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关键词： axial spondyloarthritis   anti-TNF therapy   NSAIDs   swept-source optical coherence tomography angiography   retinal microvascular changes   choroidal thickness   vascular density  

摘要： Objectives: The aim of this study was to investigate retinal and choroidal microvascular changes in patients with axial spondyloarthritis (axSpA) treated with long-term anti-TNF therapy and NSAIDs and in healthy control subjects using optical coherence tomography angiography (SS-OCT-A). Methods: A total of 162 eyes from 81 participants were included: 52 eyes from 26 axSpA patients treated with anti-TNF therapy (>= 5 years), 44 eyes from 22 axSpA patients treated with NSAIDs, and 66 eyes from 33 healthy control subjects. SS-OCT-A imaging was used to assess retinal thickness, ganglion cell layer thickness, retinal nerve fiber layer thickness, and the vessel densities of the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC). Disease activity was assessed with ASDAS-CRP. Results: Both axSpA subgroups showed a significant expansion of the foveal avascular zone and reduced SCP and DCP densities compared to the controls. The CC vessel density was higher in axSpA patients than in healthy subjects. The anti-TNF group had a lower CC vascular density than the NSAIDs group. The disease duration correlated with a decreased central DCP density and increased paracentral SCP and CC densities. Conclusions: SS-OCT-A revealed subclinical retinal and choroidal changes in axSpA patients, highlighting the impact of chronic inflammation on the retinal vasculature. While anti-TNF therapy effectively controls systemic inflammation, it cannot completely prevent microvascular changes. Further studies are needed to assess the clinical relevance of these results.

关键词： Esculentoside A   MRL/lpr mice   CD19+IL-35+Breg cell   Interleukin-35   Interleukin-17   Lupus nephritis  

摘要： Introduction: Esculentoside A (EsA) is one of the main components of the traditional Chinese medicine Phytolacca esculenta. The possible mechanism of action of EsA in the treatment of lupus nephritis (LN) was explored by observing the effects of EsA on CD19(+) IL-35(+)regulatory B (IL-35(+)Breg) cells. Methods: Twenty-four MRL/lpr mice were randomly divided into control, EsA, and EsA+IL-12p35 antibody groups. Mice were administered the respective treatments intraperitoneally once a day for 4 weeks. The urine protein/ creatinine ratio (UPCR) and blood creatinine (Cr) and IL-35, IL-10, and IL-17 expression levels were measured. Body and spleen weight were measured to calculate the splenic index (SI). Flow cytometry was performed to determine the proportion of CD19(+) IL-35(+) Breg cells in the spleen. Hematoxylin-eosin and PASM-Masson staining of renal tissues were performed, and the " Austin " acute index (AI) system for LN was determined. Results: The most severe conditions were seen in mice in the control group, with the highest UPCR, Cr, and IL-17 levels and SI and AI scores;the most severe renal histopathology, and the lowest proportion of CD19(+) IL-35(+) Breg cells and IL-35 and IL-10 levels. This was followed by the EsA+IL-12p35 antibody group. The EsA group had the lowest UPCR, Cr, and IL-17 levels and SI and AI scores;the mildest renal lesions;and the highest proportion CD19(+) IL-35(+) Breg cells and IL-35 and IL-10 levels. Conclusion: EsA delayed the progression of LN by promoting the proliferation of CD19(+)IL-35(+) Breg cells, upregulating the expression of IL-35, and decreasing the secretion of IL-17.

关键词： BK virus   Hemorrhagic Cystitis   Post-transplant   cyclophosphamide   Sirolimus   Mycophenolate mofetil  

摘要： BK hemorrhagic cystitis (BK-HC) is a common complication following hematopoietic (PTCy) is used as graft-versus-host disease (GVHD) prophylaxis. However, comparative studies of BK-HC incidence in matched sibling donors (MSD) and unrelated donors (MUD) often include small haploidentical (HAPLO) donor cohorts and usually lack detailed information on disease evolution, coinfections, management and impact on outcomes. This study aimed to evaluate the incidence, risk factors, and outcomes in patients with hematologic malignancies undergoing HSCT from MSD, MUD, HAPLO donors using PTCy as GVHD prophylaxis. Furthermore, we analyze risk factors for BK-HC and its impact on renal function and transplant outcomes. Retrospective analysis of BK-HC episodes in patients undergoing HSCT from 167 MSD, 129 MUD and 103 HAPLO from a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus and mycophenolate mofetil was given, irrespective of donor type or conditioning intensity, and mesna was used

关键词： Rs1800896 (-1082 A > G)   Rs1800871 (-819 C > T)   Rs1800872 (-592 C > A)   Severe acute respiratory syndrome-related   coronavirus   Polymorphism   Single nucleotide   Interleukin-10   Polymorphism   Single nucleotide   Interleukin-10  

摘要： Background: Elevated concentrations of IL-10 have been detected in coronavirus disease (COVID-19) patients and are a possible disease severity marker. Single nucleotide variants (SNVs) and their haplotypes can be associated with differences in IL-10 levels and with viral disease susceptibility. Aim: Evaluate the associations of SNVs and their haplotypes in Brazilian patients with COVID-19 severity and outcome. Methods: In this cross-sectional and case-control study, the patients were selected from the University Hospital of State University of Londrina (HU-UEL) (n = 367) and were subdivided into mild (n = 165), moderate (n = 72) and severe (n = 130) groups. The DNA samples of the participants were subjected to real-time PCR for the detection of rs1800896 (A>G), rs1800871 (C>T) and rs1800872 (C>A) genotypes. The haplotypes were inferred with PHASE v2.1.1. Results: The severe cases of COVID-19 were independently associated with the GG genotype (rs1800896) (P = 0.038, OR 2.522, 95 % CI 1.053-6.038) as well as with the GCC haplotype in homozygosity (P = 0.037, OR 2.767, 95 % CI 1.065-7.191). Conclusion: These results showed that the GG genotype of rs1800896 or the GCC haplotype are associated with COVID-19 severity in Brazilian patients.

关键词： HLA-B*15:11:08   novel allele   sequencing-based typing  

摘要： The HLA-B*15:11:08 allele differs from HLA-B*15:11:01 by a single non-synonymous nucleotide change in exon 4.

关键词： Haploidentical   transplantation   Haplotypes   HLA-E ligand   NKG2 receptor   Relapse   Survival  

摘要： Background: Recurrence of blood malignancy is the major cause of mortality after hematopoietic cell transplantation. NKG2 receptor/HLA-E ligand complexes play a fundamental role in the surveillance and elimination of transformed cells but their role in the control of leukemia in transplantation is unknown. Objective: We tested the hypothesis that gene variation of patient and/or donor HLA-E ligand and donor NKG2C-NKG2A receptors are associated with the risks of relapse and mortality (primary endpoints) and GVHD and non-relapse mortality (secondary endpoints) after haploidentical transplantation. Study Design: We retrospectively defined donor NKG2 receptor haplotypes and patient HLA-E ligands in 1629 haploidentical related transplantations. HLA-E residue 107 was genotyped in patients and donors. Single nucleotide polymorphisms descriptive of NKG2C and NKG2A haplotypes were characterized in donors. Overall mortality, relapse, nonrelapse mortality and chronic GVHD were studied using Cox regression models. Acute GVHD was studied by logistic regression. Results: The hazard of relapse for patients transplanted from NKG2C-del/del donors was 51% lower than that from wt/wt donors (hazard ratio, HR, .49 [95% CI, .26 to .89) contributing to a HR for mortality of .62 (95% CI, .38 to 1.02). The HR of mortality among patients transplanted from a donor with 2 vs. 0 copies of the NKG2A rs35909400-rs2734440rs12824474 CCC haplotype was HR 2.28 (95% CI, 1.34 to 3.86). The HRs of mortality for ArgArg and ArgGly patients compared to GlyGly patients were 1.42 (95% CI, 1.11 to 1.82) and 1.43 (95% CI, 1.13 to 1.81), respectively. Hazard ratios for nonrelapse mortality for patients with ArgGly or ArgArg genotypes compared to patients with GlyGly genotype were HR 1.60 (95% CI, 1.06 to 2.41) and HR 1.79 (95% CI, 1.21 to 2.66), respectively. Assessment of donor receptor/patient ligand pairings showed that among Arg-positive patients, the HR of mortality from donors with any wt-CCC/CCC haplotyp

关键词： monoclonal antibodies   psoriasis   pharmacokinetics   plaque psoriasis   interleukin-23   psoriasis area and severity index  

摘要： Importance Psoriasis is a chronic, immune-mediated skin disease with an unmet need for biologic treatment options. Objective To assess the safety, pharmacokinetics, and efficacy of QX004N in healthy individuals and patients with moderate to severe plaque psoriasis in China. Design, Setting, and Participants This randomized clinical trial was composed of 2 parts. Part 1 was a first-in-human, single-ascending-dose, phase 1a clinical trial conducted from November 2, 2021, to January 16, 2023. Part 2 was a double-blind, multiple dose-escalation, phase 1b clinical trial conducted from February 15, 2023, to January 5, 2024, at 5 clinical centers in China, involving patients with moderate to severe plaque psoriasis. Interventions In part 1, healthy participants in each cohort were assigned in a 4:1 ratio to receive a single subcutaneous injection of QX004N (ranging from 10 mg to 600 mg) or placebo. In part 2, patients in each cohort were assigned in a 4:1 ratio to receive QX004N or placebo at doses of 150 mg, 300 mg, and 600 mg once every 2 weeks. Main Outcomes and Measures For part 1, the primary outcome was the safety of a single dose of QX004N in healthy participants, and the secondary outcome was the pharmacokinetic profile. For part 2, the primary efficacy end point was the proportion of patients achieving at least 75% improvement in Psoriasis Area and Severity Index (PASI 75) by week 12;other efficacy end points were considered secondary. Results The phase 1a clinical trial (part 1) enrolled 55 healthy participants (mean [SD] age, 35.9 [6.0] years;30 [54.5%] female), and the phase 1b clinical trial (part 2) enrolled 30 patients with moderate to severe plaque psoriasis. The mean (SD) age of QX004N-treated participants in part 2 was 41.4 (7.5) years, and 19 of 24 QX004N-treated participants (79.2%) were male. The mean (SD) age of the placebo cohort in part 2 was 35.3 (8.4) years, and 5 of 6 placebo-treated participants (83.3%) were male. QX004N exhibited linear pharmac

摘要： COVID-19 is associated with diverse neurological abnormalities, but the underlying mechanisms are unclear. We hypothesized that microglia, the resident immune cells of the brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy, protein and mRNA datasets in postmortem mirror blocks of brain and peripheral organ samples from cases of COVID-19. We observed focal loss of microglial P2Y12R, CX3CR1-CX3CL1 axis deficits and metabolic failure at sites of virus-associated vascular inflammation in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction is linked to mitochondrial injury at sites of excessive synapse and myelin phagocytosis and loss of glutamatergic terminals, in line with proteomic changes of synapse assembly, metabolism and neuronal injury. Furthermore, regionally heterogeneous microglial changes are associated with viral load and central and systemic inflammation related to interleukin (IL)-1 or IL-6 via virus-sensing pattern recognition receptors and inflammasomes. Thus, SARS-CoV-2-induced inflammation might lead to a primarily gliovascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.

关键词： Auto-inflammatory disease   Interleukin 18   Hemophagocytic lymphohistiocytosis   Actinopathies   PSTPIP1   XIAP   CDC42   Still disease  

摘要： Autoinflammatory diseases (AIDs) are conditions characterized by dysfunction of innate immunity, causing systemic inflammation and various clinical symptoms. The field of AIDs has expanded due to improved comprehension of pathophysiological mechanisms and advancements in genomics techniques. A new emerging category of AIDs is characterized by a significant increase in interleukin 18 (IL-18), a pro-inflammatory cytokine synthesized in macrophages and activated by caspase 1 via various inflammasomes. IL-18 plays a role in the regulation of innate and adaptive immunity. IL-18 is involved in various functions, such as the proliferation, survival, and differentiation of immune cells, tissue infiltration of immune cells, polarization of immune responses, and production of other pro-inflammatory cytokines. This review analyzes the literature on IL-18 regarding its functions and its implications in the diagnosis and treatment of AIDs. IL-18-associated AIDs comprise Still's disease and diseases associated with mutations in NLRC4, XIAP, CDC42, and PSTPIP1, as well as IL-18BP deficiencies. With the exception of PSTPIP1-associated diseases, these conditions all carry a risk of macrophagic activation syndrome. Measuring IL-18 levels in serum can aid in the diagnosis, prognosis, and monitoring of these diseases. Therapies targeting IL-18 and its signaling pathways are currently under investigation. (c) 2024 Societe Nationale Francaise de Medecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Gout   HLA-B5801   allopurinol   characteristics   flare  

摘要： Background/Aim: Allopurinol is a standard agent used for lowering uric acid levels. Human leukocyte antigen (HLA)- B5801 positivity increases the incidence of severe cutaneous adverse reactions (SCARs) in allopurinol users. HLA alleles HLA-B27 and HLA-B51 are frequently found in patients with ankylosing spondylitis and Beh & ccedil;et's disease, showing an association with distinct clinical features. In this study, we investigated the association between the HLA- B5801 genotype and patient characteristics and outcomes in gout. Patients and Methods: We retrospectively reviewed the medical records of 263 patients with gout who were not receiving uric acid-lowering therapy and were tested for HLA-B5801 positivity between March 2020 and February 2024. Patients were classified according to their HLA-B5801 status, and patient demographics and laboratory variables were compared. The incidence of gout flares or severe flares requiring hospital care within one year was investigated. Results: A total of 37 participants were HLA-B5801 positive (37/263, 14.1%). However, no significant differences were observed in demographic or laboratory variables between the HLA-B5801 positive and negative groups. Subgroup analyses of patients with new-onset gout, males, and those with an estimated glomerular filtration rate >= 60 ml/min/1.73 m2 also demonstrated no significant differences related to HLA-B5801 genotype positivity. The incidence of disease flares or severe flares between patients in the HLA-B5801 positive and negative groups was comparable during the one-year follow-up. Conclusion: Although HLA-B5801 was a significant predictor of allopurinol-associated SCARs, the impact of HLA- B5801 positivity on the clinical characteristics or flares was not evident in this population of patients with gout.