health sciences, 030104 developmental biology, Aneurysm, Internal medicine, medicine, Cardiology, Cardiology and Cardiovascular Medicine, business
Published: 2018
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21. P3441Anti-arrhythmic effects of nitrated fatty acids during acute myocardial ischemia

Author: M Mollenhauer, M Lange, L Remane, K Friedrichs, M Wagner, A Geisler, T K Rudolph, L Carrier, A El-Armouche, A Klinke, S Baldus, and V Rudolph
Subjects: medicine.medical_specialty, Myocardial ischemia, business.industry, Internal medicine, Cardiology, Medicine, Cardiology and Cardiovascular Medicine, business
Published: 2018
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22. Doppelniere mit Nierenbeckenabgangsstenose im Kindesalter: Retroperitoneoskopische Pyeloplastik

Author: E. Reichenbach-Klinke and S. Subotic
Subjects: Gynecology, medicine.medical_specialty, business.industry, Urology, medicine, Retroperitoneoscopic pyeloplasty, business
Abstract: Zusammenfassung: Die laparoskopische Pyeloplastik für die Therapie der Nierenbeckenabgangsstenose bei Kindern gilt nach wie vor als einer der anspruchvollsten Eingriffe in der Urologie. Wir berichten über einen 12-jährigen Jungen mit Nierenbeckenabgangsstenose, Doppelniere und hohem Ureter fissus. Der Junge stellte sich wegen seit einem Jahr zunehmender Flankenschmerzen rechts und zuvor diagnostizierter Nierenbeckenabgangsstenose des unteren Doppelnierenanteils bei uns vor. Wir führten eine retroperitoneoskopische Pyeloplastik nach Anderson-Hynes durch
Published: 2018

23. Degradation of Extracellular DNA Significantly Ameliorates Necrotizing Enterocolitis Severity in Mice

Author: Michaela Klinke, Birgit Appl, Bastian Tiemann, Magdalena Trochimiuk, Michael Boettcher, Deirdre Vincent, Robert Bergholz, and Konrad Reinshagen
Subjects: medicine.medical_specialty, Drug Evaluation, Preclinical, Inflammation, medicine.disease_cause, Gastroenterology, Extracellular Traps, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Enterocolitis, Necrotizing, Pregnancy, Internal medicine, medicine, Animals, Deoxyribonuclease I, chemistry.chemical_classification, biology, business.industry, Glutathione peroxidase, Neutrophil extracellular traps, medicine.disease, Malondialdehyde, digestive system diseases, Intestines, Mice, Inbred C57BL, chemistry, Animals, Newborn, 030220 oncology & carcinogenesis, Neutrophil elastase, Myeloperoxidase, Necrotizing enterocolitis, biology.protein, 030211 gastroenterology & hepatology, Surgery, Female, medicine.symptom, business, Oxidative stress
Abstract: Background Necrotizing enterocolitis (NEC) is one of the most devastating diseases in neonates and is characterized by high morbidity and mortality. It has been suggested that neutrophils play a crucial role in NEC pathogenesis and contribute to the hyperinflammatory reaction after bacterial colonization, which ultimately induces NEC. The aim of this study was to investigate whether dissolution of neutrophil extracellular traps (NETs) by systemic DNase1 therapy reduces NEC manifestation and morbidity. Methods NEC was induced in neonatal mice by gavage feeding of lipopolysaccharide mixed in Neocate, followed by hypoxia q12 h for 5d. Inactivated DNase1 and DNase1 were administered intraperitoneally twice daily in the control and treatment groups, respectively, starting on day 5 for 72 h. Survival, NEC score, intestinal damage (Chiu score, malondialdehyde [MDA], glutathione peroxidase [GPx]), inflammation (neutrophil elastase [NE], myeloperoxidase [MPO], toll-like receptor 4 [TLR4]), and NETs markers (SYTOX orange, cell-free DNA [cfDNA], DNase, citrullinated Histone 3 [H3cit]) were then assessed. Results In total, 44 neonatal mice were used in the experiment. Mice in the treatment group demonstrated significantly reduced NEC rates (44 versus 86%, P = 0.029) and improved survival in comparison to controls (65 versus 35%, P = 0.01). Furthermore, mice treated with DNase1 showed significantly less tissue damage (cfDNA, Chiu score), oxidative stress (MDA, GPx), and inflammation (NE, MPO, H3cit, TLR4), which ultimately lead to a significant reduction in mortality. Conclusions The results of the study indicate that systemic DNase1 treatment leads to a significant reduction in tissue damage, NEC severity, and mortality. Therefore, after validation of our findings in human subjects, DNase1 treatment should be considered as a therapeutic option in neonates diagnosed with NEC.
Published: 2018

24. Spatial neglect in stroke patients after discharge from rehabilitation to own home: a mixed method study

Author: Thóra B. Hafsteinsdóttir, Haukur Hjaltason, Marianne E. Klinke, and Helga Jónsdóttir
Subjects: Male, medicine.medical_specialty, media_common.quotation_subject, medicine.medical_treatment, Qualitative property, Neuropsychological Tests, 050105 experimental psychology, Neglect, Developmental psychology, Perceptual Disorders, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, medicine, Humans, 0501 psychology and cognitive sciences, Prospective Studies, Screening procedures, Aged, media_common, Rehabilitation, 05 social sciences, Stroke Rehabilitation, Contrast (statistics), Cerebral Infarction, Middle Aged, After discharge, Patient Discharge, Vignette, Female, Psychology, Psychomotor Performance, 030217 neurology & neurosurgery, Spatial Navigation
Abstract: To explore the usefulness of conventional tests for assessing spatial neglect and contrast these tests with daily challenges encountered by patients after discharge from rehabilitation to home.A mixed method prospective study of 15 patients with neglect after a right hemisphere stroke, 1 month after discharge to home. Data were obtained from: (1) Catherine Bergego Scale (CBS), (2) star cancellation and figure copying and (3) observations and interviews. Qualitative data were analysed with content analysis and quantitative data with non-parametric statistics. The data were presented in a 'mixing matrix' and integrated by 'following threads'. Finally, a synthesis was written into a vignette.The CBS significantly underestimated fluctuations and did not capture important items of neglect. The star cancellation and figure copying did not identify neglect in mildly affected participants. Left starting point in the star cancellation and a characteristic process of drawing in figure copying were observed in all participants.Traditional numerical interpretations of paper-pencil tests inadequately confirmed mild neglect. Starting points of the star cancellation and observation of drawing should be incorporated into screening procedures. Assessment strategies need improvement to identify patients with subtle forms of neglect. Implications for Rehabilitation Findings demonstrate that identification of spatial neglect and the way symptoms of neglect impact on daily life functioning of stroke patients must be carefully pursued by health-care professionals working in stroke rehabilitation. Areas that should receive professional attention in the rehabilitation process include: preparing patients and their family for fluctuations related to neglect in the patient's own home, locating issues that might impact safety, and identifying unique factors that either enhance or diminish neglect within each patient's daily life context. The results of this study could be used to develop more wide-ranging assessment strategies to assist health-care professionals in identifying neglect after hospital discharge, for instance by expanding existing ecological assessment tools and including qualitative evaluation of test performance in paper-pencil tests, such as the star cancellation and figure copying.
Published: 2016
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25. Lung Neutrophilia in Myeloperoxidase Deficient Mice during the Course of Acute Pulmonary Inflammation

Author: Jason P. Eiserich, Tomas Perecko, Stephan Baldus, Silvie Kremserová, Lukáš Kubala, Anna Klinke, and Karel Souček
Subjects: Lipopolysaccharides, Male, 0301 basic medicine, Aging, Pathology, medicine.medical_specialty, Article Subject, Neutrophils, Acute Lung Injury, Inflammation, Lung injury, Systemic inflammation, Biochemistry, Proinflammatory cytokine, Mice, 03 medical and health sciences, medicine, Animals, lcsh:QH573-671, Peroxidase, Mice, Knockout, Lung, medicine.diagnostic_test, biology, lcsh:Cytology, business.industry, Pneumonia, Cell Biology, General Medicine, Neutrophilia, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Bronchoalveolar lavage, Myeloperoxidase, Acute Disease, Immunology, biology.protein, medicine.symptom, business, Leukocyte Disorders, Metabolism, Inborn Errors, Research Article
Abstract: Systemic inflammation accompanying diseases such as sepsis affects primarily lungs and induces their failure. This remains the most common cause of sepsis induced mortality. While neutrophils play a key role in pulmonary failure, the mechanisms remain incompletely characterized. We report that myeloperoxidase (MPO), abundant enzyme in neutrophil granules, modulates the course of acute pulmonary inflammatory responses induced by intranasal application of lipopolysaccharide. MPO deficient mice had significantly increased numbers of airway infiltrated neutrophils compared to wild-type mice during the whole course of lung inflammation. This was accompanied by higher levels of RANTES in bronchoalveolar lavage fluid from the MPO deficient mice. Other markers of lung injury and inflammation, which contribute to recruitment of neutrophils into the inflamed lungs, including total protein and other selected proinflammatory cytokines did not significantly differ in bronchoalveolar lavage fluid from the wild-type and the MPO deficient mice. Interestingly, MPO deficient neutrophils revealed a decreased rate of cell death characterized by phosphatidylserine surface expression. Collectively, the importance of MPO in regulation of pulmonary inflammation, independent of its putative microbicidal functions, can be potentially linked to MPO ability to modulate the life span of neutrophils and to affect accumulation of chemotactic factors at the inflammatory site.
Published: 2016
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26. LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann–Pick diseases

Author: Marianne Rohrbach, Martin Hersberger, Déborah Mathis, Matthias R. Baumgartner, Christel Tran, Roberto Giugliani, Matthias Gautschi, Patricie Burda, and Glynis Klinke
Subjects: Male, medicine.medical_specialty, Adolescent, Clinical Biochemistry, Gastroenterology, Limit of Detection, Reference Values, Tandem Mass Spectrometry, Internal medicine, Lc ms ms, medicine, Humans, Child, Ketocholesterols, Niemann-Pick Diseases, Detection limit, Chromatography, Chemistry, Infant, Newborn, Infant, General Medicine, medicine.disease, Reference intervals, Child, Preschool, Reference values, Female, Niemann–Pick disease, Biomarkers, Cholestanols, Chromatography, Liquid, Pediatric population
Abstract: Background Niemann–Pick type C (NP-C) is a rare progressive neurodegenerative lipid storage disorder with heterogeneous clinical presentation and challenging diagnostic procedures. Recently oxysterols have been reported to be specific biomarkers for NP-C but knowledge on the intra-individual variation and on reference intervals in children and adolescents are lacking. Methods We established a LC-MS/MS assay to measure Cholestane-3β, 5α, 6β-triol (C-triol) and 7-Ketocholesterol (7-KC) following Steglich esterification. To assess reference intervals and intra-individual variation we determined oxysterols in 148 children and adolescents from 0 to 18 years and repeat measurements in 19 of them. Results The reported method is linear (r > 0.99), sensitive (detection limit of 0.03 ng/mL [0.07 nM] for C-triol, and 0.54 ng/mL [1.35 nM] for 7-KC) and precise, with an intra-day imprecision of 4.8% and 4.1%, and an inter-day imprecision of 7.0% and 11.0% for C-triol (28 ng/ml, 67 nM) and 7-KC (32 ng/ml, 80 nM), respectively. Recoveries for 7-KC and C-triol range between 93% and 107%. The upper reference limit obtained for C-triol is 40.4 ng/mL (95% CI: 26.4–61.7 ng/mL, 96.0 nM, 95% CI: 62.8–146.7 nM) and 75.0 ng/mL for 7-KC (95% CI: 55.5–102.5 ng/mL, 187.2 nM, 95% CI: 138.53–255.8 nM), with no age or gender dependency. Both oxysterols have a broad intra-individual variation of 46% ± 23% for C-triol and 52% ± 29% for 7-KC. Nevertheless, all Niemann–Pick patients showed increased C-triol levels including Niemann–Pick type A and B patients. Conclusions The LC-MS/MS assay is a robust assay to quantify C-triol and 7-KC in plasma with well documented reference intervals in children and adolescents to screen for NP-C in the pediatric population. In addition our results suggest that especially the C-triol is a biomarker for all three Niemann–Pick diseases.
Published: 2015
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27. A systematic review of characteristics of couple-based intervention studies addressing sexuality following cancer

Author: Jona Ingibjorg Jonsdottir, Helga Jónsdóttir, and Marianne E. Klinke
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, media_common.quotation_subject, Sexual Behavior, Psychological intervention, Fidelity, Human sexuality, CINAHL, 03 medical and health sciences, Sexual and Gender Minorities, Young Adult, 0302 clinical medicine, Cancer Survivors, Medicine, Humans, Narrative, 030212 general & internal medicine, Spouses, General Nursing, media_common, Aged, Protocol (science), Aged, 80 and over, business.industry, Middle Aged, Systematic review, 030220 oncology & carcinogenesis, Family medicine, Female, business, Citation, Sexuality, Clinical psychology
Abstract: Aim To describe the characteristics of couple-based intervention studies that address sexuality following cancer. Background Sexuality-related problems are common among cancer survivors and their partners. Design Systematic literature review with a narrative summary of results. Data sources Electronic searches were conducted in PubMed, CINAHL and PsychINFO. We included studies published from 1 January 2009 - 31 December 2016. Additional information was retrieved by scrutinizing reference lists, conducting citation tracking and contacting authors. We included all types of quantitative intervention studies published in the English language which contained outcome measures corresponding to the neo-theoretical framework of sexuality—sexual function, sexual relationship and sexual self-concept. Review Methods Our review was guided by the Joanna Briggs Institute reviewer's manual. Data were extracted and appraised using the standardized checklists for quantitative studies. This assessment was conducted independently by two reviewers. A third reviewer was involved if consensus could not be reached. Results Fourteen studies were included. Interventions were delivered face-to-face, by telephone or via the Internet. Sessions ranged from 1-8, with a duration from 2-22 weeks. Most studies offered ≥3 sessions. Interventions addressed unique concerns and/or provided general education. There was little agreement on the use of outcome measures. Most studies inadequately described fidelity to the study protocol and the training of interventionists. Conclusion There was no clear consensus about how couple-based interventions are best structured. The results provide tentative evidence for how the quality of future research studies can be improved and how knowledge can be used in clinical practice.
Published: 2017

28. P2310Cardiac hypertrophy, fibrosis and diastolic dysfunction are attenuated upon administration of nitro oleic acid in a murine model of hypertensive heart disease

Author: Stephan Baldus, Matti Adam, Dennis Mehrkens, Simon Geissen, Martin Mollenhauer, A.K. Schaetzle, Anna Klinke, and Volker Rudolph
Subjects: medicine.medical_specialty, business.industry, Diastole, medicine.disease, Hypertensive heart disease, Muscle hypertrophy, Oleic acid, chemistry.chemical_compound, Endocrinology, chemistry, Murine model, Fibrosis, Internal medicine, medicine, Cardiology, Nitro, Cardiology and Cardiovascular Medicine, business
Published: 2017
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29. The diagnostic dilemma of non-convulsive status epilepticus in sporadic Creutzfeldt-Jakob disease

Author: Matthias Wittstock, Jan Klinke, Kyrylo Kurtieiev, Annette Grossmann, Johannes Rösche, Uwe Walter, and Daniela Schirrmeister
Subjects: 0301 basic medicine, non-convulsive status epilepticus, Pediatrics, medicine.medical_specialty, Neurology, Convulsive status epilepticus, business.industry, Pharmacology toxicology, sporadic Creutzfeldt-Jakob disease, Pharmacy, Diagnostic dilemma, Sporadic Creutzfeldt-Jakob disease, lcsh:RC346-429, Clinical pharmacy, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine, EEG, business, 030217 neurology & neurosurgery, lcsh:Neurology. Diseases of the nervous system
Abstract: SummaryIntroduction.The differentiation between the clinical and electroencephalographic changes in nonconvulsive status epilepticus (NCSE) and those in sporadic Creutzfeldt-Jakob disease (sCJD) is a crucial question.Case report.A 77-year old woman was admitted because of fluctuating behavioural chancaseges, adynamia and apraxia since several months for diagnostic. The diagnosis of sCJD was suggested. Subsequently, she had a generalized tonic clonic seizure (GTCS) and the EEG revealed periodic lateralized epileptiform discharges and NCSE was considered.Discussion.The presented case illustrates the dilemma in the differential diagnosis of sCJD and (symptomatic) NCSE in the light of the recently published new Salzburg consensus criteria and unified EEG terminology. Concerning these criteria, the patient showed after an initial generalized seizure and substantial clinical improvement after administration of antiepileptic drugs, persisting epileptic discharges and only subtle clinical ictal phenomena during the EEG patterns with typical spatiotemporal evolution as a correlate of a symptomatic NCSE. During the further course of the disease in the presented patient the picture changed into an encephalopathic pattern.Conclusion.EEG criteria for the diagnosis of NCSE are complex. In our case the EEG resembled the pattern of NCSE in the postictal phase of a GTCS according to a classification of NCSE in use at this time. After initial responsiveness to antiepileptic medication the patient lost responsiveness to therapy displaying the typical encephalopathic EEG findings in sCJD. These findings may support the hypothesis of initial NCSE and transformation into prion protein induced encephalopathic EEG and demonstrated clinical usefulness of the Salzburg consensus criteria for NCSE.
Published: 2017

30. Newborn Screening for Vitamin B12 Deficiency in Germany—Strategies, Results, and Public Health Implications

Author: Ulrike Mütze, Junmin Fang-Hoffmann, Péter Monostori, Karl Heinz Weiss, Georg F. Hoffmann, Roland Posset, Gwendolyn Gramer, Patrik Feyh, Glynis Klinke, and Jürgen G. Okun
Subjects: Newborn screening, Pediatrics, medicine.medical_specialty, Homocysteine, business.industry, Incidence (epidemiology), Public health, Methylmalonic acid, nutritional and metabolic diseases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Human nutrition, chemistry, 030225 pediatrics, Pediatrics, Perinatology and Child Health, Cohort, medicine, 030212 general & internal medicine, Vitamin B12, business
Abstract: Objective To evaluate a systematic newborn screening (NBS) strategy for vitamin B12 deficiency. Study design In a prospective single-center NBS study, a systematic screening strategy for vitamin B12 deficiency was developed and evaluated. Tandem-mass spectrometry screening was complemented by 2 second-tier strategies, measuring methylmalonic/3-OH-propionic/methylcitric acid, and homocysteine from dried blood spots. Results In a cohort of 176 702 children screened over 27 months, 33 children were detected by NBS in whom (maternal) vitamin B12 deficiency was confirmed. Homocysteine was the most sensitive marker for vitamin B12 deficiency, but only combination with a second-tier strategy evaluating methylmalonic acid allowed for detection of all 33 children. Mothers were of various ethnic origins, and 89% adhered to a balanced diet. Treatment in children was performed predominantly by oral vitamin B12 supplementation (84%), and all children remained without clinical symptoms at short-term follow-up. Conclusions Vitamin B12 deficiency is a treatable condition but can cause severe neurologic sequelae in infants if untreated. The proposed screening strategy is feasible and effective to identify moderate and severe cases of vitamin B12 deficiency. With an incidence of 1:5355 newborns, vitamin B12 deficiency is more frequent than inborn errors of metabolism included in NBS panels. Treatment of vitamin B12 deficiency is easy, and additional benefits can be achieved for previously undiagnosed affected mothers. This supports inclusion of vitamin B12 deficiency into NBS but also stresses the need for increased awareness of vitamin B12 deficiency in caregivers of pregnant women.
Published: 2020
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31. Multiorgan transplantation from a deceased donor with intravascular diffuse large B-cell lymphoma: transmission of the disease and results of treatment

Author: Malgorzata Klinke, Miłosz Parczewski, Krzysztof Dziewanowski, and Radosław Drozd
Subjects: Pathology, medicine.medical_specialty, medicine.medical_treatment, Antineoplastic Agents, Liver transplantation, Malignancy, Postoperative Complications, Risk Factors, Cadaver, medicine, Humans, Transplantation, Homologous, Kidney transplantation, Transplantation, Chemotherapy, Kidney, business.industry, Liver Diseases, Graft Survival, Middle Aged, Prognosis, medicine.disease, Kidney Transplantation, Tissue Donors, Liver Transplantation, Lymphoma, medicine.anatomical_structure, Female, Kidney Diseases, Lymphoma, Large B-Cell, Diffuse, business, Diffuse large B-cell lymphoma
Abstract: This report presents the transplantation of two kidneys and the liver from a deceased donor with suspected autoimmune encephalomeningitis (ADEM). Due to an atypical post-transplantation clinical course, the transplanted kidneys were biopsied and this disclosed diffuse large B-cell (DLBC) lymphoma of the intravascular type in each kidney. The same malignancy was found in the postmortem donor brain examination. The renal allografts from the two recipients were removed: despite every effort, one patient died, while chemotherapy was successful in the second. No malignancy was observed in the liver transplant recipient, who received prophylactic chemotherapy. These cases highlight the occasional failure of organ donor disease screening and the consequent unforeseen complications.
Published: 2014
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32. Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice

Author: Ulrich Wenzel, Jun Oh, Rolf A.K. Stahl, Stephan Baldus, Ralf A. Benndorf, Catherine Meyer-Schwesinger, Alexander Lehners, Heimo Ehmke, Sascha Lange, Gianina Niemann, Alva Rosendahl, and Anna Klinke
Subjects: Male, Pathology, medicine.medical_specialty, Physiology, medicine.medical_treatment, urologic and male genital diseases, Nephrectomy, Mice, Fibrosis, Autophagy, medicine, Animals, Renal Insufficiency, Chronic, Peroxidase, Mice, Knockout, Myeloperoxidase deficiency, biology, business.industry, Monocyte, Glomerulosclerosis, medicine.disease, Chemotaxis, Leukocyte, medicine.anatomical_structure, Myeloperoxidase, biology.protein, Albuminuria, medicine.symptom, business, Metabolism, Inborn Errors, Kidney disease
Abstract: Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/macrophages. Beside its well-defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wild-type mice. CKD was induced by 5/6 nephrectomy. Mice were followed for 10 wk to evaluate the impact of MPO deficiency on renal morbidity. Renal ablation induced CKD in wild-type mice with increased plasma levels of MPO compared with controls. No difference was found between MPO-deficient and wild-type mice regarding albuminuria 1 wk after renal ablation, indicating similar acute responses to renal ablation. Over the next 10 wk, however, MPO-deficient mice developed significantly less albuminuria and glomerular injury than wild-type mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes plasminogen activator inhibitor-I, collagen type III, and collagen type IV as well as matrix metalloproteinase-2 and matrix metalloproteinase-9. MPO-deficient mice also developed less renal inflammation after renal ablation, as indicated by a lower infiltration of CD3-positive T cells and F4/80-positive monocytes/macrophages compared with wild-type mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO-deficient mice was impaired compared with wild-type mice. No significant differences were observed for mortality and blood pressure after renal ablation. In conclusion, these results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice.
Published: 2014
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33. Insulin pump use in pregnancy is associated with lower HbA1c without increasing the rate of severe hypoglycaemia or diabetic ketoacidosis in women with type 1 diabetes

Author: Sonia Butalia, Qiuli M. Duan, Jason M. Kong, Lois E. Donovan, Melissa M. Kallas-Koeman, Abhay Lodha, Jennifer A. Klinke, and Ken I. Lim
Subjects: Adult, Male, Insulin pump, medicine.medical_specialty, Pediatrics, Diabetic ketoacidosis, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Diabetic Ketoacidosis, Young Adult, Insulin Infusion Systems, Pregnancy, Internal medicine, Diabetes mellitus, Internal Medicine, Humans, Hypoglycemic Agents, Insulin, Medicine, Young adult, Retrospective Studies, Glycated Hemoglobin, Type 1 diabetes, business.industry, Retrospective cohort study, medicine.disease, Hypoglycemia, Diabetes Mellitus, Type 1, Endocrinology, Female, business
Abstract: The aim of this study was to compare glycaemic control and maternal-fetal outcomes in women with type 1 diabetes managed on insulin pumps compared with multiple daily injections of insulin (MDI).In a retrospective study, glycaemic control and outcomes of 387 consecutive pregnancies in women with type 1 diabetes who attended specialised clinics at three centres 2006-2010 were assessed.Women using insulin pumps (129/387) were older and had a longer duration of diabetes, more retinopathy, smoked less in pregnancy, and had more preconception care (p0.01 for each). Among 113 pregnancies20 weeks' gestation in women on insulin pumps and 218 in women on MDI, there was a significant difference in HbA1c in the first trimester (mean HbA1c 6.90 ± 0.71% (52 ± 7.8 mmol/mol) vs 7.60 ± 1.38% (60 ± 15.1 mmol/mol), p0.001), which persisted until the third trimester (mean HbA1c 6.49 ± 0.52% (47 ± 5.7 mmol/mol) vs 6.81 ± 0.85% (51 ± 9.3 mmol/mol), p = 0.002). Rates of diabetic ketoacidosis were similar in women on insulin pumps vs MDI (1.8% vs 3.0%, p = 0.72). Despite lower HbA1c, women on insulin pumps did not have an increased incidence of severe hypoglycaemia (8.0% vs 7.6%, p = 0.90) or more weight gain (16.3 ± 8.7 vs 15.2 ± 6.2 kg, p = 0.18). More large-for-gestational-age infants in the pump group (55.0% vs 39.2%, p = 0.007) may have resulted from confounding by parity.In this large multicentre study, women using insulin pumps in pregnancy had lower HbA1c without increased risk of severe hypoglycaemia or diabetic ketoacidosis but no improvement in other pregnancy outcomes. This information can help inform care providers and patients about the glycaemic effectiveness and safety of insulin pumps in pregnancy.
Published: 2014
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34. Myeloperoxidase induces the priming of platelets

Author: Jason P. Eiserich, M. Adam, Hana Kolarova, Silvie Kremserová, Stephan Baldus, Michaela Pekarova, Anna Klinke, and Lukáš Kubala
Subjects: Blood Platelets, medicine.medical_specialty, Platelet Aggregation, animal diseases, Inflammation, Cell Communication, Nitric Oxide, Biochemistry, Nitric oxide, Pathogenesis, Mice, chemistry.chemical_compound, Physiology (medical), Internal medicine, medicine, Animals, Humans, Platelet, Receptor, Peroxidase, chemistry.chemical_classification, Reactive oxygen species, biology, Platelet Activation, Mice, Inbred C57BL, Endocrinology, chemistry, Myeloperoxidase, Hemostasis, Immunology, biology.protein, medicine.symptom
Abstract: The release of myeloperoxidase (MPO) from polymorphonuclear neutrophils is a hallmark of vascular inflammation and contributes to the pathogenesis of vascular inflammatory processes. However, the effects of MPO on platelets as a contributory mechanism in vascular inflammatory diseases remain unknown. Thus, MPO interaction with platelets and its effects on platelet function were examined. First, dose-dependent binding of MPO (between 1.7 and 13.8nM) to both human and mouse platelets was observed. This was in direct contrast to the absence of MPO in megakaryocytes. MPO was localized both on the surface of and inside platelets. Cytoskeleton inhibition did not prevent MPO localization inside the three-dimensional platelet structure. MPO peroxidase activity was preserved upon the MPO binding to platelets. MPO sequestered in platelets catabolized NO, documented by the decreased production of NO (on average, an approximately 2-fold decrease). MPO treatment did not affect the viability of platelets during short incubations; however, it decreased platelet viability after long-term storage for 7 days (an approximately 2-fold decrease). The activation of platelets by MPO was documented by an MPO-mediated increase in the expression of surface platelet receptors P-selectin and PECAM-1 (of about 5 to 20%) and the increased formation of reactive oxygen species (of about 15 to 200%). However, the activation was only partial, as MPO did not induce the aggregation of platelets nor potentiate platelet response to classical activators. Nor did MPO induce a significant release of the content of granules. The activation of platelets by MPO was connected with increased MPO-treated platelet interaction with polymorphonuclear leukocytes (an approximately 1.2-fold increase) in vitro. In conclusion, it can be suggested that MPO can interact with and activate platelets, which can induce priming of platelets, rather than the classical robust activation of platelets. This can contribute to the development of chronic inflammatory processes in vessels.
Published: 2013
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35. Ezetimibe added to statin therapy after acute coronary syndromes

Author: Cannon, Christopher P., Blazing, Michael A., Giugliano, Robert P., Mccagg, Amy, White, Jennifer A., Theroux, Pierre, Darius, Harald, Lewis, Basil S., Ophuis, Ton Oude, Jukema, J. Wouter, De Ferrari, Gaetano M., Ruzyllo, Witold, De Lucca, Paul, Kyungah, Im, Bohula, Erin A., Reist, Craig, Wiviott, Stephen D., Tershakovec, Andrew M., Musliner, Thomas A., Braunwald, Eugene, Califf, Musliner T, Robert M., Tershakovec, A, Gurfinkel, E, Aylward, P, Tonkin, A, Maurer, G, Van de Werf, F, Nicolau, Jc, Theroux, P, Genest, J, Armstrong, P, Corbalan, R, Isaza, D, Spinar, J, Grande, P, Voitk, J, Kesaniemi, A, Bassand, Jp, Farnier, M, Darius, H, Keltai, M, Mathur, A, Mittal, S, Reddy, K, Lewis, B, De Ferrari GM, Ophuis, To, Jukema, J, White, H, Pedersen, T, Britto, F, Ruzyllo, W, Carrageta, M, Duris, T, Dalby, A, Seung, Kb, Lopez-Sendon, J, Dellborg, M, Mach, F, Guneri, S, Parkhomenko, A, Brady, A, Cannon, C, Blazing, M, Ballantyne, C, de Lemos, J, Kleiman, N, Mcguire, Dk, Centeno, E, Casalins, M, Cartasegna, L, Beltrano, Mc, Guerrero, R, Fanuele, M, Berra, F, Egido, J, Colombo, H, Dellatorre, M, Terns, P, Blumberg, E, Reges, P, Azize, G, Ramos, H, Fernandez, R, Carlessi, C, Milesi, R, Schmuck, R, Duronto, E, Procopio, G, Carlevaro, O, Maffeo, H, Beloscar, J, Viso, M, Hominal, M, Castoldi, M, Bluguermann, J, Mauro, D, Macin, S, Cocco, N, Ruiz, N, Ricart, J, Lozada, A, Nani, S, Turri, D, Fernandez, H, Caruso, O, Zarandon, R, Bono, J, Arias, V, Allall, O, Marino, J, Cusimano, S, Schygiel, P, Buzetti, C, Penaloza, N, Berli, M, Worthley, S, Roach, A, Chew, D, Wright, T, Leitch, J, Hicks, E, Rankin, J, Venn-Edmonds, C, Lehman, R, Morrison, H, Shaw, J, Mak, V, Hii, C, Smith, K, Cross, D, Lilwall, L, Nelson, G, Loxton, A, Horowitz, J, Rose, J, Steinwender, C, Leisch, F, Kammler, J, Brussee, H, Zweiker, R, Niederl, E, Weihs, W, Giorgio, G, Lang, I, Drexel, H, Zanolin, D, Hoppe, U, Atzenhofer-Baumgartner, K, Pichler, M, Hainzer, D, Eber, B, Pichler, F, Foeger, B, Wechselberger, T, Mayr, H, Hofer, J, Stockenhuber, F, Warlits, B, Huber, K, Egger, F, Weidinger, F, Ziegler, B, Jirak, P, Metzler, B, Pachinger, O, Wanitschek, M, Auer, J, Grabscheit, G, Podczeck-Schweighofer, A, Priesnitz, T, Frank, H, El Allaf, D, Marechal, P, Roosen, J, Joly, E, Lefebvre, P, Arend, C, Sinnaeve, P, De Velder, L, Hellemans, S, Vanhauwaert, B, Van Dorpe, A, Heyse, A, Vantomme, C, Striekwold, H, Van Den Broeck, D, Lancellotti, P, Schoors, D, Lemoine, I, Taeymans, Y, De Wolf, L, Brike, C, Vercauteren, S, Tahon, S, Vervoort, G, Mestdagh, I, Pirenne, B, Cardinal, F, Lips, S, Dujardin, K, Debrouwer, K, Dhooghe, G, Holvoet, G, van de Borne, P, Renard, M, De Clippel, M, Lesseliers, H, Van Miert, N, Saraiva, J, Vicente, C, Rossi, P, Dos Santos LB, Duda, N, Tognon, Ap, Serrano, C, Gomes, Fl, Manenti, Er, Silveira, Ds, Maia, L, Mouco, Om, Paiva, M, Antonangelo, A, de Souza, J, Lino, Ea, Leães, P, Blacher, Mg, Kormann, A, Ultramari, Ft, Dutra, O, Mendelski, Am, Morgado, S, Ardito, W, Greque, G, Ardito, Rv, Pimentel Filho, P, Zucchetti, C, Alves, A, Seabra, Am, Mattos, M, Miranda, Lf, Silva, D, Uehara, Rm, Marin Neto, J, Schmidt, A, Braga, J, Rodrigues, A, Abrantes, J, Pinheiro, L, Bodanese, L, Magedanz, Éh, Piegas, L, Dos Santos ES, Wainstein, M, Ribeiro, J, Stein, R, Marino, R, Machado, Vm, Moraes Junior, J, Guimarães, S, da Costa FA, Ferraz, Rf, Albuquerque, D, Rocha, Rm, de Carvalho Moreira, R, Dohmann, H, Costantini, C, Tarastchuk, Jc, Coelho, O, Cirillo, W, Sousa, A, Almeira, As, Stefanini, E, Silva, F, Teixeira, M, da Cunha, C, Précoma, D, Facchi, Tl, Rupka, D, Thiessen, S, Warnica, J, Smith, B, Della Siega, A, Klinke, P, Nelson, S, Dion, D, Gilbert, N, Hui, W, Kvill, L, Sussex, B, Luther, A, Dupuis, R, Ouimet, F, Pandey, A, Clarus, S, Senaratne, M, Ferdinandis, H, Mukherjee, A, Bozek, B, Vizel, S, Markov, G, Zimmermann, R, Stephens, W, Tremblay, B, Wong, G, Uchida, N, Brossoit, R, Peck, C, Van Kieu, C, Forgione, M, Bata, I, Cossett, J, Kostuk, W, Arnold, M, Bone, C, Grondin, F, Bilodeau, N, Gosselin, G, David, M, Giannoccaro, J, Beresford, P, Polasek, P, Roberts, P, Doucet, M, Beaudry, M, Cheung, S, Cleveland, T, Bhargava, R, Mccallum, A, Ma, P, Morrissette, J, Cleveland, D, Chadwyn, D, Nigro, F, Weeks, A, Cryderman, C, Leader, R, Houde, G, Rousseau, S, Pearce, M, Radyk, M, Lonn, E, Magi, A, Lefkowitz, C, Sandrin, F, Coffin, N, Lubelsky, B, Coldwell, J, Habot, J, Mcpherson, C, De Larochelliere, R, Roy, M, Haichin, R, Barber, C, Bhesania, T, Kitagawa, H, To, T, Donnelly, B, Tymchak, W, Harris, L, Kouz, S, Huynh, T, St Jacques, B, Lamy, A, Rizzo, A, Stein, J, Childs, C, Wong, B, Poirier, R, Gupta, M, Dela Cruz, C, Constance, C, Gauthier, M, Ervin, F, Ouellette, M, Kokis, A, Lemay, C, Kwok, K, Leung, C, Lee, D, Nesmith, J, Renton, J, Syan, G, Turek, M, Hogan, D, Griffin, P, Lipson, A, Winestock, J, Abramson, B, Fogel, A, Gagne, C, Bergeron, J, Clarke, A, Slipp, S, Darcel, I, Carling-Chambers, L, Kannampuzha, P, Pallie, S, Krekorian, S, Vertes, G, Roth, S, Lai, K, Heath, J, Perez, L, Arriagada, G, Castro, P, Villa, F, Rodríguez, M, Ramos, G, Baraona, F, Núñez, A, García, M, Jofre, C, Silva, P, Lamich, R, Yovaniniz, P, Escobar, E, Dussaubat, A, Segura, E, Ramirez, M, Lapostol, C, Palma, A, Encina, L, Zapata, M, Baeza, N, Varela, P, Pérez, L, Jaramillo, C, Ruiz, S, Sanchez, G, Perdomo, I, Manzur, F, Cohen, Le, Velasquez, J, Arana, C, Alvarez, Y, Triana, M, Balaguera, J, de Salazar, D, Rendon, N, Botero, R, Ruiz, A, Saaibi, J, Medina, J, Jaramillo, M, Calderón, Mj, Delgado, J, Bohorquez, R, Medina, Mf, Herrera, M, Rosales, D, Mendoza, F, Martinez, S, Ternera, A, Castro, R, Baiz, A, Martinez, M, Orozco, A, Suarez, M, Fonseca, Y, Beltran, R, Cepeda, M, Jaramillo, N, Valenzuela, C, Gutierrez, M, Sanchez, A, Vitovec, J, Hlinomaz, O, Poloczek, M, Mayer, O, Veselka, J, Vejvoda, J, Soucek, M, Spac, J, Novobilsky, K, Srp, V, Francek, L, Branny, M, Sknouril, L, Motovska, Z, Rohac, F, Stankova, A, Fiala, T, Holub, M, Zeman, K, Pohludkova, L, Pospisilova, E, Tuma, P, Cihalik, C, Oral, I, Podpera, I, Stepanovova, R, Uricar, M, Solar, M, Pelouch, R, Porzer, M, Grussmannova, K, Stipal, R, Reichert, P, Hradec, J, Kral, J, Sejkova, B, Janek, B, Pitha, J, Linhart, A, Polacek, P, Koeber, L, Clemmensen, P, Hebin, Ch, Schmidt, E, Pedersen, Ms, Roseva-Nielsen, N, Kristensen, K, Bang-Hansen, T, Jensen, J, Laage-Petersen, J, Nielsen, H, Stokholm, E, Thayssen, P, Cappelen, H, Jensen, T, Winther-Friis, B, Klausen, I, Hedegaard, B, May, O, Andersen, M, Bottzauw, J, Lush, A, Markenvard, J, Vestager, Km, Bronnum-Schou, J, Hempel, H, Petersen, J, Nielsen, Aj, Thomsen, K, Nielsen, T, Nygaard, A, Sykulski, R, Jensen, Bs, Ralfkiaer, N, Gottschalck, H, Rasmussen, S, Pedersen, Lr, Dodt, K, Skovsbøl, M, Andersen, O, Tuxen, C, Meier, Aw, Kristensen, T, Rasmussen, O, Lopez, J, Salazar, D, Sanchez, L, Rosero, F, Penaherrera, E, Duarte, Yc, Marmol, R, Andrade, G, Guzman, E, Morillo, A, Aug, L, Loogna, I, Laanmets, P, Mustonen, J, Mäntylä, P, Kesäniemi, A, Ukkola, O, Kervinen, H, Juhela, S, Juvonen, J, Toppinen, A, Jarvenpaa, J, Syvanne, M, Svahn, T, Voutilainen, S, Huotari, A, Nikkila, M, Raiskinmäki, S, Kotila, M, Rajala, A, Laukkanen, J, Hiltunen, P, Melin, J, Nyman, K, Luukkonen, J, Kosonen, P, Huttunen, M, Seppänen, V, Airaksinen, J, Juonala, M, Lehto, S, Savolainen, K, Halkosaari, M, Sia, J, Palomaki, A, Luoma, J, Utriainen, S, Valpas, S, Tiensuu, T, Lilleberg, J, Kainulainen, R, Schiele, F, Bassand, J, Meneveau, N, Galinier, M, Jean, M, Martelet, M, Mouallem, J, Elbaz, M, Puel, J, Carrié, D, Coisne, D, Varroud-Vial, N, Jaboureck, O, Dujardin, J, Leroy, F, Mansourati, J, Funck, F, Jourdain, P, Guillard, N, Coviaux, F, Gay, A, Dourmap-Collas, C, Froger-Bompas, C, Paillard, F, Tricot, O, Maquin-Mavier, I, Dubois-Rande, Jl, Pongas, D, Paris, Ap, Delahaye, F, Ovize, M, Benyahya, L, Bonnet, J, Belle, L, Mangin, L, Lafitte, B, Zemour, G, Doux, N, Agraou, B, El Mansour, N, Traisnel, G, El Jarroudi, M, Ohlmann, P, Diadema, B, Escande, M, Legros, G, Demarcq, Jm, Haftel, Y, Alsagheer, S, Dambrine, P, Cottin, Y, Ghostine, S, Caussin, C, Gacem, A, Bouvier, Jm, Poulard, J, Davy, J, Furber, A, Prunier, F, Muenzel, T, Genth-Zotz, S, Appel, K, Kretzschmar, D, Ferrari, M, Terres, W, Uher, T, Schulze, H, Ochs, H, Morbach, S, Duengen, H, Gross, M, Oezcelik, C, Tahirovic, E, Heuer, H, Laschewski, B, Kadel, C, Rahn, G, Steiner, S, Kreuzer, J, Tsoy, I, Zeiher, A, Muegge, A, Hanefeld, C, Boehm, S, Boudriot, E, Hodenberg, E, Lippe, B, Hausdorf, C, Sydow, K, Baldus, S, Schlesner, C, Tiroch, K, Haltern, G, Guelker, H, Wilhelm, J, Dietz, S, Ebelt, H, Buerke, M, Rupprecht, H, Rittgen, J, Schaeufele, T, Meinhardt, G, Schieber, M, Honold, M, Sieprath, S, Nienaber, C, Hacker, J, Butter, C, Lapp, H, Hirn, S, Pauschinger, M, Zahn, R, Scheffler, U, Schaefer, A, Schieffer, B, Tebbe, U, Kriete, M, Mudra, H, Raeder, T, Braun, P, Zeymer, U, Kouraki, K, Reppel, M, Schunkert, H, Weil, J, Olbrich, H, Schwaiger, P, Mueller, O, Blessing, E, Buss, I, Bohlscheid, V, Kaddatz, J, Skowasch, D, Nickenig, G, Twelker, K, Osterhues, H, Varghese, T, Burghard, S, Kaeaeb, S, Klauss, V, Sohn, Hy, Hauptmann, K, 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Jinich, D., Tam, K., Vogel, C., Aggarwal, R., Zakhary, B., Curtis, S., Lyster, M., Humphrey, K., Lavine, P., Fujise, K., Birnbaum, Y., Allen, J., Kesselbrenner, M., Michel, K., Staniloae, C., Liu, M., Sonel, A., Macioce-Caffas, A., Amidon, T., Leggett, J., Yedinak, S., Gudmundsson, G., Sabharwal, J., Dagefoerde, N., Wu, W., Meyerrose, G., Roongsritong, C., Jenkins, L., Lieberman, S., Sokol, S., Gutierrez, C., Nelson, C., Barrett, J., Hotchkiss, D., Farley, A., Atassi, K., Christy, L., Baig, M., Di Fazio, J., Meengs, M., Thomas, K., Surmitis, J., DeVault, S., Farhat, N., Hulyalkar, A., Riddell, L., Rivera, W., Sheynberg, B., Kobayashi, J., Katsaropoulos, J., Jan, M., Krucoff, M., Paterno, C., Chandrasekaran, S., Curry, R., Cassavar, D., Wheeler, M., McGarvey, J., Schwarz, L., Miller, E., Andrea, B., Carswell, B.S., Lurie, M., Patti, J., Bowden, W., Vasiliauskas, T., Latham, R., Schwartz, B., Bradford, L., Mattleman, S., Wertheimer, J., Goulden, D., Khan, M., Hawkins, B., Ostfeld, R., Mueller, H., Ash, Y., Wilson, V., Bayer, M., Marshall, J., Dobies, D., Dawson, G., Osman, A., Saba, F., Costello, T., Fuentes, F., Underwood, C., Vijay, N., Washam, M., Dietz, W., Glasgow, B., Mukherjee, S., Hinchion, N., Speirs, S., Thornley, A., Lee, K., Movahed, M., Strootman, D., Chernick, R., Parrott, C., Flock, C., Marques, V., Syzmanski, E., Rama, P., Domingo, D., Wu, L., Bauer, B., Dionisopoulos, P., Aggarwal, A., Holcomb, R., Foster, R., Hancock, T., Hargrove, J., Fletcher, A., Stine, R., Bullivant, M., Adams, K., Lohman, J., Klepper, V., Kabour, A., Neidhardt, J., Phillips, W., Tardiff, S., Aji, J., Corut, S., Foster, G., Firek, C., St Goar, F., Sumner, R., Davis, T., Schneider, R., Schneider, W., Villa, A., Desai, V., Chhabra, A., Banks, K., Herzog, W., Burley, T., Quyyumi, A., Smiley, W., Manocha, P., Fishbein, G., Weller, C., Coffman, A., Kim, C., Kedia, A., Firth, B., Rizvi, M., Dahiya, R., Foster, B., Balcells, E., Metzger, D.C., Lester, J., Bissett, J., Fahdi, I., Sides, E.A., Azrin, M., Martin, C., Quick, A., Conaway, D., Garg, M., Schallert, G., Lancaster, L., Mckissick, S., Atieh, M., Garbarino, J., Eisenberg, D., Uusinarkaus, K., Wirtemburg, P., Ellis, J., Cristaldi, J., Berglund, R., Negus, B., Pappas, J., Rocha, R., Nguyen, T., Stone, J., Janosik, D., Labovitz, A., Elmore, N., Dave, R., Loffredo, K., Gabriel, G., Snyder, C., Ahmed, O., Stone, H., Kelley, M., Diffenback, M., Friedman, B., Zirkle, J., Severa, L., Sample, S., Dignen, K., Raisinghani, A., Ben-Yehuda, O., Ghannadian, B., Moscoso, R., Mankowski, J., Boliek, W., Rukavina, M., Davis, W., Ledbetter, S., Handel, F., Mastouri, R., Mahenthiran, J., Foltz, J., Malhotra, V., Jonas, J., Berk, M., Singh, V., Nelson, M., Elsner, G., Gall, J., Kondo, N., Frank, S., Chandraratna, P., Ranasinghe, S., Ebrahimi, R., Treadwell, M., Walters, B., Hughes, L., Kramer, J., Kumar, K., Mente, T., Lachterman, B., Schifferdecker, B., Munshi, K., Sease, D., Waldo, D., Chandler, G., Manns, D., Nahhas, A., Kamalesh, M., Williams, V., Reich, D., Desalca, M., Sharma, S., Liston, M., Gupta, K., Costa, M., Altschuller, A., Lemmertz, K., Shanes, J., Hansen, C., Therrien, M., Mendelson, R., Ramnarine, R., Myers, G., Donovan, C., Klein, M., Fine, D., Owens, S., Murray, C., Ketroser, R., Heifetz, S., Darnell, Z., Touchon, R., Taghizadeh, B., Bohle, D., Norwood, D., Forrest, T., Jackson, S., Shumate, K., Bayles, A., Masroor, M., North, W.K., Fishberg, R., Merveil-Ceneus, B., Butcher, R., Menapace, F., Kilbride, S., Ramabadran, R.S., Loukinen, K., Khalil, J., Ramabadran, R., Walsh, S., Gill, S., Cyncar, R., McLachlan, J., Surakanti, V., Rusterholtz, L., Shoukfeh, F., Stephenson, L., Tsang, M., Nolan, V., Gilchrist, I., Jefferson, D., Feldman, T., Reyes, L., Santos, R., Little, W., Wesley, D., Gharib, W., Mendell, A., Esham, G., Kakavas, P., Whitcomb, C., Book, K., Bazzi, A., Alvarez, J., Cohen, Y., Ayres, T., Rhule, V., Labib, A., Schuler, P., Zughaib, M., Telck, K., Bikkina, M., Turnbull, K., Sharma, T., Orosz, S., Shah, R., Petrino, M., Hughes, M., Hershey, J., Hudock, D., Hui, P., Von Bakonyi, A., Arnold, A., Kappel, D., Pennock, G., Cloud, B., Tucker, K., Harp, L., Hoover, C., Eisenhauer, M., Roth, J., Young, C., Thai, H., Escalante, A., Bautista, J., Gazmuri, R., Nyland, J., Cubeddu, L., DeFranco, A., Dias, D., Fielding, M., Reeves, R., Hermany, P., Meissner-Dengler, S., Evans, M., Flores, E., Tannenbaum, A., McGarr, K., Moran, J., Stout, E., Allred, S., Henderson, D., Crandall, L., Strote, J., Voyles, W., Robeson, D., Bedoya, R., Omar, B., Pettyjohn, F., Revere, C., Coy, K., Margolis, J., Sotolongo, C., Scheffel, M., Munir, A., Shirwany, A., Douglas, L., Girala, R., Humphreys, R., Agarwal, J., Bankowski, D., Watson, R., Bishop, B., Klementowicz, P., Blais, D., Cohen, B., Lobur, E., Dimenna, J., Dempsey, K., Izzo, M., Bondi, L., Carell, E., Eaton, C., Saltiel, F., Grewal, G., Connolly, T., Little, T., Wiegman, P., Gips, S., Held, J., Paraschos, A., Quesada, R., Goudreau, E., Sears, M., Istfan, P., Holt, S., McClung, J., Nguyen, N., Quintana, O., Gottlieb, D., Knutson, T., Barringhaus, K., Lester, F., Sullivan, P., Rodriguez-Ospina, L., Cannon, Cp, Blazing, Ma, Giugliano, Rp, Mccagg, A, White, Ja, Theroux, P, Darius, H, Lewis, B, Ophuis, To, Jukema, Jw, De Ferrari, Gm, Ruzyllo, W, De Lucca, P, Im, K, Bohula, Ea, Reist, C, Wiviott, Sd, Tershakovec, Am, Musliner, Ta, Braunwald, E, Califf, Rm, for the IMPROVE-IT, Investigator, Cianflone, D, Cardiovascular Division (SZG), Brigham and Women's Hospital [Boston], College of Information Science and Engineering, Ritsumeikan University, Montreal Heart Institute (MONTREAL HEART INSTITUTE), Laboratoire des Micro-algues toxiques, Institut Louis Malardé [Papeete] (ILM), Institut de Recherche pour le Développement (IRD)-Institut de Recherche pour le Développement (IRD), Interuniversity Cardiology Institute Netherlands, Institute of Cardiology (WARSAW - Cardiology), Institute of Cardiology, Merck Sharp & Dohme Corp., Merck & Co. Inc, DIPARTIMENTO DI MEDICINA SPECIALISTICA, DIAGNOSTICA E SPERIMENTALE, Facolta' di MEDICINA e CHIRURGIA, AREA MIN. 06 - Scienze mediche, Cannon, C.P., Blazing, M.A., Giugliano, R.P., Mccagg, A., White, J.A., Lewis, B.S., Jukema, J.W., De Lucca, P., Im, K., Bohula, E.A., Reist, C., Wiviott, S.D., Tershakovec, A.M., Musliner, T.A., Braunwald, E., Califf, R.M., for the IMPROVE-IT Investigators [.., C. Rapezzi, ], Other departments, Cannon, Christopher P, Blazing, Michael A., Giugliano, Robert P., Mccagg, Amy, White, Jennifer A., Theroux, Pierre, Darius, Harald, Lewis, Basil S., Ophuis, Ton Oude, Jukema, J. Wouter, De Ferrari, Gaetano M., Ruzyllo, Witold, De Lucca, Paul, Kyungah, Im, Bohula, Erin A., Reist, Craig, Wiviott, Stephen D., Tershakovec, Andrew M., Musliner, Thomas A., Braunwald, Eugene, and Califf, Robert M.
Subjects: Male, Simvastatin, acute coronary syndrome, aged, anticholesteremic agents, azetidines, cardiovascular diseases, cholesterol, ldl, double-blind method, drug therapy, combination, ezetimibe, female, humans, hydroxymethylglutaryl-coa reductase inhibitors, kaplan-meier estimate, male, middle aged, simvastatin, triglycerides, medicine (all, [SDV]Life Sciences [q-bio], Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Bococizumab, Triglyceride, chemistry.chemical_compound, 0302 clinical medicine, Azetidine, Cardiovascular Disease, Anticholesteremic Agent, Acute Coronary Syndrome, Aged, Anticholesteremic Agents, Azetidines, Cardiovascular Diseases, Cholesterol, LDL, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Middle Aged, Triglycerides, 030212 general & internal medicine, Medicine (all), Research Support, Non-U.S. Gov't, Hazard ratio, General Medicine, Acute Coronary Syndrome, Aged, Anticholesteremic Agents, Azetidines, Cardiovascular Diseases, Ezetimibe, Female, Humans, Male, Middle Aged, 3. Good health, Multicenter Study, Editorial, Cholesterol, Randomized Controlled Trial, Combination, Ezetimibe, lipids (amino acids, peptides, and proteins), Human, medicine.drug, medicine.medical_specialty, Acute Coronary Syndroms, Urology, Acute Coronary Syndrome/drug therapy, Anticholesteremic Agents/adverse effects, Anticholesteremic Agents/therapeutic use, Azetidines/adverse effects, Azetidines/therapeutic use, Cardiovascular Diseases/epidemiology, Cardiovascular Diseases/mortality, Cardiovascular Diseases/prevention & control, Cholesterol, LDL/blood, Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use, Simvastatin/therapeutic use, Triglycerides/blood, NO, LDL, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Drug Therapy, Internal medicine, Journal Article, medicine, Comparative Study, Alirocumab, business.industry, PCSK9, ta3121, Lomitapide, DOENÇAS CARDIOVASCULARES, Endocrinology, chemistry, Statin Therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitor, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known.METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years.RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (PCONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).
Published: 2015
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36. Patients' Experiences With Multiple Myeloma: A Meta-Aggregation of Qualitative Studies

Author: Kristín Björnsdóttir, Marianne E. Klinke, Brynja Hauksdóttir, and Sigríður Gunnarsdóttir
Subjects: Adult, Male, medicine.medical_specialty, Alternative medicine, Scopus, 03 medical and health sciences, Nursing care, 0302 clinical medicine, Quality of life (healthcare), Nursing, 030502 gerontology, Credibility, Patient experience, Adaptation, Psychological, Medicine, Humans, Qualitative Research, Aged, Aged, 80 and over, business.industry, Middle Aged, 030220 oncology & carcinogenesis, Chronic Disease, Quality of Life, Female, 0305 other medical science, business, Citation, Multiple Myeloma, Stress, Psychological, Qualitative research
Abstract: Problem identification To systematically review qualitative evidence regarding patients' experiences of living with multiple myeloma. The main objective was to gain structured understanding of this experience, which is a prerequisite for advancing nursing care and ensuring it is effective. . Literature search Qualitative research articles from January 2005 to March 2016 were located in CINAHL®, PubMed, and Scopus. Supplementary resources were found by scrutinizing reference lists and performing citation tracking. All included articles fulfilled predetermined criteria. . Data evaluation Three reviewers independently assessed the risk of methodologic bias by using the Joanna Briggs Institute (JBI) Qualitative Assessment and Review Instrument. The JBI methodology of meta-aggregation was used to synthesize findings. . Synthesis Eleven studies fulfilled the eligibility criteria. From these, 84 findings were extracted. Each finding was assigned a level of credibility. Conclusions Patients with myeloma require a different form of follow-up compared to patients with many other cancers because of its chronic nature. Results demonstrate that widespread physical, emotional, and social challenges were experienced by patients throughout their illness trajectories, even in periods of remission. Nursing care should incorporate knowledge of patients' experiences. . Implications for practice The results provide directions for nurses to improve supportive strategies in the care of patients with multiple myeloma. The categories provide a useful framework for developing clinical assessment tools.
Published: 2017

37. Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling

Author: Florian Deuschl, Max Lange, Matti Adam, Stanley L. Hazen, Yuping Wu, Martina Maass, Johanna Schneider, W.H. Wilson Tang, Tomo Saric, Jan Gesenberg, Jenny Krause, Lukáš Kubala, Volker Rudolph, Tanja K. Rudolph, Stephan Baldus, Marcel Halbach, Thorben Ravekes, Christina Kerkenpaß, Lisa Remane, Kashish Manchanda, Dennis Mehrkens, Kai Friedrichs, Birgit Geertz, Anna Klinke, Thomas Eschenhagen, Gabriel Peinkofer, Martin Mollenhauer, and Denise Lau
Subjects: 0301 basic medicine, Tachycardia, Male, medicine.medical_specialty, Physiology, Myocardial Ischemia, Infarction, Inflammation, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Organ Culture Techniques, Fibrosis, Internal medicine, medicine, Animals, Humans, Myocytes, Cardiac, Ventricular remodeling, Heme, Cells, Cultured, Cause of death, Peroxidase, Mice, Knockout, biology, Ventricular Remodeling, business.industry, Arrhythmias, Cardiac, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, chemistry, Myeloperoxidase, biology.protein, Cardiology, medicine.symptom, Cardiology and Cardiovascular Medicine, business
Abstract: Rationale: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling. Objective: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias. Methods and Results: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin–deficient (CD11b −/− ) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo −/− ) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wild-type mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo −/− mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/H 2 O 2 incubation. Mapping of induced pluripotent stem cell–derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo −/− mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias, sudden cardiac death, or implantable cardioverter–defibrillator implantation in a cohort of 2622 stable patients with an ejection fraction >35% undergoing elective diagnostic cardiac evaluation. Conclusions: Myeloperoxidase emerges as a crucial mediator of postischemic myocardial remodeling and may evolve as a novel pharmacological target for secondary disease prevention after myocardial ischemia.
Published: 2017

38. Prasugrel as opposed to clopidogrel improves endothelial nitric oxide bioavailability and reduces platelet-leukocyte interaction in patients with unstable angina pectoris: A randomized controlled trial

Author: Alexander Fuchs, Kai Friedrichs, Martin Mollenhauer, Martin Hellmich, Andrea Schlichting, Stephan Baldus, Tanja K. Rudolph, Volker Rudolph, Anna Klinke, and Edzard Schwedhelm
Subjects: 0301 basic medicine, Blood Platelets, Male, medicine.medical_specialty, Prasugrel, Ticlopidine, medicine.medical_treatment, Biological Availability, 030204 cardiovascular system & hematology, Nitric Oxide, Nitric oxide, Coronary artery disease, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, Internal medicine, medicine, Leukocytes, Humans, Platelet, cardiovascular diseases, Angina, Unstable, Aged, Unstable angina, business.industry, Percutaneous coronary intervention, Middle Aged, medicine.disease, Clopidogrel, 030104 developmental biology, chemistry, Conventional PCI, Cardiology, Female, Endothelium, Vascular, Cardiology and Cardiovascular Medicine, business, Prasugrel Hydrochloride, Platelet Aggregation Inhibitors, medicine.drug
Abstract: Background Platelet inhibition has been linked to improved endothelial function, a prognostic factor in coronary artery disease. Whether prasugrel, a potent platelet inhibitor, affects endothelial function remains unknown. Methods This was a double-blind, randomized, active-controlled, parallel trial. Patients with unstable angina pectoris undergoing percutaneous coronary intervention (PCI) received either a daily dose of clopidogrel 75mg (n=23) or prasugrel 10mg (n=22). Flow-mediated dilation (FMD), circulating nitrate and nitrite, inflammatory markers and platelet-leukocyte aggregates (PLAs) were assessed the day after PCI and after 3months. Results Baseline patient demographics were well matched between treatment groups. Prasugrel led to a significant improvement of FMD after 3months (9.01±3.64% vs. 6.65±3.24%, p=0.001). In contrast, no significant change was observed in the clopidogrel group (7.21±2.84% vs. 6.30±2.97%, p=0.187). Adjusted for baseline FMD, hyperlipidemia and statin use, the treatment effect on change in FMD favoured prasugrel by an absolute 1.97% (95% CI 0.29% to 3.66%, p=0.023). A significant reduction of plasma hsCRP, myeloperoxidase and neutrophil elastase and an increase of nitrate levels were noted in both treatment arms. Interestingly, only prasugrel significantly reduced sCD40 ligand and RANTES and increased nitrite levels. Prasugrel reduced the ADP-stimulated increase in PLAs by 40% (IR: 82 to 13), whereas clopidogrel revealed no such effect (1% increase (IR: 13 to 50) (p=0.01). Conclusion Prasugrel exhibits beneficial mid-term effects on endothelial nitric oxide bioavailability and inflammatory markers. (EudraCT number: 2009-015406-19).
Published: 2017

39. Hemispatial neglect following right hemisphere stroke: clinical course and sensitivity of diagnostic tasks

Author: Helga Jónsdóttir, Guðný Bergþóra Tryggvadóttir, Haukur Hjaltason, and Marianne E. Klinke
Subjects: Adult, Male, 030506 rehabilitation, medicine.medical_specialty, Time Factors, Stroke patient, Hemispheric stroke, medicine.medical_treatment, Symptom assessment, Sensitivity and Specificity, Functional Laterality, Perceptual Disorders, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Aged, Retrospective Studies, Aged, 80 and over, Community and Home Care, Rehabilitation, business.industry, Clinical course, Hemispatial neglect, Figure copying, Middle Aged, Stroke, Physical therapy, Female, Neurology (clinical), medicine.symptom, 0305 other medical science, business, Psychomotor Performance, 030217 neurology & neurosurgery
Abstract: Stroke patients with severe symptoms of hemispatial neglect (HN) are known to experience a weaker recovery than those less affected from the outset. Correct identification of HN is therefore important throughout the course of rehabilitation. To explore: (i) the course of clinical symptoms in stroke patients with moderate/severe HN from acute setting to home, (ii) changes in sensitivity of diagnostic tasks over time, and (iii) agreement between the researcher’s and patients’ HN assessments. Out of 79 consecutive patients, we included 23 patients with moderate/severe HN following right hemisphere stroke. The Catherine Bergego Scale was used as a benchmark for HN and to measure the congruence between the researcher’s and patients’ HN assessments. Diagnostic tasks included star cancellation, line crossing, line bisection, m-fluff test, figure copying, and clock drawing. Data were collected at t1: sub-acute stroke (days: M ± SD = 10.3 ± 5.25), t2: during rehabilitation (days: M ± SD = 51 ± 8), and t3: following discharge (days: M ± SD = 141.5 ± 47.3). (i) 20 out of 23 patients had HN at t3. Associated stroke challenges included paralysis, sensory loss, visual deficits, and extinction. (ii) Combining the star cancellation and figure copying yielded the highest sensitivity at all time points, even in patients with mild HN at t3. (iii) Patients’ HN scores differed from the researcher’s at t1. The difference was insignificant at t3. Joint consideration of stroke severity, functional difficulties, and patients’ insight into neglect provides new knowledge to increase clinicians’ recognition of HN. More extensive studies are needed to validate bedside screening with star cancellation and figure copying.
Published: 2017
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40. S1-Leitlinie zur Diagnostik und Therapie der Skabies - Kurzfassung

Author: Julia C. Stingl, Henning Hamm, Alexander Nast, Cord Sunderkötter, Regina Fölster-Holst, Sabine Klinke-Rehbein, Sandra Philipp, Bernhardt Sachs, Hermann Feldmeier, Bertram Geisel, and Johanna Stoevesandt
Subjects: Gynecology, 030207 dermatology & venereal diseases, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, business.industry, MEDLINE, Medicine, 030212 general & internal medicine, Dermatology, business
Published: 2016

41. Retrospective analysis on thermal injuries in children-Demographic, etiological and clinical data of German and Austrian pediatric hospitals 2006-2015-Approaching the new German burn registry

Author: Georg R. Herrnstadt, Sarah L. Maier, Konrad Reinshagen, Michaela Klinke, Oliver C. Thamm, Laura C. Tegtmeyer, and Ingo Koenigs
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, Population, Critical Care and Intensive Care Medicine, German, 03 medical and health sciences, 0302 clinical medicine, Age Distribution, 030225 pediatrics, Germany, Epidemiology, medicine, Retrospective analysis, Humans, Hospital Mortality, Registries, education, Child, Retrospective Studies, education.field_of_study, Trauma Severity Indices, business.industry, Infant, 030208 emergency & critical care medicine, Burn center, General Medicine, Length of Stay, Hospitals, Pediatric, language.human_language, Accidents, Home, Austria, Child, Preschool, Emergency medicine, Emergency Medicine, language, Etiology, Surgery, Observational study, Female, business, Burns, Total body surface area
Abstract: The purpose of this observational, multi-center study was to reveal epidemiologic, etiological and clinical aspects of hospitalized children with thermal injuries in Germany and Austria and the workup of a renewed web-based pediatric burn registry.From 2006 to 2015, comprehensive patient data of thermally injured children in Germany and Austria were collected prospectively. Retrospective analysis of age, gender, mechanism of injury, total body surface area burned, way of admission and length of stay was performed, followed by the comparative analysis between designated burn centers and other pediatric hospitals.32 hospitals participated in the study including data of 13,460 thermally injured hospitalized children. The majority was 12-36 months of age with a share of 48%. 56.5% were boys. The most frequent cause of injury was scalding representing 74.4%. Designated pediatric burn centers treated 82.2% of all patients. In relation to non-centers, no significant differences were seen concerning the affected total body surface area and the amount of patients1 year of age in contrast to a significant difference regarding the amount of fire injuries, all being parameters indicating the severity of thermal injuries. Overall mortality was 0.1%.This study extends our knowledge about population characterization of thermally injured children, highlights risk factors and serves as a basis for the renewed pediatric burn registry from 2016 on.
Published: 2016

42. Nitro-Oleic Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial Dysfunction

Author: Tanja K. Rudolph, Radek Kuchta, Michaela Pekarova, Jaroslav Kadlec, Hana Martiskova, Lukáš Kubala, Gabriela Ambrozova, Bruce A. Freeman, Tana Fidlerova, Adolf Koudelka, Zdenka Kuchtova, Anna Klinke, and Steven R. Woodcock
Subjects: 0301 basic medicine, STAT3 Transcription Factor, medicine.medical_specialty, Nitric Oxide Synthase Type III, Cell Survival, Oleic Acids, 030204 cardiovascular system & hematology, Pulmonary Artery, Arginine, Nitric Oxide, Article, Nitric oxide, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Enos, Cell Movement, Internal medicine, medicine, Cell Adhesion, Humans, Pharmacology (medical), Endothelial dysfunction, Cells, Cultured, Pharmacology, biology, business.industry, Interleukin-6, Endothelial Cells, General Medicine, Hypoxia (medical), medicine.disease, biology.organism_classification, Hypoxia-Inducible Factor 1, alpha Subunit, Intercellular Adhesion Molecule-1, Pulmonary hypertension, Cell Hypoxia, 030104 developmental biology, Endocrinology, Hypoxia-inducible factors, chemistry, Cardiology, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Asymmetric dimethylarginine
Abstract: Pulmonary hypertension (PH) represents a serious health complication accompanied with hypoxic conditions, elevated levels of asymmetric dimethylarginine (ADMA), and overall dysfunction of pulmonary vascular endothelium. Since the prevention strategies for treatment of PH remain largely unknown, our study aimed to explore the effect of nitro-oleic acid (OA-NO2), an exemplary nitro-fatty acid (NO2-FA), in human pulmonary artery endothelial cells (HPAEC) under the influence of hypoxia or ADMA. HPAEC were treated with OA-NO2 in the absence or presence of hypoxia and ADMA. The production of nitric oxide (NO) and interleukin-6 (IL-6) was monitored using the Griess method and ELISA, respectively. The expression or activation of different proteins (signal transducer and activator of transcription 3, STAT3; hypoxia inducible factor 1α, HIF-1α; endothelial nitric oxide synthase, eNOS; intercellular adhesion molecule-1, ICAM-1) was assessed by the Western blot technique. We discovered that OA-NO2 prevents development of endothelial dysfunction induced by either hypoxia or ADMA. OA-NO2 preserves normal cellular functions in HPAEC by increasing NO production and eNOS expression. Additionally, OA-NO2 inhibits IL-6 production as well as ICAM-1 expression, elevated by hypoxia and ADMA. Importantly, the effect of OA-NO2 is accompanied by prevention of STAT3 activation and HIF-1α stabilization. In summary, OA-NO2 eliminates the manifestation of hypoxia- and ADMA-mediated endothelial dysfunction in HPAEC via the STAT3/HIF-1α cascade. Importantly, our study is bringing a new perspective on molecular mechanisms of NO2-FAs action in pulmonary endothelial dysfunction, which represents a causal link in progression of PH.
Published: 2016

43. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author: Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. Vietsch, Anton Wellstein, Martin Wythes, Stefano Crosignani, Joseph Tumang, Shilpa Alekar, Patrick Bingham, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, JunLi Feng, Kim Frederix, Samantha Greasley, Jie Guo, James Hardwick, Stephen Kaiser, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Kevin Ryan, Stephanie Scales, Jay Srirangam, Jim Solowiej, Al Stewart, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Xianxian Zheng, Gregory Driessens, Bruno Gomes, Manfred Kraus, Chunxiao Xu, Yanping Zhang, Giorgio Kradjian, Guozhong Qin, Jin Qi, Xiaomei Xu, Bo Marelli, Huakui Yu, Wilson Guzman, Rober Tighe, Rachel Salazar, Kin-Ming Lo, Jessie English, Laszlo Radvanyi, Yan Lan, Michael Postow, Yasin Senbabaoglu, Billel Gasmi, Hong Zhong, Cailian Liu, Daniel Hirschhorhn-Cymerman, Yuanyuan Zha, Gregory Malnassy, Noreen Fulton, Jae-Hyun Park, Wendy Stock, Yusuke Nakamura, Hongtao Liu, Xiaoming Ju, Rachelle Kosoff, Kimberly Ramos, Brandon Coder, Robert Petit, Michael Princiotta, Kyle Perry, Jun Zou, Ainhoa Arina, Christian Fernandez, Wenxin Zheng, Michael A. Beckett, Helena J. Mauceri, Yang-Xin Fu, Ralph R. Weichselbaum, Whitney Lewis, Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Dongyun Wu, Jin Li, Xiaoling Liang, Xiangjun Zhou, Jinlin Hou, Raffit Hassan, Thierry Jahan, Scott J. Antonia, Hedy L. Kindler, Evan W. Alley, Somayeh Honarmand, Weiqun Liu, Meredith L. Leong, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Edward E. Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M. Coussens, Aimee L. Murphy, Dirk G. Brockstedt, Sven D. Koch, Martin Sebastian, Christian Weiss, Martin Früh, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geissler, Frank Griesinger, Jens Kollmeier, Alexandros Papachristofilou, Fatma Doener, Mariola Fotin-Mleczek, Madeleine Hipp, Henoch S. Hong, Karl-Josef Kallen, Ute Klinkhardt, Claudia Stosnach, Birgit Scheel, Andreas Schroeder, Tobias Seibel, Ulrike Gnad-Vogt, Alfred Zippelius, Ha-Ram Park, Yong-Oon Ahn, Tae Min Kim, Soyeon Kim, Seulki Kim, Yu Soo Lee, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A. Sarnaik, Luke Pike, Andrew Bang, Tracy Balboni, Allison Taylor, Alexander Spektor, Tyler Wilhite, Monica Krishnan, Daniel Cagney, Brian Alexander, Ayal Aizer, Elizabeth Buchbinder, Mark Awad, Leena Ghandi, Jonathan Schoenfeld, Elizabeth Lessey-Morillon, Lisa Ridnour, Neil H. Segal, Manish Sharma, Dung T. Le, Robert L. Ferris, Andrew D. Zelenetz, Ronald Levy, Izidore S. Lossos, Caron Jacobson, Radhakrishnan Ramchandren, John Godwin, A. Dimitrios Colevas, Roland Meier, Suba Krishnan, Xuemin Gu, Jaclyn Neely, John Timmerman, Claire I. Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Erik Wennerberg, Aranzazu Mediero, Bruce N. Cronstein, Michael P. Gustafson, AriCeli DiCostanzo, Courtney Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz, Cameron MacDonald, Mark Bucsek, Guanxi Qiao, Bonnie Hylander, Elizabeth Repasky, William J. Turbitt, Yitong Xu, Andrea Mastro, Connie J. Rogers, Sita Withers, Ziming Wang, Lam T. Khuat, Cordelia Dunai, Bruce R. Blazar, Dan Longo, Robert Rebhun, Steven K. Grossenbacher, Arta Monjazeb, William J. Murphy, Scott Rowlinson, Giulia Agnello, Susan Alters, David Lowe, Nicole Scharping, Ashley V. Menk, Ryan Whetstone, Xue Zeng, Greg M. Delgoffe, Patricia M. Santos, Jian Shi, Greg Delgoffe, Misako Nagasaka, Ammar Sukari, Miranda Byrne-Steele, Wenjing Pan, Xiaohong Hou, Brittany Brown, Mary Eisenhower, Jian Han, Natalie Collins, Robert Manguso, Hans Pope, Yashaswi Shrestha, Jesse Boehm, W. Nicholas Haining, Kyle R. Cron, Ayelet Sivan, Keston Aquino-Michaels, Marco Orecchioni, Davide Bedognetti, Wouter Hendrickx, Claudia Fuoco, Filomena Spada, Francesco Sgarrella, Gianni Cesareni, Francesco Marincola, Kostas Kostarelos, Alberto Bianco, Lucia Delogu, Jessica Roelands, Sabri Boughorbel, Julie Decock, Scott Presnell, Ena Wang, Franco M. Marincola, Peter Kuppen, Michele Ceccarelli, Darawan Rinchai, Damien Chaussabel, Lance Miller, Andrew Nguyen, J. Zachary Sanborn, Charles Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Steven Benz, Shashank Patel, Nicholas Restifo, James White, Sam Angiuoli, Mark Sausen, Sian Jones, Maria Sevdali, John Simmons, Victor Velculescu, Luis Diaz, Theresa Zhang, Jennifer S. Sims, Sunjay M. Barton, Angela Kadenhe-Chiweshe, Filemon Dela Cruz, Andrew T. Turk, Christopher F. Mazzeo, Andrew L. Kung, Jeffrey N. Bruce, Darrell J. Yamashiro, Eileen P. Connolly, Jason Baird, Marka Crittenden, David Friedman, Hong Xiao, Rom Leidner, Bryan Bell, Kristina Young, Michael Gough, Zhen Bian, Koby Kidder, Yuan Liu, Emily Curran, Xiufen Chen, Leticia P. Corrales, Justin Kline, Ethan G. Aguilar, Jennifer Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Suzan Lazo, Roderick Bronson, Anthony Letai, Richard S. Kornbluth, Sachin Gupta, James Termini, Elizabeth Guirado, Geoffrey W. Stone, Christina Meyer, Laura Helming, Nicholas Wilson, Robert Hofmeister, Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser, Tara S. Abraham, Bo Xiang, Michael S. Magee, Scott A. Waldman, Adam E. Snook, Wojciech Blogowski, Ewa Zuba-Surma, Marta Budkowska, Daria Salata, Barbara Dolegowska, Teresa Starzynska, Leo Chan, Srinivas Somanchi, Kelsey McCulley, Dean Lee, Nico Buettner, Feng Shi, Paisley T. Myers, Stuart Curbishley, Sarah A. Penny, Lora Steadman, David Millar, Ellen Speers, Nicola Ruth, Gabriel Wong, Robert Thimme, David Adams, Mark Cobbold, Remy Thomas, Mariam Al-Muftah, Michael KK Wong, Michael Morse, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Tharak Rao, Janice P. Dutcher, Kai Kang, Yogen Saunthararajah, Vamsidhar Velcheti, Vikas Kumar, Firoz Anwar, Amita Verma, Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Shruti Shrivastav, Diego A. Carrera, Shuming Liu, Naznin Jahan, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada, Jessica J. Field, Weiping Zeng, Vincent FS Shih, Che-Leung Law, Peter D. Senter, Shyra J. Gardai, Nicole M. Okeley, Jennifer G. Abelin, Abu Z. Saeed, Stacy A. Malaker, Jeffrey Shabanowitz, Stephen T. Ward, Donald F. Hunt, Pam Profusek, Laura Wood, Dale Shepard, Petros Grivas, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt, Julian P. Sefrin, Lars Hillringhaus, Valeria Lifke, Alexander Lifke, Anna Skaletskaya, Jose Ponte, Thomas Chittenden, Yulius Setiady, Eva Sivado, Vincent Thomas, Meddy El Alaoui, Sébastien Papot, Charles Dumontet, Mike Dyson, John McCafferty, Said El Alaoui, Praveen K. Bommareddy, Andrew Zloza, Frederick Kohlhapp, Ann W. Silk, Sachin Jhawar, Tomas Paneque, Jenna Newman, Pedro Beltran, Felicia Cao, Bang-Xing Hong, Tania Rodriguez-Cruz, Xiao-Tong Song, Stephen Gottschalk, Hugo Calderon, Sam Illingworth, Alice Brown, Kerry Fisher, Len Seymour, Brian Champion, Emma Eriksson, Jessica Wenthe, Ann-Charlotte Hellström, Gabriella Paul-Wetterberg, Angelica Loskog, Ioanna Milenova, Magnus Ståhle, Justyna Jarblad-Leja, Gustav Ullenhag, Anna Dimberg, Rafael Moreno, Ramon Alemany, Sharad Goyal, Ann Silk, Janice Mehnert, Nashat Gabrail, Jennifer Bryan, Daniel Medina, Leah Mitchell, Kader Yagiz, Fernando Lopez, Daniel Mendoza, Anthony Munday, Harry Gruber, Douglas Jolly, Steven Fuhrmann, Sasa Radoja, Wei Tan, Aldo Pourchet, Alan Frey, Ian Mohr, Matthew Mulvey, Robert H. I. Andtbacka, Merrick Ross, Sanjiv Agarwala, Kenneth Grossmann, Matthew Taylor, John Vetto, Rogerio Neves, Adil Daud, Hung Khong, Stephanie M. Meek, Richard Ungerleider, Scott Welden, Maki Tanaka, Matthew Williams, Sigrun Hallmeyer, Bernard Fox, Zipei Feng, Christopher Paustian, Carlo Bifulco, Sadia Zafar, Otto Hemminki, Simona Bramante, Lotta Vassilev, Hongjie Wang, Andre Lieber, Silvio Hemmi, Tanja de Gruijl, Anna Kanerva, Tameem Ansari, Srividya Sundararaman, Diana Roen, Paul Lehmann, Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Jay A. Berzofsky, Fanny Chapelin, Eric T. Ahrens, Jeff DeFalco, Michael Harbell, Amy Manning-Bog, Alexander Scholz, Danhui Zhang, Gilson Baia, Yann Chong Tan, Jeremy Sokolove, Dongkyoon Kim, Kevin Williamson, Xiaomu Chen, Jillian Colrain, Gregg Espiritu Santo, Ngan Nguyen, Wayne Volkmuth, Norman Greenberg, William Robinson, Daniel Emerling, Charles G. Drake, Daniel P. Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem A. Sheikh, David I. Quinn, Peter Kirk, Murali Addepalli, Thomas Chang, Ping Zhang, Marina Konakova, Katsunobu Hagihara, Steven Pai, Laurie VanderVeen, Palakshi Obalapur, Peiwen Kuo, Phi Quach, Lawrence Fong, Deborah H. Charych, Jonathan Zalevsky, John L. Langowski, Yolanda Kirksey, Ravi Nutakki, Shalini Kolarkar, Rhoneil Pena, Ute Hoch, Stephen K. Doberstein, John Cha, Zach Mallon, Myra Perez, Amanda McDaniel, Snjezana Anand, Darrin Uecker, Richard Nuccitelli, Eva Wieckowski, Ravikumar Muthuswamy, Roshni Ravindranathan, Ariana N. Renrick, Menaka Thounaojam, Portia Thomas, Samuel Pellom, Anil Shanker, Duafalia Dudimah, Alan Brooks, Yu-Lin Su, Tomasz Adamus, Qifang Zhang, Sergey Nechaev, Marcin Kortylewski, Spencer Wei, Clark Anderson, Chad Tang, Jonathan Schoenhals, Efrosini Tsouko, John Heymach, Patricia de Groot, Joe Chang, Kenneth R. Hess, Adi Diab, Padmanee Sharma, David Hong, James Welsh, Andrea J. Parsons, Jardin Leleux, Stephane Ascarateil, Marie Eve Koziol, Dina Bai, Peihong Dai, Weiyi Wang, Ning Yang, Stewart Shuman, Liang Deng, Patrick Dillon, Gina Petroni, David Brenin, Kim Bullock, Walter Olson, Mark E. Smolkin, Kelly Smith, Carmel Nail, Craig L. Slingluff, Meenu Sharma, Faisal Fa’ak, Louise Janssen, Hiep Khong, Zhilan Xiao, Yared Hailemichael, Manisha Singh, Christina Vianden, Willem W. Overwijk, Andrea Facciabene, Pierini Stefano, Fang Chongyung, Stavros Rafail, Michael Nielsen, Peter Vanderslice, Darren G. Woodside, Robert V. Market, Ronald J. Biediger, Upendra K. Marathi, Kevin Hollevoet, Nick Geukens, Paul Declerck, Nathalie Joly, Laura McIntosh, Eustache Paramithiotis, Magnus Rizell, Malin Sternby, Bengt Andersson, Alex Karlsson-Parra, Rui Kuai, Lukasz Ochyl, Anna Schwendeman, James Moon, Weiwen Deng, Thomas E. Hudson, Bill Hanson, Chris S. Rae, Joel Burrill, Justin Skoble, George Katibah, Michele deVries, Peter Lauer, Thomas W. Dubensky, Xin Chen, Li Zhou, Xiubao Ren, Charu Aggarwal, Drishty Mangrolia, Roger Cohen, Gregory Weinstein, Matthew Morrow, Joshua Bauml, Kim Kraynyak, Jean Boyer, Jian Yan, Jessica Lee, Laurent Humeau, Sandra Oyola, Susan Duff, David Weiner, Zane Yang, Mark Bagarazzi, Douglas G. McNeel, Jens Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu, Marit Melssen, William Grosh, Nikole Varhegyi, Nadejda Galeassi, Donna H. Deacon, Elizabeth Gaughan, Maurizio Ghisoli, Minal Barve, Robert Mennel, Gladice Wallraven, Luisa Manning, Neil Senzer, John Nemunaitis, Masahiro Ogasawara, Shuichi Ota, Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Anne Toms, Na Qiao, Jennifer Litton, George E. Peoples, Elizabeth A. Mittendorf, Lila Ghamsari, Emilio Flano, Judy Jacques, Biao Liu, Jonathan Havel, Vladimir Makarov, Timothy A. Chan, Jessica B. Flechtner, John Facciponte, Stefano Ugel, Francesco De Sanctis, George Coukos, Sébastien Paris, Agnes Pottier, Laurent Levy, Bo Lu, Federica Cappuccini, Emily Pollock, Richard Bryant, Freddie Hamdy, Adrian Hill, Irina Redchenko, Hussein Sultan, Takumi Kumai, Valentyna Fesenkova, Esteban Celis, Ingrid Fernando, Claudia Palena, Justin M. David, Elizabeth Gabitzsch, Frank Jones, James L. Gulley, Mireia Uribe Herranz, Hiroshi Wada, Atsushi Shimizu, Toshihiro Osada, Satoshi Fukaya, Eiji Sasaki, Milad Abolhalaj, David Askmyr, Kristina Lundberg, Ann-Sofie Albrekt, Lennart Greiff, Malin Lindstedt, Dallas B. Flies, Tomoe Higuchi, Wojciech Ornatowski, Jaryse Harris, Sarah F. Adams, Todd Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis Kariolis, Dadi Jang, Rie vonEbyen, Edward Graves, Lesley Ellies, Erinn Rankin, Albert Koong, Amato Giaccia, Reham Ajina, Shangzi Wang, Jill Smith, Mariaelena Pierobon, Sandra Jablonski, Emanuel Petricoin, Louis M. Weiner, Lorcan Sherry, John Waller, Mark Anderson, Alison Bigley, Chantale Bernatchez, Cara Haymaker, Harriet Kluger, Michael Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Tagliaferri, Patrick Hwu, Mario Snzol, Michael Hurwitz, Theresa Barberi, Allison Martin, Rahul Suresh, David Barakat, Sarah Harris-Bookman, Charles Drake, Alan Friedman, Sara Berkey, Stephanie Downs-Canner, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, Tullia C. Bruno, Brandon Moore, Olivia Squalls, Peggy Ebner, Katherine Waugh, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent Palmer, Jeffrey Kern, Dario Vignali, Jill Slansky, Anissa S. H. Chan, Xiaohong Qiu, Kathryn Fraser, Adria Jonas, Nadine Ottoson, Keith Gordon, Takashi O. Kangas, Steven Leonardo, Kathleen Ertelt, Richard Walsh, Mark Uhlik, Jeremy Graff, Nandita Bose, Ravi Gupta, Nitin Mandloi, Kiran Paul, Ashwini Patil, Rekha Sathian, Aparna Mohan, Malini Manoharan, Amitabha Chaudhuri, Yu Chen, Jing Lin, Yun-bin Ye, Chun-wei Xu, Gang Chen, Zeng-qing Guo, Andrey Komarov, Alex Chenchik, Michael Makhanov, Costa Frangou, Yi Zheng, Carla Coltharp, Darryn Unfricht, Ryan Dilworth, Leticia Fridman, Linying Liu, Milind Rajopadhye, Peter Miller, Fernando Concha-Benavente, Julie Bauman, Sumita Trivedi, Raghvendra Srivastava, James Ohr, Dwight Heron, Uma Duvvuri, Seungwon Kim, Heather Torrey, Toshi Mera, Yoshiaki Okubo, Eva Vanamee, Rosemary Foster, Denise Faustman, Edward Stack, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Douglas Marks, Bret Taback, Basil Horst, Laura Hix Glickman, David B. Kanne, Kelsey S. Gauthier, Anthony L. Desbien, Brian Francica, Justin L. Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal
Subjects: 0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract: O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1
Published: 2016
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44. Uric acid modulates vascular endothelial function through the down regulation of nitric oxide production

Author: Stephan Baldus, Michaela Pekarova, Lukáš Kubala, Anna Klinke, Ivana Papežíková, Antonín Lojek, Hana Kolářová, and Denise Lau
Subjects: Male, medicine.medical_specialty, Nitric Oxide Synthase Type III, Endothelium, Down-Regulation, Coronary Artery Disease, Hyperuricemia, Biology, Nitric Oxide, urologic and male genital diseases, Biochemistry, Cell Line, Nitric oxide, Mice, chemistry.chemical_compound, Superoxides, Internal medicine, Human Umbilical Vein Endothelial Cells, medicine, Animals, Humans, Phosphorylation, Endothelial dysfunction, chemistry.chemical_classification, Reactive oxygen species, Arginase, Superoxide, nutritional and metabolic diseases, General Medicine, medicine.disease, Acetylcholine, Uric Acid, Bioavailability, Mice, Inbred C57BL, medicine.anatomical_structure, Endocrinology, chemistry, Uric acid, Endothelium, Vascular, Reactive Oxygen Species
Abstract: Endothelial dysfunction characterized by decreased nitric oxide (NO) bioavailability is the first stage of coronary artery disease. It is known that one of the factors associated with an increased risk of coronary artery disease is a high plasma level of uric acid. However, causative associations between hyperuricaemia and cardiovascular risk have not been definitely proved. In this work, we tested the effect of uric acid on endothelial NO bioavailability. Electrochemical measurement of NO production in acetylcholine-stimulated human umbilical endothelial cells (HUVECs) revealed that uric acid markedly decreases NO release. This finding was confirmed by organ bath experiments on mouse aortic segments. Uric acid dose-dependently reduced endothelium-dependent vasorelaxation. To reveal the mechanism of decreasing NO bioavailability we tested the effect of uric acid on reactive oxygen species production by HUVECs, on arginase activity, and on acetylcholine-induced endothelial NO synthase phosphorylation. It was found that uric acid increases arginase activity and reduces endothelial NO synthase phosphorylation. Interestingly, uric acid significantly increased intracellular superoxide formation. In conclusion, uric acid decreases NO bioavailability by means of multiple mechanisms. This finding supports the idea of a causal association between hyperuricaemia and cardiovascular risk.
Published: 2012
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45. A Second-Generation MicroRNA-Based Assay for Diagnosing Tumor Tissue Origin

Author: Elizabeth Klinke, Wolf Mueller, Franz Fogt, Mats Sanden, Tina Bocker Edmonston, Yael Spector, Monica Huszar, Eti Meiri, Ulrike Lass, Karin Ashkenazi, Meora Feinmesser, Ilanit Burnstein, Shai Rosenwald, Iris Barshack, Nir Dromi, Eran Goren, Ranit Aharonov, Ayelet Chajut, Margot Werner, Merav Zepeniuk, and Orit Zion
Subjects: Adult, Male, Cancer Research, Pathology, medicine.medical_specialty, Cancer Diagnostics and Molecular Pathology, Real-Time Polymerase Chain Reaction, medicine.disease_cause, Sensitivity and Specificity, law.invention, law, microRNA, Biomarkers, Tumor, Humans, Medicine, Gene, Polymerase chain reaction, Aged, Aged, 80 and over, Regulation of gene expression, business.industry, Gene Expression Profiling, Decision Trees, Cancer, Middle Aged, medicine.disease, United States, Gene Expression Regulation, Neoplastic, Gene expression profiling, MicroRNAs, Real-time polymerase chain reaction, Oncology, Cancer research, Neoplasms, Unknown Primary, Biological Assay, Female, business, Carcinogenesis, Signal Transduction
Abstract: Background. Cancers of unknown primary origin (CUP) constitute 3%–5% (50,000 to 70,000 cases) of all newly diagnosed cancers per year in the United States. Including cancers of uncertain primary origin, the total number increases to 12%–15% (180,000 to 220,000 cases) of all newly diagnosed cancers per year in the United States. Cancers of unknown/uncertain primary origins present major diagnostic and clinical challenges because the tumor tissue of origin is crucial for selecting optimal treatment. MicroRNAs are a family of noncoding, regulatory RNA genes involved in carcinogenesis. MicroRNAs that are highly stable in clinical samples and tissue specific serve as ideal biomarkers for cancer diagnosis. Our first-generation assay identified the tumor of origin based on 48 microRNAs measured on a quantitative real-time polymerase chain reaction platform and differentiated 25 tumor types. Methods. We present here the development and validation of a second-generation assay that identifies 42 tumor types using a custom microarray. A combination of a binary decision-tree and a k-nearest-neighbor classifier was developed to identify the tumor of origin based on the expression of 64 microRNAs. Results. Overall assay sensitivity (positive agreement), measured blindly on a validation set of 509 independent samples, was 85%. The sensitivity reached 90% for cases in which the assay reported a single answer (>80% of cases). A clinical validation study on 52 true CUP patients showed 88% concordance with the clinicopathological evaluation of the patients. Conclusion. The abilities of the assay to identify 42 tumor types with high accuracy and to maintain the same performance in samples from patients clinically diagnosed with CUP promise improved utility in the diagnosis of cancers of unknown/uncertain primary origins.
Published: 2012
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46. Non-red blood cell transfusion as a risk factor for mortality following percutaneous coronary intervention

Author: W. Peter Klinke, Gerald Simkus, J. David Hilton, Brian R. Berry, Anthony Fung, Eric Fretz, Christian Janssen, Alex Chase, Ronald G. Carere, Simon D. Robinson, and Anthony Della Siega
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, Hemorrhage, Platelet Transfusion, Plasma, Risk Factors, Blood product, Internal medicine, Humans, Medicine, Platelet, Angioplasty, Balloon, Coronary, Risk factor, Aged, Aged, 80 and over, business.industry, Contraindications, Percutaneous coronary intervention, Middle Aged, Surgery, Cardiac surgery, Survival Rate, Cryoprecipitate, Conventional PCI, Cohort, Female, Erythrocyte Transfusion, Cardiology and Cardiovascular Medicine, business
Abstract: Bleeding following percutaneous coronary intervention (PCI) is common and may lead to transfusion and death. Although previous work has examined the effect of red blood cell (RBC) transfusion in patients with coronary disease, no study had investigated whether transfusion of non-RBC components was associated with mortality following PCI.All subjects transfused in the 10 days following PCI were identified using the British Columbia Cardiac and Central Transfusion Registries. Patients undergoing cardiac surgery following PCI were excluded as transfusion was assumed to be due to surgical related bleeding. Transfusion products were categorised as RBC and non-RBC comprising platelets, plasma and cryoprecipitate. Blood product use was compared according to thirty day mortality using multivariate regression and propensity adjustment for confounding variables.From a total of 32,580 patients who underwent PCI, 952 patients received at least 1 blood product within 10 days of PCI. Non-RBC transfusion occurred more commonly in the cohort of transfused patients dying within 30 days (p0.001). After adjustment for baseline risk, transfusion of plasma/cryoprecipitate (HR 5.17; 95% C.I. 2.87-9.32, p0.001) and platelets (HR 2.13; 95% C.I. 1.10-4.13, p=0.03) was associated with increased 30 day mortality. In a propensity risk adjusted model, transfusion of plasma/cryoprecipitate and RBC transfusion volume remained as significant predictors of 30-day mortality (p0.001).Transfusion following PCI appears to be associated with an increased risk of death within 30 days. We now report that transfusion with plasma rich non-RBC products may confer an additional mortality risk to patients undergoing PCI.
Published: 2012
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47. TECHNIKI OBRAZOWANIA Single round shadow of the lung: carcinoma or round pneumonia? – diagnostic problem, differential diagnosis

Author: Jerzy Kozielski, Jan Głowacki, Joanna Witkowska-Klinke, Edyta Machura, Ewa Kluczewska, and Franciszek Halkiewicz
Subjects: Pathology, medicine.medical_specialty, Lung, business.industry, medicine.disease, Pneumonia, medicine.anatomical_structure, medicine, Carcinoma, Surgery, Differential diagnosis, Cardiology and Cardiovascular Medicine, business, Shadow (psychology)
Published: 2012
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48. Diagnostic value of MPO plasma levels in patients admitted for suspected myocardial infarction

Author: Karl Wegscheider, Constantin Bös, Britta U. Goldmann, Kai Friedrichs, Munif Haddad, Stephan Baldus, Anna Klinke, Denise Lau, Volker Rudolph, Thomas Meinertz, and Tanja K. Rudolph
Subjects: Male, medicine.medical_specialty, Myocardial Infarction, Chest pain, Gastroenterology, Patient Admission, Internal medicine, Troponin I, medicine, Humans, In patient, Myocardial infarction, Aged, Peroxidase, biology, business.industry, Plasma levels, Middle Aged, medicine.disease, Confidence interval, Surgery, Myeloperoxidase, biology.protein, Female, Myocardial infarction diagnosis, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract: Background Besides its well-established role in atherosclerosis, myeloperoxidase (MPO) has gained attention as a prognostic indicator in cardiovascular disease. Previous studies assessed MPO retrospectively and at a single time point. The current study aimed to evaluate the prognostic information of MPO prospectively and in consecutive measurements in patients presenting with chest pain. Methods MPO plasma levels were determined in 274 consecutive chest pain patients admitted to the emergency room. Results A total of 100 patients (36.5%) were finally diagnosed for acute myocardial infarction (AMI). Patients with AMI had significantly higher MPO levels than patients without AMI. Importantly, MPO levels were elevated in patients finally diagnosed for AMI even when troponin I (TNI) was negative (cutoff: 0.032ng/ml). Overall, MPO yielded a negative predictive value (NPV) of 85.5% (95% confidence interval (CI): 82.6–88.4) and a sensitivity for diagnosing AMI of 80.0% (95% CI: 75.8–84.2) compared to a NPV of 91.7% (95% CI: 89.5–94.0) and a sensitivity of 85.9% (95% CI: 82.3–89.5) for TNI. For patients with a symptom onset of ≤2h the sensitivity of MPO increased to 95.8% (95% CI: 93.7–97.9) whereas the sensitivity of TNI dropped to 50.0% (95% CI: 44.8–55.2). The negative predictive value of MPO for this group of patients was 95.6% (95% CI: 94.0–97.3) compared to 73.3% (95% CI: 69.8–76.9) for TNI. Discussion The current data underscore the role of MPO as diagnostic marker in acute coronary disease; however the additive information derived from MPO is restricted to patients presenting in the early phase of symptom onset.
Published: 2011
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49. Prothetische Planungsansätze im hohen Alter

Author: Amro Daboul, Reiner Biffar, Th Klinke, and S Samietz
Subjects: Gynecology, medicine.medical_specialty, business.industry, Medicine, General Medicine, business
Abstract: Die Erfolge der zahnarztlichen Prophylaxe fuhren dazu, dass im Vergleich zu vorangegangenen Generationen bei alteren Patienten eine hohere Anzahl von Zahnen vorhanden ist. Die prothetische Versorgung alterer Patienten stellt den Behandler vor eine grose Herausforderung: Die Therapieplanung muss die altersassoziierte Compliance, ihre Mobilitat und spezifisch veranderte Lebensumstande berucksichtigen. Prothetische Fragestellungen mussen in diesem Licht hinterfragt werden. Die Einordnung des oralen Gesundheitszustands und der Mobilitat als ein Ausdruck des Allgemeinzustands konnen als Hilfestellung fur eine suffiziente Therapiestrategie herangezogen werden.
Published: 2011
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50. Myeloperoxidase deficiency preserves vasomotor function in humans

Author: Kay Knöll, Christian Detter, Anna Klinke, Edzard Schwedhelm, Heimo Ehmke, R H Boeger, Sabine Wipper, Denise Lau, Volker Rudolph, Thomas Rau, Anja Coym, B Reiter, Kai Friedrichs, Detlef Russ, Bernd Schroeder, Mandy Kolk, Michaela Pekarova, Hilke Andresen, Tanja K. Rudolph, Karl Wegscheider, and Stephan Baldus
Subjects: Adult, Male, medicine.medical_specialty, Nicotine, Endothelium, Neutrophils, Sus scrofa, Hemodynamics, Vasomotion, Vasodilation, Nitric Oxide, Neutrophil Activation, Nitric oxide, Coronary circulation, chemistry.chemical_compound, Young Adult, Basic Science, Internal medicine, Coronary Circulation, medicine, Animals, Humans, Mammary Arteries, Vascular tone, Aged, Peroxidase, Myeloperoxidase deficiency, Myeloperoxidase, biology, business.industry, Leucocyte, Middle Aged, medicine.disease, Vasomotor System, Endocrinology, medicine.anatomical_structure, chemistry, Matrix Metalloproteinase 9, biology.protein, Endothelium, Vascular, Cardiology and Cardiovascular Medicine, business, Blood Flow Velocity
Abstract: Aims Observational studies have suggested a mechanistic link between the leucocyte-derived enzyme myeloperoxidase (MPO) and vasomotor function. Here, we tested whether MPO is systemically affecting vascular tone in humans. Methods and results A total of 12 135 patients were screened for leucocyte peroxidase activity. We identified 15 individuals with low MPO expression and activity (MPOlow), who were matched with 30 participants exhibiting normal MPO protein content and activity (control). Nicotine-dependent activation of leucocytes caused attenuation of endothelial nitric oxide (NO) bioavailability in the control group ( P < 0.01), but not in MPOlow individuals ( P = 0.12); here the MPO burden of leucocytes correlated with the degree of vasomotor dysfunction ( P = 0.008). To directly test the vasoactive properties of free circulating MPO, the enzyme was injected into the left atrium of anaesthetized, open-chest pigs. Myeloperoxidase plasma levels peaked within minutes and rapidly declined thereafter, reflecting vascular binding of MPO. Blood flow in the left anterior descending artery and the internal mammary artery (IMA) as well as myocardial perfusion decreased following MPO injection when compared with albumin-treated animals ( P < 0.001). Isolated IMA-rings from animals subjected to MPO revealed markedly diminished relaxation in response to acetylcholine ( P < 0.01) and nitroglycerine as opposed to controls ( P < 0.001). Conclusion Myeloperoxidase elicits profound effects on vascular tone of conductance and resistance vessels in vivo . These findings not only call for revisiting the biological functions of leucocytes as systemic and mobile effectors of vascular tone, but also identify MPO as a critical systemic regulator of vasomotion in humans and thus a potential therapeutic target.
Published: 2011

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