146 results on '"Hinze, C."'
Search Results
102. Experiences with IL-1 blockade in systemic juvenile idiopathic arthritis - data from the German AID-registry.
- Author
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Lainka E, Baehr M, Raszka B, Haas JP, Hügle B, Fischer N, Foell D, Hinze C, Weissbarth-Riedel E, Kallinich T, Horneff G, Windschall D, Lilienthal E, Niehues T, Neudorf U, Berendes R, Küster RM, Oommen PT, Rietschel C, Lutz T, Weller-Heinemann F, Tenbrock K, Heubner GL, Klotsche J, and Wittkowski H
- Subjects
- Adolescent, Child, Child, Preschool, Germany, Humans, Infant, Registries, Retrospective Studies, Young Adult, Antibodies, Monoclonal, Humanized therapeutic use, Antirheumatic Agents therapeutic use, Arthritis, Juvenile drug therapy, Interleukin 1 Receptor Antagonist Protein therapeutic use, Interleukin-1beta antagonists & inhibitors
- Abstract
Background: Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with dysregulation of the innate immune system driven by cytokines. A major role is ascribed to interleukin-1β (IL-1β), supporting the autoinflammatory character of the disease and offering an effective blocking mechanism for treatment. Here we present clinical practice data from the German AID-registry for patients treated with IL-1 inhibition (IL-1i)., Methods: In 2009 a clinical and research consortium (AID-Net) was established, including an online AID-registry. Patients with documented sJIA diagnosis were identified. Data for this retrospective IL-1i study were recorded by 17 centers. Response to treatment was evaluated according to Wallace criteria and additionally by an own classifying clinical response system., Results: In 6 years, 202 patients with confirmed sJIA were recorded in the AID-registry. Out of these, 111 children received therapy with Anakinra (ANA) (n = 84, 39 f) and/or Canakinumab (CANA) (n = 27, 15 f) at a median age of 8.7 y (range 0.6-19.1). During the first 12 months 75/111 (ANA 55, CANA 20) patients were evaluated according to Wallace criteria (achievement of inactive disease 28/55 and 17/20, remission over 6 months under medication 13/55 and 7/20 cases). Over the whole period of time, clinical response was preserved in the majority of patients (ANA 54/80, CANA 20/27). Arthritis mostly persisted in polyarticular (PA) courses. During treatment with IL-1i concomitant medication could be tapered in about 15%. IL-1i was discontinued in 59/111 patients. 45 (15) adverse events (AE)s in ANA (CANA) treated patients (19.7 (26.6) AE/100 ANA (CANA) exposure years, 95%CI: 14.4-26.4 (14.9-43.9)) were reported., Conclusion: In a large cohort of sJIA patients from Germany, we can confirm an overall favorable clinical response to both available IL-1 blocking agents. IL-1i was well tolerated with acceptable safety and effectiveness in a real-life clinical setting.
- Published
- 2021
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103. Kidney Single-cell Transcriptomes Predict Spatial Corticomedullary Gene Expression and Tissue Osmolality Gradients.
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Hinze C, Karaiskos N, Boltengagen A, Walentin K, Redo K, Himmerkus N, Bleich M, Potter SS, Potter AS, Eckardt KU, Kocks C, Rajewsky N, and Schmidt-Ott KM
- Subjects
- Animals, Disease Models, Animal, Gene Expression Regulation, In Situ Hybridization, Kidney Tubules metabolism, Kidney Tubules pathology, Mice, Mice, Inbred C57BL, Osmolar Concentration, Kidney Cortex metabolism, Kidney Cortex pathology, Kidney Medulla metabolism, Kidney Medulla pathology, Transcriptome
- Abstract
Background: Single-cell transcriptomes from dissociated tissues provide insights into cell types and their gene expression and may harbor additional information on spatial position and the local microenvironment. The kidney's cells are embedded into a gradient of increasing tissue osmolality from the cortex to the medulla, which may alter their transcriptomes and provide cues for spatial reconstruction., Methods: Single-cell or single-nuclei mRNA sequencing of dissociated mouse kidneys and of dissected cortex, outer, and inner medulla, to represent the corticomedullary axis, was performed. Computational approaches predicted the spatial ordering of cells along the corticomedullary axis and quantitated expression levels of osmo-responsive genes. In situ hybridization validated computational predictions of spatial gene-expression patterns. The strategy was used to compare single-cell transcriptomes from wild-type mice to those of mice with a collecting duct-specific knockout of the transcription factor grainyhead-like 2 (Grhl2
CD-/- ), which display reduced renal medullary osmolality., Results: Single-cell transcriptomics from dissociated kidneys provided sufficient information to approximately reconstruct the spatial position of kidney tubule cells and to predict corticomedullary gene expression. Spatial gene expression in the kidney changes gradually and osmo-responsive genes follow the physiologic corticomedullary gradient of tissue osmolality. Single-nuclei transcriptomes from Grhl2CD-/- mice indicated a flattened expression gradient of osmo-responsive genes compared with control mice, consistent with their physiologic phenotype., Conclusions: Single-cell transcriptomics from dissociated kidneys facilitated the prediction of spatial gene expression along the corticomedullary axis and quantitation of osmotically regulated genes, allowing the prediction of a physiologic phenotype., (Copyright © 2021 by the American Society of Nephrology.)- Published
- 2021
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104. Measuring Endocytosis During Proliferative Cell Quiescence.
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Hinze C, McGourty K, and Boucrot E
- Subjects
- Cell Cycle genetics, Cell Differentiation genetics, Clathrin ultrastructure, Hepatocytes, Humans, Telomerase genetics, Cell Proliferation genetics, Endocytosis genetics, Endothelial Cells ultrastructure, Microscopy methods, Molecular Imaging methods
- Abstract
Quiescence (also called "G0") is the state in which cells have exited the cell cycle but are capable to reenter as required. Though poorly understood, it represents one of the most prevalent cell states across all life. Many biologically important cell types reside in quiescence including mature hepatocytes, endothelial cells, and dormant adult stem cells. Furthermore, the quiescence program occurs in both short- and long-term varieties, depending on the physiological environments. A barrier slowing our understanding of quiescence has been a scarcity of available in vitro model systems to allow for the exploration of key regulatory pathways, such as endocytosis. Endocytosis, the internalization of extracellular material into the cell, is a fundamental and highly regulated process that impacts many cell biological functions. Accordingly, we have developed an in vitro model of deep quiescence in hTERT-immortalized RPE1 cells, combining both long-term contact inhibition and mitogen removal, to measure endocytosis. In addition, we present an analytical approach employing automated high-throughput microscopy and image analysis that yields high-content data allowing for meaningful and statistically robust interpretation. Importantly, the methods presented herein provide a suitable platform that can be easily adapted to investigate other regulatory processes across the cell cycle.
- Published
- 2021
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105. CD86 Is a Selective CD28 Ligand Supporting FoxP3+ Regulatory T Cell Homeostasis in the Presence of High Levels of CTLA-4.
- Author
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Halliday N, Williams C, Kennedy A, Waters E, Pesenacker AM, Soskic B, Hinze C, Hou TZ, Rowshanravan B, Janman D, Walker LSK, and Sansom DM
- Subjects
- B7-2 Antigen genetics, CD28 Antigens genetics, CTLA-4 Antigen genetics, Homeostasis genetics, Humans, T-Lymphocytes, Regulatory cytology, B7-2 Antigen immunology, CD28 Antigens immunology, CTLA-4 Antigen immunology, Homeostasis immunology, T-Lymphocytes, Regulatory immunology
- Abstract
CD80 and CD86 are expressed on antigen presenting cells and are required to engage their shared receptor, CD28, for the costimulation of CD4 T cells. It is unclear why two stimulatory ligands with overlapping roles have evolved. CD80 and CD86 also bind the regulatory molecule CTLA-4. We explored the role of CD80 and CD86 in the homeostasis and proliferation of CD4+FoxP3+ regulatory T cells (Treg), which constitutively express high levels of CTLA-4 yet are critically dependent upon CD28 signals. We observed that CD86 was the dominant ligand for Treg proliferation, survival, and maintenance of a regulatory phenotype, with higher expression of CTLA-4, ICOS, and OX40. We also explored whether CD80-CD28 interactions were specifically compromised by CTLA-4 and found that antibody blockade, clinical deficiency of CTLA-4 and CRISPR-Cas9 deletion of CTLA-4 all improved Treg survival following CD80 stimulation. Taken together, our data suggest that CD86 is the dominant costimulatory ligand for Treg homeostasis, despite its lower affinity for CD28, because CD80-CD28 interactions are selectively impaired by the high levels of CTLA-4. These data suggest a cell intrinsic role for CTLA-4 in regulating CD28 costimulation by direct competition for CD80, and indicate that that CD80 and CD86 have discrete roles in CD28 costimulation of CD4 T cells in the presence of high levels of CTLA-4., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Halliday, Williams, Kennedy, Waters, Pesenacker, Soskic, Hinze, Hou, Rowshanravan, Janman, Walker and Sansom.)
- Published
- 2020
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106. [Still's disease as biphasic disorder : Current knowledge on pathogenesis and novel treatment approaches].
- Author
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Föll D, Wittkowski H, and Hinze C
- Subjects
- Adult, Cytokines, Humans, Immunity, Innate, Arthritis, Juvenile immunology, Still's Disease, Adult-Onset immunology
- Abstract
Still's disease covers a range of disorders from systemic juvenile idiopathic arthritis (SJIA) up to adult onset Still's disease (AOSD). The overlapping clinical features suggest that SJIA and AOSD are different manifestations of a phenotypic continuum in different age stages. Still's disease is clinically characterized by fever, rash, joint involvement, lymphadenopathy and serositis. In this review the more recent pathogenetic model of a biphasic disease course is presented. The initial autoinflammation with predominant dysregulation of innate immunity is the basis of the "window of opportunity" hypothesis for the early use of a cytokine blockade. If the disease is not stopped in this phase, a phenotype change to a disease with destructive arthritis regularly occurs, in which dysregulation of the mechanisms of adaptive immunity plays a special role. The understanding of Still's disease as a biphasic disease enables the monitoring of molecular signatures. At the same time, this opens up perspectives for phase-specific targeted treatment using modern treat-to-target strategies.
- Published
- 2020
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107. [Classification of autoinflammatory diseases based on pathophysiological mechanisms].
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Kallinich T, Hinze C, and Wittkowski H
- Subjects
- Humans, Inflammation genetics, Signal Transduction, Hereditary Autoinflammatory Diseases classification, Hereditary Autoinflammatory Diseases genetics
- Abstract
Monogenic autoinflammatory diseases present with systemic inflammation with the involvement of multiple organs. With the help of modern molecular genetic techniques a large number of diseases with previously unknown pathomechanisms have been described in recent years. This knowledge can be utilized to group autoinflammatory diseases according to the signalling pathways involved and thus provide a better understanding of these entities.
- Published
- 2020
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108. Comparative Study of a Biomechanical Model-based and Black-box Approach for Subject-Specific Movement Prediction .
- Author
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Walter JR, Saini H, Maier B, Mostashiri N, Aguayo JL, Zarshenas H, Hinze C, Shuva S, Kohler J, Sahrmann AS, Chang CM, Csiszar A, Galliani S, Cheng LK, and Rohrle O
- Subjects
- Elbow, Electromyography, Humans, Torque, Elbow Joint, Movement
- Abstract
The performance and safety of human robot interaction (HRI) can be improved by using subject-specific movement prediction. Typical models include biomechanical (parametric) or black-box (non-parametric) models. The current work aims to investigate the benefits and drawbacks of these approaches by comparing elbow-joint torque predictions based on electromyography signals of the elbow flexors and extensors. To this end, a parameterized biomechanical model is compared to a non-parametric (Gaussian-process) approach. Both models showed adequate results in predicting the elbow-joint torques. While the non-parametric model requires minimal modeling effort, the parameterized biomechanical model can lead to deeper insight of the underlying subject specific musculoskeletal system.
- Published
- 2020
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109. Impact of IL1RN Variants on Response to Interleukin-1 Blocking Therapy in Systemic Juvenile Idiopathic Arthritis.
- Author
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Hinze C, Fuehner S, Kessel C, Wittkowski H, Lainka E, Baehr M, Hügle B, Haas JP, Ganser G, Weißbarth-Riedel E, Jansson A, and Foell D
- Subjects
- Adolescent, Arthritis, Juvenile drug therapy, Child, Child, Preschool, Cohort Studies, Female, Germany, Haplotypes, Humans, Infant, Interleukin 1 Receptor Antagonist Protein genetics, Interleukin-1 antagonists & inhibitors, Male, Registries, Treatment Outcome, Antibodies, Monoclonal, Humanized pharmacology, Antirheumatic Agents pharmacology, Arthritis, Juvenile genetics, Interleukin 1 Receptor Antagonist Protein pharmacology, Polymorphism, Single Nucleotide drug effects
- Abstract
Objective: To analyze the reported association of IL1RN polymorphisms with response to interleukin-1 (IL-1) blockade in a German cohort of patients with systemic juvenile idiopathic arthritis (JIA), and to assess the impact of other factors on treatment response., Methods: Sixty-one patients with systemic JIA who had received IL-1 blockade were identified within the German Autoinflammatory Disease registry DNA biobank. Response to IL-1 blockade was assessed according to 1) the clinical response (initially at least a transient response or good response compared to a poor response), 2) switch (or no switch) to anti-IL-6 receptor therapy following IL-1 blockade, 3) achievement of clinically inactive disease within 6 months of IL-1 blockade, 4) improvement in disease activity measured using the modified Juvenile Arthritis Disease Activity Score, and 5) achievement of a glucocorticoid-free state. In addition, basic demographic data, key features of the disease course, laboratory data, and IL1RN single-nucleotide polymorphisms (SNPs) were assessed., Results: Six of 7 IL1RN SNPs reported to be associated with response to anakinra therapy were analyzed. These 6 IL1RN SNPs were inherited as haplotypes. An association of IL1RN haplotypes and SNPs with response to IL-1 blockade could not be confirmed in this cohort of patients with systemic JIA. Patients who received tocilizumab following IL-1 blockade had a longer duration from disease onset to diagnosis than those who did not receive tocilizumab (median 0.27 years versus 0.08 years)., Conclusion: The results of this study could not confirm an impact of IL1RN SNPs on response to IL-1 blockade therapy with either anakinra or canakinumab in a cohort of patients with systemic JIA. However, a longer time frame from disease onset to diagnosis was associated with poorer long-term treatment response, thereby supporting the "window of opportunity" hypothesis that suggests improved long-term treatment response with shorter time from disease onset to diagnosis (and treatment)., (© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)
- Published
- 2020
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110. Synergistic Signaling of TLR and IFNα/β Facilitates Escape of IL-18 Expression from Endotoxin Tolerance.
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Verweyen E, Holzinger D, Weinhage T, Hinze C, Wittkowski H, Pickkers P, Albeituni S, Verbist K, Nichols KE, Schulert G, Grom A, Foell D, and Kessel C
- Subjects
- Adult, Animals, Antibodies, Monoclonal, Humanized pharmacology, Disease Models, Animal, Endotoxins, Gene Expression, Humans, In Vitro Techniques, Interferon-alpha drug effects, Interferon-beta drug effects, Interleukin 1 Receptor Antagonist Protein pharmacology, Interleukin-18 genetics, Interleukin-18 metabolism, Interleukin-1beta drug effects, Interleukin-1beta immunology, Janus Kinase Inhibitors pharmacology, Lipopolysaccharides pharmacology, Macrophage Activation Syndrome genetics, Macrophage Activation Syndrome metabolism, Male, Mice, Monocytes drug effects, Monocytes immunology, Piperidines pharmacology, Pyrimidines pharmacology, Pyrroles pharmacology, Signal Transduction, Tumor Necrosis Factor Inhibitors pharmacology, Immune Tolerance immunology, Interferon-alpha immunology, Interferon-beta immunology, Interleukin-18 immunology, Macrophage Activation Syndrome immunology, Toll-Like Receptors immunology
- Abstract
Rationale: IL-18 is a member of the IL-1 cytokine family, and elevated blood IL-18 concentrations associate with disease activity in macrophage activation syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions. Objectives: Although recent investigations provide mechanistic evidence for a contribution of IL-18 to inflammation and hyperinflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression. Methods: Samples from in vivo and in vitro endotoxin rechallenge experiments, patients with inflammatory disease, and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK/STAT inhibition was analyzed in two MAS mouse models and in a patient with recurrent MAS. Measurements and Main Results: Peripheral blood and monocytic IL-18 expression escaped LPS-induced immunoparalysis. LPS-stimulated primary human monocytes revealed specific IL-18 expression kinetics controlled by IFNα/β signaling. JAK/STAT inhibition or IFNβ neutralization during LPS stimulation blunted cytokine expression. Similarly, microtubule-destabilizing drugs abrogated LPS-induced IL18 expression, but this effect could be fully reversed by addition of IFNα/β. Ex vivo analysis of inflammatory disease patients' whole blood revealed strong correlation of type I IFN score and IL18 expression, whereas JAK/STAT inhibition strongly reduced IL-18 serum levels in two MAS mouse models and in a patient with recurrent MAS. Conclusions: Our data indicate that IL-18 (but not IL-1β) production from human monocytes requires cooperative Toll-like receptor and IFNα/β signaling. Interference with IFNα/β expression or signaling following JAK/STAT inhibition may control catastrophic hyperinflammation in MAS.
- Published
- 2020
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111. Limited utility of qPCR-based detection of tumor-specific circulating mRNAs in whole blood from clear cell renal cell carcinoma patients.
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Simonovic S, Hinze C, Schmidt-Ott KM, Busch J, Jung M, Jung K, and Rabien A
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- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor blood, Carcinoma, Renal Cell blood, Female, Genetic Association Studies methods, Humans, Kidney Neoplasms blood, Male, Middle Aged, RNA, Messenger blood, Biomarkers, Tumor genetics, Carcinoma, Renal Cell genetics, Kidney Neoplasms genetics, Neoplastic Cells, Circulating metabolism, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction methods
- Abstract
Background: RNA sequencing data is providing abundant information about the levels of dysregulation of genes in various tumors. These data, as well as data based on older microarray technologies have enabled the identification of many genes which are upregulated in clear cell renal cell carcinoma (ccRCC) compared to matched normal tissue. Here we use RNA sequencing data in order to construct a panel of highly overexpressed genes in ccRCC so as to evaluate their RNA levels in whole blood and determine any diagnostic potential of these levels for renal cell carcinoma patients., Methods: A bioinformatics analysis with Python was performed using TCGA, GEO and other databases to identify genes which are upregulated in ccRCC while being absent in the blood of healthy individuals. Quantitative Real Time PCR (RT-qPCR) was subsequently used to measure the levels of candidate genes in whole blood (PAX gene) of 16 ccRCC patients versus 11 healthy individuals. PCR results were processed in qBase and GraphPadPrism and statistics was done with Mann-Whitney U test., Results: While most analyzed genes were either undetectable or did not show any dysregulated expression, two genes, CDK18 and CCND1, were paradoxically downregulated in the blood of ccRCC patients compared to healthy controls. Furthermore, LOX showed a tendency towards upregulation in metastatic ccRCC samples compared to non-metastatic., Conclusions: This analysis illustrates the difficulty of detecting tumor regulated genes in blood and the possible influence of interference from expression in blood cells even for genes conditionally absent in normal blood. Testing in plasma samples indicated that tumor specific mRNAs were not detectable. While CDK18, CCND1 and LOX mRNAs might carry biomarker potential, this would require validation in an independent, larger patient cohort.
- Published
- 2020
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112. [Juvenile dermatomyositis-what's new?]
- Author
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Hinze C
- Subjects
- Child, Diagnosis, Differential, Disease Progression, Glucocorticoids therapeutic use, Humans, Immunoglobulins, Intravenous therapeutic use, Methotrexate therapeutic use, Rituximab therapeutic use, Dermatomyositis diagnosis, Dermatomyositis drug therapy
- Abstract
Juvenile dermatomyositis (JDM) is the most common chronic inflammatory myopathy of childhood, which is still frequently characterized by a complicated disease course. In this review, novel findings relating to JDM are presented based on a review of the literature. Myositis-specific antibodies are often detected and may correlate with clinical phenotypes and disease course. Activation of type I interferon pathways plays an important pathogenic role and relates to the main clinical manifestations of the disease. This may lead to targeted therapies in the future. Currently, there are no treatments specifically approved for the treatment of JDM. Standard therapy is currently considered to include glucocorticoids and methotrexate based on a randomized controlled study and expert consensus. Several medications are commonly used in cases of refractory JDM, including azathioprine, ciclosporin, intravenous immune globulins, mycophenolate mofetil, and rituximab. An optimal treatment of JDM has not yet been established; however, there are national and international consensus recommendations and treatment plans that may aid in the decision-making process. Several validated tools are available to assess disease activity, disease damage, and treatment responses. Such tools should be routinely used in patients with JDM, and ideally be documented in registries in order to allow comparative effectiveness studies. The PRO-KIND initiative of the German Society for Pediatric Rheumatology has developed a diagnostic and a treat-to-target strategy based on a practice- and consensus-based process.
- Published
- 2019
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113. Fluconazole Increases Osmotic Water Transport in Renal Collecting Duct through Effects on Aquaporin-2 Trafficking.
- Author
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Vukićević T, Hinze C, Baltzer S, Himmerkus N, Quintanova C, Zühlke K, Compton F, Ahlborn R, Dema A, Eichhorst J, Wiesner B, Bleich M, Schmidt-Ott KM, and Klussmann E
- Subjects
- Analysis of Variance, Animals, Cell Membrane metabolism, Cells, Cultured, Diabetes Insipidus, Nephrogenic metabolism, Disease Models, Animal, Kidney Tubules, Collecting cytology, Kidney Tubules, Collecting drug effects, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Phosphorylation genetics, Random Allocation, Signal Transduction, Statistics, Nonparametric, Aquaporin 2 metabolism, Biological Transport genetics, Colforsin pharmacology, Diabetes Insipidus, Nephrogenic drug therapy, Fluconazole pharmacology, rhoA GTP-Binding Protein drug effects
- Abstract
Background: Arginine-vasopressin (AVP) binding to vasopressin V2 receptors promotes redistribution of the water channel aquaporin-2 (AQP2) from intracellular vesicles into the plasma membrane of renal collecting duct principal cells. This pathway fine-tunes renal water reabsorption and urinary concentration, and its perturbation is associated with diabetes insipidus. Previously, we identified the antimycotic drug fluconazole as a potential modulator of AQP2 localization., Methods: We assessed the influence of fluconazole on AQP2 localization in vitro and in vivo as well as the drug's effects on AQP2 phosphorylation and RhoA (a small GTPase, which under resting conditions, maintains F-actin to block AQP2-bearing vesicles from reaching the plasma membrane). We also tested fluconazole's effects on water flow across epithelia of isolated mouse collecting ducts and on urine output in mice treated with tolvaptan, a VR2 blocker that causes a nephrogenic diabetes insipidus-like excessive loss of hypotonic urine., Results: Fluconazole increased plasma membrane localization of AQP2 in principal cells independent of AVP. It also led to an increased AQP2 abundance associated with alterations in phosphorylation status and ubiquitination as well as inhibition of RhoA. In isolated mouse collecting ducts, fluconazole increased transepithelial water reabsorption. In mice, fluconazole increased collecting duct AQP2 plasma membrane localization and reduced urinary output. Fluconazole also reduced urinary output in tolvaptan-treated mice., Conclusions: Fluconazole promotes collecting duct AQP2 plasma membrane localization in the absence of AVP. Therefore, it might have utility in treating forms of diabetes insipidus ( e.g. , X-linked nephrogenic diabetes insipidus) in which the kidney responds inappropriately to AVP., (Copyright © 2019 by the American Society of Nephrology.)
- Published
- 2019
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114. Canonical BMP signaling in tubular cells mediates recovery after acute kidney injury.
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Vigolo E, Markó L, Hinze C, Müller DN, Schmidt-Ullrich R, and Schmidt-Ott KM
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- Acute Kidney Injury etiology, Animals, Bone Morphogenetic Protein Receptors, Type I genetics, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Disease Models, Animal, Disease Progression, Humans, Inhibitor of Differentiation Proteins metabolism, Kidney Tubules cytology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Renal Insufficiency, Chronic pathology, Reperfusion Injury complications, Signal Transduction, Smad Proteins, Receptor-Regulated metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Acute Kidney Injury pathology, Bone Morphogenetic Protein Receptors, Type I metabolism, Bone Morphogenetic Proteins metabolism, Kidney Tubules pathology
- Abstract
Bone morphogenetic protein (BMP) signaling has been shown to modulate the development of renal fibrosis in animal models of kidney injury, but the downstream mediators are incompletely understood. In wild-type mice, canonical BMP signaling mediated by SMAD1/5/8 transcription factors was constitutively active in healthy renal tubules, transiently down-regulated after ischemia reperfusion injury (IRI), and reactivated during successful tubular regeneration. We then induced IRI in mice with a tubular-specific BMP receptor 1A (BMPR1A) deletion. These mice failed to reactivate SMAD1/5/8 signaling in the post-ischemic phase and developed renal fibrosis after injury. Using unbiased genomic analyses, we identified three genes encoding inhibitor of DNA-binding (ID) proteins (Id1, Id2, and Id4) as key targets of BMPR1A-SMAD1/5/8 signaling. BMPR1A-deficient mice failed to re-induce these targets following IRI. Instead, BMPR1A-deficiency resulted in activation of pro-fibrotic signaling proteins that are normally repressed by ID proteins, namely, p38 mitogen-activated protein kinase and cell cycle inhibitor p27. These data indicate that the post-ischemic activation of canonical BMP signaling acts endogenously to repress pro-fibrotic signaling in tubular cells and may help to prevent the progression of acute kidney injury to chronic kidney disease., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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115. Endocytosis in proliferating, quiescent and terminally differentiated cells.
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Hinze C and Boucrot E
- Subjects
- Cell Differentiation, Cell Proliferation, Humans, Signal Transduction, Endocytosis physiology
- Abstract
Endocytosis mediates nutrient uptake, receptor internalization and the regulation of cell signaling. It is also hijacked by many bacteria, viruses and toxins to mediate their cellular entry. Several endocytic routes exist in parallel, fulfilling different functions. Most studies on endocytosis have used transformed cells in culture. However, as the majority of cells in an adult body have exited the cell cycle, our understanding is biased towards proliferating cells. Here, we review the evidence for the different pathways of endocytosis not only in dividing, but also in quiescent, senescent and terminally differentiated cells. During mitosis, residual endocytosis is dedicated to the internalization of caveolae and specific receptors. In non-dividing cells, clathrin-mediated endocytosis (CME) functions, but the activity of alternative processes, such as caveolae, macropinocytosis and clathrin-independent routes, vary widely depending on cell types and functions. Endocytosis supports the quiescent state by either upregulating cell cycle arrest pathways or downregulating mitogen-induced signaling, thereby inhibiting cell proliferation. Endocytosis in terminally differentiated cells, such as skeletal muscles, adipocytes, kidney podocytes and neurons, supports tissue-specific functions. Finally, uptake is downregulated in senescent cells, making them insensitive to proliferative stimuli by growth factors. Future studies should reveal the molecular basis for the differences in activities between the different cell states., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)
- Published
- 2018
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116. Drying and Rainfall Shape the Structure and Functioning of Nitrifying Microbial Communities in Riverbed Sediments.
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Arce MI, von Schiller D, Bengtsson MM, Hinze C, Jung H, Alves RJE, Urich T, and Singer G
- Abstract
Non-flow periods in fluvial ecosystems are a global phenomenon. Streambed drying and rewetting by sporadic rainfalls could drive considerable changes in the microbial communities that govern stream nitrogen (N) availability at different temporal and spatial scales. We performed a microcosm-based experiment to investigate how dry period duration (DPD) (0, 3, 6, and 9 weeks) and magnitude of sporadic rewetting by rainfall (0, 4, and 21 mm applied at end of dry period) affected stocks of N in riverbed sediments, ammonia-oxidizing bacteria (AOB) and archaea (AOA) and rates of ammonia oxidation (AO), and emissions of nitrous oxide (N
2 O) to the atmosphere. While ammonium (NH4 + ) pool size decreased, nitrate (NO3 - ) pool size increased in sediments with progressive drying. Concomitantly, the relative and absolute abundance of AOB and, especially, AOA (assessed by 16S rRNA gene sequencing and quantitative PCR of ammonia monooxygenase genes) increased, despite an apparent decrease of AO rates with drying. An increase of N2 O emissions occurred at early drying before substantially dropping until the end of the experiment. Strong rainfall of 21 mm increased AO rates and NH4 + in sediments, whereas modest rainfall of 4 mm triggered a notable increase of N2 O fluxes. Interestingly, such responses were detected only after 6 and 9 weeks of drying. Our results demonstrate that progressive drying drives considerable changes in in-stream N cycling and the associated nitrifying microbial communities, and that sporadic rainfall can modulate these effects. Our findings are particularly relevant for N processing and transport in rivers with alternating dry and wet phases - a hydrological scenario expected to become more important in the future.- Published
- 2018
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117. Calcium and zinc tune autoinflammatory Toll-like receptor 4 signaling by S100A12.
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Kessel C, Fuehner S, Zell J, Zimmermann B, Drewianka S, Brockmeyer S, Holzinger D, Hinze C, Wittkowski H, and Foell D
- Subjects
- Adolescent, Adult, Child, Female, Granulocytes metabolism, HEK293 Cells, Humans, Inflammation metabolism, Lymphocyte Antigen 96 metabolism, Male, Monocytes metabolism, Recombinant Proteins metabolism, Signal Transduction, THP-1 Cells, Young Adult, Calcium metabolism, S100A12 Protein metabolism, Toll-Like Receptor 4 metabolism, Zinc metabolism
- Published
- 2018
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118. [Back to school physical education despite rheumatism : Development and testing of a sport scientific-based physical education certification].
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Hartmann M, Merker J, Schrödl S, König M, Georgi M, Hinze C, Schwirtz A, and Haas JP
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- Certification, Child, Humans, Physical Examination, Physical Education and Training, Rheumatic Diseases diagnosis, Sports
- Abstract
Background: Taking part in physical education is an important element of social participation for children with chronic diseases. Nevertheless, children suffering from rheumatism mostly receive recommendations to stop sport activities either completely or partially, without underlying scientific guidelines., Objective: The aim was the development of an IT-tool based on scientific data in order to create individualized recommendations for sport activities plus verification of its practical feasibility., Material and Methods: An interdisciplinary group of experts developed and approved a prototype of the rheumatism and sports compass (Rheuma und Sport Kompass, RSK) based on the literature and own experience. They considered individual health factors and biomechanics of sports functions. The prototype was tested, revised and reconsidered in an interim evaluation. The resulting RSKv1 was evaluated in a clinical observation phase with 61 patients. The results were subsequently incorporated into the final version of RSK during an interdisciplinary decision-making process. This was verified in a feasibility study with a follow-up survey of rheumatic patients with a RSK partial participation certification for physical education including: clinical assessment during 8 lessons of physical education and after 8 lessons of physical education. Teachers rated the RSK online after 8 lessons. The evaluation was descriptive and differences in mean values were tested., Results and Discussion: In this study 50 patients and 31 teachers were evaluated. The affliction of pain decreased in terms of frequency, amount and duration after physical education with RSK. No worsening in health was reported after participation in sports. The teachers rated the RSK as understandable, practicable and they felt confident to allow the patients to participate in classes. The RSK was rated significantly better than a standard certification text. With the RSK, patients can be advised to safely take part in physical education.
- Published
- 2018
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119. The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma.
- Author
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Schleussner N, Merkel O, Costanza M, Liang HC, Hummel F, Romagnani C, Durek P, Anagnostopoulos I, Hummel M, Jöhrens K, Niedobitek A, Griffin PR, Piva R, Sczakiel HL, Woessmann W, Damm-Welk C, Hinze C, Stoiber D, Gillissen B, Turner SD, Kaergel E, von Hoff L, Grau M, Lenz G, Dörken B, Scheidereit C, Kenner L, Janz M, and Mathas S
- Subjects
- Binding Sites, CRISPR-Cas Systems, Carrier Proteins metabolism, Cell Death genetics, Cell Line, Tumor, Cell Survival, Cytokines metabolism, Gene Editing, Gene Expression Regulation, Neoplastic drug effects, Gene Knockdown Techniques, Humans, Lymphoma, Large-Cell, Anaplastic pathology, Protein Binding, Protein Kinase Inhibitors pharmacology, RNA, Small Interfering genetics, Transcriptome, Basic-Leucine Zipper Transcription Factors metabolism, Lymphoma, Large-Cell, Anaplastic etiology, Lymphoma, Large-Cell, Anaplastic metabolism, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Th17 Cells immunology, Th17 Cells metabolism, Transcription Factor AP-1 metabolism
- Abstract
Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK
+ and ALK- anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17/group 3 innate lymphoid cells (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORγt. Elevated IL-17A and IL-17F levels were detected in a subset of children and adolescents with ALK+ ALCL. Furthermore, a comprehensive analysis of primary lymphoma data confirms TH17-, and in particular ILC3-skewing in ALCL compared with PTCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK+ ALCL. Our data highlight the crucial role of AP-1/BATFs in ALCL and lead to the concept that some ALCL might originate from ILC3.- Published
- 2018
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120. Local actin polymerization during endocytic carrier formation.
- Author
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Hinze C and Boucrot E
- Subjects
- Animals, Clathrin metabolism, Glycosylphosphatidylinositols metabolism, Humans, Actins metabolism, Endocytosis, Polymerization
- Abstract
Extracellular macromolecules, pathogens and cell surface proteins rely on endocytosis to enter cells. Key steps of endocytic carrier formation are cargo molecule selection, plasma membrane folding and detachment from the cell surface. While dedicated proteins mediate each step, the actin cytoskeleton contributes to all. However, its role can be indirect to the actual molecular events driving endocytosis. Here, we review our understanding of the molecular steps mediating local actin polymerization during the formation of endocytic carriers. Clathrin-mediated endocytosis is the least reliant on local actin polymerization, as it is only engaged to counter forces induced by membrane tension or cytoplasmic pressure. Two opposite situations are coated pit formation in yeast and at the basolateral surface of polarized mammalian cells which are, respectively, dependent and independent on actin polymerization. Conversely, clathrin-independent endocytosis forming both nanometer [CLIC (clathrin-independent carriers)/GEEC (glycosylphosphatidylinositol (GPI)-anchored protein enriched endocytic compartments), caveolae, FEME (fast endophilin-mediated endocytosis) and IL-2β (interleukin-2β) uptake] and micrometer carriers (macropinocytosis) are dependent on actin polymerization to power local membrane deformation and carrier budding. A variety of endocytic adaptors can recruit and activate the Cdc42/N-WASP or Rac1/WAVE complexes, which, in turn, engage the Arp2/3 complex, thereby mediating local actin polymerization at the membrane. However, the molecular steps for RhoA and formin-mediated actin bundling during endocytic pit formation remain unclear., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2018
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121. GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation.
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Hinze C, Ruffert J, Walentin K, Himmerkus N, Nikpey E, Tenstad O, Wiig H, Mutig K, Yurtdas ZY, Klein JD, Sands JM, Branchi F, Schumann M, Bachmann S, Bleich M, and Schmidt-Ott KM
- Subjects
- Animals, Aquaporin 2 metabolism, Aquaporin 4 metabolism, Arginine Vasopressin metabolism, Azotemia etiology, Biological Transport genetics, Creatinine urine, Gene Expression Profiling, Male, Mice, Osmolar Concentration, Signal Transduction, Urea metabolism, Urine, Water metabolism, Water Deprivation physiology, Epithelium physiology, Kidney Tubules, Collecting physiology, Osmoregulation genetics, Tight Junctions genetics, Tight Junctions physiology, Transcription Factors genetics
- Abstract
Collecting ducts make up the distal-most tubular segments of the kidney, extending from the cortex, where they connect to the nephron proper, into the medulla, where they release urine into the renal pelvis. During water deprivation, body water preservation is ensured by the selective transepithelial reabsorption of water into the hypertonic medullary interstitium mediated by collecting ducts. The collecting duct epithelium forms tight junctions composed of barrier-enforcing claudins and exhibits a higher transepithelial resistance than other segments of the renal tubule exhibit. However, the functional relevance of this strong collecting duct epithelial barrier is unresolved. Here, we report that collecting duct-specific deletion of an epithelial transcription factor, grainyhead-like 2 (GRHL2), in mice led to reduced expression of tight junction-associated barrier components, reduced collecting duct transepithelial resistance, and defective renal medullary accumulation of sodium and other osmolytes. In vitro , Grhl2 -deficient collecting duct cells displayed increased paracellular flux of sodium, chloride, and urea. Consistent with these effects, Grhl2 -deficient mice had diabetes insipidus, produced dilute urine, and failed to adequately concentrate their urine after water restriction, resulting in susceptibility to prerenal azotemia. These data indicate a direct functional link between collecting duct epithelial barrier characteristics, which appear to prevent leakage of interstitial osmolytes into urine, and body water homeostasis., (Copyright © 2018 by the American Society of Nephrology.)
- Published
- 2018
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122. Proinflammatory Cytokine Environments Can Drive Interleukin-17 Overexpression by γ/δ T Cells in Systemic Juvenile Idiopathic Arthritis.
- Author
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Kessel C, Lippitz K, Weinhage T, Hinze C, Wittkowski H, Holzinger D, Fall N, Grom AA, Gruen N, and Foell D
- Subjects
- Adaptive Immunity immunology, Adolescent, Adult, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Antirheumatic Agents therapeutic use, Arthritis, Juvenile drug therapy, CD4-Positive T-Lymphocytes immunology, Case-Control Studies, Chemokine CXCL10 immunology, Chemokine CXCL9 immunology, Child, Child, Preschool, Cytokines immunology, Female, Humans, Immunity, Innate immunology, Interferon-gamma immunology, Interleukin 1 Receptor Antagonist Protein therapeutic use, Interleukin-18 immunology, Interleukin-18 pharmacology, Interleukin-1beta immunology, Interleukin-1beta pharmacology, Interleukin-23 Subunit p19 immunology, Interleukin-6 immunology, Male, Receptors, Antigen, T-Cell, gamma-delta metabolism, S100A12 Protein immunology, S100A12 Protein pharmacology, T-Lymphocytes metabolism, Young Adult, Arthritis, Juvenile immunology, Interleukin-17 immunology, T-Lymphocytes immunology
- Abstract
Objective: Systemic-onset juvenile idiopathic arthritis (JIA) is speculated to follow a biphasic course, with an initial systemic disease phase driven by innate immune mechanisms and interleukin-1β (IL-1β) as a key cytokine and a second chronic arthritic phase that may be dominated by adaptive immunity and cytokines such as IL-17A. Although a recent mouse model points to a critical role of IL-17-expressing γ/δ T cells in disease pathology, in humans, both the prevalence of IL-17 and the role of IL-17-producing cells are still unclear., Methods: Serum samples from systemic JIA patients and healthy pediatric controls were analyzed for the levels of IL-17A and related cytokines. Whole blood samples were studied for cellular expression of IL-17 and interferon-γ (IFNγ). CD4+ and γ/δ T cells isolated from the patients and controls were assayed for cytokine secretion in different culture systems., Results: IL-17A was prevalent in sera from patients with active systemic JIA, while both ex vivo and in vitro experiments revealed that γ/δ T cells overexpressed this cytokine. This was not seen with CD4+ T cells, which expressed strikingly low levels of IFNγ. Therapeutic IL-1 blockade was associated with partial normalization of both cytokine expression phenotypes. Furthermore, culturing healthy donor γ/δ T cells in serum from systemic JIA patients or in medium spiked with IL-1β, IL-18, and S100A12 induced IL-17 overexpression at levels similar to those observed in the patients' cells., Conclusion: A systemic JIA cytokine environment may prime γ/δ T cells in particular for IL-17A overexpression. Thus, our observations in systemic JIA patients strongly support a pathophysiologic role of these cells, as proposed by the recent murine model., (© 2017, American College of Rheumatology.)
- Published
- 2017
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123. Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts.
- Author
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Werth M, Schmidt-Ott KM, Leete T, Qiu A, Hinze C, Viltard M, Paragas N, Shawber CJ, Yu W, Lee P, Chen X, Sarkar A, Mu W, Rittenberg A, Lin CS, Kitajewski J, Al-Awqati Q, and Barasch J
- Subjects
- Animals, Mice, Body Patterning, Gene Expression Regulation, Developmental, Kidney Tubules, Collecting embryology, Repressor Proteins metabolism, Transcription, Genetic
- Abstract
Although most nephron segments contain one type of epithelial cell, the collecting ducts consists of at least two: intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. In adult kidneys, these cells are organized in rosettes suggesting functional interactions. Genetic studies in mouse revealed that transcription factor Tfcp2l1 coordinates IC and PC development. Tfcp2l1 induces the expression of IC specific genes, including specific H
+ -ATPase subunits and Jag1. Jag1 in turn, initiates Notch signaling in PCs but inhibits Notch signaling in ICs. Tfcp2l1 inactivation deletes ICs, whereas Jag1 inactivation results in the forfeiture of discrete IC and PC identities. Thus, Tfcp2l1 is a critical regulator of IC-PC patterning, acting cell-autonomously in ICs, and non-cell-autonomously in PCs. As a result, Tfcp2l1 regulates the diversification of cell types which is the central characteristic of 'salt and pepper' epithelia and distinguishes the collecting duct from all other nephron segments.- Published
- 2017
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124. Unique Transcriptional Programs Identify Subtypes of AKI.
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Xu K, Rosenstiel P, Paragas N, Hinze C, Gao X, Huai Shen T, Werth M, Forster C, Deng R, Bruck E, Boles RW, Tornato A, Gopal T, Jones M, Konig J, Stauber J, D'Agati V, Erdjument-Bromage H, Saggi S, Wagener G, Schmidt-Ott KM, Tatonetti N, Tempst P, Oliver JA, Guarnieri P, and Barasch J
- Subjects
- Animals, Female, Gene Expression, Humans, Mice, Mice, Inbred C57BL, Acute Kidney Injury classification, Acute Kidney Injury genetics, Transcriptome
- Abstract
Two metrics, a rise in serum creatinine concentration and a decrease in urine output, are considered tantamount to the injury of the kidney tubule and the epithelial cells thereof (AKI). Yet neither criterion emphasizes the etiology or the pathogenetic heterogeneity of acute decreases in kidney excretory function. In fact, whether decreased excretory function due to contraction of the extracellular fluid volume (vAKI) or due to intrinsic kidney injury (iAKI) actually share pathogenesis and should be aggregated in the same diagnostic group remains an open question. To examine this possibility, we created mouse models of iAKI and vAKI that induced a similar increase in serum creatinine concentration. Using laser microdissection to isolate specific domains of the kidney, followed by RNA sequencing, we found that thousands of genes responded specifically to iAKI or to vAKI, but very few responded to both stimuli. In fact, the activated gene sets comprised different, functionally unrelated signal transduction pathways and were expressed in different regions of the kidney. Moreover, we identified distinctive gene expression patterns in human urine as potential biomarkers of either iAKI or vAKI, but not both. Hence, iAKI and vAKI are biologically unrelated, suggesting that molecular analysis should clarify our current definitions of acute changes in kidney excretory function., (Copyright © 2017 by the American Society of Nephrology.)
- Published
- 2017
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125. Munchausen by proxy syndrome mimicking systemic autoinflammatory disease: case report and review of the literature.
- Author
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Wittkowski H, Hinze C, Häfner-Harms S, Oji V, Masjosthusmann K, Monninger M, Grenzebach U, and Foell D
- Subjects
- Child, Preschool, Diagnosis, Differential, Humans, Male, Hereditary Autoinflammatory Diseases diagnosis, Munchausen Syndrome by Proxy diagnosis
- Abstract
Background: Systemic autoinflammatory diseases (SAIDs) represent a growing number of monogenic, polygenic or multifactorial disorders that are often difficult to diagnose., Case Presentation: Here we report a patient who was initially erroneously diagnosed and treated for SAID. Symptoms consisted of recurrent fever, erythematous and/or blistering skin lesions, angioedema, susceptibility to bleeding, external ear infections and reversible anisocoria in the absence of laboratory evidence of systemic inflammation. After two and a half years of extensive diagnostic work-up and multiple empirical therapies, a final diagnosis of Munchausen by proxy syndrome (MBPS) was established., Conclusions: The diagnosis of SAID needs to be carefully reassessed if measurable systemic inflammation is missing, and MBPS should be included in the differential diagnosis.
- Published
- 2017
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126. Autoinflammatory diseases: New diagnostic criteria for CAPS - turning horses into zebras?
- Author
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Hinze C and Foell D
- Subjects
- Adult, Child, Humans, Mutation, Cryopyrin-Associated Periodic Syndromes, Hereditary Autoinflammatory Diseases
- Published
- 2017
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127. Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever.
- Author
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Gohar F, Orak B, Kallinich T, Jeske M, Lieber M, von Bernuth H, Giese A, Weissbarth-Riedel E, Haas JP, Dressler F, Holzinger D, Lohse P, Neudorf U, Lainka E, Hinze C, Masjosthusmann K, Kessel C, Weinhage T, Foell D, and Wittkowski H
- Subjects
- Adolescent, Adult, Case-Control Studies, Caspase 1 blood, Child, Child, Preschool, Familial Mediterranean Fever blood, Familial Mediterranean Fever immunology, Female, Genotype, Heterozygote, Homozygote, Humans, In Vitro Techniques, Interleukin-18 blood, Interleukin-1beta blood, Male, Middle Aged, Neutrophils immunology, S100A12 Protein blood, Young Adult, Caspase 1 metabolism, Familial Mediterranean Fever genetics, Interleukin-18 metabolism, Interleukin-1beta metabolism, Neutrophils metabolism, Pyrin genetics, S100A12 Protein metabolism
- Abstract
Objective: Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF., Methods: Neutrophils from FMF patients carrying the p.M694V mutation (1 compound heterozygous and 5 homozygous) and neutrophils from 4 healthy control subjects were purified and stimulated in vitro. Neutrophil secretion of S100A12, interleukin-18 (IL-18), IL-1β, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1β were also analyzed in 128 clinically and genetically characterized patients with FMF., Results: In vitro, unstimulated neutrophils from p.M694V-positive patients spontaneously secreted more S100A12, IL-18, and caspase 1 compared to neutrophils from healthy controls. Serum concentrations of S100A12 correlated with disease activity and genotype, with the levels being highest in homozygous patients and with compound heterozygotes displaying higher levels than heterozygotes. Compared to individuals negative for the p.M694V mutation, heterozygous, compound heterozygous, or homozygous p.M694V-positive patients had higher serum levels of S100A12 and IL-18 during inactive and subclinical disease., Conclusion: The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markers might help to improve patient care and outcomes., (© 2016, American College of Rheumatology.)
- Published
- 2016
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128. Tubular Epithelial NF-κB Activity Regulates Ischemic AKI.
- Author
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Markó L, Vigolo E, Hinze C, Park JK, Roël G, Balogh A, Choi M, Wübken A, Cording J, Blasig IE, Luft FC, Scheidereit C, Schmidt-Ott KM, Schmidt-Ullrich R, and Müller DN
- Subjects
- Animals, Apoptosis, Disease Models, Animal, Kidney Tubules, Male, Mice, Reperfusion Injury, Signal Transduction, Urothelium, Acute Kidney Injury etiology, NF-kappa B physiology
- Abstract
NF-κB is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of AKI. The cell type-specific functions of NF-κB in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue parenchymal cells. We analyzed tubular epithelial-specific NF-κB signaling in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. NF-κB reporter activity and nuclear localization of phosphorylated NF-κB subunit p65 analyses in mice revealed that IRI induced widespread NF-κB activation in renal tubular epithelia and in interstitial cells that peaked 2-3 days after injury. To genetically antagonize tubular epithelial NF-κB activity, we generated mice expressing the human NF-κB super-repressor IκBαΔN in renal proximal, distal, and collecting duct epithelial cells. Compared with control mice, these mice exhibited improved renal function, reduced tubular apoptosis, and attenuated neutrophil and macrophage infiltration after IRI-induced AKI. Furthermore, tubular NF-κB-dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from IκBαΔN-expressing mice and exposed to hypoxia-mimetic agent cobalt chloride exhibited less apoptosis and expressed lower levels of chemokines than cells from control mice did. Our results indicate that postischemic NF-κB activation in renal tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response., (Copyright © 2016 by the American Society of Nephrology.)
- Published
- 2016
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129. The basal chorionic trophoblast cell layer: An emerging coordinator of placenta development.
- Author
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Walentin K, Hinze C, and Schmidt-Ott KM
- Subjects
- Animals, Cell Differentiation, Cell Polarity, Chorioallantoic Membrane cytology, Chorioallantoic Membrane enzymology, Female, Humans, Morphogenesis, Peptide Hydrolases metabolism, Placenta physiology, Pregnancy, Chorion cytology, Placenta cytology, Placentation, Trophoblasts physiology
- Abstract
During gestation, fetomaternal exchange occurs in the villous tree (labyrinth) of the placenta. Development of this structure depends on tightly coordinated cellular processes of branching morphogenesis and differentiation of specialized trophoblast cells. The basal chorionic trophoblast (BCT) cell layer that localizes next to the chorioallantoic interface is of critical importance for labyrinth morphogenesis in rodents. Gcm1-positive cell clusters within this layer initiate branching morphogenesis thereby guiding allantoic fetal blood vessels towards maternal blood sinuses. Later these cells differentiate and contribute to the syncytiotrophoblast of the fetomaternal barrier. Additional cells within the BCT layer sustain continued morphogenesis, possibly through a repopulating progenitor population. Several mouse mutants highlight the importance of a structurally intact BCT epithelium, and a growing number of studies addresses its patterning and epithelial architecture. Here, we review and discuss emerging concepts in labyrinth development focussing on the biology of the BCT cell layer., (© 2016 WILEY Periodicals, Inc.)
- Published
- 2016
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130. A Grainyhead-Like 2/Ovo-Like 2 Pathway Regulates Renal Epithelial Barrier Function and Lumen Expansion.
- Author
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Aue A, Hinze C, Walentin K, Ruffert J, Yurtdas Y, Werth M, Chen W, Rabien A, Kilic E, Schulzke JD, Schumann M, and Schmidt-Ott KM
- Subjects
- Animals, Binding Sites, Cell Nucleus metabolism, Chromatin Immunoprecipitation, Claudin-4 metabolism, DNA chemistry, Gene Transfer Techniques, Histones chemistry, Humans, Immunohistochemistry, Kidney metabolism, Kidney Tubules, Collecting metabolism, Mice, Oligonucleotide Array Sequence Analysis, Phenotype, Protein Binding, Proteins metabolism, Signal Transduction, Transcription, Genetic, Epithelium metabolism, Gene Expression Regulation, Kidney embryology, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
Grainyhead transcription factors control epithelial barriers, tissue morphogenesis, and differentiation, but their role in the kidney is poorly understood. Here, we report that nephric duct, ureteric bud, and collecting duct epithelia express high levels of grainyhead-like homolog 2 (Grhl2) and that nephric duct lumen expansion is defective in Grhl2-deficient mice. In collecting duct epithelial cells, Grhl2 inactivation impaired epithelial barrier formation and inhibited lumen expansion. Molecular analyses showed that GRHL2 acts as a transcriptional activator and strongly associates with histone H3 lysine 4 trimethylation. Integrating genome-wide GRHL2 binding as well as H3 lysine 4 trimethylation chromatin immunoprecipitation sequencing and gene expression data allowed us to derive a high-confidence GRHL2 target set. GRHL2 transactivated a group of genes including Ovol2, encoding the ovo-like 2 zinc finger transcription factor, as well as E-cadherin, claudin 4 (Cldn4), and the small GTPase Rab25. Ovol2 induction alone was sufficient to bypass the requirement of Grhl2 for E-cadherin, Cldn4, and Rab25 expression. Re-expression of either Ovol2 or a combination of Cldn4 and Rab25 was sufficient to rescue lumen expansion and barrier formation in Grhl2-deficient collecting duct cells. Hence, we identified a Grhl2/Ovol2 network controlling Cldn4 and Rab25 expression that facilitates lumen expansion and barrier formation in subtypes of renal epithelia., (Copyright © 2015 by the American Society of Nephrology.)
- Published
- 2015
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131. Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.
- Author
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Holzinger D, Fassl SK, de Jager W, Lohse P, Röhrig UF, Gattorno M, Omenetti A, Chiesa S, Schena F, Austermann J, Vogl T, Kuhns DB, Holland SM, Rodríguez-Gallego C, López-Almaraz R, Arostegui JI, Colino E, Roldan R, Fessatou S, Isidor B, Poignant S, Ito K, Epple HJ, Bernstein JA, Jeng M, Frankovich J, Lionetti G, Church JA, Ong PY, LaPlant M, Abinun M, Skinner R, Bigley V, Sachs UJ, Hinze C, Hoppenreijs E, Ehrchen J, Foell D, Chae JJ, Ombrello A, Aksentijevich I, Sunderkoetter C, and Roth J
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adolescent, Alarmins genetics, Alarmins metabolism, Calgranulin A genetics, Calgranulin A metabolism, Child, Cytokines metabolism, Cytoskeletal Proteins genetics, Female, Genotype, Humans, Leukocyte L1 Antigen Complex genetics, Male, Metal Metabolism, Inborn Errors genetics, Mutation, Missense genetics, Phenotype, Phosphorylation, Protein Binding genetics, Protein Interaction Maps genetics, Protein Multimerization, Pyrin, Young Adult, Adaptor Proteins, Signal Transducing metabolism, Cytoskeletal Proteins metabolism, Leukocyte L1 Antigen Complex metabolism, Metal Metabolism, Inborn Errors immunology
- Abstract
Background: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin)., Objective: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc., Methods: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA., Results: Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 ± 1300 μg/mL) compared with those with PAPA syndrome (116 ± 74 μg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1., Conclusion: Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E→K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
- Published
- 2015
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132. Management of juvenile idiopathic arthritis: hitting the target.
- Author
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Hinze C, Gohar F, and Foell D
- Subjects
- Antirheumatic Agents therapeutic use, Biological Factors therapeutic use, Child, Clinical Protocols, Consensus, Disease Management, Guidelines as Topic, Humans, Rheumatology methods, Rheumatology standards, Arthritis, Juvenile drug therapy
- Abstract
The treatment of juvenile idiopathic arthritis (JIA) is evolving. The growing number of effective drugs has led to successful treatment and prevention of long-term sequelae in most patients. Although patients with JIA frequently achieve lasting clinical remission, sustained remission off medication is still elusive for most. Treatment approaches vary substantially among paediatric rheumatologists owing to the inherent heterogeneity of JIA and, until recently, to the lack of accepted and well-evidenced guidelines. Furthermore, many pertinent questions related to patient management remain unanswered, in particular regarding treatment targets, and selection, intensity and sequence of initiation or withdrawal of therapy. Existing JIA guidelines and recommendations do not specify treat-to-target or tight control strategies, in contrast to adult rheumatology in which these approaches have been successful. The concepts of window of opportunity (early treatment to improve long-term outcomes) and immunological remission (abrogation of subclinical disease activity) are also fundamental when defining treatment methodologies. This Review explores the application of these concepts to JIA and their possible contribution to the development of future clinical guidelines or consensus treatment protocols. The article also discusses how diverse forms of standardized, guideline-led care and personalized treatment can be combined into a targeted, patient-centred approach to optimize management strategies for patients with JIA.
- Published
- 2015
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133. A Grhl2-dependent gene network controls trophoblast branching morphogenesis.
- Author
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Walentin K, Hinze C, Werth M, Haase N, Varma S, Morell R, Aue A, Pötschke E, Warburton D, Qiu A, Barasch J, Purfürst B, Dieterich C, Popova E, Bader M, Dechend R, Staff AC, Yurtdas ZY, Kilic E, and Schmidt-Ott KM
- Subjects
- Binding Sites genetics, Chromatin Immunoprecipitation, Female, Fluorescent Antibody Technique, Gene Regulatory Networks genetics, Humans, Immunohistochemistry, Microarray Analysis, Microscopy, Electron, Pregnancy, Proteinase Inhibitory Proteins, Secretory genetics, Real-Time Polymerase Chain Reaction, DNA-Binding Proteins metabolism, Gene Regulatory Networks physiology, Morphogenesis physiology, Placentation, Transcription Factors metabolism, Trophoblasts physiology
- Abstract
Healthy placental development is essential for reproductive success; failure of the feto-maternal interface results in pre-eclampsia and intrauterine growth retardation. We found that grainyhead-like 2 (GRHL2), a CP2-type transcription factor, is highly expressed in chorionic trophoblast cells, including basal chorionic trophoblast (BCT) cells located at the chorioallantoic interface in murine placentas. Placentas from Grhl2-deficient mouse embryos displayed defects in BCT cell polarity and basement membrane integrity at the chorioallantoic interface, as well as a severe disruption of labyrinth branching morphogenesis. Selective Grhl2 inactivation only in epiblast-derived cells rescued all placental defects but phenocopied intraembryonic defects observed in global Grhl2 deficiency, implying the importance of Grhl2 activity in trophectoderm-derived cells. ChIP-seq identified 5282 GRHL2 binding sites in placental tissue. By integrating these data with placental gene expression profiles, we identified direct and indirect Grhl2 targets and found a marked enrichment of GRHL2 binding adjacent to genes downregulated in Grhl2(-/-) placentas, which encoded known regulators of placental development and epithelial morphogenesis. These genes included that encoding the serine protease inhibitor Kunitz type 1 (Spint1), which regulates BCT cell integrity and labyrinth formation. In human placenta, we found that human orthologs of murine GRHL2 and its targets displayed co-regulation and were expressed in trophoblast cells in a similar domain as in mouse placenta. Our data indicate that a conserved Grhl2-coordinated gene network controls trophoblast branching morphogenesis, thereby facilitating development of the site of feto-maternal exchange. This might have implications for syndromes related to placental dysfunction., (© 2015. Published by The Company of Biologists Ltd.)
- Published
- 2015
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134. Development of positive antinuclear antibodies and rheumatoid factor in systemic juvenile idiopathic arthritis points toward an autoimmune phenotype later in the disease course.
- Author
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Hügle B, Hinze C, Lainka E, Fischer N, and Haas JP
- Subjects
- Antirheumatic Agents therapeutic use, Arthritis, Juvenile blood, Arthritis, Juvenile drug therapy, Autoimmune Diseases blood, Biomarkers blood, Child, Child, Preschool, Female, Follow-Up Studies, Health Surveys, Humans, Infant, Male, Predictive Value of Tests, Prognosis, Retrospective Studies, Time Factors, Tumor Necrosis Factor-alpha antagonists & inhibitors, Antibodies, Antinuclear blood, Arthritis, Juvenile diagnosis, Autoimmune Diseases diagnosis, Disease Progression, Phenotype, Rheumatoid Factor blood
- Abstract
Background: Systemic juvenile idiopathic arthritis (sJIA) is commonly considered an autoinflammatory disease. However, sJIA patients may develop aggressive arthritis without systemic inflammation later in the disease, resembling an autoimmune phenotype similar to other subtypes of JIA. The objective of this study was to determine whether antinuclear antibodies (ANA) and rheumatoid factor (RF) will develop in patients with sJIA over the course of the disease., Findings: A single center sample of sJIA patients with follow-up of more than one year was obtained. A retrospective chart survey was used to extract demographic and clinical data as well as presence and titers of ANA and RF at diagnosis and during follow-up. 32 patients were included in the study, with a median age of 4.2 years and median follow-up of 6.0 years. 8/32 patients had ANA titers ≥ 1:80 at diagnosis, with 22/32 patients showing rising ANA titers with titers ≥ 1:80 at last follow-up (p =0.001). 10/32 patients had a positive RF at least once during follow-up, compared to 0/32 at diagnosis (p = 0.001). In 5/10 patients, positive RF was documented at least twice, more than twelve weeks apart. Patients treated with TNF antagonists were not significantly more likely to develop positive ANA titers (p = 0.425) or positive RF (p = 0.703)., Conclusions: Patients with sJIA developed increased ANA titers and positive RF over the course of the disease, independent of treatment with TNF antagonists. This might point towards an autoimmune, rather than an autoinflammatory phenotype later in the course of sJIA.
- Published
- 2014
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135. Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists.
- Author
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Schunk S, Linz K, Frormann S, Hinze C, Oberbörsch S, Sundermann B, Zemolka S, Englberger W, Germann T, Christoph T, Kögel BY, Schröder W, Harlfinger S, Saunders D, Kless A, Schick H, and Sonnenschein H
- Abstract
We report the discovery of spiro[cyclohexane-pyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone 1 and tryptophol in an oxa-Pictet-Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3-5, ethers 6 and 7, amines 8-10, 22-24, and 26-28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors.
- Published
- 2014
- Full Text
- View/download PDF
136. Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol.
- Author
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Schunk S, Linz K, Hinze C, Frormann S, Oberbörsch S, Sundermann B, Zemolka S, Englberger W, Germann T, Christoph T, Kögel BY, Schröder W, Harlfinger S, Saunders D, Kless A, Schick H, and Sonnenschein H
- Abstract
In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.
- Published
- 2014
- Full Text
- View/download PDF
137. [Definition, diagnosis and therapy of chronic widespread pain and so-called fibromyalgia syndrome in children and adolescents. Systematic literature review and guideline].
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Zernikow B, Gerhold K, Bürk G, Häuser W, Hinze CH, Hospach T, Illhardt A, Mönkemöller K, Richter M, Schnöbel-Müller E, and Häfner R
- Subjects
- Activities of Daily Living classification, Activities of Daily Living psychology, Adolescent, Anxiety Disorders diagnosis, Anxiety Disorders psychology, Anxiety Disorders rehabilitation, Child, Chronic Pain psychology, Combined Modality Therapy, Comorbidity, Cooperative Behavior, Depressive Disorder diagnosis, Depressive Disorder psychology, Depressive Disorder rehabilitation, Evidence-Based Medicine, Fibromyalgia psychology, Germany, Humans, Interdisciplinary Communication, Patient Admission, Patient Care Team, Quality of Life psychology, Rehabilitation Centers, Chronic Pain diagnosis, Chronic Pain rehabilitation, Fibromyalgia diagnosis, Fibromyalgia rehabilitation
- Abstract
Background: The scheduled update to the German S3 guidelines on fibromyalgia syndrome (FMS) by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF; registration number 041/004) was planned starting in March 2011., Materials and Methods: The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy ("Deutsche Interdisziplinären Vereinigung für Schmerztherapie", DIVS), 9 scientific medical societies and 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Centre for Evidence-Based Medicine. The formulation and grading of recommendations was accomplished using a multi-step, formal consensus process. The guidelines were reviewed by the boards of the participating scientific medical societies., Results and Conclusion: The diagnosis FMS in children and adolescents is not established. In so-called juvenile FMS (JFMS) multidimensional diagnostics with validated measures should be performed. Multimodal therapy is warranted. In the case of severe pain-related disability, therapy should be primarily performed on an inpatient basis. The English full-text version of this article is available at SpringerLink (under "Supplemental").
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- 2012
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138. Effectiveness of dexamethasone iontophoresis for temporomandibular joint involvement in juvenile idiopathic arthritis.
- Author
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Mina R, Melson P, Powell S, Rao M, Hinze C, Passo M, Graham TB, and Brunner HI
- Subjects
- Administration, Cutaneous, Adolescent, Anti-Inflammatory Agents adverse effects, Arthralgia drug therapy, Arthralgia physiopathology, Arthritis, Juvenile diagnosis, Arthritis, Juvenile physiopathology, Biomechanical Phenomena, Child, Child, Preschool, Dexamethasone adverse effects, Facial Pain drug therapy, Facial Pain physiopathology, Female, Glucocorticoids adverse effects, Hospitals, Pediatric, Humans, Male, Ohio, Pain Measurement, Pilot Projects, Range of Motion, Articular, Recovery of Function, Retrospective Studies, Temporomandibular Joint physiopathology, Temporomandibular Joint Disorders diagnosis, Temporomandibular Joint Disorders physiopathology, Time Factors, Treatment Outcome, Young Adult, Anti-Inflammatory Agents administration & dosage, Arthritis, Juvenile drug therapy, Dexamethasone administration & dosage, Glucocorticoids administration & dosage, Iontophoresis adverse effects, Temporomandibular Joint drug effects, Temporomandibular Joint Disorders drug therapy
- Abstract
Objective: Temporomandibular joint (TMJ) involvement is common in juvenile idiopathic arthritis (JIA). Dexamethasone iontophoresis (DIP) uses low-grade electric currents for transdermal dexamethasone delivery into deeper anatomic structures. The purpose of this study was to assess the safety and effectiveness of DIP for the treatment of TMJ involvement in JIA, and to delineate variables that are associated with improvement after DIP., Methods: Medical records of all JIA patients who underwent DIP for TMJ involvement at a larger tertiary pediatric rheumatology center from 1997-2011 were reviewed. DIP was performed using a standard protocol. The effectiveness of DIP was assessed by comparing the maximal interincisor opening (MIO(TMJ) ) and the maximal lateral excursion (MLE(TMJ) ) before and after treatment., Results: Twenty-eight patients (ages 2-21 years) who received an average of 8 DIP treatment sessions per involved TMJ were included in the analysis. Statistically significant improvement in the median MIO(TMJ) (P < 0.0001) was observed in 68%. The median MLE(TMJ) (P = 0.03) improved in 69%, and resolution of TMJ pain occurred in 73% of the patients who had TMJ pain at baseline. Side effects of DIP were transient site erythema (86%), skin blister (4%), and metallic taste (4%). Improvement in TMJ range of motion from DIP is associated with lower MIO(TMJ) , lower MLE(TMJ) , and absence of TMJ crepitus at baseline., Conclusion: In this pilot study, DIP appeared to be an effective and safe initial treatment of TMJ involvement in JIA, especially among patients with decreased TMJ measurements. Prospective controlled studies are needed., (Copyright © 2011 by the American College of Rheumatology.)
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- 2011
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139. Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke.
- Author
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Xin B, Jones S, Puffenberger EG, Hinze C, Bright A, Tan H, Zhou A, Wu G, Vargus-Adams J, Agamanolis D, and Wang H
- Subjects
- Adolescent, Adult, Age of Onset, Base Sequence, Cerebrovascular Disorders pathology, Child, Child, Preschool, DNA Mutational Analysis, Ethnicity genetics, Female, Humans, Infant, Infant, Newborn, Male, Pedigree, SAM Domain and HD Domain-Containing Protein 1, Stroke pathology, Young Adult, Cerebrovascular Circulation, Cerebrovascular Disorders genetics, Homozygote, Monomeric GTP-Binding Proteins genetics, Mutation, Stroke genetics
- Abstract
We describe an autosomal recessive condition characterized with cerebral vasculopathy and early onset of stroke in 14 individuals in Old Order Amish. The phenotype of the condition was highly heterogeneous, ranging from severe developmental disability to normal schooling. Cerebral vasculopathy was a major hallmark of the condition with a common theme of multifocal stenoses and aneurysms in large arteries, accompanied by chronic ischemic changes, moyamoya morphology, and evidence of prior acute infarction and hemorrhage. Early signs of the disease included mild intrauterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud's phenomenon, chilblain lesions, low-pitch hoarse voice, glaucoma, migraine headache, and arthritis were frequently observed. The early onset or recurrence of strokes secondary to cerebral vasculopathy seems to always be associated with poor outcomes. The elevated erythrocyte sedimentation rate (ESR), IgG, neopterin, and TNF-α found in these patients suggested an immune disorder. Through genomewide homozygosity mapping, we localized the disease gene to chromosome (Chr) 20q11.22-q12. Candidate gene sequencing identified a homozygous mutation, c.1411-2A > G, in the SAMHD1 gene, being associated with this condition. The mutation appeared at the splice-acceptor site of intron 12, resulted in the skipping of exon 13, and gave rise to an aberrant protein with in-frame deletion of 31 amino acids. Immunoblotting analysis showed lack of mutant SAMHD1 protein expression in affected cell lines. The function of SAMHD1 remains unclear, but the inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis.
- Published
- 2011
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140. Pediatric rheumatology--its own specialty.
- Author
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Hinze C and Brunner HI
- Subjects
- Child, Humans, Rheumatic Diseases therapy, Pediatrics, Rheumatology
- Published
- 2008
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141. Biomolecular-chemical screening: a novel screening approach for the discovery of biologically active secondary metabolites. III. New DNA-binding metabolites.
- Author
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Maul C, Sattler I, Zerlin M, Hinze C, Koch C, Maier A, Grabley S, and Thiericke R
- Subjects
- Chromatography, Thin Layer, Fermentation, DNA metabolism, Fungi metabolism, Streptomyces metabolism
- Abstract
Based on the chemical screening technique, biomolecular-chemical screening has been developed which makes use of two-dimensional TLC analysis of microbial extracts and combines thin-layer chromatography (RP-18) with binding studies towards DNA. In the first dimension the metabolites of the crude microbial extract are separated, and in the second dimension binding properties towards DNA are analysed. An initial screening program with 500 microbial extracts prepared by solid-phase extraction with XAD-16 resin resulted in 17 samples which contained metabolites with significant DNA-binding behavior. Fermentation, isolation and structural characterization led to already known metabolites [phenazine-1,6-dicarboxylate (1), phencomycin (2), 11-carboxy-menoxymycin B (3), soyasaponine I (4), and (8S)-3-(2-hydroxypropyl)-cyclohexanone (5)], as well as to new secondary metabolites. Fermentation of the producing organisms of the new DNA-binding metabolites, ent-8,8adihydro-ramulosin (6). (2R,4R)-4-hydroxy-2-(1,3-pentadienyl)-piperidine (7), (5R)-dihydro-5-pentyl-4'-methyl-4'-hydroxy-2(3H)-furanone (8), and seco-4,23-hydroxyoleane-12-en-22-one-3-carboxylic acid (9), as well as isolation, structural characterization, and physico-chemical properties are reported.
- Published
- 1999
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142. Selectivity of MDL 72,974A for MAO-B inhibition based on substrate and metabolite concentrations in plasma.
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Huebert ND, Schwach V, Hinze C, and Haegele KD
- Subjects
- Adult, Analysis of Variance, Humans, Male, Methoxyhydroxyphenylglycol analogs & derivatives, Methoxyhydroxyphenylglycol blood, Norepinephrine blood, Allyl Compounds pharmacology, Butylamines pharmacology, Catecholamines blood, Monoamine Oxidase Inhibitors pharmacology
- Abstract
Plasma concentrations of 3,4-dihydroxyphenylethylglycol (DOPEG), noradrenaline (NA), adrenaline (A), 3,4-dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA) and phenylethylamine (PEA) were analyzed in samples taken prior to, during and following the administration of single, daily doses of 12 or 24 mg MDL 72,974A to healthy male volunteers. No effects on the concentrations of DOPA, A, DA or DOPAC were seen during the administration of either dose over 10 days. No treatment-related changes in the concentration of NA were evident at either dose. No changes in DOPEG or PEA concentrations were seen with the 12 mg dose; however, small but significant decreases in plasma DOPEG concentrations and a significant increase in PEA were seen during the administration of the 24 mg dose. This would suggest that at the 24 mg dose some intraneuronal inhibition of MAO-A may be occurring although the lack of increases in NA and A concentrations indicates no accompanying change in sympatho-adrenal activity. Plasma PEA concentrations do not provide a more sensitive or functional indication of MAO-B inhibition. The increase in PEA concentrations at the higher dose may suggest that the inhibition of both forms of the enzyme is necessary to increase its plasma concentration.
- Published
- 1995
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143. Kinetics and metabolism of p-tyramine during monoamine oxidase inhibition by mofegiline.
- Author
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Huebert ND, Dulery BD, Schoun J, Schwach V, Hinze C, and Haegele KD
- Subjects
- Adult, Biological Availability, Double-Blind Method, Humans, Male, Phenylacetates blood, Tyramine blood, Tyramine metabolism, Allyl Compounds pharmacology, Butylamines pharmacology, Monoamine Oxidase Inhibitors pharmacology, Phenylacetates pharmacokinetics, Tyramine pharmacokinetics
- Abstract
The effects of monoamine oxidase B (MAO-B) inhibition by mofegiline on the pharmacokinetics of p-tyramine and its major metabolite, p-hydroxyphenylacetic acid, were investigated in 24 healthy male volunteers. p-Tyramine doses were administered before and after a 14-day treatment period of 1, 12, or 24 mg mofegiline or placebo. Normalized p-tyramine for area under the plasma concentration-time curve after treatment were not significantly different from their respective before-treatment values for any of the dose groups. The relative bioavailability of p-tyramine after treatment was not significantly different from before treatment, although a tendency to a greater bioavailability was seen with the 12 and 24 mg doses. There were no significant differences between pharmacokinetic parameters for p-hydroxyphenylacetic acid. The data suggest that mofegiline maintains its selectivity for MAO-B in the intestine and liver at doses up to and including 24 mg. Therefore these doses would not be expected to be associated with the hypertensive crises normally associated with the "cheese effect."
- Published
- 1994
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144. The measurement of beta-phenylethylamine in human plasma and rat brain.
- Author
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Huebert ND, Schuurmans Schwach V, Richter G, Zreika M, Hinze C, and Haegele KD
- Subjects
- Adult, Animals, Chromatography, High Pressure Liquid, Humans, Phenethylamines blood, Rats, Brain Chemistry, Phenethylamines analysis
- Abstract
A sensitive and specific analytical method has been developed for the measurement of beta-phenylethylamine (PEA) in human plasma and rat brain extracts. The method involves solvent extraction of PEA with cyclohexane in the presence of amphetamine or phenylpropylamine (PPA) as internal standards. Automated precolumn derivatization with o-phthalaldehyde and 2-mercaptoethanol followed by reverse-phase HPLC separated PEA and PPA from endogenous interferences. Detection and quantification were carried out by amperometric detection at +0.75 V relative to a Ag/AgCl reference electrode or by coulometric detection with analytical cell potentials set at +0.29 and +0.50 V. The limit of detection for PEA was 10 pg and the limit of quantification in plasma was 60 pg/ml. The within-day and day-to-day coefficients of variation were 16.1% (n = 3) and 40.6% (n = 8), respectively, at a plasma concentration of 154 pg/ml and 15.2% (n = 5) and 28% (n = 10) at a brain extract concentration of 110 pg/ml. Basal endogenous plasma PEA concentrations of 335 +/- 255 pg/ml (n = 12, range 127-1002 pg/ml) were found for normal volunteers and single, daily doses of 24 mg but not 12 mg of the MAO-B inhibitor, mofegiline, were shown to increase plasma PEA significantly. Basal whole brain and striatal concentrations were 0.584 +/- 0.243 ng/g wet wt (n = 3) and 2.89 +/- 1.03 ng/g wet wt (n = 4), respectively. Statistically significant increases (5.7-fold) in rat whole brain PEA concentrations were seen 3 and 6 h following the administration of a single dose of 0.3 mg/kg mofegiline to rats.
- Published
- 1994
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145. Pharmacokinetics of and monoamine oxidase B inhibition by (E)-4-fluoro-beta-fluoromethylene benzene butanamine in man.
- Author
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Dulery BD, Schoun J, Zreika M, Dow J, Huebert N, Hinze C, and Haegele KD
- Subjects
- Blood Platelets enzymology, Double-Blind Method, Gas Chromatography-Mass Spectrometry, Half-Life, Humans, Indicators and Reagents, Allyl Compounds, Butylamines pharmacokinetics, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacokinetics
- Abstract
MDL 72974A ((E)-4-fluoro-beta-fluoromethylene benzene butanamine HCl salt, CAS 120635-25-8) is a new irreversible inhibitor of the B form of monoamine oxidase (MAO-B). MDL 72974A's pharmacokinetic parameters were evaluated after administration of a single oral dose and after multiple oral doses. The concentration of parent drug was determined in plasma using a solid-liquid extraction method and gas chromatographic-mass spectrometric analysis. MDL 72974A produced significant inhibition of platelet MAO-B activity at all of the doses > or = 0.5 mg (> 95% after 1 h). The pharmacokinetic parameters showed a short plasma half-life (1 h) and a high total body clearance (Cltot) both probably due to extensive and rapid metabolism as suggested by the low urinary excretion of unchanged drug (< 1% of the administered dose). After the administration of multiple doses of MDL 72974A, a decrease in Cltot and a concomitant increase in the AUC and t1/2, was observed, probably due to a change in the elimination rate of MDL 72974A. Due to the once-a-day dosing schedule and the short plasma t1/2, no drug accumulation occurred.
- Published
- 1993
146. Effects of a standardized meal on the pharmacokinetics of the new cardiotonic agent piroximone.
- Author
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Haegele KD, Hinze C, Joder-Ohlenbusch AM, Cremer G, and Borlak J
- Subjects
- Adolescent, Adult, Humans, Imidazoles urine, Male, Food, Imidazoles pharmacokinetics
- Abstract
The influence of food on the pharmacokinetics of piroximone (MDL 19.205, CAS 84490-12-0) was evaluated in two groups of 6 healthy male volunteers receiving either 25 or 50 mg of the drug. Single doses were administered intravenously and orally under fasting conditions or orally with a standard breakfast on 3 different days with a washout period of at least 3 days in-between doses, according to an open, 3-way crossover, randomized design. Pharmacokinetic parameters (Cmax, tmax, AUC, t1/2, Cl, aVd, UEx) were not affected by food administration, but significant differences were found in t1/2 calculated from the decay of plasma concentrations in response to oral administration of 25 mg and 50 mg treatment doses. The urinary excretion of piroximone was significantly reduced after oral administration, when compared with the values obtained after intravenous application. In addition, extra-renal clearance was significantly reduced in the 50 mg treatment group, when compared with the values obtained in response to 25 mg. Bioavailability of piroximone calculated from AUC data compared favorably with data obtained from urinary recovery results.
- Published
- 1991
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