Publications by authors named "Christian Appenzeller-Herzog"

50 Publications

Using citation tracking for systematic literature searching - study protocol for a scoping review of methodological studies and a Delphi study.

F1000Res 2020 1;9:1386. Epub 2020 Dec 1.

University Medical Library, University of Basel, Basel, Switzerland.

Up-to-date guidance on comprehensive study identification for systematic reviews is crucial. According to current recommendations, systematic searching should combine electronic database searching with supplementary search methods. One such supplementary search method is citation tracking. It aims at collecting directly and/or indirectly cited and citing references from "seed references". Tailored and evidence-guided recommendations concerning the use of citation tracking are strongly needed. We intend to develop recommendations for the use of citation tracking in systematic literature searching for health-related topics. Our study will be guided by the following research questions: What is the benefit of citation tracking for systematic literature searching for health-related topics? Which methods, citation indexes, and other tools are used for citation tracking? What terminology is used for citation tracking methods? Our study will have two parts: a scoping review and a Delphi study. The scoping review aims at identifying methodological studies on the benefit and use of citation tracking in systematic literature searching for health-related topics with no restrictions on study design, language, and publication date. We will perform database searching in MEDLINE (Ovid), CINAHL (EBSCOhost), Web of Science Core Collection, two information science databases, web searching, and contact experts in the field. Two reviewers will independently perform study selection. We will conduct direct backward and forward citation tracking on included articles. Data from included studies will be extracted using a prespecified extraction sheet and presented in both tabular and narrative form. The results of the scoping review will inform the subsequent Delphi study through which we aim to derive consensus recommendations for the future practice and research of citation tracking.
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http://dx.doi.org/10.12688/f1000research.27337.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474097PMC
December 2020

Diagnosing Overtraining Syndrome: A Scoping Review.

Sports Health 2021 Sep 9:19417381211044739. Epub 2021 Sep 9.

Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland.

Context: Overtraining syndrome (OTS) is a condition characterized by a long-term performance decrement, which occurs after a persisting imbalance between training-related and nontraining-related load and recovery. Because of the lack of a gold standard diagnostic test, OTS remains a diagnosis of exclusion.

Objective: To systematically review and map biomarkers and tools reported in the literature as potentially diagnostic for OTS.

Data Sources: PubMed, Web of Science, and SPORTDiscus were searched from database inception to February 4, 2021, and results screened for eligibility. Backward and forward citation tracking on eligible records were used to complement results of database searching.

Study Selection: Studies including athletes with a likely OTS diagnosis, as defined by the European College of Sport Science and the American College of Sports Medicine, and reporting at least 1 biomarker or tool potentially diagnostic for OTS were deemed eligible.

Study Design: Scoping review following the guidelines of the Joanna Briggs Institute and PRISMA Extension for Scoping Reviews (PRISMA-ScR).

Level Of Evidence: Level 4.

Data Extraction: Athletes' population, criteria used to diagnose OTS, potentially diagnostic biomarkers and tools, as well as miscellaneous study characteristics were extracted.

Results: The search yielded 5561 results, of which 39 met the eligibility criteria. Three diagnostic scores, namely the EROS-CLINICAL, EROS-SIMPLIFIED, and EROS-COMPLETE scores (EROS = Endocrine and Metabolic Responses on Overtraining Syndrome study), were identified. Additionally, basal hormone, neurotransmitter and other metabolite levels, hormonal responses to stimuli, psychological questionnaires, exercise tests, heart rate variability, electroencephalography, immunological and redox parameters, muscle structure, and body composition were reported as potentially diagnostic for OTS.

Conclusion: Specific hormones, neurotransmitters, and metabolites, as well as psychological, electrocardiographic, electroencephalographic, and immunological patterns were identified as potentially diagnostic for OTS, reflecting its multisystemic nature. As exemplified by the EROS scores, combinations of these variables may be required to diagnose OTS. These scores must now be validated in larger samples and within female athletes.
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http://dx.doi.org/10.1177/19417381211044739DOI Listing
September 2021

Monitoring Changes in the Oxidizing Milieu in the Endoplasmic Reticulum of Mammalian Cells Using HyPerER.

Bio Protoc 2021 Jul 5;11(13):e4076. Epub 2021 Jul 5.

Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.

The production of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress are tightly linked. The generation of ROS can be both the cause and a consequence of ER stress pathways, and an increasing number of human diseases are characterized by tissue atrophy in response to ER stress and oxidative injury. For the assessment of modulators of ER luminal ROS generation and for mechanistic studies, methods to monitor changes in ER reduction-oxidation (redox) states in a time-resolved and organelle-specific manner are needed. This has been greatly facilitated by the development of genetically encoded fluorescent probes, which can be targeted to different subcellular locations by specific amino acid extensions. One of these probes is the yellow fluorescent protein-based redox biosensor, HyPer. Here, we provide a protocol for the time-resolved monitoring of the oxidizing milieu in the ER of adherent mammalian cells using the ratiometric sensor, HyPerER, which is specifically targeted to the ER lumen.
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http://dx.doi.org/10.21769/BioProtoc.4076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292116PMC
July 2021

Outcome of right ventricular assist device implantation following left ventricular assist device implantation: Systematic review and meta-analysis.

Perfusion 2021 Jun 11:2676591211024817. Epub 2021 Jun 11.

Department of Cardiac Surgery, University Hospital Basel, Basel, Switzerland.

Objectives: The main aim was a systematic evaluation of the current evidence on outcomes for patients undergoing right ventricular assist device (RVAD) implantation following left ventricular assist device (LVAD) implantation.

Methods: This systematic review was registered on PROSPERO (CRD42019130131). Reports evaluating in-hospital as well as follow-up outcome in LVAD and LVAD/RVAD implantation were identified through Ovid Medline, Web of Science and EMBASE. The primary endpoint was mortality at the hospital stay and at follow-up. Pooled incidence of defined endpoints was calculated by using random effects models.

Results: A total of 35 retrospective studies that included 3260 patients were analyzed. 30 days mortality was in favour of isolated LVAD implantation 6.74% (1.98-11.5%) versus 31.9% (19.78-44.02%) p = 0.001 in LVAD with temporary need for RVAD. During the hospital stay the incidence of major bleeding was 18.7% (18.2-19.4%) versus 40.0% (36.3-48.8%) and stroke rate was 5.6% (5.4-5.8%) versus 20.9% (16.8-28.3%) and was in favour of isolated LVAD implantation. Mortality reported at short-term as well at long-term was 19.66% (CI 15.73-23.59%) and 33.90% (CI 8.84-59.96%) in LVAD respectively versus 45.35% (CI 35.31-55.4%) p ⩽ 0.001 and 48.23% (CI 16.01-80.45%) p = 0.686 in LVAD/RVAD group respectively.

Conclusion: Implantation of a temporary RVAD is allied with a worse outcome during the primary hospitalization and at follow-up. Compared to isolated LVAD support, biventricular mechanical circulatory support leads to an elevated mortality and higher incidence of adverse events such as bleeding and stroke.
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http://dx.doi.org/10.1177/02676591211024817DOI Listing
June 2021

Abductor Muscle Strength Deficit in Patients After Total Hip Arthroplasty: A Systematic Review and Meta-Analysis.

J Arthroplasty 2021 08 25;36(8):3015-3027. Epub 2021 Mar 25.

Department of Orthopaedics and Traumatology, University Hospital Basel, Basel, Switzerland; Department of Clinical Research, University of Basel, Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Basel, Switzerland; Department of Spine Surgery, University Hospital Basel, Basel, Switzerland.

Background: The aims of this study were to assess and quantify hip abductor muscle strength deficits after total hip arthroplasty (THA) and to determine associations with external factors.

Methods: Studies reporting on hip abductor muscle strength before and/or after THA performed for osteoarthritis or atraumatic osteonecrosis of the hip were considered for inclusion. Data sources were Embase, Medline, and the Cochrane Central Register of Controlled Trials. Muscle strength on the affected side was compared with the healthy contralateral side or with control subjects. Study quality was assessed using a modified Newcastle-Ottawa Scale.

Results: Nineteen studies reporting on 875 subjects met the inclusion criteria. Patients scheduled for THA had a mean strength deficit of 18.6% (95% confidence interval (CI) [-33.9, -3.2%]) compared with control subjects. Abductor muscle strength then increased by 20.2% (CI [5.6, 34.8%]) at 4-6 months, 29.6% (CI [4.7, 54.4%]) at 9-12 months, and 49.8% (CI [-31.0, 130.6%]) at 18-24 months postoperatively compared with preoperative values. For unilateral THA, the mean torque ratio was 86.3% (CI [75.4, 97.2%]) and 93.4% (CI [75.1, 111.6%]) before and >24 months after THA, respectively. Study quality was low to moderate.

Conclusion: Hip abductor muscle strength deficits may gradually improve during 24 months after THA possibly without complete recovery. Cautious interpretation of these findings is warranted because high-quality evidence is largely missing.
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http://dx.doi.org/10.1016/j.arth.2021.03.042DOI Listing
August 2021

Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: A scoping review.

Am J Transplant 2021 10 1;21(10):3312-3323. Epub 2021 May 1.

Institute of Liver Studies, King's College Hospital, London, UK.

Indefinite allograft acceptance after immunosuppression withdrawal (ISW), also known as operational tolerance (OT), can occur spontaneously after liver transplantation (LT), but reliable and reproducible prognosis of OT versus non-OT outcomes remains elusive. To prime this, systematic extraction of OT-predictive factors from the literature is crucial. We provide the first comprehensive identification and synthesis of clinical parameters and biomarkers predicting spontaneous OT in non-autoimmune/non-replicative viral LT recipients selected for ISW. We searched Embase, Medline, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform for articles, conference abstracts, and ongoing trials. We contacted principal investigators of stand-alone abstracts and ongoing trials for unpublished data and screened citations and references of eligible articles. Twenty-three articles reporting on 11 completed ISW studies, 13 abstracts, and five trial registry entries were included. Longer time between LT and ISW was the only clinical parameter that may increase the incidence of OT. Prognostic biomarkers conspicuously differed between pediatric and adult ISW candidates. These included allograft gene expression patterns and peripheral blood immune exhaustion markers for adults, and histological allograft scores for children. Our results will foster cross-validation efforts to facilitate safe and harmonized candidate selection for successful ISW.
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http://dx.doi.org/10.1111/ajt.16585DOI Listing
October 2021

A systematic review on conservative treatment options for OSGOOD-Schlatter disease.

Phys Ther Sport 2021 May 9;49:178-187. Epub 2021 Mar 9.

Department of Sport, Exercise and Health, University of Basel, Birsstrasse 320 B, 4052, Basel, Switzerland. Electronic address:

Objectives: Osgood-Schlatter disease (OSD) is a sport- and growth-associated knee pathology with locally painful alterations around the tibial tuberosity apophysis. Up to 10% of adolescents are affected by OSD. Treatment is predominantly conservative. The aims of this systematic review are to comprehensively identify conservative treatment options for OSD, compare their effectiveness in selected outcomes, and describe potential research gaps.

Methods: A systematic literature search was conducted using CENTRAL, CINAHL, EMBASE, MEDLINE, and PEDro databases. In addition, ongoing and unpublished clinical studies, dissertations, and other grey literature on OSD were searched. We also systematically retrieved review articles for extraction of treatment recommendations.

Results: Of 767 identified studies, thirteen were included, comprising only two randomised controlled trials (RCTs). The included studies were published from 1948 to 2019 and included 747 patients with 937 affected knees. Study quality was poor to moderate. In addition to the studies, 15 review articles were included, among which the most prevalent treatment recommendations were compiled.

Conclusion: Certain therapeutic approaches, such as stretching, have apparent efficacy, but no RCT comparing specific exercises with sham or usual-care treatment exists. Carefully controlled studies on well-described treatment approaches are needed to establish which conservative treatment options are most effective for patients with OSD.
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http://dx.doi.org/10.1016/j.ptsp.2021.03.002DOI Listing
May 2021

The metabolic signature of cardiorespiratory fitness: a protocol for a systematic review and meta-analysis.

BMJ Open Sport Exerc Med 2021 19;7(1):e001008. Epub 2021 Feb 19.

Division of Sports and Exercise Medicine, Department of Sport, Exercise and Health, University of Basel, Basel, Switzerland.

Introduction: A low cardiorespiratory fitness (CRF) is a strong and independent predictor of cardiometabolic, cancer and all-cause mortality. To date, the mechanisms linking CRF with reduced mortality remain largely unknown. Metabolomics, which is a powerful metabolic phenotyping technology to unravel molecular mechanisms underlying complex phenotypes, could elucidate how CRF fosters human health.

Methods And Analysis: This study aims at systematically reviewing and meta-analysing the literature on metabolites of any human tissue sample, which are positively or negatively associated with CRF. Studies reporting estimated CRF will not be considered. No restrictions will be placed on the metabolomics technology used to measure metabolites. PubMed, Web of Science and EMBASE will be searched for relevant articles published until the date of the last search. Two authors will independently screen full texts of selected abstracts. References and citing articles of included articles will be screened for additional relevant publications. Data regarding study population, tissue samples, analytical technique, quality control, data processing, metabolites associated to CRF, cardiopulmonary exercise test protocol and exercise exhaustion criteria will be extracted. Methodological quality will be assessed using a modified version of QUADOMICS. Narrative synthesis as well as tabular/charted presentation of the extracted data will be included. If feasible, meta-analyses will be used to investigate the associations between identified metabolites and CRF. Potential sources of heterogeneity will be explored in meta-regressions.

Ethics And Dissemination: No ethics approval is required. The results will be published in a peer-reviewed journal and as conference presentation.

Prospero Registration Number: CRD42020214375.
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http://dx.doi.org/10.1136/bmjsem-2020-001008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898858PMC
February 2021

Interventions Facilitating Family Communication of Genetic Testing Results and Cascade Screening in Hereditary Breast/Ovarian Cancer or Lynch Syndrome: A Systematic Review and Meta-Analysis.

Cancers (Basel) 2021 Feb 23;13(4). Epub 2021 Feb 23.

Department of Clinical Research, Faculty of Medicine, University of Basel, 4055 Basel, Switzerland.

Evidence-based guidelines recommend cascade genetic testing of blood relatives of known Hereditary Breast and Ovarian Cancer (HBOC) or Lynch Syndrome (LS) cases, to inform individualized cancer screening and prevention plans. The study identified interventions designed to facilitate family communication of genetic testing results and/or cancer predisposition cascade genetic testing for HBOC and LS. We conducted a systematic review and meta-analysis of randomized trials that assessed intervention efficacy for these two outcomes. Additional outcomes were also recorded and synthesized when possible. Fourteen articles met the inclusion criteria and were included in the narrative synthesis and 13 in the meta-analysis. Lack of participant blinding was the most common risk of bias. Interventions targeted HBOC ( 5); both HBOC and LS ( 4); LS ( 3); or ovarian cancer ( 2). All protocols ( 14) included a psychoeducational and/or counseling component. Additional components were decision aids ( 4), building communication skills ( 4), or motivational interviewing ( 1). The overall effect size for family communication was small ( 0.085) and not significant ( 0.344), while for cascade testing, it was small ( 0.169) but significant ( 0.014). Interventions show promise for improving cancer predisposition cascade genetic testing for HBOC and LS. Future studies should employ family-based approaches and include racially diverse samples.
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http://dx.doi.org/10.3390/cancers13040925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926393PMC
February 2021

Reply by Authors.

J Urol 2021 04 3;205(4):998. Epub 2021 Feb 3.

Department of Urology, University Hospital Basel, Basel, Switzerland.

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http://dx.doi.org/10.1097/JU.0000000000001513.03DOI Listing
April 2021

Antimicrobial Prophylaxis for Postoperative Urinary Tract Infections in Transurethral Resection of Bladder Tumors: A Systematic Review and Meta-Analysis.

J Urol 2021 Apr 7;205(4):987-998. Epub 2020 Dec 7.

Department of Urology, University Hospital Basel, Basel, Switzerland.

Purpose: The administration of antimicrobial prophylaxis for postoperative urinary tract infections following transurethral resection of bladder tumors is controversial. We aimed to systematically review evidence on the potential effect of antimicrobial prophylaxis on postoperative urinary tract infections and asymptomatic bacteriuria.

Materials And Methods: We conducted a systematic search in Embase®, Medline® and the Cochrane Central Register of Controlled Trials. Randomized controlled trials and nonrandomized controlled trials assessing the effect of any form of antimicrobial prophylaxis in patients with transurethral resection of bladder tumors on postoperative urinary tract infections or asymptomatic bacteriuria were included. Risk of bias was assessed using RoB 2.0 or the Newcastle-Ottawa Scale. Fixed and random effects meta-analyses were conducted. As a potential basis for a scoping review, we exploratorily searched Medline for risk factors for urinary tract infections after transurethral resection of bladder tumors. The protocol was registered on PROSPERO (CRD42019131733).

Results: Of 986 screened publications, 7 studies with 1,725 participants were included; the reported effect sizes varied considerably. We found no significant effect of antimicrobial prophylaxis on urinary tract infections: the pooled odds ratio of the random effects model was 1.55 (95% CI 0.73-3.31). The random effects meta-analysis examining the effect of antimicrobial prophylaxis on asymptomatic bacteriuria showed an OR of 0.43 (0.18-1.04). Risk of bias was moderate. Our exploratory search identified 3 studies reporting age, preoperative pelvic radiation, preoperative hospital stay, duration of operation, tumor size, preoperative asymptomatic bacteriuria and pyuria as risk factors for urinary tract infections following transurethral resection of bladder tumors.

Conclusions: We observed insufficient evidence supporting routine antimicrobial prophylaxis in patients undergoing transurethral resection of bladder tumors for the prevention of postoperative urinary tract infections; our findings may inform harmonization of international guidelines.
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http://dx.doi.org/10.1097/JU.0000000000001513DOI Listing
April 2021

The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days.

F1000Res 2020;9:1193. Epub 2020 Oct 2.

Department of Clinical Research, University of Basel, Basel, Switzerland.

: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.
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http://dx.doi.org/10.12688/f1000research.26707.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539080PMC
November 2020

Hip abductor muscle strength in patients after total or unicompartmental knee arthroplasty for knee osteoarthritis or avascular necrosis: a systematic review and meta-analysis protocol.

BMJ Open 2020 08 13;10(8):e038770. Epub 2020 Aug 13.

Department of Orthopaedics and Traumatology, University Hospital Basel, Basel, Switzerland.

Introduction: Reduced hip abductor strength may indirectly lead to changes in knee kinematics and functional impairment and has been reported in patients with patellofemoral pain and knee osteoarthritis (OA). Limited information is available regarding hip abductor strength following total or unicompartmental knee arthroplasty (TKA/UKA). The aims of this systematic review are to synthesise the evidence of hip abductor muscle strength deficits in patients following TKA/UKA and to determine influencing factors for these deficits.

Methods And Analysis: Embase, Medline, SportDiscus, the Web of Science Core Collection and Scopus will be searched for human-based clinical studies investigating hip abductor muscle strength after TKA/UKA for knee OA or avascular necrosis (AVN). Articles studying hip abductor strength after knee arthroplasty for post-traumatic OA will not be considered. No restriction on study design, prosthesis design, surgical approach, patient characteristics or severity of OA/AVN will be applied. We will search articles published between 1 January 1990 and the date of our last search. Only articles in English or German language will be considered for inclusion. Studies reporting manually measured muscle strength or measurements performed at hip abduction angles other than 0° will be excluded. References will be screened by two reviewers independently. Where necessary, a third author will make the final decision. The assessment of quality and risk of bias will be performed with the modified Newcastle-Ottawa scale. Data will be extracted and presented in a tabular form. Depending on availability, comparable subgroup and meta-analyses will be conducted. Patient characteristics such as age, sex and surgical approach or rehabilitation programme will be analysed, if sufficient data are available.

Ethics And Dissemination: No ethics approval is required. The results will be published in a peer-reviewed journal and as conference presentation.
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http://dx.doi.org/10.1136/bmjopen-2020-038770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430403PMC
August 2020

Abductor muscle strength deficit in patients after total hip arthroplasty for hip osteoarthritis: a protocol for a systematic review and meta-analysis.

BMJ Open 2020 07 19;10(7):e035413. Epub 2020 Jul 19.

Department of Orthopaedics and Traumatology, University Hospital of Basel, Basel, Switzerland.

Introduction: Conservation of abductor muscle strength is directly associated with physical function after total hip replacement (THA). Although many studies have tried to explore and quantify a potential abductor muscle strength deficit after THA as well as identify possible causes and treatment options, this topic has not been addressed systematically.

Methods And Analysis: Human-based studies reporting measurements of hip abductor strength will be included in this review. Studies reporting on hip abductor strength measured manually or isometric measurements at an abduction angle other than 0° will not be considered. No restriction will be placed on study design, publication date operative approach, prosthesis design, age and sex of the patients or severity of OA. Data sources will be Embase via embase.com, Medline ALL via Ovid and the Cochrane Central Register of Controlled Trials. The preliminary search was conducted on 5 May 2019. Data regarding absolute values or torque ratio of hip abductor torque between sides as well as patient demographic data, surgical approaches and rehabilitation protocols will be extracted. The assessment of quality and risk of bias will be performed with the modified Newcastle-Ottawa Scale. The screening, data extraction and quality assessment will be performed by two reviewers independently. Where necessary, a third review author will make a final judgement. Narrative synthesis as well as tabular presentation of the extracted data will be included. Whenever possible, metaregression and subgroup specific meta-analyses will be used to investigate the influence of time since THA and type of measurement (isokinetic or isometric) on the different outcomes. In case of sufficient information, these analyses will be extended to include characteristics such as age, sex, surgical approach or rehabilitation programme.

Ethics And Dissemination: No ethics approval is required. The results will be disseminated through peer-reviewed publications and conference presentations.

Prospero Registration Number: CRD42020153185.
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http://dx.doi.org/10.1136/bmjopen-2019-035413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371135PMC
July 2020

Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: a scoping review protocol.

F1000Res 2019 5;8:2059. Epub 2019 Dec 5.

Institute of Liver Studies, King's College Hospital, London, London, UK.

This scoping review aims at systematically mapping reported prognostic factors for spontaneous immunosuppression (IS) free allograft tolerance (operational tolerance, OT) in non-viral hepatitis and non-autoimmune disease liver transplant (LT) recipients who are undergoing immunosuppression withdrawal (ISW). The results may inform the subsequent conduct of a systematic review with a more specific review question. LT is currently the most effective treatment for end-stage liver diseases. Whereas the short-term outcomes after LT have dramatically improved over the last decades, the long-term outcomes remain unsatisfactory, mainly because of side effects of lifelong IS, such as infections, cardiovascular diseases, malignancies, and nephrotoxicity. ISW studies have shown that OT can be achieved by a subset of LT recipients and recent research has identified biomarkers of OT in these patients. However, an evidence-based selection algorithm for patients that can predictably benefit from ISW is not available to date. The planned review will, therefore, map existing knowledge on prognostic clinical parameters and biomarkers for OT. We will consider studies that record any clinical parameter or biomarker before the initiation of ISW in paediatric or adult non-viral hepatitis and non-autoimmune disease LT recipients and analyse their possible association with ISW outcomes (OT or non-tolerance). Studies addressing the effectiveness of OT-inducing treatments will be excluded. Embase, MEDLINE, and Cochrane Library will be searched for relevant articles or conference abstracts. Full-texts of selected abstracts will be independently screened for inclusion by two reviewers. References and citing articles of included records will be screened for additional relevant records. Clinical trial registries will be searched for ongoing studies, and their investigators contacted for the sharing of unpublished data. Data from included records will be independently extracted by two reviewers using a prespecified data extraction table and presented in both tabular and narrative form.
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http://dx.doi.org/10.12688/f1000research.21501.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194345PMC
October 2020

Antibiotic prophylaxis in transurethral resection of bladder tumours: study protocol for a systematic review and meta-analysis.

Syst Rev 2020 04 23;9(1):89. Epub 2020 Apr 23.

Department of Urology, University Hospital Basel, Spitalstrasse 21, 4031, Basel, Switzerland.

Background: The necessity of antibiotic prophylaxis for postoperative urinary tract infections (UTIs) after transurethral resection of bladder tumours is controversial. This potentially leads to the overuse of antibiotic prophylaxis and rising antimicrobial resistance rates. The objective of this systematic review and meta-analysis is to compare the impact of different antimicrobial prophylaxis schemes versus placebo on the prevention of postoperative UTI and asymptomatic bacteriuria.

Methods: We designed and registered a study protocol for a systematic review and meta-analysis of randomized controlled trials and non-randomized (e.g. cohort, case-control) studies examining any form of antibiotic prophylaxis in patients with transurethral resection of bladder tumours. Literature searches will be conducted in several electronic databases (from inception onwards), including MEDLINE (Ovid), EMBASE (Ovid), and the Cochrane Central Register of Controlled Trials (CENTRAL). Grey literature will be identified through searching conference abstracts. The primary outcome will be postoperative urinary tract infections. The secondary outcome will be asymptomatic bacteriuria. Two reviewers will independently screen all citations, full-text articles, and abstract data. Potential conflicts will be resolved through discussion. The study methodological quality (or bias) will be appraised using appropriate tools (e.g. Risk of Bias 2.0 tool and Newcastle-Ottawa Scale). If feasible, we will conduct random-effects meta-analysis of outcome data. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g. study design, publication year, the setting of the study, and antibiotics regimen). We will also search, identify, and discuss potential risk factors for urinary tract infections following transurethral resection of bladder tumours. This may serve as basis for a scoping review.

Discussion: In times of rising antimicrobial resistance rates, sound evidence on the necessity of antibiotic prophylaxis is essential for implementation into guideline recommendations and for decision-making in clinical practice.

Systematic Review Registration: PROSPERO, CRD42019131733.
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http://dx.doi.org/10.1186/s13643-020-01353-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181504PMC
April 2020

Ca mobilization-dependent reduction of the endoplasmic reticulum lumen is due to influx of cytosolic glutathione.

BMC Biol 2020 02 26;18(1):19. Epub 2020 Feb 26.

Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.

Background: The lumen of the endoplasmic reticulum (ER) acts as a cellular Ca store and a site for oxidative protein folding, which is controlled by the reduced glutathione (GSH) and glutathione-disulfide (GSSG) redox pair. Although depletion of luminal Ca from the ER provokes a rapid and reversible shift towards a more reducing poise in the ER, the underlying molecular basis remains unclear.

Results: We found that Ca mobilization-dependent ER luminal reduction was sensitive to inhibition of GSH synthesis or dilution of cytosolic GSH by selective permeabilization of the plasma membrane. A glutathione-centered mechanism was further indicated by increased ER luminal glutathione levels in response to Ca efflux. Inducible reduction of the ER lumen by GSH flux was independent of the Ca-binding chaperone calreticulin, which has previously been implicated in this process. However, opening the translocon channel by puromycin or addition of cyclosporine A mimicked the GSH-related effect of Ca mobilization. While the action of puromycin was ascribable to Ca leakage from the ER, the mechanism of cyclosporine A-induced GSH flux was independent of calcineurin and cyclophilins A and B and remained unclear.

Conclusions: Our data strongly suggest that ER influx of cytosolic GSH, rather than inhibition of local oxidoreductases, is responsible for the reductive shift upon Ca mobilization. We postulate the existence of a Ca- and cyclosporine A-sensitive GSH transporter in the ER membrane. These findings have important implications for ER redox homeostasis under normal physiology and ER stress.
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http://dx.doi.org/10.1186/s12915-020-0749-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043043PMC
February 2020

Impact of sedentary behavior on large artery structure and function in children and adolescents: a systematic review.

Eur J Pediatr 2020 Jan 27;179(1):17-27. Epub 2019 Nov 27.

Department of Sport, Exercise and Health, Division Sports and Exercise Medicine, University of Basel, Birsstr. 320 B, 4052, Basel, Switzerland.

Sedentary behavior contributes to increased atherosclerotic risk in adults. Whether or not this can be extended to pediatric populations is unclear. This systematic review assessed associations of sedentary behavior with large artery structure and function in pediatric populations. MEDLINE, EMBASE, CENTRAL, and Web of Science were searched from the earliest available date to 31st of December 2018. Analyses of associations of sedentary behavior with large artery structure or function in a pediatric (sub-)population were included, adhering to the PRISMA guidelines. The protocol was published in advance on PROSPERO (CRD42018112996). Study quality and quality of evidence were analyzed using NHLBI Study Quality assessment tools and GRADE. Six observational studies found no association of exposure and outcome variables, and one had contradicting results. One intervention found reduced flow-mediated dilation after 3 h of uninterrupted sitting. Exposure and outcome measures were highly heterogeneous. Study quality was low to moderate. Quality of evidence was very low or low in the observational studies and high in the intervention.Conclusion: In pediatric populations, current evidence is limited and of low quality about how acute effects of sedentary behavior translate into early vascular aging and the long-term development of vascular dysfunction and atherosclerotic risk. Future studies should emphasize a careful choice of the adequate type and measurement site of a biomarker for large artery structure and function as well as conduct a detailed assessment of sedentary behavior patterns.Trial registration: PROSPERO Registration Number: CRD42018112996What is known: • An independent association of sedentary behavior and biomarkers of large artery structure and function has been demonstrated in adults. • In children, sedentary behavior is directly associated with classical cardiovascular risk factors like elevated blood glucose levels, insulin resistance, high blood pressure, obesity, and elevated blood lipids.What is new: • Currently, only few studies of low quality in children and adolescents provide limited evidence about how acute effects of sedentary behavior translate into early vascular aging and the long-term development of atherosclerosis. • The type and measurement site of vascular biomarker need to be chosen carefully, and a detailed assessment of sedentary behavior patterns is important to minimize the methodological bias.
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http://dx.doi.org/10.1007/s00431-019-03497-3DOI Listing
January 2020

Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta-analysis of controlled studies.

Liver Int 2019 11 10;39(11):2136-2152. Epub 2019 Jul 10.

University Medical Library, University of Basel, Basel, Switzerland.

Background & Aims: Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD.

Methods: We included WD patients of any age or stage and the study drugs D-penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non-randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random-effects meta-analyses.

Results: The 23 included studies reported on 2055 patients and mostly compared D-penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post-decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D-penicillamine may have a greater impact on side effects and treatment discontinuations than zinc.

Conclusions: There are some indications that zinc is safer than D-penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings.
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http://dx.doi.org/10.1111/liv.14179DOI Listing
November 2019

Human ER Oxidoreductin-1α (Ero1α) Undergoes Dual Regulation through Complementary Redox Interactions with Protein-Disulfide Isomerase.

J Biol Chem 2016 Nov 4;291(46):23952-23964. Epub 2016 Oct 4.

From the Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Aoba-ku, Sendai 980-8577, Japan,

In the mammalian endoplasmic reticulum, oxidoreductin-1α (Ero1α) generates protein disulfide bonds and transfers them specifically to canonical protein-disulfide isomerase (PDI) to sustain oxidative protein folding. This oxidative process is coupled to the reduction of O to HO on the bound flavin adenine dinucleotide cofactor. Because excessive thiol oxidation and HO generation cause cell death, Ero1α activity must be properly regulated. In addition to the four catalytic cysteines (Cys, Cys, Cys, and Cys) that are located in the flexible active site region, the Cys-Cys pair located at the base of another flexible loop is necessary for Ero1α regulation, although the mechanistic basis is not fully understood. The present study revealed that the Cys-Cys disulfide was reduced by PDI and other PDI family members during PDI oxidation. Differential scanning calorimetry and small angle X-ray scattering showed that mutation of Cys and Cys did not grossly affect the thermal stability or overall shape of Ero1α, suggesting that redox regulation of this cysteine pair serves a functional role. Moreover, the flexible loop flanked by Cys and Cys provides a platform for functional interaction with PDI, which in turn enhances the oxidative activity of Ero1α through reduction of the Cys-Cys disulfide. We propose a mechanism of dual Ero1α regulation by dynamic redox interactions between PDI and the two Ero1α flexible loops that harbor the regulatory cysteines.
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http://dx.doi.org/10.1074/jbc.M116.735662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104921PMC
November 2016

ER-luminal thiol/selenol-mediated regulation of Ca2+ signalling.

Biochem Soc Trans 2016 Apr;44(2):452-9

Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G2H7

The endoplasmic reticulum (ER) is the main cellular Ca(2+)storage unit. Among other signalling outputs, the ER can release Ca(2+)ions, which can, for instance, communicate the status of ER protein folding to the cytosol and to other organelles, in particular the mitochondria. As a consequence, ER Ca(2+)flux can alter the apposition of the ER with mitochondria, influence mitochondrial ATP production or trigger apoptosis. All aspects of ER Ca(2+)flux have emerged as processes that are intimately controlled by intracellular redox conditions. In this review, we focus on ER-luminal redox-driven regulation of Ca(2+)flux. This involves the direct reduction of disulfides within ER Ca(2+)handling proteins themselves, but also the regulated interaction of ER chaperones and oxidoreductases such as calnexin or ERp57 with them. Well-characterized examples are the activating interactions of Ero1α with inositol 1,4,5-trisphosphate receptors (IP3Rs) or of selenoprotein N (SEPN1) with sarco/endoplasmic reticulum Ca(2+)transport ATPase 2 (SERCA2). The future discovery of novel ER-luminal modulators of Ca(2+)handling proteins is likely. Based on the currently available information, we describe how the variable ER redox conditions govern Ca(2+)flux from the ER.
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http://dx.doi.org/10.1042/BST20150233DOI Listing
April 2016

Transit of H2O2 across the endoplasmic reticulum membrane is not sluggish.

Free Radic Biol Med 2016 05 27;94:157-60. Epub 2016 Feb 27.

Erasmus University Medical Center, Department of Hematology, PO Box 2040, Rotterdam, The Netherlands.

Cellular metabolism provides various sources of hydrogen peroxide (H2O2) in different organelles and compartments. The suitability of H2O2 as an intracellular signaling molecule therefore also depends on its ability to pass cellular membranes. The propensity of the membranous boundary of the endoplasmic reticulum (ER) to let pass H2O2 has been discussed controversially. In this essay, we challenge the recent proposal that the ER membrane constitutes a simple barrier for H2O2 diffusion and support earlier data showing that (i) ample H2O2 permeability of the ER membrane is a prerequisite for signal transduction, (ii) aquaporin channels are crucially involved in the facilitation of H2O2 permeation, and (iii) a proper experimental framework not prone to artifacts is necessary to further unravel the role of H2O2 permeation in signal transduction and organelle biology.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.02.030DOI Listing
May 2016

Cysteines 208 and 241 in Ero1α are required for maximal catalytic turnover.

Redox Biol 2016 Apr 14;7:14-20. Epub 2015 Nov 14.

Division of Molecular & Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4056, Basel, Switzerland. Electronic address:

Endoplasmic reticulum (ER) oxidoreductin 1α (Ero1α) is a disulfide producer in the ER of mammalian cells. Besides four catalytic cysteines (Cys(94), Cys(99), Cys(394), Cys(397)), Ero1α harbors four regulatory cysteines (Cys(104), Cys(131), Cys(208), Cys(241)). These cysteines mediate the formation of inhibitory intramolecular disulfide bonds, which adapt the activation state of the enzyme to the redox environment in the ER through feedback signaling. Accordingly, disulfide production by Ero1α is accelerated by reducing conditions, which minimize the formation of inhibitory disulfides, or by mutations of regulatory cysteines. Here we report that reductive stimulation enhances Ero1α activity more potently than the mutation of cysteines. Specifically, mutation of Cys(208)/Cys(241) does not mechanistically mimic reductive stimulation, as it lowers the turnover rate of Ero1α in presence of a reducing agent. The Cys(208)/Cys(241) pair therefore fulfills a function during catalysis that reaches beyond negative regulation. In agreement, we identify a reciprocal crosstalk between the stabilities of the Cys(208)-Cys(241) disulfide and the inhibitory disulfide bonds involving Cys(104) and Cys(131), which also controls the recruitment of the H2O2 scavenger GPx8 to Ero1α. Two possible mechanisms by which thiol-disulfide exchange at the Cys(208)/Cys(241) pair stimulates the catalytic turnover under reducing conditions are discussed.
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http://dx.doi.org/10.1016/j.redox.2015.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683387PMC
April 2016

The antioxidant machinery of the endoplasmic reticulum: Protection and signaling.

Free Radic Biol Med 2015 Jun 2;83:341-51. Epub 2015 Mar 2.

BFG Baselland, 4142 Münchenstein, Switzerland. Electronic address:

Cellular metabolism is inherently linked to the production of oxidizing by-products, including reactive oxygen species (ROS) hydrogen peroxide (H2O2). When present in excess, H2O2 can damage cellular biomolecules, but when produced in coordinated fashion, it typically serves as a mobile signaling messenger. It is therefore not surprising that cell health critically relies on both low-molecular-weight and enzymatic antioxidant components, which protect from ROS-mediated damage and shape the propagation and duration of ROS signals. This review focuses on H2O2-antioxidant cross talk in the endoplasmic reticulum (ER), which is intimately linked to the process of oxidative protein folding. ER-resident or ER-regulated sources of H2O2 and other ROS, which are subgrouped into constitutive and stimulated sources, are discussed and set into context with the diverse antioxidant mechanisms in the organelle. These include two types of peroxide-reducing enzymes, a high concentration of glutathione derived from the cytosol, and feedback-regulated thiol-disulfide switches, which negatively control the major ER oxidase ER oxidoreductin-1. Finally, new evidence highlighting emerging principles of H2O2-based cues at the ER will likely set a basis for establishing ER redox processes as a major line of future signaling research. A fundamental problem that remains to be solved is the specific, quantitative, time resolved, and targeted detection of H2O2 in the ER and in specialized ER subdomains.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.02.019DOI Listing
June 2015

A PDI-catalyzed thiol-disulfide switch regulates the production of hydrogen peroxide by human Ero1.

Free Radic Biol Med 2015 Jun 17;83:361-72. Epub 2015 Feb 17.

Division of Molecular & Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland. Electronic address:

Oxidative folding in the endoplasmic reticulum (ER) involves ER oxidoreductin 1 (Ero1)-mediated disulfide formation in protein disulfide isomerase (PDI). In this process, Ero1 consumes oxygen (O2) and releases hydrogen peroxide (H2O2), but none of the published Ero1 crystal structures reveal any potential pathway for entry and exit of these reactants. We report that additional mutation of the Cys(208)-Cys(241) disulfide in hyperactive Ero1α (Ero1α-C104A/C131A) potentiates H2O2 production, ER oxidation, and cell toxicity. This disulfide clamps two helices that seal the flavin cofactor where O2 is reduced to H2O2. Through its carboxyterminal active site, PDI unlocks this seal by forming a Cys(208)/Cys(241)-dependent mixed-disulfide complex with Ero1α. The H2O2-detoxifying glutathione peroxidase 8 also binds to the Cys(208)/Cys(241) loop region. Supported by O2 diffusion simulations, these data describe the first enzymatically controlled O2 access into a flavoprotein active site, provide molecular-level understanding of Ero1α regulation and H2O2 production/detoxification, and establish the deleterious consequences of constitutive Ero1 activity.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.02.011DOI Listing
June 2015

Redox controls UPR to control redox.

J Cell Sci 2014 Sep 8;127(Pt 17):3649-58. Epub 2014 Aug 8.

Division of Molecular & Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland

In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca(2+) efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.
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http://dx.doi.org/10.1242/jcs.153643DOI Listing
September 2014

Biochemical evidence that regulation of Ero1β activity in human cells does not involve the isoform-specific cysteine 262.

Biosci Rep 2014 04 1;34(2). Epub 2014 Apr 1.

Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark

In the ER (endoplasmic reticulum) of human cells, disulfide bonds are predominantly generated by the two isoforms of Ero1 (ER oxidoreductin-1): Ero1α and Ero1β. The activity of Ero1α is tightly regulated through the formation of intramolecular disulfide bonds to help ensure balanced ER redox conditions. Ero1β is less tightly regulated, but the molecular details underlying control of activity are not as well characterized as for Ero1α. Ero1β contains an additional cysteine residue (Cys), which has been suggested to engage in an isoform-specific regulatory disulfide bond with Cys However, we show that the two regulatory disulfide bonds in Ero1α are likely conserved in Ero1β (Cys-Cys and Cys-Cys). Molecular modelling of the Ero1β structure predicted that the side chain of Cys is completely buried. Indeed, we found this cysteine to be reduced and partially protected from alkylation in the ER of living cells. Furthermore, mutation of Cys-but not of Cys-rendered Ero1β hyperactive in cells, as did mutation of Cys Ero1β hyperactivity induced the UPR (unfolded protein response) and resulted in oxidative perturbation of the ER redox state. We propose that features other than a distinct pattern of regulatory disulfide bonds determine the loose redox regulation of Ero1β relative to Ero1α.
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http://dx.doi.org/10.1042/BSR20130124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971451PMC
April 2014

Cell biology of cysteine-based molecular switches.

Int J Cell Biol 2014 6;2014:157038. Epub 2014 Feb 6.

CEA Life Sciences Division, Oxidative Stresses and Cancer Laboratory, CEA Saclay, 91191 Gif sur Yvette, France.

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http://dx.doi.org/10.1155/2014/157038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933513PMC
March 2014

GPx8 peroxidase prevents leakage of H2O2 from the endoplasmic reticulum.

Free Radic Biol Med 2014 May 22;70:106-16. Epub 2014 Feb 22.

Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland. Electronic address:

Unbalanced endoplasmic reticulum (ER) homeostasis (ER stress) leads to increased generation of reactive oxygen species (ROS). Disulfide-bond formation in the ER by Ero1 family oxidases produces hydrogen peroxide (H2O2) and thereby constitutes one potential source of ER-stress-induced ROS. However, we demonstrate that Ero1α-derived H2O2 is rapidly cleared by glutathione peroxidase (GPx) 8. In 293 cells, GPx8 and reduced/activated forms of Ero1α co-reside in the rough ER subdomain. Loss of GPx8 causes ER stress, leakage of Ero1α-derived H2O2 to the cytosol, and cell death. In contrast, peroxiredoxin (Prx) IV, another H2O2-detoxifying rough ER enzyme, does not protect from Ero1α-mediated toxicity, as is currently proposed. Only when Ero1α-catalyzed H2O2 production is artificially maximized can PrxIV participate in its reduction. We conclude that the peroxidase activity of the described Ero1α-GPx8 complex prevents diffusion of Ero1α-derived H2O2 within and out of the rough ER. Along with the induction of GPX8 in ER-stressed cells, these findings question a ubiquitous role of Ero1α as a producer of cytoplasmic ROS under ER stress.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.01.018DOI Listing
May 2014

Erratum: Green fluorescent protein-based monitoring of endoplasmic reticulum redox poise.

Front Genet 2013 26;4:255. Epub 2013 Nov 26.

Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel Basel, Switzerland.

[This corrects the article on p. 108 in vol. 4, PMID: 23781233.].
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http://dx.doi.org/10.3389/fgene.2013.00255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840325PMC
November 2013
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