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关键词： COVID-19   coronavirus disease   heart injury   NT-proBNP   PIMS   pediatric inflammatory multisystem syndrome   TNF   tumor necrosis factor   TNF-R   tumor necrosis factor-receptor  

摘要： (1) Pediatric inflammatory multisystem syndrome (PIMS) is a relatively rare complication of coronavirus disease (COVID-19). So far, it is unclear why COVID-19 in children has usually mild or asymptomatic courses, whereas PIMS, which develops several weeks after COVID-19, is a serious life-threatening condition. (2) In this proof-of-concept study, using the ELISA method, we compared selected clinical and immunological parameters in small groups of children with PIMS and COVID-19. Children with various inflammatory diseases were included as a control. (3) Patients with PIMS revealed significantly higher levels of pro-inflammatory molecules (C-reactive protein and IL-6) and markers of heart injury (troponin I and N-terminal prohormone of brain natriuretic peptide) as compared to other groups. Moreover, these markers correlated with increased levels of soluble receptors for tumor necrosis factor (sTNF-R1 and sTNF-R2). (4) Our observation may be a step forward to better understand the phenomenon of mild COVID-19 in children and its severe complications in PIMS. It is hypothesized that the delayed inflammation results in excessive cardiomyocyte damage and the release of sTNF-R1 and -R2. Therefore, possibly the involvement of the TNF pathway in PIMS could be explored as a potential therapeutic target. However, further studies are required to validate this approach.

关键词： HLA new allele   HLA-DQB1*06:304N   next generation sequencing  

摘要： The full-length sequence of HLA-DQB1*06:304N covers the 5 '-untranslated region (UTR), all introns and exons, and the 3 ' UTR.

关键词： HLA-DPB1*1483:01   next-generation sequencing   novel allele  

摘要： We describe the novel HLA-DPB1*1483:01 allele found in a deceased Hispanic/Latino male.

关键词： HLA-DPA1*02:02:02:19   new allele   third-generation sequencing  

摘要： HLA-DPA1*02:02:02:19 differs from HLA-DPA1*02:02:02:02 by one nucleotide change in intron 1.

关键词： adverse drug reactions   allopurinol   Filipino   genotyping   gout   Hawaii   HLA-B*58:01  

摘要： Introduction: Allopurinol, a first-line treatment for gout and hyperuricemia, is associated with severe cutaneous adverse reactions (SCAR) in individuals carrying the HLA-B*58:01 allele. Genotyping is conditionally recommended in Han Chinese, Korean, and Thai populations with an allele prevalence of 7.4%, and in African Americans at 3.8%. The prevalence in Filipino patients has not been studied. We investigate the prevalence of HLA-B*58:01 among Filipino patients in Hawai'i and evaluate the incidence of allopurinol-induced adverse reactions following genotyping. Methods: We conducted a retrospective chart review of 312 patients who underwent HLA-B*58:01 genotyping at a primary care clinic in Hawai'i between November 2021 and July 2024. After excluding patients with missing ethnicity data, non-Filipino ethnicity, or prior allopurinol use, 237 Filipino patients were included in the analysis. The prevalence of the HLA-B*58:01 allele and the incidence of allopurinol-induced adverse reactions were calculated. Results: Among the 237 Filipino patients, 17 (7.2%) were HLA-B*58:01 positive. A total of 97 patients were started on allopurinol after genotyping and 1 (1.0%) developed mild cutaneous reactions, 0 (0%) developed SCAR, and 2 (2.1%) experienced gastrointestinal symptoms (nausea and diarrhea). Conclusion: The high prevalence of HLA-B*58:01 allele among Filipino patients in Hawai'i suggests that genotyping may be considered before initiating allopurinol treatment. Given no instances of SCAR were observed in patients who were administered allopurinol after undergoing HLA-B*58:01 genotyping, genotyping may play a crucial role in reducing the risk of allopurinol-induced SCAR in this population. Further studies with larger cohorts are suggested to confirm our findings and assess broader clinical utility of genotyping.

关键词： aerosol mechanics   drug delivery   ex vivo lung perfusion   interleukin-10   lung transplantation  

摘要： Background:The immunoregulatory cytokine interleukin-10 (IL-10) has been shown to be a promising therapy for donor lung injuries before transplantation. However, the very short half-life of IL-10 in vivo (∼2 hours) has necessitated the use of gene therapy in almost all animal models of lung transplantation. Because isolation of the donor lung on the ex vivo lung perfusion (EVLP) circuit removes it from the influence of renal and hepatic clearance mechanisms, a much-prolonged half-life of IL-10 is anticipated. Thus, we hypothesized that delivery of recombinant IL-10 (rIL-10) to injured donor lungs isolated on EVLP could be a clinically relevant and a logistically simpler method of employing IL-10 therapy in lung transplantation. Methods:Injured human donor lungs clinically rejected for transplantation were split into single lungs and the better of the 2 subjected to 12 hours of EVLP and randomized ( = 5/group) to receive either saline (control), rIL-10 (5 µg in 2-liter perfusate), or rIL-10 (25 µg) aerosolized into the airways. Results:Perfusate and intratracheal delivery of rIL-10 did not provide the therapeutic anti-inflammatory action that has been traditionally achieved with gene therapy. It appears that intratracheally delivered rIL-10 moves into the perfusate where it seems to be biologically inactive. Conclusions:Gene therapy remains superior as it allows for continued production of IL-10 within the alveoli where it has the potential to continuously act on alveolar macrophages and epithelial cells in a paracrine fashion.

关键词： craniosynostosis   cytokine signalling   IL11RA   IL6ST   interleukin 11   JAK/STAT pathway   signalling complex  

摘要： Interleukin 11 (IL-11), a member of the IL-6 family of cytokines, has roles in haematopoiesis, inflammation, bone metabolism, and craniofacial development. IL-11 also has pathological roles in chronic inflammatory diseases, fibrosis, and cancer. In this structural snapshot, we explore our recently published cryo-EM structure of the human IL-11 signalling complex to understand the molecular mechanisms of complex formation and disease-associated mutations. IL-11 signals by binding to its cell surface receptors, the IL-11 receptor alpha subunit (IL-11R alpha) and glycoprotein 130 (gp130), to form a hexameric signalling complex. We examine the locations within the complex of receptor sequence variants that are associated with craniosynostosis and craniosynostosis-like phenotypes and speculate on potential molecular mechanisms leading to defects in signalling function. While these causative amino acid sequence changes in IL-11R alpha are generally distal to interfaces between components of the complex, important structural residues are highly represented, including proline residues, cysteine residues involved in disulfide bonds, and residues within or surrounding the tryptophan-arginine ladder. We also note the locations and potential effects of amino acid substitutions within the extracellular domains of gp130 that are associated with craniosynostosis. As focus on the physiological and pathological functions of IL-11 grows, the importance of high-resolution structural knowledge of IL-11 signalling to understand disease-associated mutations and to inform therapeutic strategies will only increase.

关键词： BMP-7   fracture hematoma   IL-10   immunomodulation   mineralization  

摘要： Following biomaterial implantation, a failure to resolve inflammation during the formation of a fracture hematoma can significantly limit the biomaterial's ability to facilitate bone regeneration. This study aims to combine the immunomodulatory and osteogenic effects of BMP-7 and IL-10 with the regenerative capacity of collagen-hydroxyapatite (CHA) scaffolds to enhance in vitro mineralization in a hematoma-like environment. Incubation of CHA scaffolds with human whole blood leads to rapid adsorption of fibrinogen, significant stiffening of the scaffold, and the formation of a hematoma-like environment characterized by a limited capacity to support the infiltration of human bone progenitor cells, a significant upregulation of inflammatory cytokines and acute phase proteins, and significantly reduced osteoconductivity. CHA scaffolds functionalized with BMP-7 and IL-10 significantly downregulate the production of key inflammatory cytokines, including IL-6, IL-8, and leptin, creating a more permissive environment for mineralization, ultimately enhancing the biomaterial's osteoconductivity. In conclusion, targeting the onset of inflammation in the early phase of bone healing using BMP-7 and IL-10 functionalized CHA scaffolds is a promising approach to effectively downregulate inflammatory processes, while fostering a more permissive environment for bone regeneration. This study presents BMP-7 and IL-10-functionalized collagen-hydroxyapatite scaffolds as an immunomodulatory therapy for bone repair. The impact of a hematoma-like environment on cell-material interactions, inflammatory cytokine production, and osteogenesis is presented. BMP-7 and IL-10 target inflammation, downregulating key inflammatory cytokines to create a more environment for mineralization and effective bone healing. image

关键词： recurrent pregnancy loss   recurrent implantation failure   NK cells   T regulatory cells   Th17   Th1   Th2   macrophages   cytokines   HLA  

摘要： Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses before 24 weeks of gestation. It affects 3-5% of women who are attempting to conceive. RPL can stem from a variety of causes and is frequently associated with psychological distress and a diminished quality of life. By contrast, recurrent implantation failure (RIF) refers to the inability to achieve a successful pregnancy after three or more high-quality embryo transfers or at least two instances of egg donation. RIF shares several causative factors with RPL. The immunological underpinnings of these conditions involve alterations in uterine NK cells, reductions in M2 macrophages and myeloid-derived suppressor cells, an increased Th1/Th2 ratio, a decreased Treg/Th17 ratio, the presence of shared >= 3 HLA alleles between partners, and autoimmune disorders. Various therapeutic approaches have been employed to address these immunological concerns, achieving varying degrees of success, although some therapies remain contentious within the medical community. This review intends to explore the immunological factors implicated in RPL and RIF and to analyze the immunological treatments employed for these conditions, which may include steroids, intravenous immunoglobulins, calcineurin inhibitors, anti-TNF antibodies, intralipid infusions, granulocyte colony-stimulating factor, and lymphocyte immunotherapy.