The current work aims to propose an adequate thermodynamic model, in addition to proposing and evaluating two composite models for the thermal decomposition of insulating mineral oil (IMO), ...considering that the models based on classical diagnostic methods do not have the ability to satisfactorily reproduce empirical data. The simulation results obtained using the proposed model showed better agreement with the presented data than the results obtained using classical models. The proposed model was also used in the development of a phenomenological based diagnostic method. The characteristics of this new phenomenological proposal and the classical diagnostic methods of dissolved gas analysis are compared and discussed; the proposed method showed better performance when compared to Rogers, Doernenburg, or IEC and equivalent performance to Duval triangle method commonly used in this field of knowledge. The general procedure for applying the new diagnostic method is also described. In order to account for the event's dynamics, the suggested model in particular made it feasible to replicate intermediate scenes of equilibrium C(s). Compared to the findings from the classical models found in the literature, the two-dimensional simulation results generated with this model demonstrated a better agreement with the actual data.
Summary
One common mechanism of resistance against antimicrobial peptides in Gram‐negative bacteria is the addition of 4‐amino‐4‐deoxy‐l‐arabinose (l‐Ara4N) to the lipopolysaccharide (LPS) molecule. ...Burkholderia cenocepacia exhibits extraordinary intrinsic resistance to antimicrobial peptides and other antibiotics. We have previously discovered that unlike other bacteria, B. cenocepacia requires l‐Ara4N for viability. Here, we describe the isolation of B. cenocepacia suppressor mutants that remain viable despite the deletion of genes required for l‐Ara4N synthesis and transfer to the LPS. The absence of l‐Ara4N is the only structural difference in the LPS of the mutants compared with that of the parental strain. The mutants also become highly sensitive to polymyxin B and melittin, two different classes of antimicrobial peptides. The suppressor phenotype resulted from a single amino acid replacement (aspartic acid to histidine) at position 31 of LptG, a protein component of the multi‐protein pathway responsible for the export of the LPS molecule from the inner to the outer membrane. We propose that l‐Ara4N modification of LPS provides a molecular signature required for LPS export and proper assembly at the outer membrane of B. cenocepacia, and is the most critical determinant for the intrinsic resistance of this bacterium to antimicrobial peptides.
Periorbital edema as a sole initial manifestation, without any evidence of other significant cutaneous or systemic involvement, is rare in systemic lupus erythematosus (SLE). We report a 16 year-old ...female who presented with bilateral periorbital edema as the sole initial manifestation of SLE. As the disease progressed, a kidney biopsy was performed demonstrating lupus nephritis stage II. This report emphasizes the importance of the index of suspicion of SLE as one of the differential diagnosis of patients with periorbital edema in the relevant clinical context.
To study short and long-term disease activity and vaccine-related adverse events in a cohort of JIA patients who received the live attenuated measles-mumps-rubella (MMR) booster vaccine while being ...treated with immunosuppressive and immunomodulatory therapies.
A retrospective study was performed in the UMC Utrecht, clinical and therapeutic data were collected from electronic medical records for two visits before and two visits after the MMR booster vaccine of JIA patients. Drug therapy was collected and adverse events related to the vaccine were requested from the patients during clinical visits or by short phone interviews. Associations between MMR booster vaccination and the active joint count, physician global assessment of disease activity, patient-reported visual analogue scale (VAS) for well-being and clinical Juvenile Arthritis Disease Activity Score (cJADAS) were analyzed using multivariable linear mixed effects analyses.
A total of 186 JIA patients were included in the study. At the time of vaccination, 51% of the patients used csDMARD and 28% used bDMARD therapy. Overall, adjusted disease activity scores after MMR booster vaccination were not significantly different compared to pre-vaccination. Mild adverse events related to the MMR booster were reported for 7% of the patients. No serious adverse events were reported.
MMR booster vaccination was safe and did not worsen disease activity during long-term follow-up in a large cohort of JIA patients being treated with both csDMARDs and biological DMARDs.
•The MMR booster vaccine demonstrated long-term immunogenicity in the majority of children with JIA.•Percentages of protective antibody levels against measles were lower in bDMARD users compared to ...non-bDMARD users.•Clinicians should consider to measure antibody levels at least five years after MMR booster in bDMARD users and advice an extra booster accordingly.
Vaccines, especially live attenuated vaccines, in children with JIA pose a great challenge due to both potential lower immunogenicity and safety as a result of immunosuppressive treatment. For many years, in the Netherlands, JIA patients receive a measles-mumps-rubella (MMR) booster vaccine at the age of nine years as part of the national immunization program.
To study long-term humoral immunoprotection in a large cohort of JIA patients who received the MMR booster vaccine while being treated with immunomodulatory therapies at the Wilhelmina Children’s Hospital in Utrecht, the Netherlands.
MMR-specific IgG antibody concentrations in stored serum samples of vaccinated JIA patients were determined with chemiluminescent microparticle immunoassays (CMIA). Samples were analyzed five years after MMR booster vaccination and at last available follow-up visit using both crude and adjusted analyses. Additional clinical data were collected from electronic medical records.
In total, 236 samples from 182 patients were analyzed, including 67 samples that were available five years post-vaccination, and an additional 169 samples available from last visits with a median duration after vaccination of 6.9 years (IQR: 2.8–8.8). Twenty-eight patients were using biologic disease-modifying antirheumatic drugs (bDMARDS) of whom 96% anti-TNF agents and 4% tocilizumab. Percentages of protective antibody levels against measles after five years were significantly lower for patients who used bDMARD therapy at vaccination compared to patients who did not: 60% versus 86% (P = 0.03). For mumps (80% versus 94%) and rubella (60% versus 83%) this difference did not reach statistical significance (P = 0.11 and P = 0.07, respectively). Antibody levels post-vaccination decreased over time, albeit not significantly different between bDMARD users and non-bDMARD users.
The MMR booster vaccine demonstrated long-term immunogenicity in the majority of children with JIA from a large cohort, although lower percentages of protective measles antibody levels were observed in bDMARD users. Hence, it might be indicated to measure antibody levels at least five years after MMR booster vaccination in the latter group and advice an extra booster accordingly.
Lung infection by Burkholderia species, in particular Burkholderia cenocepacia, accelerates tissue damage and increases post-lung transplant mortality in cystic fibrosis patients. Host-microbe ...interplay largely depends on interactions between pathogen-specific molecules and innate immune receptors such as Toll-like receptor 4 (TLR4), which recognizes the lipid A moiety of the bacterial lipopolysaccharide (LPS). The human TLR4·myeloid differentiation factor 2 (MD-2) LPS receptor complex is strongly activated by hexa-acylated lipid A and poorly activated by underacylated lipid A. Here, we report that B. cenocepacia LPS strongly activates human TLR4·MD-2 despite its lipid A having only five acyl chains. Furthermore, we show that aminoarabinose residues in lipid A contribute to TLR4-lipid A interactions, and experiments in a mouse model of LPS-induced endotoxic shock confirmed the proinflammatory potential of B. cenocepacia penta-acylated lipid A. Molecular modeling combined with mutagenesis of TLR4-MD-2 interactive surfaces suggests that longer acyl chains and the aminoarabinose residues in the B. cenocepacia lipid A allow exposure of the fifth acyl chain on the surface of MD-2 enabling interactions with TLR4 and its dimerization. Our results provide a molecular model for activation of the human TLR4·MD-2 complex by penta-acylated lipid A explaining the ability of hypoacylated B. cenocepacia LPS to promote proinflammatory responses associated with the severe pathogenicity of this opportunistic bacterium.
Background: The Burkholderia cenocepacia lipid A is hypoacylated.
Results: Aminoarabinose residues in lipid A contribute to Burkholderia lipid A binding to the TLR4·MD-2 complex.
Conclusion: A novel mode of Burkholderia lipopolysaccharide-TLR4·MD-2 interactions promotes inflammation.
Significance: Modifications of the lipid A structure enhance proinflammatory responses of hypoacylated lipopolysaccharide.
How the opportunistic Gram-negative pathogens of the genus Achromobacter interact with the innate immune system is poorly understood. Using three Achromobacter clinical isolates from two species, we ...show that the type 3 secretion system (T3SS) is required to induce cell death in human macrophages by inflammasome-dependent pyroptosis. Macrophages deficient in the inflammasome sensors NLRC4 or NLRP3 undergo pyroptosis upon bacterial internalization, but those deficient in both NLRC4 and NLRP3 do not, suggesting either sensor mediates pyroptosis in a T3SS-dependent manner. Detailed analysis of the intracellular trafficking of one isolate indicates that the intracellular bacteria reside in a late phagolysosome. Using an intranasal mouse infection model, we observe that Achromobacter damages lung structure and causes severe illness, contingent on a functional T3SS. Together, we demonstrate that Achromobacter species can survive phagocytosis by promoting macrophage cell death and inflammation by redundant mechanisms of pyroptosis induction in a T3SS-dependent manner.
Display omitted
•The Achromobacter T3SS induces pyroptosis in human macrophages•The inflammasome sensors NLRC4 or NLRP3 mediate Achromobacter-induced pyroptosis•Achromobacter bacteria traffic intracellularly to a late phagolysosome compartment•Achromobacter T3SS is required to damage lung structure in a mouse infection model
Turton et al. show that, upon phagocytosis, the Achromobacter T3SS activates either NLRC4 or NLRP3 sensors, causing pro-inflammatory cell death in human macrophages, and mediates lung damage in infected mice, together demonstrating that Achromobacter bacteria overcome phagocytosis via pro-inflammatory cell death induction by redundant T3SS-dependent mechanisms.
To evaluate immunogenicity, effectiveness and safety of COVID-19 vaccination in patients with pediatric autoimmune inflammatory rheumatic disease (pedAIIRD).
A prospective cohort study was performed ...at the pediatric rheumatology department of the Wilhelmina Children’s Hospital in Utrecht, the Netherlands. Vaccination dates, COVID-19 cases and vaccine-related adverse events (AEs) were registered for all pedAIIRD patients during regular clinic visits from March 2021 – August 2022. SARS-CoV-2 IgG antibody levels and T-cell responses were measured from serum samples after vaccination, and clinical and drug therapy data were collected from electronic medical records. Rate of COVID-19 disease was compared between vaccinated and unvaccinated patients in a time-varying Cox regression analysis.
A total of 157 patients were included in this study and 88 % had juvenile idiopathic arthritis (JIA). One hundred thirty-seven patients were fully vaccinated, of which 47 % used biological agents at the time of vaccination, and 20 patients were unvaccinated. Geometric mean concentrations (GMCs) of post-vaccine antibody levels against SARS-CoV-2 were above the threshold for positivity in patients who did and did not use biological agents at the time of vaccination, although biological users demonstrated significantly lower antibody levels (adjusted GMC ratio: 0.38, 95 % CI: 0.21 – 0.70). T-cell responses were adequate in all but two patients (9 %). The adjusted rate of reported COVID-19 was significantly lower for fully vaccinated patients compared to non-vaccinated patients (HR: 0.53, 95 % CI: 0.29 – 0.97). JIA disease activity scores were not significantly different after vaccination, and no serious AEs were reported.
COVID-19 mRNA vaccines were immunogenic (both cellular and humoral), effective and safe in a large cohort of pedAIIRD patients despite their use of immunosuppressive medication.
PDF
