Publications by authors named "Christian Herzog"

75 Publications

Real-Time Bibliometrics: Dimensions as a Resource for Analyzing Aspects of COVID-19.

Front Res Metr Anal 2020 12;5:595299. Epub 2021 Jan 12.

Digital Science, London, United Kingdom.

Dimensions was built as a platform to allow stakeholders in the research community, including academic bibliometricians, to more easily create and understand the context of different types of research object through the linkages between these objects. Links between objects are created via persistent identifiers and machine learning techniques, while additional context is introduced via data enhancements such as per-object categorisations and person and institution disambiguation. While these features make analytical use cases accessible for end users, the COVID-19 crisis has highlighted a different set of needs to analyze trends in scholarship as they occur: Real-time bibliometrics. The combination of full-text search, daily data updates, a broad set of scholarly objects including pre-prints and a wider set of data fields for analysis, broadens opportunities for a different style of analysis. A subset of these emerging capabilities is discussed and three basic analyses are presented as illustrations of the potential for real-time bibliometrics.
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http://dx.doi.org/10.3389/frma.2020.595299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104272PMC
January 2021

Serine Protease HTRA1 as a Novel Target Antigen in Primary Membranous Nephropathy.

J Am Soc Nephrol 2021 May 5. Epub 2021 May 5.

Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts

Background: Identification of target antigens PLA2R, THSD7A, NELL1, or Semaphorin-3B can explain the majority of cases of primary membranous nephropathy (MN). However, target antigens remain unidentified in 15%-20% of patients.

Methods: A multipronged approach, using traditional and modern technologies, converged on a novel target antigen, and capitalized on the temporal variation in autoantibody titer for biomarker discovery. Immunoblotting of human glomerular proteins followed by differential immunoprecipitation and mass spectrometric analysis was complemented by laser-capture microdissection followed by mass spectrometry, elution of immune complexes from renal biopsy specimen tissue, and autoimmune profiling on a protein fragment microarray.

Results: These approaches identified serine protease HTRA1 as a novel podocyte antigen in a subset of patients with primary MN. Sera from two patients reacted by immunoblotting with a 51-kD protein within glomerular extract and with recombinant human HTRA1, under reducing and nonreducing conditions. Longitudinal serum samples from these patients seemed to correlate with clinical disease activity. As in PLA2R- and THSD7A- associated MN, anti-HTRA1 antibodies were predominantly IgG4, suggesting a primary etiology. Analysis of sera collected during active disease versus remission on protein fragment microarrays detected significantly higher titers of anti-HTRA1 antibody in active disease. HTRA1 was specifically detected within immune deposits of HTRA1-associated MN in 14 patients identified among three cohorts. Screening of 118 "quadruple-negative" (PLA2R-, THSD7A-, NELL1-, EXT2-negative) patients in a large repository of MN biopsy specimens revealed a prevalence of 4.2%.

Conclusions: Conventional and more modern techniques converged to identify serine protease HTRA1 as a target antigen in MN.
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http://dx.doi.org/10.1681/ASN.2020101395DOI Listing
May 2021

Three Risks That Caution Against a Premature Implementation of Artificial Moral Agents for Practical and Economical Use.

Authors:
Christian Herzog

Sci Eng Ethics 2021 Jan 26;27(1). Epub 2021 Jan 26.

Ethical Innovation Hub, Institute for Electrical Engineering in Medicine, University of Lübeck, Ratzeburger Allee 160, 23562, Lübeck, Germany.

In the present article, I will advocate caution against developing artificial moral agents (AMAs) based on the notion that the utilization of preliminary forms of AMAs will potentially negatively feed back on the human social system and on human moral thought itself and its value-e.g., by reinforcing social inequalities, diminishing the breadth of employed ethical arguments and the value of character. While scientific investigations into AMAs pose no direct significant threat, I will argue against their premature utilization for practical and economical use. I will base my arguments on two thought experiments. The first thought experiment deals with the potential to generate a replica of an individual's moral stances with the purpose to increase, what I term, 'moral efficiency'. Hence, as a first risk, an unregulated utilization of premature AMAs in a neoliberal capitalist system is likely to disadvantage those who cannot afford 'moral replicas' and further reinforce social inequalities. The second thought experiment deals with the idea of a 'moral calculator'. As a second risk, I will argue that, even as a device equally accessible to all and aimed at augmenting human moral deliberation, 'moral calculators' as preliminary forms of AMAs are likely to diminish the breadth and depth of concepts employed in moral arguments. Again, I base this claim on the idea that the current most dominant economic system rewards increases in productivity. However, increases in efficiency will mostly stem from relying on the outputs of 'moral calculators' without further scrutiny. Premature AMAs will cover only a limited scope of moral argumentation and, hence, over-reliance on them will narrow human moral thought. In addition and as the third risk, I will argue that an increased disregard of the interior of a moral agent may ensue-a trend that can already be observed in the literature.
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http://dx.doi.org/10.1007/s11948-021-00283-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838071PMC
January 2021

Hepatitis A vaccination and its immunological and epidemiological long-term effects - a review of the evidence.

Hum Vaccin Immunother 2021 May 16;17(5):1496-1519. Epub 2020 Dec 16.

Centre for the Evaluation of Vaccination, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.

Hepatitis A virus (HAV) infections continue to represent a significant disease burden causing approximately 200 million infections, 30 million symptomatic illnesses and 30,000 deaths each year. Effective and safe hepatitis A vaccines have been available since the early 1990s. Initially developed for individual prophylaxis, HAV vaccines are now increasingly used to control hepatitis A in endemic areas. The human enteral HAV is eradicable in principle, however, HAV eradication is currently not being pursued. Inactivated HAV vaccines are safe and, after two doses, elicit seroprotection in healthy children, adolescents, and young adults for an estimated 30-40 years, if not lifelong, with no need for a later second booster. The long-term effects of the single-dose live-attenuated HAV vaccines are less well documented but available data suggest they are safe and provide long-lasting immunity and protection. A universal mass vaccination strategy (UMV) based on two doses of inactivated vaccine is commonly implemented in endemic countries and eliminates clinical hepatitis A disease in toddlers within a few years. Consequently, older age groups also benefit due to the herd protection effects. Single-dose UMV programs have shown promising outcomes but need to be monitored for many more years in order to document an effective immune memory persistence. In non-endemic countries, prevention efforts need to focus on 'new' risk groups, such as men having sex with men, prisoners, the homeless, and families visiting friends and relatives in endemic countries. This narrative review presents the current evidence regarding the immunological and epidemiological long-term effects of the hepatitis A vaccination and finally discusses emerging issues and areas for research.
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http://dx.doi.org/10.1080/21645515.2020.1819742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078665PMC
May 2021

Neural cell adhesion molecule 1 is a novel autoantigen in membranous lupus nephritis.

Kidney Int 2020 Oct 9. Epub 2020 Oct 9.

Arkana Laboratories, Little Rock, Arkansas, USA.

Membranous lupus nephritis is a frequent cause of nephrotic syndrome in patients with systemic lupus erythematosus. It has been shown in phospholipase A2 receptor positive membranous nephropathy that known antibodies can be detected within sera, determination of the target autoantigen can have diagnostic significance, inform prognosis, and enable non-invasive monitoring of disease activity. Here we utilized mass spectrometry for antigen discovery in laser captured microdissected glomeruli from formalin-fixed paraffin embedded tissue and tissue protein G immunoprecipitation studies to interrogate immune complexes from frozen kidney biopsy tissue. We identified neural cell adhesion molecule 1 (NCAM1) to be a target antigen in some cases of membranous lupus nephritis and within rare cases of primary membranous nephropathy. The prevalence of NCAM1 association was 6.6% of cases of membranous lupus nephritis and in 2.0% of primary membranous nephropathy cases. NCAM1 was found to colocalize with IgG within glomerular immune deposits by confocal microscopy. Additionally, serum from patients with NCAM1-associated membranous nephropathy showed reactivity to NCAM1 recombinant protein on Western blotting and by indirect immunofluorescence assay, demonstrating the presence of circulating antibodies. Thus, we propose that NCAM1 is a target autoantigen in a subset of patients with membranous lupus nephritis. Future studies are needed to determine whether anti-NCAM1 antibody levels correlate with disease activity or response to therapy.
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http://dx.doi.org/10.1016/j.kint.2020.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032825PMC
October 2020

NELL1 is a target antigen in malignancy-associated membranous nephropathy.

Kidney Int 2021 04 20;99(4):967-976. Epub 2020 Aug 20.

Arkana Laboratories, Little Rock, Arkansas, USA.

Patients with membranous nephropathy have an increased risk of malignancy compared to the general population, but the target antigen for malignancy-associated membranous nephropathy is unknown. To explore this, we utilized mass spectrometry for antigen discovery in malignancy-associated membranous nephropathy examining immune complexes eluted from frozen kidney biopsy tissue using protein G bead immunoglobulin capture. Antigen discovery was performed comparing cases of membranous nephropathy of unknown and known type. Mass spectrophotometric analysis revealed that nerve epidermal growth factor-like 1 (NELL1) immune complexes were uniquely present within the biopsy tissue in membranous nephropathy. Additional NELL1-positive cases were subsequently identified by immunofluorescence. In a consecutive series, 3.8% of PLA2R- and THSD7A-negative cases were NELL1-positive. These NELL1-positive cases had segmental to incomplete IgG capillary loop staining (93.4%) and dominant or co-dominant IgG1-subclass staining (95.5%). The mean age of patients with NELL1-positive membranous nephropathy was 66.8 years, with a slight male predominance (58.2%) and 33% had concurrent malignancy. Compared with PLA2R- and THSD7A-positive cases of membranous nephropathy, there was a greater proportion of cases with malignancies in the NELL1-associated group. Thus, NELL1-associated membranous nephropathy has a unique histopathology characterized by incomplete capillary loop staining, IgG1-predominance, and is more often associated with malignancy than other known types of membranous nephropathy.
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http://dx.doi.org/10.1016/j.kint.2020.07.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895854PMC
April 2021

Serum amyloid P deposition is a sensitive and specific feature of membranous-like glomerulopathy with masked IgG kappa deposits.

Kidney Int 2020 03 9;97(3):602-608. Epub 2019 Nov 9.

University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) is a recently described pattern of glomerulonephritis with a unique histopathology. The pattern is characterized by subepithelial and/or mesangial immune deposits that are "masked", to immunoglobulin staining by routine immunofluorescence but strongly stain for IgG and kappa light chain after protease digestion. Patients with this pattern of glomerulonephritis are most commonly young females presenting with proteinuria and a vague history of autoimmune disease such as low titer antinuclear antibodies. Here we compared the mass spectrometry profile of laser capture microdissected glomeruli from nine MGMID renal biopsies with eight biopsies showing other patterns of membranous glomerulopathy. The protein most significantly increased in MGMID was serum amyloid P. Immunostaining showed serum amyloid P colocalized with IgG in the glomeruli of MGMID but not with PLA2R-associated membranous glomerulopathy. Serum amyloid P was positive in the glomeruli of all 32 MGMID biopsies but negative in biopsies of other types of membranous glomerulopathies such as those associated with PLA2R and THSD7A. There were four biopsies with glomerular serum amyloid P staining among the 173 biopsies that did not fulfill criteria for MGMID or amyloidosis. All four of these biopsies with positive serum amyloid P staining had a membranous pattern of glomerulopathy with IgG kappa deposits that only differed from MGMID by the lack of "masking". Thus, positive staining within glomerular deposits for serum amyloid P identifies a unique form of glomerulonephritis likely sharing a common pathophysiologic mechanism of disease.
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http://dx.doi.org/10.1016/j.kint.2019.10.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869973PMC
March 2020

Hepatitis A vaccination in immunocompromised patients - the need for individualized vaccination strategies and correct methodology.

Travel Med Infect Dis 2019 Nov 20:101526. Epub 2019 Nov 20.

Medical Department, Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Switzerland.

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http://dx.doi.org/10.1016/j.tmaid.2019.101526DOI Listing
November 2019

[Four years after the Ebola crisis : Challenges, experiences, and implications in the German public health context].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019 Sep;62(9):1041-1051

Zentrum für Biologische Gefahren und Spezielle Pathogene, Robert Koch-Institut, Seestraße 10, 13353, Berlin, Deutschland.

The Ebola virus disease outbreak in West Africa in 2014/2015 was by far the biggest, most prolonged, and geographically most widespread outbreak of this disease since the discovery of the Ebola virus in 1976. Although no cases of Ebola virus disease were confirmed in Germany, a number of crisis management activities were initiated.Based on a combination of local, national, and international lessons learned, literature research, and a large number of discussions among German colleagues as well as German and foreign colleagues, the experiences of selected German public health actors as well as implications for health protection activities in Germany are presented.On the one hand, preparedness for managing unusual high consequence health events-caused by rare, highly pathogenic biological agents-including the provision of adequate material and personnel resources remains important in Germany. On the other hand, more German engagement in global health is necessary, because the dividing line between global health and local health is increasingly disappearing.
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http://dx.doi.org/10.1007/s00103-019-02995-xDOI Listing
September 2019

Safety and immunogenicity of tetanus/diphtheria vaccination in patients with rheumatic diseases-a prospective multi-centre cohort study.

Rheumatology (Oxford) 2019 09;58(9):1585-1596

Department of Public Health/Division of Infectious Diseases, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Objectives: We aimed to assess the safety and immunogenicity of a diphtheria/tetanus vaccine booster dose in three different patient groups with rheumatic diseases on a variety of immunosuppressive/immunomodulatory medications compared with healthy controls (HCs).

Methods: We conducted a multi-centre prospective cohort study in Switzerland. We enrolled patients with RA, axial SpA/PsA, vasculitis (Behçet's disease, ANCA-associated vasculitis) and HCs. Diphtheria/tetanus vaccination was administered according to the Swiss vaccination recommendations. Blood samples were drawn before vaccination, and 1 month and 3 months afterwards. Antibody concentrations against vaccine antigens were measured by ELISA. Immunogenicity was compared between patient and medication groups. A mixed model was applied for multivariate analysis. Missing data were dealt with using multiple imputation.

Results: Between January 2014 and December 2015, we enrolled 284 patients with rheumatic diseases (131 RA, 114 SpA/PsA, 39 vasculitis) and 253 HCs. Of the patients, 89% were on immunosuppressive/immunomodulatory medication. Three months post-vaccination 100% of HCs vs 98% of patients were protected against tetanus and 84% vs 73% against diphtheria. HCs and SpA/PsA patients had significantly higher responses than RA and vasculitis patients. Assessing underlying diseases and medications in a multivariate model, rituximab was the only factor negatively influencing tetanus immunogenicity, whereas only MTX treatment had a negative influence on diphtheria antibody responses. No vaccine-related serious adverse events were recorded.

Conclusion: Diphtheria/tetanus booster vaccination was safe. Tetanus vaccination was immunogenic; the diphtheria component was less immunogenic. Vaccine responses were blunted by rituximab and MTX.

Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, Identifier: NCT01947465.
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http://dx.doi.org/10.1093/rheumatology/kez045DOI Listing
September 2019

Role of meprin metalloproteinases in cytokine processing and inflammation.

Cytokine 2019 02 20;114:18-25. Epub 2018 Dec 20.

Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Department of Biochemistry, Little Rock, AR, USA. Electronic address:

Meprin metalloendopeptidases, comprising α and β isoforms, are widely expressed in mammalian cells and organs including kidney, intestines, lungs, skin, and bladder, and in a variety of immune cells and cancer cells. Meprins proteolytically process many inflammatory mediators, including cytokines, chemokines, and other bioactive proteins and peptides that control the function of immune cells. The knowledge of meprin-mediated processing of inflammatory mediators and other target substrates provides a pathophysiologic link for the involvement of meprins in the pathogenesis of many inflammatory disorders. Meprins are now known to play important roles in inflammatory diseases including acute kidney injury, sepsis, urinary tract infections, bladder inflammation, and inflammatory bowel disease. The proteolysis of epithelial and endothelial barriers including cell junctional proteins by meprins promotes leukocyte influx into areas of tissue damage to result in inflammation. Meprins degrade extracellular matrix proteins; this ability of meprins is implicated in the cell migration of leukocytes and the invasion of tumor cells that express meprins. Proteolytic processing and maturation of procollagens provides evidence that meprins are involved in collagen maturation and deposition in the fibrotic processes involved in the formation of keloids and hypertrophic scars and lung fibrosis. This review highlights recent progress in understanding the role of meprins in inflammatory disorders in both human and mouse models.
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http://dx.doi.org/10.1016/j.cyto.2018.11.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414266PMC
February 2019

Corrigendum to " An extra priming dose of hepatitis A vaccine to adult patients with rheumatoid arthritis and drug induced immunosuppression - A prospective, open-label, multi-center study" [Trav. Med. Infect. Dis. 21, January-February 2018, 43-50].

Travel Med Infect Dis 2019 Jan - Feb;27:115. Epub 2018 Oct 3.

Karolinska Institutet, Dept. of Medicine/Solna, Unit for Infectious Diseases, SE 171 76, Stockholm, Sweden; Dept. of Communicable Diseases Control and Prevention, Sörmland, SE 631 88, Eskilstuna, Sweden.

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http://dx.doi.org/10.1016/j.tmaid.2018.09.008DOI Listing
October 2018

Response to the letter 'Field classification of publications in Dimensions: a first case study testing its reliability and validity'.

Scientometrics 2018 27;117(1):641-645. Epub 2018 Jul 27.

Digital Science, 90 York Way, London, N1 9AG UK.

With Dimensions, Digital Science provides the research community a new approach on research related information, bringing formerly siloed content types such as grants, patents, clinical trials with publications and citations together, making it as openly available as possible (see app.dimensions.ai). Due to the different content types, (controversial) journal based classifications were not an option since it would not allow to categorise grants etc. Hence Digital Science opted for applying a categorisation approach using machine learning and based on the content of the documents and well established classification systems for which a training set was available. The implementation at launch was a first step and requires to be improved-although we observe a reliability comparably to manual coding for grants, the implementation at launch comes with some shortcomings as observed by Bornmann (2018), mostly due to challenges with the training set coverage. To overcome the shortcomings of the initial categorization approach we implemented an improvement process with the research community and Lutz Bornmann's analysis presented a great opportunity to provide more transparency and insights in the ongoing improvements.
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http://dx.doi.org/10.1007/s11192-018-2854-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132978PMC
July 2018

Serologic differential diagnosis of hepatitis A virus (HAV) infected and vaccinated individuals: How long persist antibodies to non-structural HAV proteins?

Vaccine 2018 06;36(27):3883-3884

Department of Microbiology and Parasitology, Faculty of Medical Sciences, National Autonomous University, León, Nicaragua. Electronic address:

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http://dx.doi.org/10.1016/j.vaccine.2018.05.015DOI Listing
June 2018

An extra priming dose of hepatitis A vaccine to adult patients with rheumatoid arthritis and drug induced immunosuppression - A prospective, open-label, multi-center study.

Travel Med Infect Dis 2018 Jan - Feb;21:43-50. Epub 2017 Dec 8.

Karolinska Institutet, Dept. of Medicine/Solna, Unit for Infectious Diseases, SE 171 76 Stockholm, Sweden; Dept. of Communicable Diseases Control and Prevention, Sörmland, SE 631 88 Eskilstuna, Sweden. Electronic address:

Background: Previous studies have indicated that a pre-travel single dose of hepatitis A vaccine is not sufficient as protection against hepatitis A in immunocompromised travelers. We evaluated if an extra dose of hepatitis A vaccine given shortly prior to traveling ensures seroconversion.

Method: Patients with rheumatoid arthritis (n = 69, median age = 55 years) treated with Tumor Necrosis Factor inhibitor(TNFi) and/or Methotrexate (MTX) were immunized with two doses of hepatitis A vaccine, either as double dose or four weeks apart, followed by a booster dose at six months. Furthermore, 48 healthy individuals, median age = 60 years were immunized with two doses, six months apart. Anti-hepatitis A antibodies were measured at 0, 1, 2, 6, 7 and 12 months.

Results: Two months after the initial vaccination, 88% of the RA patients had protective antibodies, compared to 85% of the healthy individuals. There was no significant difference between the two vaccine schedules. At twelve months, 99% of RA patients and 100% of healthy individuals had seroprotective antibodies.

Conclusion: An extra priming dos of hepatitis A vaccine prior to traveling offered an acceptable protection in individuals treated with TNFi and/or MTX. This constitutes an attractive pre-travel solution to this vulnerable group of patients.
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http://dx.doi.org/10.1016/j.tmaid.2017.12.004DOI Listing
May 2018

Control measures following a case of imported Lassa fever from Togo, North Rhine Westphalia, Germany, 2016.

Euro Surveill 2017 Sep;22(39)

Centre of Integrated Oncology Köln, University of Cologne, Germany.

In a patient transferred from Togo to Cologne, Germany, Lassa fever was diagnosed 12 days post mortem. Sixty-two contacts in Cologne were categorised according to the level of exposure, and gradual infection control measures were applied. No clinical signs of Lassa virus infection or Lassa specific antibodies were observed in the 62 contacts. Thirty-three individuals had direct contact to blood, other body fluids or tissue of the patients. Notably, with standard precautions, no transmission occurred between the index patient and healthcare workers. However, one secondary infection occurred in an undertaker exposed to the corpse in Rhineland-Palatinate, who was treated on the isolation unit at the University Hospital of Frankfurt. After German authorities raised an alert regarding the imported Lassa fever case, an American healthcare worker who had cared for the index patient in Togo, and who presented with diarrhoea, vomiting and fever, was placed in isolation and medevacked to the United States. The event and the transmission of Lassa virus infection outside of Africa underlines the need for early diagnosis and use of adequate personal protection equipment (PPE), when highly contagious infections cannot be excluded. It also demonstrates that larger outbreaks can be prevented by infection control measures, including standard PPE.
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http://dx.doi.org/10.2807/1560-7917.ES.2017.22.39.17-00088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709954PMC
September 2017

Proteolytic processing and inactivation of CCL2/MCP-1 by meprins.

Biochem Biophys Rep 2016 Dec 21;8:146-150. Epub 2016 Aug 21.

Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.

Monocyte chemotactic protein 1 (CCL2/MCP-1) is a small chemokine involved in the recruitment and trafficking of mononuclear immune cells to inflammation sites. Our studies demonstrate that the metalloendopeptidases meprin A (purified from kidney cortex), recombinant meprin α, and recombinant meprin β can all process CCL2/MCP-1. The cleavage sites were determined by amino acid sequencing and mass spectrometry analysis of the generated products, and the biological activity of the products was evaluated by chemotactic migration assay using THP-1 cells. The cleavage sites generated by the meprin isoforms revealed that meprin A and meprin α cleaved the N-terminal domain of mouse CCL2/MCP-1 at the Asn and Ala bond, resulting in significant reduction in the chemotactic activity of the cleaved CCL2/MCP-1. Meprin β was unable to cleave the N-terminus of mouse CCL2/MCP-1 but cleaved the C-terminal region between Ser and Glu. Human CCL2/MCP-1 that lacks the murine C-terminal region was also cleaved by meprin α at the N-terminus resulting in significant loss of CCL2/MCP-1 biological activity, whereas meprin β did not affect the biological activity. These studies suggest that meprin α and meprin β may play important roles in regulating the CCL2/MCP-1 chemokine activity during inflammation.
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http://dx.doi.org/10.1016/j.bbrep.2016.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613766PMC
December 2016

Single-Dose Hepatitis A Immunization: 7.5-Year Observational Pilot Study in Nicaraguan Children to Assess Protective Effectiveness and Humoral Immune Memory Response.

J Infect Dis 2016 11 6;214(10):1498-1506. Epub 2016 Sep 6.

Medical Department, Swiss Tropical and Public Health Institute.

Background: Universal 2-dose hepatitis A virus (HAV) vaccination of toddlers effectively controls hepatitis A. High vaccine costs, however, impede implementation in endemic countries. To test single-dose vaccination as a possible alternative, we initiated an observational, longitudinal study in Nicaragua, to assess protective effectiveness and-through challenge vaccination-humoral immune memory response.

Methods: After a 2003 serosurvey, 130 originally seronegative children received one dose of virosomal HAV vaccine in 2005, followed by yearly serological and clinical assessments until 2012. After 7.5 years, a vaccine booster was administered. Concurrent antibody screening of patients presenting with hepatitis symptoms documented persistent HAV circulation in the communities studied.

Results: Between serosurvey and vaccination, 25 children contracted hepatitis A subclinically (>8000 mIU/mL anti-HAV). In the remaining 105 children, immunization resulted in anti-HAV levels of 17-572 mIU/mL. Based on the ≥15% annual infection risk, an estimated 60% of children were exposed to HAV encounters during follow-up. No child presented with hepatitis symptoms. Serological breakthrough infection (7106 mIU/mL) was documented in 1 child, representing an estimated protective effectiveness of 98.3% (95% confidence interval, 87.9-99.8). Boosting elicited an average 29.7-fold increase of anti-HAV levels.

Conclusions: In children living in hyperendemic settings, a single dose of virosomal HAV vaccine is sufficient to activate immune memory and may provide long-term protection.
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http://dx.doi.org/10.1093/infdis/jiw411DOI Listing
November 2016

[On-site detection of bioterrorism-relevant agents : Rapid detection methods for viruses, bacteria and toxins - capabilities and limitations].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2016 Dec;59(12):1577-1586

Zentrum für Biologische Gefahren und Spezielle Pathogene (ZBS), Robert Koch-Institut, Seestraße 10, 13353, Berlin, Deutschland.

In Europe, besides the threat of terrorist attacks involving conventional methods such as explosive devices and automatic weapons, there is also a potential threat of terrorist groups using non-conventional material like biological agents in the scope of future attacks. Consequently, rapid and reliable detection systems for biological agents are being developed and tested continuously to inform crisis management. For environmental detection, a broad spectrum of different laboratory-based techniques has been developed for relevant biological agents. However for environmental samples, fast and reliable on-site detection methods are desired by first responders for rapid assessment.Based on different functional principles, generic, immunological and nucleic-acid-based on-site detection methods can be distinguished. Those should be facile, fast, sensitive, and specific. However, commercially available kits usually have limited sensitivity and often have not been validated independently. Furthermore in this context, the multitude of relevant biological agents that potentially have to be considered present in complex environmental matrices poses a serious challenge for reliable detection. Therefore, detailed knowledge of the specific scope of applications and the limitations of different analytical systems is necessary to evaluate the results obtained purposefully.The aim of this article is to provide an overview of the analytical principles, benefits and limitations of prevailing on-site environmental detection systems for bioterrorism-relevant viruses, bacteria and toxins. Despite promising developments the informative value of currently available on-site tests is still limited. Thus, expert laboratories have to conduct confirmatory testing.
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http://dx.doi.org/10.1007/s00103-016-2463-zDOI Listing
December 2016

Successful comeback of the single-dose live oral cholera vaccine CVD 103-HgR.

Authors:
Christian Herzog

Travel Med Infect Dis 2016 Jul-Aug;14(4):373-7. Epub 2016 Jul 16.

Medical Department, Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4051 Basel, Switzerland. Electronic address:

Effective and easy to administer cholera vaccines are in need more than ever, for at risk populations and travellers alike. In many parts of the world cholera is still endemic, causing outbreaks and constituting repeatedly serious public health problems. The oral live cholera vaccine CVD 103-HgR (Orochol, Mutachol), the first genetically modified organism (GMO) used as vaccine, was in its time (launched 1993, Switzerland) the ideal cholera vaccine: single-dose, protective efficacy of 80-100% against moderate to severe cholera, acting within 8 days and exhibiting excellent safety, indiscernible from placebo. However, there were strong headwinds: In the 1990s the indication for cholera vaccines was generally downplayed by experts and in 1997 the European Commission called for a moratorium of GMOs which blocked the registration in the European Union. Thus, demand for this vaccine remained low and in 2003 it was taken off the market for economic reasons. After a decade in obscurity it (Vaxchora) has resurfaced again, now produced in the U.S. and equipped with a U.S. FDA license (June 10, 2016). What had happened? This commentary gives a critical account of an almost unbelievable string of misadventures, emerging adverse circumstances and man-made failures which nearly killed this single-dose live oral cholera vaccine. The good news is that patience and persistence lead to success in the end, allowing good science to prevail for the benefit of those in need.
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http://dx.doi.org/10.1016/j.tmaid.2016.07.003DOI Listing
April 2017

Changing from whole-cell to acellular pertussis vaccines would trade superior tolerability for inferior protection.

Authors:
Christian Herzog

Expert Rev Vaccines 2015 22;14(8):1065-72. Epub 2015 Jun 22.

Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4051 Basel, Switzerland.

Notifications of infant deaths, assumed to be related to the introduction of new pentavalent DTwP-Hib-HBV childhood vaccines, caused, during 2008-2010 in few Asian countries, temporary interruptions of the respective vaccination programs. The sudden appearance of fatal cases was due to increased awareness/publicity and improved safety monitoring/reporting in countries with relatively high background infant mortalities. WHO investigations could not establish any causal relationships and vaccinations were again resumed. Recently, questions were raised in one concerned country as to why not to change to less reactogenic acellular pertussis (aP)-containing vaccines that are available in private practice and are generally perceived as 'better'. For resource-poor countries, the financial impacts render such a switch impossible and would also not be supported by external funding. Furthermore, it would be a disservice to the children, as in recent years evidence of inferior long-term efficacy of aP vaccines has accumulated. This report summarizes current knowledge on comparative whole-cell pertussis (wP) and aP vaccine performance, outlines the new July 2014 WHO guidance on the choice of pertussis vaccines and presents recent data on outbreak protection, antibody waning, long-term protection, wP-priming, pathogen adaptation, transmission and herd immunity.
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http://dx.doi.org/10.1586/14760584.2015.1059759DOI Listing
April 2016

[Not Available].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2015 Jul;58(7):655-6

FA für Innere Medizin/Infektiologie und Öffentliches Gesundheitswesen, Gesundheitsamt der Stadt Frankfurt am Main, Breite Gasse 28, 60313, Frankfurt am Main, Deutschland,

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http://dx.doi.org/10.1007/s00103-015-2178-6DOI Listing
July 2015

[General procedures in response to suspected attacks with highly contagious and pathogenic agents].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2015 Jul;58(7):699-704

Zentrum für Biologische Gefahren und Spezielle Pathogene, Informationsstelle des Bundes für Biologische Gefahren und Spezielle Pathogene, Robert Koch-Institut, Berlin, Deutschland,

The discovery of undefined powders that are content of letters or parcels with or without threats in writing addressed to institutions, groups or persons, often raises the suspicion of an attack involving biological agents such as anthrax. Subsequent investigations and analyses by local authorities often aim at excluding anthrax or anthrax spores. Suspicion and actions are then mistakenly justified by referring to the 2001 anthrax letter attacks in the USA, which now lie more than 10 years in the past. In Germany to date there has never been a terrorist attack involving dangerous biological agents, neither in letters nor in any other possible form. In addition, it cannot be assumed that anthrax bacteria or spores will be used again in a bioterrorist event. In the case of a valid suspicion of a threatening letter, neither analyses to exclude only a certain group of substances (e.g. biological, chemical or radiological) nor analyses to exclude only one biological agent (e.g. anthrax) in particular would provide sufficient information for decision makers to conduct further actions in coping with the given situation. Moreover, a sequence of procedures such as consultation, exclusion, and analyses should be followed in order to systematically exclude all relevant threats. Therefore, and in respect to the current CBRNE threat assessment for Germany, the following article provides recommendations of actions to be taken for coping with a valid suspicion of an intentional release of biological agents utilizing powder letters as an example.
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http://dx.doi.org/10.1007/s00103-015-2160-3DOI Listing
July 2015

Basement membrane protein nidogen-1 is a target of meprin β in cisplatin nephrotoxicity.

Toxicol Lett 2015 Jul 6;236(2):110-6. Epub 2015 May 6.

Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA; University of Arkansas for Medical Sciences, Department of Internal Medicine, Little Rock, AR 72205, USA; University of Arkansas for Medical Sciences, Department of Biochemistry, Little Rock, AR 72205, USA. Electronic address:

Meprins are oligomeric metalloproteinases that are abundantly expressed in the brush-border membranes of renal proximal tubules. During acute kidney injury (AKI) induced by cisplatin or ischemia-reperfusion, membrane-bound meprins are shed and their localization is altered from the apical membranes toward the basolateral surface of the proximal tubules. Meprins are capable of cleaving basement membrane proteins in vitro, however, it is not known whether meprins are able to degrade extracellular matrix proteins under pathophysiological conditions in vivo. The present study demonstrates that a basement membrane protein, nidogen-1, is cleaved and excreted in the urine of mice subjected to cisplatin-induced nephrotoxicity, a model of AKI. Cleaved nidogen-1 was not detected in the urine of untreated mice, but during the progression of cisplatin nephrotoxicity, the excretion of cleaved nidogen-1 increased in a time-dependent manner. The meprin inhibitor actinonin markedly prevented urinary excretion of the cleaved nidogen-1. In addition, meprin β-deficient mice, but not meprin α-deficient mice, subjected to cisplatin nephrotoxicity significantly suppressed excretion of cleaved nidogen-1, further suggesting that meprin β is involved in the cleavage of nidogen-1. These studies provide strong evidence for a pathophysiological link between meprin β and urinary excretion of cleaved nidogen-1 during cisplatin-induced AKI.
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http://dx.doi.org/10.1016/j.toxlet.2015.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457671PMC
July 2015

ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A.

J Biol Chem 2014 May 24;289(19):13308-22. Epub 2014 Mar 24.

From the Central Arkansas Veterans Healthcare System and.

Meprin A, composed of α and β subunits, is a membrane-bound metalloproteinase in renal proximal tubules. Meprin A plays an important role in tubular epithelial cell injury during acute kidney injury (AKI). The present study demonstrated that during ischemia-reperfusion-induced AKI, meprin A was shed from proximal tubule membranes, as evident from its redistribution toward the basolateral side, proteolytic processing in the membranes, and excretion in the urine. To identify the proteolytic enzyme responsible for shedding of meprin A, we generated stable HEK cell lines expressing meprin β alone and both meprin α and meprin β for the expression of meprin A. Phorbol 12-myristate 13-acetate and ionomycin stimulated ectodomain shedding of meprin β and meprin A. Among the inhibitors of various proteases, the broad spectrum inhibitor of the ADAM family of proteases, tumor necrosis factor-α protease inhibitor (TAPI-1), was most effective in preventing constitutive, phorbol 12-myristate 13-acetate-, and ionomycin-stimulated shedding of meprin β and meprin A in the medium of both transfectants. The use of differential inhibitors for ADAM10 and ADAM17 indicated that ADAM10 inhibition is sufficient to block shedding. In agreement with these results, small interfering RNA to ADAM10 but not to ADAM9 or ADAM17 inhibited meprin β and meprin A shedding. Furthermore, overexpression of ADAM10 resulted in enhanced shedding of meprin β from both transfectants. Our studies demonstrate that ADAM10 is the major ADAM metalloproteinase responsible for the constitutive and stimulated shedding of meprin β and meprin A. These studies further suggest that inhibiting ADAM 10 activity could be of therapeutic benefit in AKI.
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http://dx.doi.org/10.1074/jbc.M114.559088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036340PMC
May 2014

Caspase protocols in mice.

Methods Mol Biol 2014 ;1133:141-54

Biology Department, Hendrix College, Conway, AR, USA.

Members of the caspase family of proteases are evolutionarily conserved cysteine proteases that play a crucial role as the central executioners of the apoptotic pathway. Since the discovery of caspases, many methods have been developed to detect their activation and are widely used in basic and clinical studies. In a mouse tissue, caspase activation can be monitored by cleavage of caspase-specific synthetic substrates and by detecting cleaved caspase by western blot analysis of the tissue extract. In tissue sections, active caspase can be detected by immunostaining using specific antibodies to the active caspase. In addition, among the myriads of caspase-specific substrates known so far, cleaved fragments produced by caspases from the substrates such as PARP, lamin A, and cytokeratin-18 can be monitored in tissue sections by immunostaining as well as western blots of tissue extracts. In general, more than one method should be used to ascertain detection of activation of caspases in a mouse tissue.
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http://dx.doi.org/10.1007/978-1-4939-0357-3_9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084876PMC
October 2014

Hepatitis A vaccine for immunosuppressed patients with rheumatoid arthritis: a prospective, open-label, multi-centre study.

Travel Med Infect Dis 2014 Mar-Apr;12(2):134-42. Epub 2014 Jan 29.

Division of Infectious Diseases, Department of Medicine, Helsinki University Central Hospital, FI-00029 HUCH Helsinki, Finland; Department of Medicine, FI-00014 University of Helsinki, Finland. Electronic address:

Background: Hepatitis A vaccine is the most frequently used travel vaccine, yet data are scarce about its ability to induce protection in patients with concurrent immunosuppressive treatment. We assessed the immunogenicity of this vaccine in rheumatoid arthritis (RA) patients treated with tumour necrosis factor-inhibitors (TNFi) and/or methotrexate (MTX).

Methods: Hepatitis A vaccine was administered to non-immune RA patients at 0 and 6 months. Hepatitis A virus (HAV) antibodies were assessed at 0, 1, 6, 7, 12, and 24 months with a quantitative Chemiluminescent Microparticle Immuno Assay (CMIA) for HAV-IgG. Samples from month 1, 6, and 7 were, in addition, analysed with a microparticle EIA (MEIA) for anti-HAV IgM + IgG.

Results: The final study population consisted of 53 patients treated with TNFi (n = 15), TNFi + MTX (n = 21) or MTX (n = 17). One and six months after the first dose, 10% and 33% of the patients had attained seroprotection. One and six months after the second dose 83% and 72% were seroprotected. At month 24, 86% of the vaccinees showed protective levels.

Conclusions: Two doses of hepatitis A vaccine at a 6-month interval provided protection for most immunosuppressed RA patients. A single dose does not seem to afford sufficient protection to this group of patients.
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http://dx.doi.org/10.1016/j.tmaid.2014.01.005DOI Listing
December 2014

Decreasing risk of hepatitis A infection in León, Nicaragua: evidence from cross-sectional and longitudinal seroepidemiology studies.

PLoS One 2014 11;9(2):e87643. Epub 2014 Feb 11.

Institute of Social & Preventive Medicine (ISPM), University of Berne, Berne, Switzerland.

Background And Objectives: Nicaragua is highly endemic for hepatitis A. We aimed to provide an estimate of the change in the age-specific risk of hepatitis A virus (HAV) infection based on serological data from cross-sectional and longitudinal samples collected in León, Nicaragua, in 1995/96 (n = 979) and 2003 (n = 494).

Methods: The observed age-specific prevalence of anti-HAV antibodies was correlated to the age-specific risk of infection by calculating the probability of freedom from infection at a specific age.

Results: The proportion of seropositive children aged 1.5 to 6 years was 42% in 2003 compared to 67% in 1995/96. Estimated annual risk of infection for a 3-year old child was 30% (95% CI: 27.0%, 33.1%) in 1995 and 15.5% (95% CI: 12.4%, 19.0%) in 2003. There was good agreement between estimates based on cross-sectional and longitudinal data. The age-specific geometric mean of the quantified anti-HAV antibody levels assessed in 2003 was highest at age 4 and decreased steadily up to age 40.

Conclusions: The substantially lower risk of HAV infection in 2003 than in 1995 for young children indicates a beginning transition from high to intermediate endemicity in León, Nicaragua. Consecutive age-stratified serosurveys are useful to assess changes in risk of infection following public health interventions. The decreasing age-specific GMC of anti-HAV antibodies during adulthood in a country with endemic HAV indirectly suggests that ongoing HAV exposure in the community has marginal boosting effect on antibody levels once protective immunity has been established by natural infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087643PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921130PMC
October 2014

Influence of parenteral administration routes and additional factors on vaccine safety and immunogenicity: a review of recent literature.

Authors:
Christian Herzog

Expert Rev Vaccines 2014 Mar 10;13(3):399-415. Epub 2014 Feb 10.

Swiss Tropical and Public Health Institute , Socinstrasse 57, CH-4051 Basel , Switzerland.

Vaccines have to be administered via an appropriate route, i.e. a route, which is optimal regarding safety, immunogenicity and practicability. In addition, there are factors, such as body site, needle length, injection technique, depth of injection, type of antigen, vaccine formulation, adjuvants, age, sex, race/ethnicity, body mass, and pre-existing immunity, which can have an impact on the reactogenicity and tolerability and/or on the immunogenicity of a given vaccine. For parenteral vaccine administration there are currently three routes licensed: intramuscular, subcutaneous and intradermal, either by using conventional hypodermic needles or by using alternative or needle-free injection devices. The factors potentially impacting on the 'performance' of a given route of administration, as reported in recent literature, are outlined and discussed in view of their importance. These factors need to be accounted and controlled for when designing vaccine studies and should be reported in a transparent and standardised way in publications.
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http://dx.doi.org/10.1586/14760584.2014.883285DOI Listing
March 2014

Cross-reactive immune response elicited by parenteral Vi polysaccharide typhoid vaccine against non-typhoid Salmonellae.

Vaccine 2014 Jan 14;32(5):544-51. Epub 2013 Dec 14.

Department of Bacteriology and Immunology, Haartman Institute, POB 21, 00014 University of Helsinki, Helsinki, Finland; Department of Medicine, Division of Infectious Diseases, POB 348, 00029 Helsinki University Hospital, Helsinki, Finland; Institute of Clinical Medicine, Department of Medicine, POB 20, 00014 University of Helsinki, Helsinki, Finland. Electronic address:

Background: Despite 155000 deaths and over 90 million cases - and the current emergence of antimicrobial resistance - no vaccines are available against non-typhoid Salmonellae (NTS). We recently presented immunological arguments for using the oral Salmonella Typhi Ty21a as surrogate vaccine against NTS strains: Ty21a elicits intestinal antibodies against typhoidal O-9,12 antigen, and numerous NTS strains share one or both of these structures with S. Typhi. The Vi polysaccharide vaccine can, presumably because of contaminating typhoidal lipopolysaccharide, also elicit a humoral response to O-9,12, although a lower one in magnitude than the Ty21a. In this study, the Vi vaccine was explored for cross-reactive immune response to various NTS strains, and compared to that elicited by the Ty21a vaccine.

Materials And Methods: Volunteers immunized with the Vi polysaccharide (Typherix(®); n=25) were investigated for circulating plasmablasts secreting antibodies reactive with six NTS serotypes. The results were compared to those for 25 age- and gender-matched volunteers vaccinated with Ty21a (Vivotif(®)), as partly presented in our previous study. The cross-reactive plasmablasts elicited by the Vi vaccine were also analyzed for homing receptor expressions.

Results: 49 out of 50 vaccinees showed a cross-reactive plasmablast response against S. Enteritidis sharing both O-9 and O-12 antigens with S. Typhi (mean: 95%CI 37: 19-55 and 363: 234-493 plasmablasts/10(6) PBMC in the Vi and the Ty21a group, respectively). The response against strains only sharing O-12 was weaker (22: 8-38 and 222: 105-338 against S. Typhimurium). Strains without typhoidal O-antigens generated no significant reactivity. The cross-reactive plasmablasts elicited by the Vi vaccine had systemic homing properties.

Conclusions: The Vi vaccine elicited an immune response cross-reactive with several NTS strains. This response was lower than that in Ty21a-vaccinated volunteers. The clinical significance of these responses deserves further research with respect to both gastrointestinal and invasive NTS (iNTS) disease.
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http://dx.doi.org/10.1016/j.vaccine.2013.12.001DOI Listing
January 2014