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关键词： leishmaniasis   mucosa   L. amazonensis   BALB/c   experimental infection  

摘要： Mucosal Leishmaniasis is one of the most aggressive clinical manifestations of Leishmania infection disease, characterized by the destruction of nasal and oral tissues. The mechanisms by which this disease occurs are still not well understood due to the lack of effective experimental models. Mucosal leishmaniasis is associated with inflammatory response, especially Th17 response. Based on that, in this work, the immunopathological aspects of the experimental infection of BALB/c mice by Leishmania amazonensis in the mucosa site were evaluated as this mice presents high susceptibility with increased Th17 mediated pathology. Three infection modes were performed and compared according to the injection site. Six weeks post infection, mice presented edema in the nasal and premaxillary region, with progressive growth until twelve weeks. The micro-Computerized Tomography and the histology images demonstrated that the parasite inoculation led to destruction of squamous and transitional tissues in NC and NB groups, with several cells harboring amastigotes. Mice infected in the mucosa tissues had higher parasite load and IgG, IgM antibody levels and increased production of cytotoxic mediators such as CD107, granzyme b and perforin, inflammatory cytokines as IFN-gamma;and IL-17, but lower frequencies of CD4+ IL-10+ cells compared to ear dermis. Taken together, our data shows that L. amazonensis parasites are more proliferative in nasal mucosa and the infection leads to an increased inflammatory response compared to ear dermis, suggesting an imbalance between the inflammatory and regulatory response in the mucosa as occurs in human MCL which point this model as an interesting approach to understand some features of the disease immunopathology. Further studies are being performed to understand the Th1-mediated tissue destruction. This study was conducted in accordance with the local legislation and institutional requirements being approved by the Ethics Committee on the Animal Us

关键词： inflammatory bowel disease   tofacitinib   tumour necrosis factor-alpha inhibitors   ulcerative colitis   vedolizumab  

摘要： Background: Management of refractory ulcerative colitis (UC) unresponsive to advanced therapies is challenging. Combination therapy is a potential strategy. Aim: To evaluate the safety and efficacy of vedolizumab and tofacitinib combination (VETO) therapy in patients with UC refractory to anti-TNF and unresponsive to either agent as monotherapy. Methods: We prospectively recruited patients with moderate-to-severe disease activity (Mayo score: 6-12). Patients were randomised to receive vedolizumab or tofacitinib. Non-responders were offered VETO therapy and followed for 24 weeks. The primary outcome was a combined clinical response and corticosteroid-free remission at week 24. Secondary outcomes included clinical response and remission at week 8, endoscopic remission at week 24 and incidence and severity of treatment-related adverse events. Results: Of 91 patients, 38 were randomised to vedolizumab and 40 to tofacitinib. Fourteen and 15, respectively, were non-responders to vedolizumab and tofacitinib;24 received VETO with follow-up of 34 +/- 16.1 weeks. Median second-line therapy duration before VETO was 21 weeks. Five non-responders received alternative interventions or were lost to follow-up. At week 8, 17 achieved clinical response and five achieved remission;three underwent colectomy. At week 24, response and corticosteroid-free remission were seen in 17 and 14, respectively;7 achieved endoscopic remission. Mayo scores improved significantly (mean difference 5.33 +/- 0.53;p < 0.01). Two patients developed pseudomembranous colitis that resolved with vancomycin. No severe adverse events occurred. Conclusion: VETO was effective and safe in patients with UC refractory to anti-TNF and second-line therapies, with over half achieving clinical remission by 24 weeks.

关键词： Crohn's disease   IBD   cytokines   mucosal immunology   ulcerative colitis  

摘要： IntroductionUlcerative colitis (UC) is a chronic inflammatory bowel disease characterized by a relapsing-remitting colonic inflammation. Despite advances in understanding UC pathogenesis, a definitive cure remains elusive. Current therapies aim to promote symptom resolution, mucosal healing, and ideally histologic remission. Moderate-to-severe UC patients may require advanced therapies, including biologics and small molecules, targeting pathways that have been implicated in the UC *** coveredThis review provides an in-depth analysis of current and emerging therapies targeting the interleukin (IL)-23 pathway in moderate-to-severe UC. It discusses both ustekinumab, a nonselective IL-12/23p40 blocker, and selective IL-23p19 inhibitors (i.e. mirikizumab, guselkumab, and risankizumab), covering their mechanisms of action, clinical efficacy, and safety profiles from registrative and post-marketing studies. The review also explores promising oral therapies under investigation, including IL-23 receptor (IL-23 R) antagonists and TYK2 inhibitors, highlighting their early-phase *** opinionIL-23p19 inhibitors have shown significant efficacy in inducing and maintaining remission in UC, with favorable safety profiles. Oral agents represent an exciting frontier, potentially improving patient adherence and accessibility. Direct comparative trials are needed to refine therapeutic positioning in personalized treatment algorithms.

关键词： activating transcription factor 6   inositol-requiring enzyme 1   Interleukin 18   phosphorylated extracellular signal-regulated kinase   post-traumatic stress disorder  

摘要： Post-traumatic stress disorder (PTSD) is a chronic mental health condition resulting from exposure to traumatic events. It is associated with long-term neurobiological changes and disturbances in emotional regulation. Understanding the sociodemographic profiles, biomarkers, and emotional control in patients with PTSD helps to better comprehend the impact of the disorder on the body and its clinical course. An analysis of biomarkers such as Interleukin-18 (IL-18), Inositol-Requiring Enzyme 1 (IRE1), Phosphorylated Extracellular Signal-Regulated Kinase (pERK), and Activating Transcription Factor-6 (ATF-6) in PTSD patients with varying durations of illness (<= 5 years and >5 years) and a control group without PTSD revealed significant differences. Patients with recently diagnosed PTSD (<= 5 years) showed markedly elevated levels of inflammatory and cellular stress markers, indicating an intense neuroinflammatory response during the acute phase of the disorder. In the chronic PTSD group (>5 years), the levels of these biomarkers were lower than in the recently diagnosed group, but still significantly higher than in the control group. An opposite trend was observed regarding the suppression of negative emotions, as measured by the Courtauld Emotional Control Scale (CECS): individuals with chronic PTSD exhibited a significantly greater suppression of anger, depression, and anxiety than those with recent PTSD or healthy controls. Correlations between biomarkers were strongest in individuals with chronic PTSD, suggesting a persistent neuroinflammatory dysfunction. However, the relationships between biomarkers and emotional suppression varied depending on the stage of PTSD. These findings highlight the critical role of PTSD duration in shaping the neurobiological and emotional mechanisms of the disorder, which may have important implications for therapeutic strategies and patient monitoring.

关键词： HLA   HLA-DQA1*01:142   next-generation sequencing   novel allele  

摘要： HLA-DQA1*01:142 differs from HLA-DQA1*01:02:01:04 by one nucleotide substitution in codon 185 in exon 4.

关键词： Haploidentical hematopoietic stem cell transplant   primary graft failure   donor-specific anti-HLA antibodies   HLA-DQA1   HLA-DQB1  

摘要： BackgroundPrimary graft failure (PGF) is a life-threatening complication of allogeneic hematopoietic stem cell transplants (HSCT) and is associated with poor outcomes. Most clinical studies have focused on donor-specific anti-HLA antibodies (DSAs) against HLA-A, -B, and -DR *** design and methodsWe present the first reported case of PGF associated with a preformed high-level DSA against HLA-DQ alone. The 39-year-old patient was diagnosed with acute myeloid leukemia. She received a haploidentical graft from her son and suffered PGF. She had persistently high levels of DSAs against her son's HLA-DQA1 and HLA-DQB1 molecules after desensitization. No alternative donor was *** circumvent the second graft failure, we adopted an approach of combining two units of unrelated cord blood (CB) and G-CSF-primed bone marrow (BM) and peripheral blood stem cells (PBSCs) from her son's transplants. The BM short tandem repeats (STRs) assay showed that one unit of the CB was fully engrafted, and the grafts from her son still failed to *** conclude that high levels of anti-HLA DQA1/DQB1 DSA could be associated with PGF in our case. Besides DSAs against HLA-A, -B, and -DR, attention should also be paid to DSAs against the HLA-DQ molecule.

关键词： Interleukin-10   Polymorphism, single nucleotide   Uterine cervical neoplasms  

摘要： Cervical cancer, a leading cancer among women, is strongly associated with Human Papillomavirus infection, but host genetic factors also contribute to the progression from high-grade squamous intraepithelial lesions (HSIL) to invasive cancer. Interleukin-10 (IL-10), an immunosuppressive cytokine, may influence susceptibility to HSIL and cervical cancer through genetic variations. This study aimed to compare IL-10 gene promoter polymorphisms, -1082 A > G and - 819T > C, in women diagnosed with HSIL or cervical cancer and those with negative for intraepithelial lesion or malignancy (NILM). In this case-control study, 309 women were analyzed, including 142 with HSIL or cervical cancer and 167 controls with NILM. Blood samples were collected for DNA extraction and genotyping of polymorphisms through PCR amplification. Statistical analyses included comparisons of genotype and allele frequencies, haplotype frequency, and assessments of Hardy-Weinberg equilibrium and linkage disequilibrium. The mean age was 33.4 years for cases and 41.7 years for controls (p < 0.05). For the - 1082 A > G polymorphism, the GG genotype was significantly associated with a decreased risk of HSIL and cervical cancer (p = 0.0266, OR = 0.35). Recessive model (GG vs. AA + AG) confirmed this association (p = 0.0045, OR = 0.29). AC/GC diplotype was associated with a 2-fold increased risk of cervical lesions. Further studies are needed to confirm our results.

关键词： HLA-C   HLA-C*06:402   NGS   novel HLA allele  

摘要： HLA-C*06:402 differs from HLA-C*06:02:01:01 by a nine-nucleotide (TCCTGGCTG) insertion in exon 5.

关键词： Uric acid   Hyperuricemia   Interleukin-6   Interleukin-1beta   Aged   Cross-sectional studies  

摘要： Previous studies have shown the role of uric acid in triggering inflammatory reactions through its influence on a large group of cytokines. Therefore, searching for possible relationships between treating hyperuricemia and the course of inflammatory processes may provide valuable knowledge for clinical practice. The study was designed to determine the relationship between uric acid levels and interleukin-6 (IL-6) and interleukin-1-beta (IL-1 beta) levels determined in older adults during hospitalization. Patients were assigned to different study groups based on the uric acid levels and effectiveness, lack of treatment, or recognition of hyperuricemia. Classical variance analysis methods or nonparametric Kruskal-Wallis tests were used for statistical analysis. The analysis showed different correlations between the concentration of uric acid and the mentioned interleukins and designated study groups. In the case of properly treated hyperuricemia, a weak negative correlation is observed between the level of uric acid and interleukin IL-1 beta. There is a statistically significant positive correlation between the value of uric acid and interleukins IL-6 and IL-1 beta in people with untreated hyperuricemia and, to a lesser extent, in people with normal uric acid levels. The study's results suggest that effective treatment may be associated with appropriate control of uric acid concentration and modulation of the inflammatory response. However, due to several measurement limitations, further research is warranted to better elucidate these associations.

关键词： D-galactose   chrysin   antioxidant   liver   aging  

摘要： Objectives Liver aging is a major cause of death all over the world. D-galactose (D-gal) induces liver aging via inflammatory pathways in Kupffer cells. Chrysin (CHR) is a flavonoid having anti-inflammatory and antioxidant effects that can protect liver from aging responses. This study aimed to clarify the hepatoprotective activity of CHR in D-gal-induced liver *** Four groups of male mice (10 mice each) were used in the study: normal control group, D-gal (200 mg/kg/day) group, D-gal group + 25 mg/kg/day CHR, and D-gal group + 50 mg/kg/day CHR. Treatment continued for 8 *** findings Elevation in cytochrome P2E1 (CYP2E1) enzyme, the chemokine (C-X-C motif) ligand-1 (CXCL-1), the cell surface adhesion receptor CD44, and tumor necrosis factor (TNF)-alpha occurred in D-gal group. Oxidative stress was evident through downregulation of catalase enzymes, nuclear factor erythroid 2-related factor 2 (Nrf2) and protein kinase B (AKT), and an increasing nitric oxide (NO) levels. Consequently, liver injury was evident with elevation of ALT and AST levels. These responses affected the morphology of the hepatic tissues. CHR managed to prevent these pathways and preserved normal morphology of the hepatic *** Our study revealed that CHR prevents D-gal-induced liver aging through its anti-inflammatory and antioxidant effects.