Publications by authors named "Christian Probst"

197 Publications

Pathogenic Activation and Therapeutic Blockage of Fc Alpha Receptor-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus.

J Invest Dermatol 2021 Jul 8. Epub 2021 Jul 8.

Luebeck Inst. of Experimental Dermatology (LIED), University of Luebeck, Luebeck, Germany; Dept. of Dermatology, University of Luebeck, Luebeck, Germany. Electronic address:

Pathomechanisms in IgA pemphigus are assumed to rely on Fc-dependent cellular activation by antigen-specific IgA autoantibodies, however, models for disease and more detailed pathophysiologic data are lacking. We here aimed to establish in vitro models of disease for IgA pemphigus, allowing to study effects of the interaction of anti-keratinocyte IgA with cell-surface Fc alpha receptors. Employing multiple in vitro assays, such as a skin cryosection assay and a human skin organ culture model, we here present mechanistic data for the pathogenesis of IgA pemphigus, mediated by anti-desmoglein 3 IgA autoantibodies. Our results reveal that this disease is dependent on Fc alpha receptor-mediated activation of leukocytes in the epidermis. Importantly, this cell-dependent pathology can be dose-dependently abrogated by peptide-mediated inhibition of Fc alpha receptor:IgA interaction, as confirmed in an additional model for IgA-dependent disease, i.e., IgA vasculitis. These data suggest that IgA pemphigus can be modeled in vitro, and IgA pemphigus and IgA vasculitis are Fc alpha receptor-dependent disease entities that can be specifically targeted in these experimental systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2021.06.007DOI Listing
July 2021

Differential Binding of Autoantibodies to MOG Isoforms in Inflammatory Demyelinating Diseases.

Neurol Neuroimmunol Neuroinflamm 2021 07 15;8(5). Epub 2021 Jun 15.

From the Clinical Department of Neurology (K.S., P.P., M.L., B.S., H.H., F.D.P., M.R.), Medical University of Innsbruck, Austria; Euroimmun Medizinische Labordiagnostika AG (S. Mindorf, N.R., C.P.), Lübeck, Germany; Institute for Quality Assurance (ifQ) affiliated to Euroimmun (M.P.), Lübeck, Germany; Department of Pediatrics (E.-M.W.), Olgahospital/Klinikum Stuttgart, Germany; Department of Pediatrics I (C.L., M.B.), Medical University of Innsbruck, Austria; Neurology Unit (S. Mariotto, S.F.), Department of Neuroscience, Biomedicine, and Movement Sciences, University of Verona, Italy; Neuroimmunology and Multiple Sclerosis Unit (A.S.), Service of Neurology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Beaumont Hospital (M.F.), Dublin, Ireland; Oxford Autoimmune Neurology Group (M.I.S.L., S.R.I., J.P., P.W.), Nuffield Department of Clinical Neurosciences, University of Oxford, UK; Neuroimmunology and MS Research (A.L.), Department of Neurology, University Hospital Zurich & University of Zurich, Switzerland; Institute of Clinical Neuroimmunology (T.K.), Biomedical Center and University Hospital, Ludwig-Maximilians University, Munich, Germany; Department of Neurology (S.V., R.M.), Hospices civils de Lyon, Hôpital neurologique Pierre Wertheimer, France; Paediatric Neurology (K.R.), Witten/Herdecke University, Children's Hospital Datteln, Germany; Department of Neurology (T.B.), Medical University of Vienna, Austria; and Division of Neuropathology and Neurochemistry (R.H.), Department of Neurology, Medical University of Vienna, Austria.

Objective: To analyze serum immunoglobulin G (IgG) antibodies to major isoforms of myelin oligodendrocyte glycoprotein (MOG-alpha 1-3 and beta 1-3) in patients with inflammatory demyelinating diseases.

Methods: Retrospective case-control study using 378 serum samples from patients with multiple sclerosis (MS), patients with non-MS demyelinating disease, and healthy controls with MOG alpha-1-IgG positive (n = 202) or negative serostatus (n = 176). Samples were analyzed for their reactivity to human, mouse, and rat MOG isoforms with and without mutations in the extracellular MOG Ig domain (MOG-ecIgD), soluble MOG-ecIgD, and myelin from multiple species using live cell-based, tissue immunofluorescence assays and ELISA.

Results: The strongest IgG reactivities were directed against the longest MOG isoforms alpha-1 (the currently used standard test for MOG-IgG) and beta-1, whereas the other isoforms were less frequently recognized. Using principal component analysis, we identified 3 different binding patterns associated with non-MS disease: (1) isolated reactivity to MOG-alpha-1/beta-1 (n = 73), (2) binding to MOG-alpha-1/beta-1 and at least one other alpha, but no beta isoform (n = 64), and (3) reactivity to all 6 MOG isoforms (n = 65). The remaining samples were negative (n = 176) for MOG-IgG. These MOG isoform binding patterns were associated with a non-MS demyelinating disease, but there were no differences in clinical phenotypes or disease course. The 3 MOG isoform patterns had distinct immunologic characteristics such as differential binding to soluble MOG-ecIgD, sensitivity to MOG mutations, and binding to human MOG in ELISA.

Conclusions: The novel finding of differential MOG isoform binding patterns could inform future studies on the refinement of MOG-IgG assays and the pathophysiologic role of MOG-IgG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000001027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207634PMC
July 2021

Autoantibodies Against the Purkinje Cell Protein RGS8 in Paraneoplastic Cerebellar Syndrome.

Neurol Neuroimmunol Neuroinflamm 2021 05 29;8(3). Epub 2021 Mar 29.

From the Institute for Experimental Immunology (R.M., M.S., A.O., Y.D., N.R., C.P., L.K.), Affiliated to EUROIMMUN Medizinische Labordiagnostika AG, Luebeck; Department of Neurology (P.S., H.D.), Krankenhaus St. Elisabeth, Damme; Laboratory Krone (C.I.B.), Bad Salzuflen; Department of Neurology (C.B., P.K.), Nordwest-Krankenhaus Sanderbusch, Sande; Clinical Immunological Laboratory Prof. Dr. Med. Winfried Stöcker (K.B., B.T.), Luebeck; and Department of Neurology (C.F.), Charité - Universitätsmedizin Berlin, Berlin, Germany.

Objective: To describe the identification of regulator of G-protein signaling 8 (RGS8) as an autoantibody target in patients with cerebellar syndrome associated with lymphoma.

Methods: Sera of 4 patients with a very similar unclassified reactivity against cerebellar Purkinje cells were used in antigen identification experiments. Immunoprecipitations with cerebellar lysates followed by mass spectrometry identified the autoantigen, which was verified by recombinant immunofluorescence assay, immunoblot, and ELISA with the recombinant protein.

Results: The sera and CSF of 4 patients stained the Purkinje cells and molecular layer of the cerebellum. RGS8 was identified as the target antigen in all 4 sera. In a neutralization experiment, recombinant human RGS8 was able to neutralize the autoantibodies' tissue reaction. Patient sera and CSF showed a specific reactivity against recombinant RGS8 in ELISA and immunoblot, whereas no such reactivity was detectable in the controls. Clinical data were available for 2 of the 4 patients, remarkably both presented with cerebellar syndrome accompanied by B-cell lymphoma of the stomach (patient 1, 53 years) or Hodgkin lymphoma (patient 2, 74 years).

Conclusion: Our results indicate that autoantibodies against the intracellular Purkinje cell protein RGS8 represent new markers for paraneoplastic cerebellar syndrome associated with lymphoma.

Classification Of Evidence: This study provided Class IV evidence that autoantibodies against the intracellular Purkinje cell protein RGS8 are associated with paraneoplastic cerebellar syndrome in lymphoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009278PMC
May 2021

GTPase Regulator Associated with Focal Adhesion Kinase 1 (GRAF1) Immunoglobulin-Associated Ataxia and Neuropathy.

Mov Disord Clin Pract 2020 Nov 14;7(8):904-909. Epub 2020 Sep 14.

Department of Neurology Mayo Clinic Rochester Minnesota USA.

Background: To date, 10 patients with GTPase Regulator Associated with Focal Adhesion Kinase 1/Rho GTPase Activating Protein 26-Immunoglobulin (GRAF1/ARHGAP26-IgG) associated neurological disorders have been described, most with ataxia.

Objective: To report the clinical, oncological, and radiological associations of GRAF1 autoantibodies.

Methods: We identified 17 patients whose serum and/or cerebrospinal fluid IgG was confirmed to target GRAF1/ARHGAP26-IgG by both tissue-based immunofluorescence and transfected cell-based assay. Clinical information was available on 14 patients.

Results: The median age at neurological symptom onset was 51 years, and 8 (47%) were men. The predominant clinical features were subacute progressive cerebellar ataxia (13) or peripheral neuropathy (2). Magnetic resonance imaging brain (7 available) showed cerebellar atrophy (4, 1 also cerebrum and brainstem atrophy). Of 7 cerebrospinal fluids available for testing, 5 showed pleocytosis with oligoclonal bands in 3. Squamous cell carcinoma was observed in 3 patients (head and neck [2], lung [1]).

Conclusion: GTPase Regulator Associated with Focal Adhesion Kinase 1 autoimmunity manifests commonly with subacute ataxia and cerebellar degeneration with a potential association with squamous cell carcinoma. Peripheral neuropathy may also be encountered. Cases in this series responded poorly to immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mdc3.13036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604666PMC
November 2020

Elective removal vs. retaining of hardware after osteosynthesis in asymptomatic patients-a scoping review.

Syst Rev 2020 10 2;9(1):225. Epub 2020 Oct 2.

Institute for Research in Operative Medicine, Witten/Herdecke University, Ostmerheimer Str. 200, 51109, Cologne, Germany.

Background: Osteosynthesis is the internal fixation of fractures or osteotomy by mechanical devices (also called hardware). After bone healing, there are two options: one is to remove the hardware, the other is to leave it in place. The removal of the hardware in patients without medical indication (elective) is controversially discussed. We performed a scoping review to identify evidence on the elective removal of hardware in asymptomatic patients compared to retaining of the hardware to check feasibility of performing a health technology assessment. In addition, we wanted to find out which type of evidence is available.

Methods: A systematic literature search was performed in PubMed, Embase, EconLit, and CINAHL (November 2019). We included studies comparing asymptomatic patients with an internal fixation in the lower or upper extremities whose internal fixation was electively (without medical indication) removed or retained. We did not restrict inclusion to any effectiveness/safety outcome and considered any comparative study design as eligible. Study selection and data extraction was performed by two reviewers.

Results: We identified 13476 titles/abstracts. Of these, we obtained 115 full-text publications which were assessed in detail against the inclusion criteria. We included 13 studies (1 RCT, 4 cohort studies, 8 before-after studies) and identified two ongoing RCTs. Nine assessed the removal of the internal fixation in the lower extremities (six of these syndesmotic screws in ankle fractures only) and two in the upper extremities. One study analysed the effectiveness of hardware removal in children in all types of extremity fractures. Outcomes reported included various scales measuring functionality, pain and clinical assessments (e.g. range of motion) and health-related quality of life.

Conclusions: We identified 13 studies that evaluated the effectiveness/safety of hardware removal in the extremities. The follow up times were short, the patient groups small and the ways of measurement differed. In general, clinical heterogeneity was high. Evidence on selected topics, e.g. syndesmotic screw removal is available nevertheless not sufficient to allow a meaningful assessment of effectiveness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13643-020-01488-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532570PMC
October 2020

Contactin-1 autoimmunity: Serologic, neurologic, and pathologic correlates.

Neurol Neuroimmunol Neuroinflamm 2020 07 27;7(4). Epub 2020 May 27.

From the Department of Laboratory Medicine and Pathology, Neurology and Immunology (D.D., J.A.H., S.S., C.J.K., J.R.M., V.A.L., S.J.P., A.M.); Department of Neurology (D.D., J.A.H., S.S., C.J.K., J.R.M., V.A.L., S.J.P., A.M.), Mayo Clinic, Rochester, MN; and Euroimmun (L.K., S.B., C.P.), Lubeck, Germany.

Objective: To determine serologic characteristics, frequency, phenotype, paraneoplastic associations, and electrodiagnostic and histopathologic features accompanying contactin-1 autoimmunity.

Methods: Archived sera known to produce synaptic tissue-based immunofluorescence patterns were reevaluated, and contactin-1 specificity was confirmed by recombinant protein assays. Screening of 233 chronic/relapsing demyelinating neuropathies for additional cases was performed.

Results: We identified 10 contactin-1 IgG seropositive cases. Frequency of contactin-1 immunoglobulin (Ig) G among tested Mayo Clinic chronic/relapsing demyelinating neuropathies was 2%. Sensory predominant presentations (n = 9, 90%), neuropathic pain (n = 6, 60%), and subacute progression (n = 5, 50%) were commonly encountered among contactin-1 neuropathies. Two patients had chronic immune sensory polyradiculopathy-like phenotype at presentation. Electrodiagnostic studies were consistent with demyelination (slowed conduction velocities and/or prolonged distal latencies) without conduction block. Markedly elevated CSF protein (median 222 mg/dL, range 69-960 mg/dL), thickening/gadolinium enhancement of nerve roots (4/5), and subperineural edema on nerve biopsy (4/4) were other characteristic features. Three cases were diagnosed with paraneoplastic demyelinating neuropathies (thymoma, n = 1; breast cancer, n = 1; plasmacytoma, n = 1). Four of the 9 patients treated with IV immunoglobulin demonstrated initial clinical improvement, but the favorable response was sustained in only 1 case (median follow-up, 60 months). Sustained clinical stabilization or improvement was observed among 3 of the 6 cases in whom second-line therapies (rituximab, cyclophosphamide, and azathioprine) were used.

Conclusion: Contactin-1 IgG has a distinct sensory predominant presentation commonly associated with neuropathic pain, with demyelinating changes on electrophysiologic studies. A paraneoplastic cause should be considered. Testing of contactin-1 IgG among cases with similar presentations may guide immunotherapy selection, especially second-line immunotherapy consideration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286654PMC
July 2020

Evaluating the re-identification risk of a clinical study report anonymized under EMA Policy 0070 and Health Canada Regulations.

Trials 2020 Feb 18;21(1):200. Epub 2020 Feb 18.

Privacy Analytics, Ottawa, Canada.

Background: Regulatory agencies, such as the European Medicines Agency and Health Canada, are requiring the public sharing of clinical trial reports that are used to make drug approval decisions. Both agencies have provided guidance for the quantitative anonymization of these clinical reports before they are shared. There is limited empirical information on the effectiveness of this approach in protecting patient privacy for clinical trial data.

Methods: In this paper we empirically test the hypothesis that when these guidelines are implemented in practice, they provide adequate privacy protection to patients. An anonymized clinical study report for a trial on a non-steroidal anti-inflammatory drug that is sold as a prescription eye drop was subjected to re-identification. The target was 500 patients in the USA. Only suspected matches to real identities were reported.

Results: Six suspected matches with low confidence scores were identified. Each suspected match took 24.2 h of effort. Social media and death records provided the most useful information for getting the suspected matches.

Conclusions: These results suggest that the anonymization guidance from these agencies can provide adequate privacy protection for patients, and the modes of attack can inform further refinements of the methodologies they recommend in their guidance for manufacturers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-4120-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029478PMC
February 2020

International multicenter examination of MOG antibody assays.

Neurol Neuroimmunol Neuroinflamm 2020 03 5;7(2). Epub 2020 Feb 5.

From the Clinical Department of Neurology (M. Reindl, K.S., M. Ramberger, H.H.), Medical University of Innsbruck, Innsbruck, Austria; Oxford Autoimmune Neurology Group (M.W., M. Ramberger, M.I.L., J.P., S.R.I., P.W.), Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom; Brain Autoimmunity Group (F.T., S.R., R.C.D., F.B.), Kids Neuroscience Centre at Kids Research at the Children's Hospital at Westmead, Brain and Mind Centre, University of Sydney, New South Wales, Australia; Department of Neurology (J.S., J.P.F., J.M., E.P.F., S.J.P.), Mayo Clinic, Rochester, MN; Euroimmun Medizinische Labordiagnostika AG (B.T., S.M., N.R., U.K., W.S., C.P.), Lübeck, Germany; Institute for Quality Assurance (ifQ) affiliated to Euroimmun (J.E., M.P.), Lübeck, Germany; Paediatric Neurology (K.R.), Witten/Herdecke University, Children's Hospital Datteln, Datteln, Germany; and Department of Neurology (T.B.), Medical University of Vienna, Austria.

Objective: To compare the reproducibility of 11 antibody assays for immunoglobulin (Ig) G and IgM myelin oligodendrocyte glycoprotein antibodies (MOG-IgG and MOG-IgM) from 5 international centers.

Methods: The following samples were analyzed: MOG-IgG clearly positive sera (n = 39), MOG-IgG low positive sera (n = 39), borderline negative sera (n = 13), clearly negative sera (n = 40), and healthy blood donors (n = 30). As technical controls, 18 replicates (9 MOG-IgG positive and 9 negative) were included. All samples and controls were recoded, aliquoted, and distributed to the 5 testing centers, which performed the following antibody assays: 5 live and 1 fixed immunofluorescence cell-based assays (CBA-IF, 5 MOG-IgG, and 1 MOG-IgM), 3 live flow cytometry cell-based assays (CBA-FACS, all MOG-IgG), and 2 ELISAs (both MOG-IgG).

Results: We found excellent agreement (96%) between the live CBAs for MOG-IgG for samples previously identified as clearly positive or negative from 4 different national testing centers. The agreement was lower with fixed CBA-IF (90%), and the ELISA showed no concordance with CBAs for detection of human MOG-IgG. All CBAs showed excellent interassay reproducibility. The agreement of MOG-IgG CBAs for borderline negative (77%) and particularly low positive (33%) samples was less good. Finally, most samples from healthy blood donors (97%) were negative for MOG-IgG in all CBAs.

Conclusions: Live MOG-IgG CBAs showed excellent agreement for high positive and negative samples at 3 international testing centers. Low positive samples were more frequently discordant than in a similar comparison of aquaporin-4 antibody assays. Further research is needed to improve international standardization for clinical care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051197PMC
March 2020

Multicenter prospective study on multivariant diagnostics of autoimmune bullous dermatoses using the BIOCHIP technology.

J Am Acad Dermatol 2020 Nov 28;83(5):1315-1322. Epub 2020 Jan 28.

Institute of Experimental Immunology, EUROIMMUN AG, Lübeck, Germany.

Background: The current standard in the serologic diagnosis of autoimmune bullous diseases (AIBD) is a multistep procedure sequentially applying different assays. In contrast, the BIOCHIP Mosaic technology combines multiple substrates for parallel analysis by indirect immunofluorescence.

Methods: Sera from 749 consecutive, prospectively recruited patients with direct immunofluorescence-positive AIBD from 13 international study centers were analyzed independently and blinded by using (1) a BIOCHIP Mosaic including primate esophagus, salt-split skin, rat bladder, monkey liver, monkey liver with serosa, recombinant BP180 NC16A, and gliadin GAF3X, as well as HEK293 cells expressing recombinant desmoglein 1, desmoglein 3, type VII collagen, and BP230 C-terminus and (2) the conventional multistep approach of the Department of Dermatology, University of Lübeck.

Results: In 731 of 749 sera (97.6%), specific autoantibodies could be detected with the BIOCHIP Mosaic, similar to the conventional procedure (725 cases, 96.8%). The Cohen κ for both serologic approaches ranged from 0.84 to 1.00. In 6.5% of sera, differences between the 2 approaches occurred and were mainly attributed to autoantigen fragments not present on the BIOCHIP Mosaic.

Limitations: Laminin 332 and laminin γ1 are not represented on the BIOCHIP Mosaic.

Conclusions: The BIOCHIP Mosaic is a standardized time- and serum-saving approach that further facilitates the serologic diagnosis of AIBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.01.049DOI Listing
November 2020

Serological Diagnosis of Autoimmune Bullous Skin Diseases.

Front Immunol 2019 20;10:1974. Epub 2019 Aug 20.

Institute for Experimental Immunology, Euroimmun AG, Lübeck, Germany.

Autoimmune bullous dermatoses (AIBD) encompass a variety of organ-specific autoimmune diseases that manifest with cutaneous and/or mucosal blisters and erosions. They are characterized by autoantibodies targeting structural proteins of the skin, which are responsible for the intercellular contact between epidermal keratinocytes and for adhesion of the basal keratinocytes to the dermis. The autoantibodies disrupt the adhesive functions, leading to splitting and blister formation. In pemphigus diseases, blisters form intraepidermally, whereas in all other disease types they occur subepidermally. Early identification of autoimmune bullous dermatoses is crucial for both treatment and prognosis, particularly as regards tumor-associated disease entities. The diagnosis is based on clinical symptoms, histopathology, direct immunofluorescence to detect antibody/complement deposits, and the determination of circulating autoantibodies. The identification of various target antigens has paved the way for the recent development of numerous specific autoantibody tests. In particular, optimized designer antigens and multiplex test formats for indirect immunofluorescence and ELISA have enhanced and refined the laboratory analysis, enabling highly efficient serodiagnosis and follow-up. This review elaborates on the current standards in the serological diagnostics for autoimmune bullous dermatoses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.01974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736620PMC
October 2020

GABA receptor autoimmunity: A multicenter experience.

Neurol Neuroimmunol Neuroinflamm 2019 05 4;6(3):e552. Epub 2019 Apr 4.

Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.

Objective: We sought to validate methods for detection and confirmation of GABA receptor (R)-IgG and clinically characterize seropositive cases.

Methods: Archived serum and CSF specimens (185 total) suspected to harbor GABAR-IgG were evaluated by indirect immunofluorescence assay (IFA). Twenty-six specimens from 19 patients appeared suspicious for GABAR-IgG positivity by IFA, based on prior reports and comparison with commercial GABAR antibody staining. Aliquots of those specimens were tested at the University of Oxford, United Kingdom, and Euroimmun, Lubeck, Germany, for GABAR-IgG by cell-based assays (CBAs) using HEK293-indicator cells transfected with plasmids encoding different GABAR subunits.

Results: Eight specimens (of 26 tested; 4 serums, 4 CSFs) from 5 patients were confirmed by CBA to be GABAR-IgG positive. Patient IgGs were always reactive with α1β3 GABAR subunits. One more patient was identified clinically after this validation study. Median age for the 6 patients at serologic diagnosis was 44 years (range, 1-71 years), and 4 of them were male. Among the 4 for whom clinical information was available (2 treated by the authors), all had encephalitis and antiepileptic drug refractory seizures. Three out of 4 patients treated with a combination of immunotherapies had good outcomes. The fourth, recognized to have an autoimmune cause late in the clinical course, had severe permanent neurologic sequelae and brain atrophy.

Conclusions: Though not as common as NMDA-R encephalitis, GABAR encephalitis generally has a characteristic clinical-radiologic presentation and is treatable, making accurate laboratory diagnosis critical.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501640PMC
May 2019

Risk factors for complications and adverse outcomes in polytrauma patients with associated upper extremity injuries.

Patient Saf Surg 2019 4;13. Epub 2019 Feb 4.

1Department of Trauma, Universitaetsspital, University of Zurich, Raemistr.100, 8091 Zurich, Switzerland.

Background: In terms of upper extremity fractures by patients with multiple injuires, a lot of studies have assessed the functional outcome following trauma to have less favorable outcomes in regards to functional recovery. We tested the hypothesis that differences in clinical outcome occur between shaft and articular injuries of the upper extremity, when patients that sustained neurologic deficits (e.g. brachial plexus lesions) are excluded.

Methods: We involved Patients with isolated or combined upper extremity fracture, ISS > 16 in a level one trauma center. The follow up was at least 10 years after the initial injury. Both clinical examination (range of motion, instability, contractures, peripheral nerve damage) and radiographic analysis were carried out. We evaluated also the development of heterotopic ossifications. To analyse patients were subdivided into 3 different subgroups (articular [IA], shaft [IS], and combined [C]).

Results: A statistically significant difference was found when ROM was compared between Group IS and C ( = 0.012), for contractures between Groups IA and C ( = 0.009) and full muscle elbow forces between Groups IS and C ( = 0.005) and Group IA and IS ( = 0.021). There was a significantly increased incidence in heterotopic ossifications when articular involvement was present. This applied for the isolated ( < 0.02) and the combined group (Group C vs Group IS,  = 0.003).When Brooker type I/II in group IA and Brooker types III/IV were combined, there was a significant difference ( < 0.001). In group IA ( = 1) and in group C ( = 6), HO developed or worsened after revision surgery, all of which were performed for malunion or nonunion.

Conclusions: In this study, patients with isolated shaft fractures of the upper extremity tend to have a more favorable outcome in comparison with combined to isolated articular fractures in terms of range of motion, pain and the ability to use the arm for everyday activities.In the clinical practice of the treatment of polytraumatized patients with upper extremity injuries, we feel that the relevance of these injuries should not be underestimated. They are especially prone to development of heterotopic ossifications, thus requiring prophylactic measures, if necessary. As their incidence increases with the rate of reoperations, we feel that even during initial care, meticulous surgery is required to avoiding the necessity of revision surgeries. Similar to injuries below the knee, upper extremity injuries, should be treated to avoid any functional disability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13037-019-0187-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360674PMC
February 2019

High prevalence of bacteria in clinically aseptic non-unions of the tibia and the femur in tissue biopsies.

Eur J Trauma Emerg Surg 2020 Oct 25;46(5):1093-1097. Epub 2018 Sep 25.

Department of Traumatology and Orthopedic Surgery, Cologne-Merheim Medical Center (CMMC), University Witten-Herdecke (UWH), Ostmerheimerstr. 200, 51109, Cologne, Germany.

Purpose: There are several hints that bacterial colonization might be an often overseen cause of non-union. Modern procedures like PCR have been reported to diagnose bacterial colonization with a high degree of accuracy. While PCR is not ubiquitously available, we hypothesize that biopsies from the non-union site are comparable to PCR results reported in the literature.

Methods: Retrospective analysis of microbiological results of biopsies from non-unions (femoral or tibial, history of revision surgery, and/or open fracture) with stable osteosynthesis, no clinical signs of local infection were analysed. CRP and leucocyte count were taken on admission. Multiple tissue samples (soft tissue and bone) were from the non-union (1-4 cm incision). Samples were cultivated for 2 weeks and tested following EUCAST protocols using VITEK 2.

Results: 11 tibia- and 7 femur non-union (44 ± 23.9 years), 11 open fractures (1 I°, 6 II°, 4 III° Gustillo Anderson), 0-5 revisions, and 4.1 (± 1.8) tissue samples were taken 8.5 (± 1.7) months after trauma. Cultures were positive in 8/18 (44,4%) (3/18 Propionibacterium acnes, 1/18 S. capitis, and 4/18 S. epidermidis). There was neither a correlation between number of biopsies taken and positive culture results (Pearson R: - 0.0503, R 0.0025), nor between positive culture results and leucocytes counts (Pearson R: - 0.0245, R 0.0006) or CRP concentration (Pearson R: 0.2823, R 0.0797).

Conclusion: The results confirm that the presence of bacteria in cases with no clinical signs of infection is a relevant issue. The prevalence of bacteria reported here is comparable that reported from cohorts tested with PCR or sonication. In most cases, there was only one positive biopsy, raising the question whether a contamination has been detected. Thus, to better understand the problem, it is necessary to gather more knowledge regarding the sensitivities and specificities of the different diagnostic procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00068-018-1010-zDOI Listing
October 2020

Immunoadsorption of Desmoglein-3-Specific IgG Abolishes the Blister-Inducing Capacity of Pemphigus Vulgaris IgG in Neonatal Mice.

Front Immunol 2018 3;9:1935. Epub 2018 Sep 3.

Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.

Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune blistering disease which is associated with autoantibodies directed against two desmosomal proteins, desmoglein (Dsg) 3 and 1. Treatment of PV is rather challenging and relies on the long-term use of systemic corticosteroids and additional immunosuppressants. More recently, autoantibody-depleting therapies such as rituximab, high-dose intravenous immunoglobulins, and immunoadsorption were shown to be valuable treatment options in PV. Specific removal of pathogenic autoantibodies would further increase efficacy and usability of immunoadsorption. Here, we tested the capacity of our recently developed prototypic Dsg1- and Dsg3-specific adsorbers to remove circulating pathogenic autoantibodies from three different PV patients. The pathogenic potential of the Dsg3/1-depleted IgG fractions and the anti-Dsg3-specific IgG was explored in two different assays based on cultured human keratinocytes, the desmosome degradation assay and the dispase-based dissociation assay. In addition, the neonatal mouse model of PV was used. In both assays, no difference between the pathogenic effect of total PV IgG and anti-Dsg3-specific IgG was seen, while Dsg3/1-depleted and control IgG were not pathogenic. For the samples of all 3 PV patients, depletion of anti-Dsg3/1 IgG resulted in a complete loss of pathogenicity when injected into neonatal mice. In contrast, injection of anti-Dsg3-specific IgG, eluted from the column, induced gross blistering in the mice. Our data clearly show that anti-Dsg3-specific IgG alone is pathogenic and , whereas Dsg3/1-depletion results in a complete loss of pathogenicity. Furthermore, our data suggest that Dsg-specific adsorption may be a suitable therapeutic modality to efficiently reduce pathogenic autoantibodies in patients with severe PV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.01935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130267PMC
September 2019

Open adrenalectomy through a makuuchi incision: A single institution's experience.

Surgery 2018 12 25;164(6):1372-1376. Epub 2018 Aug 25.

University of Rochester, Department of Surgery, Rochester, NY. Electronic address:

Background: Surgical techniques for adrenalectomy have evolved substantially over the last century. Although minimally invasive approaches are favored for benign disease, open adrenalectomy remains the gold standard for large tumors and those concerning for malignancy. Most reports describe the use of midline, subcostal, or thoracoabdominal incisions for open adrenalectomy. We studied our experience with the Makuuchi incision, designed to optimize exposure and minimize denervation of the abdominal wall.

Methods: All open adrenalectomies at the University of Rochester from 2009 to 2017 were retrospectively reviewed. Patient demographic characteristics, intraoperative details, and postoperative complications were investigated. Surgical site infection and hernia rates of Makuuchi incision were compared with non-Makuuchi incision patients and with published standards. The study was approved by the university Institutional Review Board.

Results: A total of 41 adrenalectomies were performed via Makuuchi incision. Population statistics included a mean age of 51.7 (19-86) years, a mean body mass index of 29.7 (17.3-45.8), and a mean tumor diameter of 8 cm (3.1-26 cm). Fourteen (34%) required multivisceral resection. Twenty-one (51%) were previous or current smokers, and 9 (22%) had hypercortisolemia. Median duration of stay was 6 days (4-73). Incisional hernia occurred in 5 patients (12%) and surgical site infection in 3 patients (7%), 2 patients had Cushing syndrome and 1 was immunosuppressed. Pain was managed with patient-controlled epidural anesthesia or patient-controlled anesthesia with postoperative day 1 daily morphine equivalents equating to 0.5 mg of hydromorphone q2h. Among 15 non-Makuuchi incision patients, there were 2 hernias (13%), 2 surgical site infections (13%), and 1 case of postoperative pneumonia.

Conclusion: The Makuuchi incision is well tolerated and affords outstanding exposure of the adrenals and adjacent viscera. Incisional hernia and surgical site infection rates were favorable compared with published rates for midline or subcostal incisions, despite an obese population with a high incidence of hypercortisolism and immunosuppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.surg.2018.06.045DOI Listing
December 2018

A Spectrum of Neural Autoantigens, Newly Identified by Histo-Immunoprecipitation, Mass Spectrometry, and Recombinant Cell-Based Indirect Immunofluorescence.

Front Immunol 2018 9;9:1447. Epub 2018 Jul 9.

Institute of Experimental Immunology, EUROIMMUN AG, Lübeck, Germany.

Background: A plurality of neurological syndromes is associated with autoantibodies against neural antigens relevant for diagnosis and therapy. Identification of these antigens is crucial to understand the pathogenesis and to develop specific immunoassays. Using an indirect immunofluorescence assay (IFA)-based approach and applying different immunoprecipitation (IP), chromatographic and mass spectrometric protocols was possible to isolate and identify a spectrum of autoantigens from brain tissue.

Methods: Sera and CSF of 320 patients suspected of suffering from an autoimmune neurological syndrome were comprehensively investigated for the presence of anti-neural IgG autoantibodies by IFA using mosaics of biochips with brain tissue cryosections and established cell-based recombinant antigen substrates as well as immunoblots. Samples containing unknown brain tissue-specific autoantibodies were subjected to IP with cryosections of cerebellum and hippocampus (rat, pig, and monkey) immobilized to glass slides or with lysates produced from homogenized tissue, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, tryptic digestion, and matrix-assisted laser desorption/ionization-time of flight mass spectrometry analysis. Identifications were confirmed by IFA with recombinant HEK293 cells and by neutralizing the patients' autoantibodies with the respective recombinantly expressed antigens in the tissue-based immunofluorescence test.

Results: Most samples used in this study produced speckled, granular, or homogenous stainings of the hippocampal and cerebellar molecular and/or granular layers. Others exclusively stained the Purkinje cells. Up to now, more than 20 different autoantigens could be identified by this approach, among them ATP1A3, CPT1C, Flotillin1/2, ITPR1, NBCe1, NCDN, RGS8, ROCK2, and Syntaxin-1B as novel autoantigens.

Discussion: The presented antigen identification strategy offers an opportunity for identifying up to now unknown neural autoantigens. Recombinant cell substrates containing the newly identified antigens can be used in serology and the clinical relevance of the autoantibodies can be rapidly evaluated in cohort studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.01447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046535PMC
July 2018

Reliable Serological Testing for the Diagnosis of Emerging Infectious Diseases.

Adv Exp Med Biol 2018;1062:19-43

Institute for Experimental Immunology, Euroimmun AG, Lübeck, Germany.

Climate change, increased urbanization and international travel have facilitated the spread of mosquito vectors and the viral species they carry. Zika virus (ZIKV) is currently spreading in the Americas, while dengue virus (DENV) and chikungunya virus (CHIKV) have already become firmly established in most tropical and also many non-tropical regions. ZIKV, DENV and CHIKV overlap in their endemic areas and cause similar clinical symptoms, especially in the initial stages of infection. Infections with each of these viruses can lead to severe complications, and co-infections have been reported. Therefore, laboratory analyses play an important role in differential diagnostics. A timely and accurate diagnosis is crucial for patient management, prevention of unnecessary therapies, rapid adoption of vector control measures, and collection of epidemiological data.There are two pillars to diagnosis: direct pathogen detection and the determination of specific antibodies. Serological tests provide a longer diagnostic window than direct methods, and are suitable for diagnosing acute and past infections, for disease surveillance and for vaccination monitoring. ELISA and indirect immunofluorescence test (IIFT) systems based on optimized antigens enable sensitive and specific detection of antibodies against ZIKV, DENV and CHIKV in patient serum or plasma. In recent years, Euroimmun (Lübeck, Germany) has developed numerous test systems for the serological diagnosis of (re-)emerging diseases, including a very sensitive and specific anti-ZIKV ELISA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-981-10-8727-1_3DOI Listing
November 2018

Trypanosoma cruzi transcriptome during axenic epimastigote growth curve.

Mem Inst Oswaldo Cruz 2018 9;113(5):e170404. Epub 2018 Apr 9.

Centro Politécnico, Universidade Federal do Paraná, Curitiba, PR, Brasil.

BACKGROUND Trypanosoma cruzi is an important protozoan parasite and the causative agent of Chagas disease. A critical step in understanding T. cruzi biology is the study of cellular and molecular features exhibited during its growth curve. OBJECTIVES We aimed to acquire a global view of the gene expression profile of T. cruzi during epimastigote growth. METHODS RNA-Seq analysis of total and polysomal/granular RNA fractions was performed along the 10 days T. cruzi epimastigote growth curve in vitro, in addition to cell viability and cell cycle analyses. We also analysed the polysome profile and investigated the presence of granular RNA by FISH and western blotting. FINDINGS We identified 1082 differentially expressed genes (DEGs), of which 220 were modulated in both fractions. According to the modulation pattern, DEGs were grouped into 12 clusters and showed enrichment of important gene ontology (GO) terms. Moreover, we showed that by the sixth day of the growth curve, polysomal content declined greatly and the RNA granules content appeared to increase, suggesting that a portion of mRNAs isolated from the sucrose gradient during late growth stages was associated with RNA granules and not only polyribosomes. Furthermore, we discuss several modulated genes possibly involved in T. cruzi growth, mainly during the stationary phase, such as genes related to cell cycle, pathogenesis, metabolic processes and RNA-binding proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/0074-02760170404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907844PMC
May 2018

Long-term outcome in 324 polytrauma patients: what factors are associated with posttraumatic stress disorder and depressive disorder symptoms?

Eur J Med Res 2017 Oct 30;22(1):44. Epub 2017 Oct 30.

Department of Trauma and Orthopaedic Surgery, Cologne-Merheim Medical Center, University of Witten/Herdecke, Cologne, Germany.

Background: Physical impairment is well-known to last for many years after a severe injury, and there is a high impact on the quality of the survivor's life. The purpose of this study was to examine if this is also true for psychological impairment with symptoms of posttraumatic stress disorder or depression after polytrauma.

Design: Retrospective cohort outcome study.

Setting: Level I trauma centre.

Population: 637 polytrauma trauma patients who were treated at our Level I trauma centre between 1973 and 1990. Minimum follow-up was 10 years after the injury.

Methods: Patients were asked to fill in a questionnaire, including parts of the Posttraumatic Stress Diagnostic Scale, the Impact of Event Scale-Revised and the German Hospital Anxiety and Depression Scale, to evaluate mental health. Clinical outcome was assessed before by standardised scores.

Results: Three hundred and twenty-four questionnaires were evaluated. One hundred and forty-nine (45.9%) patients presented with symptoms of mental impairment. Quality of life was significantly higher in the mentally healthy group, while the impaired group achieved a lower rehabilitation status.

Conclusions: Mental impairment can be found in multiple trauma victims, even after 10 years or more. Treating physicians should not only focus on early physical rehabilitation but also focus on early mental rehabilitation to prevent long-term problems in both physical and mental disability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40001-017-0282-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663112PMC
October 2017

Trypanosoma cruzi specific mRNA amplification by in vitro transcription improves parasite transcriptomics in host-parasite RNA mixtures.

BMC Genomics 2017 Oct 16;18(1):793. Epub 2017 Oct 16.

Functional Genomics Laboratory, Instituto Carlos Chagas, FIOCRUZ, Curitiba, PR, Brazil.

Background: Trypanosomatids are a group of protozoan parasites that includes the etiologic agents of important human illnesses as Chagas disease, sleeping sickness and leishmaniasis. These parasites have a significant distinction from other eukaryotes concerning mRNA structure, since all mature mRNAs have an identical species-specific sequence of 39 nucleotides at the 5' extremity, named spliced leader (SL). Considering this peculiar aspect of trypanosomatid mRNA, the aim of the present work was to develop a Trypanosoma cruzi specific in vitro transcription (IVT) linear mRNA amplification method in order to improve parasite transcriptomics analyses.

Methods: We designed an oligonucleotide complementary to the last 21 bases of T. cruzi SL sequence, bearing an upstream T7 promoter (T7SL primer), which was used to direct the synthesis of second-strand cDNA. Original mRNA was then amplified by IVT using T7 RNA polymerase. T7SL-amplified RNA from two distinct T. cruzi stages (epimastigotes and trypomastigotes) were deep sequenced in SOLiD platform. Usual poly(A) + RNA and and T7-oligo(dT) amplified RNA (Eberwine method) were also sequenced. RNA-Seq reads were aligned to our new and improved T. cruzi Dm28c genome assembly (PacBio technology) and resulting transcriptome pattern from these three RNA preparation methods were compared, mainly concerning the conservation of mRNA transcritional levels and DEGs detection between epimastigotes and trypomastigotes.

Results: T7SL IVT method detected more potential differentially expressed genes in comparison to either poly(A) + RNA or T7dT IVT, and was also able to produce reliable quantifications of the parasite transcriptome down to 3 ng of total RNA. Furthermore, amplification of parasite mRNA in HeLa/epimastigote RNA mixtures showed that T7SL IVT generates transcriptome quantification with similar detection of differentially expressed genes when parasite RNA mass was only 0.1% of the total mixture (R = 0.78 when compared to poly(A) + RNA).

Conclusions: The T7SL IVT amplification method presented here allows the detection of more potential parasite differentially expressed genes (in comparison to poly(A) + RNA) in host-parasite mixtures or samples with low amount of RNA. This method is especially useful for trypanosomatid transcriptomics because it produces less bias than PCR-based mRNA amplification. Additionally, by simply changing the complementary region of the T7SL primer, the present method can be applied to any trypanosomatid species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12864-017-4163-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644099PMC
October 2017

Patient Perspectives on Transitions of Surgical Care: Examining the Complexities and Interdependencies of Care.

Qual Health Res 2017 Oct 10;27(12):1856-1869. Epub 2017 May 10.

1 University of Rochester Medical Center, Rochester, NY, USA.

This study examined a thematic network aimed at identifying experiences that influence patients' outcomes (e.g., patients' satisfaction, anxiety, and discharge readiness) in an effort to improve care transitions and reduce patient burden. We drew upon the Sociology and Complexity Science Toolkit to analyze themes derived from 61 semistructured, longitudinal interviews with 20 patients undergoing either a benign or malignant colorectal resection (three interviews per patient over a 30-day after hospital discharge). Thematic interdependencies illustrate how most outcomes of care are significantly influenced by two cascades identified as patients' medical histories and home circumstances. Patients who reported previous medical or surgical histories also experienced less distress during the discharge process, whereas patients with no prior experiences reported more concerns and greater anxiety. Patient dissatisfactions and challenges were due in large part to the contrasts between hospital and home experiences. Our hybrid approach may inform patient-centered guidelines aimed at improving transitions of care among patients undergoing major surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1049732317704406DOI Listing
October 2017

Return to Sports After Multiple Trauma: Which Factors Are Responsible?-Results From a 17-Year Follow-up.

Clin J Sport Med 2017 Sep;27(5):481-486

*Department of Orthopaedics and Trauma, RWTH Aachen University Medical Center, Aachen, Germany;†Department of Orthopaedics and Trauma, Royal Adelaide Hospital, Adelaide, Australia;‡Department of Trauma and Orthopedic Surgery, Cologne-Merheim Medical Center (CMMC), Private University of Witten/Herdecke, Cologne, Germany; and§Department of Orthopaedics, Health Science Center, University of Texas, San Antonio, Texas.

Objective: We hypothesize that the majority of polytraumatised patients are unable to maintain their preinjury level of sporting activity, and that musculoskeletal injuries are a major contributing factor. We assessed the impact of such injuries on sporting prowess, with a focus on isolating, particularly debilitating musculoskeletal trauma.

Methods: We conducted a cohort study of 637 patients at a level 1 trauma centre, to assess the long-term outcome of severe trauma on return to sporting activities (RTS). Data collated on the multiply injured patient included preinjury physical activity, standardized outcome scores (SF-12, GOS, HASPOC), and clinical follow-up of at least 10 years duration. The return to preinjury sports participation was defined as a primary outcome parameter. Regression analyses were performed to identify specific injuries interfering with the RTS.

Study Design: Prognostic study; Level of evidence, II.

Results: Mean follow-up was 17 ± 5 years. We included 465 patients, including 207 athletic and 258 nonathletic individuals. Mean age at the time of injury was 26 ± 11.5 years and injury severity was comparable between the 2 cohorts. The deleterious effects on quality of life and the total duration of the rehabilitation process were also similar in athletes and nonathletes. Athletes were more likely to be unable to return to preinjury activities, or to return to a lower level of sporting prowess posttrauma. We identified knee injuries as the type of musculoskeletal trauma most likely to be career ending for the athlete (odds ratio 3.4, 95% confidence interval, 1.4-8.3; P = 0.008).

Conclusion: Our results demonstrate an enforced shift from high-impact and team sports to low-impact activities after multiple trauma. Injuries of the lower extremities, especially around the knee joint, seem to have the highest lifechanging potential, preventing individuals from returning to their previous sporting activities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JSM.0000000000000373DOI Listing
September 2017

Routine detection of serum antidesmocollin autoantibodies is only useful in patients with atypical pemphigus.

Exp Dermatol 2017 12 29;26(12):1267-1270. Epub 2017 Oct 29.

Lübeck Institute of Experimental Dermatology (LIED), Lübeck, Germany.

Autoantibodies against the 3 desmocollin (Dsc; Dsc1-Dsc3) isoforms have been described in different pemphigus variants. Here, we developed state-of-the-art detection systems for serum anti-Dsc1, Dsc2 and Dsc1 IgG and IgA. These assays were applied in 5 different cohorts including pemphigus vulgaris (PV) patients with compatible direct immunofluorescence (IF) microscopy but no reactivity against desmogleins 1 and 3 (n = 24) and sera from patients with autoimmune blistering diseases with positive direct IF microscopy taken at the time of diagnosis (n = 749). We found that detection of anti-Dsc serum reactivity is not helpful in the routine diagnosis of PV, pemphigus foliaceus and paraneoplastic pemphigus but may be valuable in pemphigus vegetans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.13409DOI Listing
December 2017

Circulating Antibodies against Thrombospondin Type-I Domain-Containing 7A in Chinese Patients with Idiopathic Membranous Nephropathy.

Clin J Am Soc Nephrol 2017 Oct 11;12(10):1642-1651. Epub 2017 Aug 11.

Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University.

Background And Objectives: Thrombospondin type-I domain-containing 7A (THSD7A) was recently identified as the target antigen in about 10% of patients with M-type phospholipase A2 receptor (PLA2R)-negative membranous nephropathy in European and North American populations. The prevalence of THSD7A in other populations and their clinical associations deserve further clarification.

Design, Setting, Participants, & Measurements: Immunofluorescence assay was performed to investigate anti-THSD7A antibodies in 578 consecutive patients with biopsy-proven idiopathic membranous nephropathy, 114 patients with secondary membranous nephropathy, 64 disease controls, and 20 healthy controls. Glomerular expression of THSD7A antigen was examined by immunohistochemistry. Anti-PLA2R antibodies and glomerular PLA2R expression were also screened.

Results: Among the 578 patients with idiopathic membranous nephropathy, 12 (2%) patients were identified as THSD7A-positive: ten patients were THSD7A-positive alone, which accounted for 16% (ten of 64) of PLA2R-negative patients; two patients were dual-positive for both anti-THSD7A and anti-PLA2R antibodies and showed enhanced expression of both antigens colocalized in glomeruli. Among the 114 patients with secondary membranous nephropathy, one among 44 (2%) patients with cancer had anti-THSD7A antibodies, whereas 18 of 44 (41%) had anti-PLA2R antibodies. No anti-THSD7A antibody was detected in other disease controls or healthy individuals. Clinical features were comparable between the patients with and without THSD7A. During follow-up, two patients who achieved remission had a clearance of circulating antibodies against THSD7A, whereas antibodies increased in parallel with proteinuria in a patient with a relapse.

Conclusions: THSD7A-associated membranous nephropathy has a low prevalence in Chinese patients. The double-positive patients suggest dual autoimmune responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.01460217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628706PMC
October 2017

Synapsin-antibodies in psychiatric and neurological disorders: Prevalence and clinical findings.

Brain Behav Immun 2017 Nov 18;66:125-134. Epub 2017 Jul 18.

Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address:

Objective: To study the prevalence of autoantibodies to synapsin in patients with psychiatric and neurological disorders and to describe clinical findings in synapsin antibody positive patients.

Methods: Sera of 375 patients with different psychiatric and neurological disorders and sera of 97 healthy controls were screened (dilution 1:320) for anti-synapsin IgG using HEK293 cells transfected with rat synapsin Ia. Positive sera were further analyzed by immunoblots with brain tissue from wild type and synapsin knock out mice and with HEK293 cells transfected with human synapsin Ia and Ib. Binding of synapsin IgG positive sera to primary neurons was studied using murine hippocampal neurons.

Results: IgG in serum from 23 (6.1%) of 375 patients, but from none of the 97 healthy controls (p=0.007), bound to rat synapsin Ia transfected cells with a median (range) titer of 1:1000 (1:320-1:100,000). Twelve of the 23 positive sera reacted with a protein of the molecular size of synapsin I in immunoblots of wild type but not of synapsin knock out mouse brain tissue. Out of 19/23 positive sera available for testing, 13 bound to human synapsin Ia and 16 to human synapsin Ib transfected cells. Synapsin IgG positive sera stained fixed and permeabilized murine hippocampal neurons. Synapsin IgG positive patients had various psychiatric and neurological disorders. Tumors were documented in 2 patients (melanoma, small cell lung carcinoma); concomitant anti-neuronal or other autoantibodies were present in 8 patients.

Conclusions: Autoantibodies to human synapsin Ia and Ib are detectable in a proportion of sera from patients with different psychiatric and neurological disorders, warranting further investigation into the potential pathophysiological relevance of these antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2017.07.011DOI Listing
November 2017

Mechanisms of Autoantibody-Induced Pathology.

Front Immunol 2017 31;8:603. Epub 2017 May 31.

Department of Biology, Institute of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.

Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.00603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449453PMC
May 2017

Comparison of transportation related injury mechanisms and outcome of young road users and adult road users, a retrospective analysis on 24,373 patients derived from the TraumaRegister DGU.

Scand J Trauma Resusc Emerg Med 2017 Jun 14;25(1):57. Epub 2017 Jun 14.

Department of Trauma and Orthopedic Surgery, Cologne-Merheim Medical Center (CMMC), University of Witten/Herdecke, Ostmerheimer Str. 200, 51109, Cologne, Germany.

Background: Most young people killed in road crashes are known as vulnerable road users. A combination of physical and developmental immaturity as well as inexperience increases the risk of road traffic accidents with a high injury severity rate. Understanding injury mechanism and pattern in a group of young road users may reduce morbidity and mortality. This study analyzes injury patterns and outcomes of young road users compared to adult road users. The comparison takes into account different transportation related injury mechanisms.

Methods: A retrospective analysis using data collected between 2002 and 2012 from the TraumaRegister DGU® was performed. Only patients with a transportation related injury mechanism (motor vehicle collision (MVC), motorbike, cyclist, and pedestrian) and an ISS ≥ 9 were included in our analysis. Four different groups of young road users were compared to adult trauma data depending on the transportation related injury mechanism.

Results: Twenty four thousand three hundred seventy three, datasets were retrieved to compare all subgroups. The mean ISS was 23.3 ± 13.1. The overall mortality rate was 8.61%. In the MVC, the motorbike and the cyclist group, we found young road users having more complex injury patterns with a higher AIS pelvis, AIS head, AIS abdomen and AIS of the extremities and also a lower GCS. Whereas in these three sub-groups the adult trauma group only had a higher AIS thorax. Only in the group of the adult pedestrians we found a higher AIS pelvis, AIS abdomen, AIS thorax, a higher AIS of the extremities and a lower GCS.

Discussion: This study reports on the most common injuries and injury patterns in young trauma patients in comparison to an adult trauma sample. Our analysis show that in contrast to more experienced road users our young collective refers to be a vulnerable trauma group with an increased risk of a high injury severity and high mortality rate. We indicate a striking difference in terms of the region of injury and the mechanism of injury when comparing the young versus the adult trauma collectives.

Conclusions: Young drivers of cars, motorbikes and bikes were shown to be on high risk to sustain a specific severe injury pattern and a high mortality rate compared to adult road users. Our data emphasize a characteristic injury pattern of young trauma patients and may be used to improve trauma care and to guide prevention strategies to decrease injury severity and mortality due to road traffic injuries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13049-017-0401-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471733PMC
June 2017

Early and late outcomes with prolonged open chest management after cardiac surgery.

J Thorac Cardiovasc Surg 2017 09 17;154(3):915-924. Epub 2017 Apr 17.

Division of Cardiac Surgery, University of Rochester Medical Center, Rochester, NY.

Objectives: Open chest management (OCM) is an important intervention for patients who are unable to undergo sternal closure after cardiac surgery. This study reviews the factors associated with a prolonged need for this intervention and investigates its association with early and late mortality.

Methods: Patients undergoing OCM from January 2009 to December 2014 were reviewed. Differences in the median duration of OCM when a perioperative variable was present versus its absence were determined and variables significant at P ≤ .1 were analyzed using Poisson regression for factors associated with prolonged OCM. Multivariable logistic regression and Cox proportional hazards models were developed to investigate perioperative factors that were associated with early and late mortality.

Results: A total of 201 patients (5%) required OCM and the overall median duration of this intervention was 3 days. The use a temporary assist device (median, 7 vs 2 days; P < .001), pneumonias (median, 11 vs 3 days; P < .001), sternal re-explorations (median, 6 vs 2 days; P < .001), and renal failure (median, 6 vs 3 days; P = .02) were among the factors that were highly associated with prolonged OCM using Poisson regression. Thirty-day mortalities occurred in 32 patients (16%) and were significantly associated with emergency surgery (P = .03), sternal re-explorations (P = .001), and OCM duration (median, 6 vs 3 days; P = .02). On multivariable logistic regression and Cox analysis, delaying sternal closure by 1-day increments increased the risk of early and late mortality by 11% (P = .01), and 9% (P < .001), respectively.

Conclusions: Prolonged OCM was associated with increasing perioperative morbidity and a higher risk of early and late mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtcvs.2017.03.143DOI Listing
September 2017

Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis.

Acta Neuropathol Commun 2017 05 29;5(1):40. Epub 2017 May 29.

Department of Neurology, St. Josef Hospital Bochum, Ruhr University Bochum, Bochum, Germany.

Onconeural antibodies are associated with cancer and paraneoplastic encephalitis. While their pathogenic role is still largely unknown, their high diagnostic value is undisputed. In this study we describe the discovery of a novel target of autoimmunity in an index case of paraneoplastic encephalitis associated with urogenital cancer.A 75-year-old man with a history of invasive bladder carcinoma 6 years ago with multiple recurrences and a newly discovered renal cell carcinoma presented with seizures and progressive cognitive decline followed by super-refractory status epilepticus. Clinical and ancillary findings including brain biopsy suggested paraneoplastic encephalitis. Immunohistochemistry of the brain biopsy was used to characterize the inflammatory response. Indirect immunofluorescence assay (IFA) was used for autoantibody screening. The autoantigen was identified by histo-immunoprecipitation and mass spectrometry and was validated by expressing the recombinant antigen in HEK293 cells and neutralization tests. Sera from 125 control patients were screened using IFA to test for the novel autoantibodies.IFA analysis of serum revealed a novel autoantibody against brain tissue. An intracellular enzyme, Rho-associated protein kinase 2 (ROCK2), was identified as target-antigen. ROCK2 was expressed in affected brain tissue and archival bladder tumor samples of this patient. Brain histopathology revealed appositions of cytotoxic CD8 T cells on ROCK2-positive neurons. ROCK2 antibodies were not found in the sera of 20 patients with bladder cancer and 17 with renal cancer, both without neurological symptoms, 49 healthy controls, and 39 patients with other antineuronal autoantibodies. In conclusion, novel onconeural antibodies targeting ROCK2 are associated with paraneoplastic encephalitis and should be screened for when paraneoplastic neurological syndromes, especially in patients with urogenital cancers, occur.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-017-0447-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448146PMC
May 2017

Patterns and Yearly Time Trends in the Use of Radiation Therapy During the Last 30 Days of Life Among Patients With Metastatic Rectal Cancer in the United States From 2004 to 2012.

Am J Hosp Palliat Care 2018 Feb 11;35(2):336-342. Epub 2017 May 11.

1 Department of Public Health Sciences, University of Rochester Medical Center, Rochester, NY, USA.

Purpose: Although radiation therapy (RT) can provide palliative benefits for patients with metastatic rectal cancer, its role at the end of life remains unclear. The objective of this study was to assess sociodemographic and clinical factors associated with the use of RT during the last 30 days of life and to evaluate yearly time trends in RT utilization among stage IV patients with rectal cancer.

Methods: The 2004 to 2012 National Cancer DataBase was queried for patients with metastatic rectal cancer who had a documented death during follow-up. A Bayesian multilevel logistic regression model was used to characterize predictive factors and yearly time trends associated with RT use in the last 30 days of life.

Results: Among 10 431 patients who met inclusion criteria, 345 (3%) received RT during the last 30 days of life. Factors independently associated with RT use included older age, female sex, African American race, nonprivate insurance, higher comorbidity burden, and worse grade. The odds of RT use at the end of life decreased by 28% between 2007 and 2009 (odds ratio [OR] = 0.72, 95% Credible Interval (CI) = 0.58-0.93), but then increased by 16% from 2010 to 2012 (OR = 1.16, 95% CI = 1.13-1.33), relative to 2004 to 2006.

Conclusion: Radiation therapy use for patients with metastatic rectal cancer is beneficial, and efforts to optimize its appropriate use are important. Several factors associated with RT use during the last 30 days of life included disparities in sociodemographic and clinical subgroups. Research is needed to understand the underlying causes of these inequalities and the role of predictive models in clinical decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1049909117706959DOI Listing
February 2018
-->