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关键词： treatment patterns   generalized pustular psoriasis   GPP   plaque psoriasis   claims data   retrospective study   All-GPP   a combined cohort of   GPP-only   and   GPP+PsO   ER   emergency room   FDA   US Food and Drug Administration   GPP   generalized pustular psoriasis   GPP-only   cohort includes patients with GPP   GPP+PsO   cohort includes patients with GPP and plaque PsO   HCRU   healthcare resource utilization   ICD-10   International Classification of Diseases, 10th revision   IL   interleukin   PsO   psoriasis   US   United States  

摘要： Background Generalized pustular psoriasis (GPP) is a chronic and life-threatening inflammatory skin disease, distinct from plaque psoriasis (PsO). There is a lack of GPP treatment guidelines. Objective To characterize treatment patterns among patients with GPP in the US during two 365-day periods (post-diagnosis and pre-diagnosis) between 2015 and 2020. Methods Using a claims database, three cohorts were identified ( All-GPP , GPP+PsO , GPP-only ) from ICD-10 codes. Results The study comprised of 2,630 patients in the All-GPP cohort (n=1,246 GPP-only , n=1,384 GPP+PsO ). Topical corticosteroids were the most frequently prescribed treatment post-diagnosis, followed by systemic corticosteroids: GPP+PsO (55.7% and 40.4%, respectively), GPP-only (51.5% and 42.0%). In the GPP+PsO vs GPP-only cohort, systemic biologics (39.6% vs 21.5%) and non-biologics (36.9% vs 29.1%) were prescribed more frequently post-diagnosis. In each cohort, use of systemic and topical corticosteroids was lower post-diagnosis vs pre-diagnosis, whereas use of other therapeutics (topical vitamin D derivates, retinoids, systemic biologics, systemic non-biologics, phototherapy) was higher. Limitations Data collected before FDA approval of the first biologic for GPP (spesolimab). Conclusions Corticosteroids were frequently prescribed, despite published reports of GPP flare following withdrawal, and fewer GPP-only than GPP+PsO patients received biologics, consistent with the lack of FDA-approved targeted therapies for GPP during the study.

关键词： Leishmaniasis   Vaccine   Bioinformatic   Peptides   Immunogenicity   MHC I molecules   Leishmania infantum   L. donovani L. major  

摘要： Leishmaniasis, caused by protozoan parasites of the genus Leishmania , is a significant global health concern, with visceral leishmaniasis (VL) being its most severe clinical form. Current therapeutic options remain limited, beside of the urgent need for effective vaccines. This study identified and analyzed antigenic epitopes from Leishmania species that interact with class MHCI molecules and are recognized by T lymphocyte receptors. Peptide sequences from Leishmania species were selected from the Immune Epitope Database (IEDB) based on their interaction with MHCI molecules and ranked for immunogenicity using IEDB's predictive tools. Sequence similarities and conservation across Leishmania species were assessed using BLAST, and the peptides were synthesized via solid-phase peptide synthesis. Female BALB/c mice were immunized with the peptides, and their humoral responses were evaluated by measuring IgG titers in serum. This study identified ten peptides that, when incorporated into a vaccine construct, were capable of inducing high levels of IgG antibodies in an animal model. Among them, two stood out as immunodominant and potential targets for the development of novel vaccine strategies. These findings provide initial evidence of the potential of these peptides in developing new vaccines and therapeutic strategies against visceral leishmaniasis.

关键词： Shigella   Shigellosis   intestinal epithelial cells   macrophages   IL-12   IFN-g   neutrophils   mouse model   innate immunity  

摘要： Bacteria of the genus Shigella replicate in intestinal epithelial cells and cause shigellosis, a severe diarrheal disease that resolves spontaneously in most healthy individuals. During shigellosis, neutrophils are abundantly recruited to the gut and have long been thought to be central to Shigella control and pathogenesis. However, how shigellosis resolves remains poorly understood due to the longstanding lack of a tractable and physiological animal model. Here, using our newly developed Nlrc4 –/– Casp11 –/– mouse model of shigellosis, we unexpectedly find no major role for neutrophils in limiting Shigella or in disease pathogenesis. Instead, we uncover an essential role for macrophages in the host control of Shigella . Macrophages respond to Shigella via Toll-like receptors (TLRs) to produce IL-12, which then induces IFN-γ, a cytokine that is essential to control Shigella replication in intestinal epithelial cells. Collectively, our findings reshape our understanding of the innate immune response to Shigella .

关键词： Autoimmunity   Celiac disease   HLA   MHC   MTORC1   Mammalian target of rapamycin   Oxidative stress   RNA sequencing   Small bowel  

摘要： BACKGROUND:Celiac disease is associated with HLA-risk haplotypes, but non-HLA genes and environmental factors are also linked to disease susceptibility. In this study, we explore the molecular pathways involved in celiac disease by analyzing the differential expression of genes in both the gut and peripheral blood across various celiac disease phenotypes. METHODS:Whole genome RNA sequencing was performed on 283 samples from intestinal mucosa and peripheral blood from 72 cases with either active, potential, or treated celiac disease and 73 disease controls. Enrichr pathway analysis of top differentially expressed genes was performed. RESULTS:Overall, 7565 genes in intestinal biopsies and 542 genes in blood samples were differentially expressed between cases and controls. Compared with controls, immunoglobulin heavy variable 5-51 (IGHV5-51) (p = 1.05 × 10) and tissue transglutaminase (TGM2) (p = 5.29 × 10), encoding for TG2, the main autoantigen in celiac disease, were two of the top up-regulated genes in intestinal biopsies from celiac cases. TGM2 was also slightly upregulated in blood cells from cases with active disease compared with controls (p = 0.05). The topmost differentially expressed genes in peripheral blood were HLA-DQB1, HLA-DQB2, and GSTM1. Among pathways identified containing transcriptionally differentiated genes were antioxidant defense systems (e.g., nuclear factor (erythroid-derived 2)-like 2 (Nrf2), glutathione, ergothioneine, and peroxisome metabolism), as well as MHC class 1 antigen presentation, amino acid transport, mTORC1, bilirubin and lipid metabolism, liver homeostasis, the complement system, and interferon signaling. CONCLUSIONS:Differentially expressed genes in cases and controls indicate crosstalk between molecular pathways involved in antioxidant defense, immune regulation, and nutrient signaling in the pathogenesis of celiac disease.

摘要： In both countries, the desire to renew the Italian and Hungarian languages, given their historical situation (Habsburg oppression) and the fact that they were the most important element of intellectual life, led to common phenomena in the development of literatures. While the Hungarian intelligentsia aimed at a complete reform of the literary and vernacular language (among others, the bodyguards of Maria Theresa in Vienna), the Italian linguistic crisis of the 18th and 19th centuries did not affect the prestige of lyrical works based on the Dantean and Petrarchan tradition. In other areas, Italian writers compensated for the linguistic deficit with other elements, mainly musical (libretto) and visual (commedia dell'arte). The Arcadia that created in Rome from the religious and secular components filled the gap left by the philosophical-poetic Enlightenment, both in its organisational system and in its poetics. The paper describes the organisation of the Hungarian colonia through the activities of Ferenc Kazinczy and the emergence of Hungarian poetry based on the musical principle. Finally, the first major literary debate among writers on the controversial meaning of the metaphor of Arcadia, which continues to have an impact today.

关键词： Beh & ccedil   et's syndrome   Monoclonal anti-TNF antibodies   Efficacy   meta-analysis  

摘要： Objectives: This study is the first meta-analysis to evaluate the efficacy and safety of monoclonal anti-TNF antibodies in patients with vascular Beh & ccedil;et's syndrome (VBS). Methods: A comprehensive literature search was conducted on PubMed, Embase, Cochrane Library, Medline Complete, and Web of Science. Pooled estimates of clinical response including complete response (CR) and partial response (PR), were calculated at 3, 6, and 12 months. Subgroup analyses were performed based on the specific monoclonal anti-TNF antibodies used. Additionally, pooled proportions of imaging response before and after 6 months were assessed. Results: Twelve studies involving 297 patients were included. The pooled proportions of clinical CR were 64.1 % (95 %CI 28.7-93.9 %), 89.1 % (95 %CI 72.4-98.6 %), and 94.5 % (95 %CI 82.5-99.8 %) at 3, 6, and 12 months, respectively. Imaging response was achieved in 92.9 % (95 %CI 77.2-100 %) of patients within 6 months and 92.5 % (95 %CI 74.8-99.9 %) after 6 months. During follow-up, 26 patients experienced a relapse while on monoclonal anti-TNF antibodies treatment. Of the 43 patients who discontinued therapy due to response, 28 % (n = 12) experienced a relapse. Adverse events (AEs) were reported in 10 studies involving 42 patients, with 31 patients experiencing severe AEs, including 5 deaths. Conclusions: Monoclonal anti-TNF antibodies are an effective treatment for VBS, demonstrating significant clinical and radiological efficacy with a favorable safety profile. Prevention of relapses and control of disease progression remain critical objectives in VBS management. Further validation of their efficacy through randomized controlled trials (RCTs) stratified by arterial and venous involvement is warranted to strengthen the evidence base and optimize therapeutic strategies.

摘要： In the face of severe outcomes from COVID-19, vaccines have proven immunogenic and safe and are strongly recommended during pregnancy. This study examines the effects of maternal COVID-19 vaccination on physical development, behavior, and neurogenesis in mouse offspring. After inoculation with inactivated SARS-CoV-2 vaccine (Vero Cell) at gestational day 14.5, antibodies were detected in the serum of dams and pups. At one month of age, offspring of vaccinated dams-but not controls-showed enhanced working memory, increased neural proliferation, neuroblast formation, stem cell activity, and more mature neurons in the dentate gyrus (DG). Luminex assay showed elevated hippocampal IFN-γ and CX3CL1, both linked to neurogenesis and memory. Conditional knockout experiments identified microglial IFNγR1 and CX3CR1 as key mediators of neuronal development through regulating microglial activation and chemotaxis. These findings suggest maternal SARS-CoV-2 vaccination transiently enhances hippocampal neurogenesis and working memory in offspring, without causing neurodevelopmental risk.

关键词： Visceral leishmaniasis   amphotericin B   anti IL-10 dictionary peptide   in-vivo   nanoparticle  

摘要： AIM:This study aimed to develop a novel nanotherapeutic approach by combining an interleukin-10 (IL-10) peptide antagonist with amphotericin B (AmB) to enhance antileishmanial efficacy while reducing cytotoxicity. MATERIALS AND METHODS:A peptide antagonist targeting IL-10, identified via analysis and showing minimal cytotoxicity (95% promastigote viability at 20 µg/mL), was synthesized and conjugated with AmB using chemical cross-linkers. The conjugate was encapsulated in gamma-cyclodextrin to produce uniform nanoparticles (~40 nm). Characterization was performed using Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and Transmission Electron Microscopy (TEM). In vitro and in vivo studies were conducted to assess parasite burden, immune response, and safety parameters. RESULTS:The nanoformulation significantly reduced parasite burden and improved amastigote clearance, as confirmed by real-time PCR. Cytokine profiling revealed elevated IL-12 and other protective cytokines, indicating enhanced immune modulation. Hematological, biochemical, and splenomegaly analyses demonstrated improved safety and therapeutic efficacy compared to AmB alone. CONCLUSION:The IL-10 antagonist - AmB nanoformulation represents a promising immunomodulatory therapeutic strategy for leishmaniasis. Its enhanced efficacy and safety highlight its potential for application, particularly in immunocompromised patients.

关键词： Cancer cachexia   Colorectal adenocarcinoma   Gut microbiota   IL-6/NF-κB   Qingxie fuzheng granules   Th17/Treg  

摘要： Cancer cachexia, a debilitating syndrome characterized by muscle wasting and systemic inflammation, remains a major unmet clinical need. Qingxie Fuzheng Granules (QFG), a traditional Chinese medicine formulation, have shown promise in cancer therapy, but their role in cachexia management is ***, we investigated the anti-cachectic effects of QFG in a murine model of colon adenocarcinoma-induced cachexia. 16S rRNA sequencing revealed gut dysbiosis in cachectic mice, with increased Enterobacteriaceae and decreased Lactobacillus. QFG treatment restored microbial balance, reduced pro-inflammatory cytokines TNF-α, IL-6, and enhanced intestinal barrier integrity by upregulating tight junction proteins ZO-1, Occludin, ***, QFG rebalanced Th17/Treg cell ratios and suppressed IL-6/NF-κB signaling, a key driver of muscle atrophy. Combining QFG with glutamine (Gln) further amplified these effects, suggesting synergistic therapeutic *** findings demonstrate that QFG ameliorates cancer cachexia through microbiota modulation and IL-6/NF-κB inhibition, providing a novel multi-targeted approach for cachexia treatment.