Nicolas Schlegel

Inflammatory bowel diseases (IBD) including Crohn’s disease (CD) are characterized by impaired intestinal epithelial barrier (IEB) function. Alterations in the desmosomal cadherin desmoglein 2 (Dsg2) have been linked to loss of IEB and intestinal inflammation in IBD. We investigated the pathogenic impact of a cytoplasmatic-truncating mutation in the desmosomal cadherin desmoglein 2 gene (DSG2) in an IBD patient. Genetic analysis of a CD patient revealed a likely pathogenic DSG2 mutation leading to a truncated protein lacking part of the intracellular domain. Generation of an enterocyte-specific mouse model to recapitulate the human mutation resulted in a lethal intestinal barrier defect which was evident in homozygous but not in heterozygous mice. In vitro, barrier defects correlated with changes in Dsg2 mobility and upregulation of pore-forming tight junction protein claudin-2. Organoids derived from heterozygous Dsg2 truncated mice exhibited increased epithelial susceptibility to proinflammatory cytokines. Bulk RNAseq followed by gene ontology analysis in homozygous mice revealed a skewed IL17/IL23 response overlapping with transcriptional changes in patients with CD. Furthermore, 16S rRNA sequencing revealed alterations in microbiome composition in animals that carried the Dsg2 truncation. In summary, a patient-derived mutation in the DSG2 gene causing cytoplasmic truncation in homozygous state induced a lethal intestinal barrier breakdown in mice paralleled by altered gut microbiota and intestinal immune response.

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Sepsis is associated with hypotension, vascular leakage, vasoplegia and microvascular dysfunction. Therefore, the endothelium is a target for sepsis therapies. Since truncated procalcitonin exerts vascular activity, we here evaluated the efficacy of targeting procalcitonin for vascular integrity and sepsis outcomes. Sepsis up-regulated >2000 genes involved in pro-inflammatory responses while similar numbers of genes involving cell growth and maintenance were down-regulated. Transcriptomic changes in endothelial cells diminished by >50% by anti-procalcitonin antibodies and this was functionally associated with preserved vascular barrier integrity in lungs and intestines, reduced sepsis-induced vasoplegia, preserved endothelial nitric oxide bioavailability, improved organ integrity and reduced sepsis severity in mice. Mechanistically, procalcitonin neutralization was associated with reduced signaling of the interleukin-17 pathway. We here show sepsis induces substantial changes to the endothelial transcriptome and vascular integrity and neutralizing procalcitonin is a suitable means to preserve endothelial homeostasis at a transcriptomic and functional level that could translate into organ protection during sepsis.

Zusammenfassung Das Auffinden von Nebenschilddrüsen bei Halsoperationen kann aufgrund ihrer Lagevariabilität herausfordernd sein. Kenntnisse über embryonale Wanderung, typische Lokalisationen und Gefäßversorgung sind deshalb für die erfolgreiche Chirurgie der Nebenschilddrüsen entscheidend. In diesem narrativen Übersichtsartikel wird unter Einbezug einer systematischen Literaturrecherche auf diese Aspekte eingegangen. Die anatomische Orientierung am N. laryngeus recurrens und der A. thyreoidea inferior als Leitstrukturen gefolgt von der systematischen zervikalen Exploration hilft beim Auffinden von Nebenschilddrüsen. Die Lagevariabilität der unteren Nebenschilddrüsen ist insgesamt höher als die der oberen Nebenschilddrüsen. Beim primären Hyperparathyreoidismus ermöglicht eine präoperative Lokalisationsdiagnostik mittels hochauflösenden Ultraschalles und funktioneller Bildgebung (z. B. Cholin-PET/CT [Positronenemissionstomographie/Computertomographie]) fokussierte Parathyreoidektomien mit reduzierter Operationsdauer und Komplikationsrate.

Background: Patients with Crohn’s disease (CD) suffer from a relevant burden of abdominal pain and psychological distress that can aggravate postoperatively. While systematic strategies for postoperative pain management are lacking, the potential benefit of perioperative epidural analgesia (EDA) in CD patients is unclear. Methods: All patients receiving an ileocecal resection due to CD at a tertiary hospital were included. The impact of epidural versus non-epidural analgesia on postoperative pain perception was evaluated by analyzing the numeric rating scale (NRS), analgesic consumption, and clinical outcomes. Results: In this monocentric study, 172 patients receiving ileocecal resection due to CD were included, with 122 receiving EDA. The epidural pain catheters were kept for an average of 4.4 days (±1.3) before being removed. EDA resulted in significantly decreased pain as well as a decreased amount of analgesic consumption (adjuvant analgesics: 16.4% vs. 32%, p = 0.021; strong opioids: 30.3% vs. 72.0%, p < 0.001) at the early postoperative course (1 vs. 3 at rest and 2 vs. 4 movement-evoked, p < 0.001). No difference in pain perception was detected on day 5 between EDA and non-EDA patients. Patients with EDA had a significantly longer length of hospital stay (7.5 versus 6 days, p = 0.002) and an increased intake of weak opioids at discharge (p = 0.024). Conclusions: While EDA in CD patients resulted in significantly decreased pain and decreased amounts of analgesic adjuvants and strong opioids at the early postoperative course, intravenous and oral analgesia provide sufficient postoperative pain control after surgery and earlier patient autonomy.

Inflammatory Bowel Diseases (IBD), including Crohn’s disease and ulcerative colitis, pose challenges due to their complex pathophysiology and high prevalence. Despite advances in immune-targeted therapies, a substantial number of patients fail to achieve mucosal healing, highlighting the need for alternative therapeutic strategies. In this issue of the JCI , D’Addio et al. identified another mechanism underlying impaired epithelial regeneration in Crohn’s disease. They found that abnormal cell death in intestinal epithelial stem cells, mediated by altered TMEM219 signaling, led to impaired mucosal healing. Targeting TMEM219 with ecto-TMEM219, which blocks its activation, restored stem cell function and promoted mucosal healing in vitro and in vivo. These findings suggest a promising therapeutic avenue focusing on epithelial repair. Additionally, patient-derived organoids (PDOs) emerge as a valuable tool for personalized treatment strategies and for advancing the field of IBD research. This study underscores the importance of epithelial cell biology in developing innovative IBD therapies.

Zusammenfassung: Das follikuläre Schilddrüsenkarzinom (FTC) ist die zweithäufigste Form des differenzierten Schilddrüsenkarzinoms und macht etwa 5–15 % aller Schilddrüsenmalignome aus. Das FTC wird gemäß der WHO(World Health Organization)-Klassifikation von 2022 in drei Subtypen gegliedert, die sich in Gesamtprognose und Rezidivwahrscheinlichkeit deutlich unterscheiden. Darüber hinaus ist die Kenntnis gutartiger follikulärer Tumoren und Low-grade-Neoplasien wichtig. Prognostische Faktoren bei den malignen Veränderungen sind neben dem Lebensalter, die Größe des Tumors, invasives Wachstum, das Vorliegen von Angioinvasionen sowie das Vorhandensein von Fernmetastasen. Die chirurgische Vorgehensweise orientiert sich an diesen Faktoren. Entsprechend unterscheidet sie sich zwischen den Subtypen des FTC. Eine genaue Kenntnis der einzelnen Subtypen von Schilddrüsentumoren ist erforderlich, um eine individuell angemessene chirurgische Therapieentscheidung treffen zu können.