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High-temperature requirement A1 (HtrA1) has been identified as a disease-susceptibility gene for age-related macular degeneration (AMD) including polypoidal choroidal neovasculopathy (PCV). We characterized the underlying phenotypic changes of transgenic (Tg) mice expressing ubiquitous CAG promoter (CAG-HtrA1 Tg). In vivo imaging modalities and histopathology were performed to investigate the possible neovascularization, drusen formation, and infiltration of macrophages. Subretinal white material deposition and scattered white-yellowish retinal foci were detected on CFP [(Tg—33% (20/60) and wild-type (WT)—7% (1/15), p < 0.05]. In 40% (4/10) of the CAG-HtrA1 Tg retina, ICGA showed punctate hyperfluorescent spots. There was no leakage on FFA and OCTA failed to confirm vascular flow signals from the subretinal materials. Increased macrophages and RPE cell migrations were noted from histopathological sections. Monocyte subpopulations were increased in peripheral blood in the CAG-HtrA1 Tg mice (p < 0.05). Laser induced CNV in the CAG-HtrA1 Tg mice and showed increased leakage from CNV compared to WT mice (p < 0.05). Finally, choroidal explants of the old CAG-HtrA1 Tg mice demonstrated an increased area of sprouting (p < 0.05). Signs of subclinical inflammation was observed in CAG-HtrA1 Tg mice. Such subclinical inflammation may have resulted in increased RPE cell activation and angiogenic potential.

Objective: Attack-free period C-reactive protein (CRP) and serum amyloid A (SAA) are reliable indicators of subclinical inflammation in familial Mediterranean fever (FMF). We aimed to compare the acute phase reactants during the attack-free period, and the presence of subclinical inflammation in FMF patients with different gene variants and different treatment modalities. Methods: CRP and SAA levels during a symptom-free period of at least 2 weeks were obtained, and the median CRP and SAA levels were calculated during the attack-free period. “Subclinical inflammation” was defined as “median attack-free CRP >10 mg/L or median attack-free SAA >10 mg/L.” Patients were classified according to MEFV variants (two, one, or zero exon 10 variants) and treatments (colchicine-only or colchicine+interleukin 1 inhibitors). Results: Seventy-six patients had two exon 10 variants, 79 had one exon 10 variant, and 17 had non-exon 10 variants. Most patients used colchicine (n=155), and 17 patients used colchicine + interleukin-1 inhibitors. Attack-free CRP, SAA, and rate of subclinical inflammation were significantly different among variant groups, higher among patients with 2 exon 10 variants. Patients receiving combination treatment had higher levels of attack-free CRP and SAA compared to the colchicine-only group. CRP and SAA were strongly correlated. Conclusion: Patients with two exon 10 variants had higher attack-free acute phase reactants and more frequent subclinical inflammation, which reflects the pathogenicity of exon 10 variants. Patients receiving interleukin 1+colchicine continue to have higher attack-free acute phase reactants, which reflects their higher inflammatory burden and severe clinical features.

ObjectivesTo investigate the ability of high-sensitivity C-reactive protein (hsCRP) and S100A12 to serve as predictive biomarkers of successful drug withdrawal in children with clinical remission of juvenile idiopathic arthritis (JIA).MethodsThis multicentre trial (PREVENT-JIA) enrolled 119 patients with JIA in clinical remission, and 100 patients reached the intervention phase in which the decision whether to continue or stop treatment was based on S100A12 and hsCRP levels. Patients were monitored for 12 months after stopping medication for flares of disease. Results were compared with withdrawal of therapy without biomarker-based stratification in patients from the German Biologika in der Kinderrheumatologie (BiKeR) pharmacovigilance registry.ResultsIn the PREVENT-JIA group, 49 patients had a flare, and 45% of patients stopping medication showed flares within the following 12 months. All patients (n=8) continuing therapy due to permanently elevated S100A12/hsCRP at more than one visit flared during the observation phase. In the BiKeR control group, the total flare rate was 62%, with 60% flaring after stopping medication. The primary outcome, time from therapy withdrawal to first flare (cumulative flare rate after therapy withdrawal), showed a significant difference in favour of the PREVENT-JIA group (p=0.046; HR 0.62, 95% CI 0.38 to 0.99). As additional finding, patients in the PREVENT-JIA trial stopped therapy significantly earlier.ConclusionBiomarker-guided strategies of therapy withdrawal are feasible in clinical practice. This study demonstrates that using predictive markers of subclinical inflammation is a promising tool in the decision-making process of therapy withdrawal, which translates into direct benefit for patients.Trial registration number ISRCTN69963079.

This study investigated the pro-inflammatory and pro-oxidative effects of popular electronic cigarette aerosols (ECAs) compared with conventional cigarette smoke (CS) in the cultured human alveolar epithelial cell line (A549). Using cytotoxicity assays and four ECAs, substantial differences in biological impact were observed. CS exposure led to significant declines in cell viability and pronounced morphological changes, consistent with the presence of toxic combustion byproducts. Most ECAs caused negligible cytotoxicity except for the tobacco-flavoured variant, which demonstrated marked toxicity. DNA damage and altered cell cycle profiles were minor. Oxidative stress analysis revealed stable superoxide dismutase activity but notable glutathione depletion, especially with watermelon- and strawberry-flavoured ECAs, and unaltered mitochondrial transmembrane potential, indicating the importance of individual flavour additives in cellular antioxidant defence. Inflammatory markers, such as TNF-α, NF-κB, and IL-6, were differentially elevated across the CS and ECA groups, with IL-6 consistently increased, underscoring its role in regulating epithelial cells. Advanced double fluorescence analysis revealed increased cellular heterogeneity and inflammation, which was distinct for all ECA flavours. Overall, the findings demonstrate considerable heterogeneity in biological effects among ECA flavourings and propose a simple ECA biomonitoring model. The results emphasise the necessity for individualised toxicity assessments, especially regarding subclinical inflammation and potential long-term health outcomes.

Gestational diabetes mellitus (GDM) is accompanied by subclinical inflammation; however, little is known about local inflammation in adipose tissue and placenta. To analyze systemic and local subclinical inflammation and adipose tissue lymphocyte content and phenotype in pregnant women with and without GDM. Observational study. Academic hospital. Twenty-one pregnant women with GDM (GDM group), 16 pregnant women without GDM (non-GDM group) and 15 nonpregnant control women (N group). Serum samples taken at 28 to 32 (visit 1 [V1]) and 36 to 38 (V2) gestational weeks and 6 to 12 months after delivery (V3) in the GDM and non-GDM group and before elective gynecological surgery in the N group. Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained during cesarean delivery or surgery. Serum levels and adipose tissue expression of proinflammatory cytokines, adipose tissue lymphocyte content and phenotype (for a subset of GDM and non-GDM subjects). Accented proinflammatory state in GDM was documented by increased circulating tumor necrosis factor-α (TNF-α) levels. In both groups of pregnant females total lymphocytes were higher in VAT compared to SAT. In GDM subjects B cells and NKT cells were higher in SAT compared to VAT and T helper cells were increased relative to SAT of non-GDM group, while no intercompartmental adipose tissue differences were seen in non-GDM women. Pregnant females had higher total lymphocyte count in VAT relative to SAT regardless of GDM. In addition to increased systemic subclinical inflammation, GDM was associated with significant differences in lymphocyte composition between subcutaneous and visceral adipose tissue depots.

Inflammatory Bowel Disease (IBD) is characterized by mucosal injury in the gastrointestinal (GI) tract. During an abnormal immune response in the GI tract, excessive secretion of immune-cell proteases occurs. Neutrophils are the first responders, infiltrating into the inflamed interstitial matrix, where type III collagen accumulates. We aimed to develop a biomarker that reflects early inflammation before clinical symptoms arise; allowing us to intervene and prevent cumulative damage. A competitive enzyme-linked immunosorbent assay targeting a human neutrophil elastase degraded neo-epitope fragment of type III collagen (C3-HNE) was developed and assessed in serum samples from DSS-treated rats and a clinical cohort ( n  = 91, UC and CD). Moreover, C3M, an MMP- mediated type III collagen degradation marker, was tested for comparison. The DSS-treated rats had elevated C3-HNE levels on day 4, while C3M increased on days 10 and 14, compared to the non-DSS treated group. Percentage change analysis showed that C3-HNE rapidly peaked (day 1), while C3M displayed a sustained elevation over time. Serum C3-HNE concentrations increased in patients with IBD, including those in remission, compared to healthy donors, possibly indicating subclinical inflammation. This biomarker may reflect initial mucosal injury and could provide early detection of inflammation for patients in remission, monitoring flare episodes.

Background: Coronary artery disease (CAD) is a multifactorial atherosclerotic disorder. Silicon (Si) is a trace mineral with potential antioxidant, anti-inflammatory, and lipid-modulating effects, but its clinical relevance in cardiovascular disease remains unclear. This study evaluated whether hair Si concentration—reflecting long-term exposure—is associated with CAD severity, clinical phenotype, risk factors, and systemic inflammation. Methods: A total of 130 patients with angiographically confirmed CAD (N = 36, 28% women) who met the inclusion criteria were enrolled. Disease severity was quantified using the Coronary Artery Surgery Study Score (CASSS) and SYNTAX score. Hair Si concentration was determined by inductively coupled plasma optical emission spectrometry (ICP-OES). Associations with demographic, clinical, biochemical, and inflammatory parameters were analyzed using non-parametric tests and multivariable ordinal logistic regression. Results: Median hair Si concentration was 21.3 ppm (range: 0.7–211.0). Hair Si levels showed no significant differences across CAD severity assessed by CASSS (H = 2.51; p = 0.47) or SYNTAX score (r = 0.079; p = 0.37). Similarly, no differences were observed between patients with stable angina and those presenting with acute coronary syndrome (p = 0.57) or between individuals with and without prior myocardial infarction. Hair Si concentration was unrelated to age, BMI, cardiovascular risk factors, lipid profile, or systemic inflammatory indices (all p > 0.2). Conclusions: Hair silicon concentration was not associated with CAD severity, phenotype, or systemic inflammation, suggesting that long-term Si exposure is metabolically neutral in advanced atherosclerosis. Unlike other minerals, silicon appears unlikely to serve as a diagnostic or prognostic biomarker in CAD, although its relevance may be confined to early vascular remodeling and primary prevention.

Aim The aim of this study is to investigate the prevalence of asymptomatic hyperuricemia in Qatar and to examine its association with changes in markers of dyslipidemia, prediabetes and subclinical inflammation. Methods A cross-sectional study of young adult participants aged 18 - 40 years old devoid of comorbidities collected between 2012 and 2017. Exposure was defined as uric acid level, and outcomes were defined as levels of different blood markers. De-identified data were collected from Qatar Biobank. T-tests, correlation tests and multiple linear regression were all used to investigate the effects of hyperuricemia on blood markers. Statistical analyses were conducted using STATA 16. Results The prevalence of asymptomatic hyperuricemia is 21.2% among young adults in Qatar. Differences between hyperuricemic and normouricemic groups were observed using multiple linear regression analysis and found to be statistically and clinically significant after adjusting for age, gender, BMI, smoking and exercise. Significant associations were found between uric acid level and HDL-c p = 0.019 (correlation coefficient -0.07 (95% CI [-0.14, -0.01]); c-peptide p = 0.018 (correlation coefficient 0.38 (95% CI [0.06, 0.69]) and monocyte to HDL ratio (MHR) p = 0.026 (correlation coefficient 0.47 (95% CI [0.06, 0.89]). Conclusions Asymptomatic hyperuricemia is prevalent among young adults and associated with markers of prediabetes, dyslipidemia, and subclinical inflammation.

Background To evaluate the factors to predict subclinical inflammation of wrist joints in patients with RA who are in clinical remission or low disease activity. Methods Gray scale and power Doppler ultrasound were performed on the dorsal radio-lunate of both wrists. The presence of synovitis, comorbidities, and use of disease modifying anti-rheumatic drugs were recorded. A Multivariable forward logistical regression model was used to identify factors associated with subclinical inflammation. Results There were 1248 patients (1010 females, 238 males; mean age: 60.0 ± 10.5 years ). 57.4% of patients in complete remission and low disease activity had sonographic inflammation. Multivariable forward logistic regression analysis indicated that male sex, smoking are positively associated with inflammation and that age, alcohol consumption, and use of methotrexate, glucocorticoid, or a biological therapy are negatively associated with inflammation. Use of biological agents decreased the risk of inflammation by 40.9%. Conclusions There was evidence of subclinical inflammation in most patients who were in low or no disease activity, those with biological therapy had lower risk of subclinical inflammation.

Objective To investigate the rate of subclinical inflammation in patients with axial spondyloarthritis (axSpA) with nonsteroidal anti-inflammatory drug (NSAID)/anti-tumor necrosis factor (TNF)-α drug-induced clinical remission and to explore factors influencing clinical and imaging remission. Methods One hundred twenty-five patients with axSpA followed up for at least 6 months were enrolled in this prospective study and randomly divided into two groups. Ninety patients were treated with anti-tumor necrosis factor (TNF)-α or anti-TNF-α combined with nonsteroidal anti-inflammatory drugs (NSAIDs) (anti-TNF-α treatment group), and thirty-five patients were treated with only NSAIDs (non anti-TNF-α treatment group). The improvements in the clinical remission rate, imaging remission rate, and disease parameters before and after the different treatments were compared. Risk factors for clinical and imaging remission were analyzed by multivariate logistic regression analysis. Results The clinical and imaging remission rate was increased after treatment especially in the anti-TNF-α group ( P  < 0.001). The remission rate of imaging in the group with clinical remission was higher than that in the group with clinical non-remission ( P  < 0.05). After treatment, the remission rates of imaging in the clinical remission and non-remission group were significantly higher than those before treatment ( P  < 0.0001). The results of multivariate logistic regression analysis showed that higher CRP was a risk factor for failure of clinical remission in axSpA (OR = 2.034, 95% CI:1.595 ~ 2.617, P < 0.001), while higher ASDAScrp was a risk factor for failure of imaging remission (OR = 1.306, 95% CI:1.026 ~ 1.688, P  < 0.05). Anti-TNF-α treatment was a protective factor for both clinical (OR = 0.234, 95% CI:0.091 ~ 0.605, P  < 0.05) and imaging remission (OR = 0.511, 95% CI:0.286 ~ 0.914, P  < 0.05). Conclusion Even after regular treatment, some clinical remission patients continued to have evidence of subclinical inflammation. Higher CRP and ASDAScrp are risk factors for clinical and imaging non-remission in axSpA respectively, Continuous NSAID treatment (more than 1 year) can effectively improve clinical and MRI inflammation in patients, but anti-TNF-α treatment is more beneficial for clinical and imaging remission. Key Points • Some patients achieving ASDAScrp remission status continue to have inflammation when assessed with objective imaging techniques. • MRI can sensitively measure bone marrow inflammation and may provide a more accurate assessment of remission. • Controlling inflammation, especially reducing CRP and ASDAScrp levels, is a key factor for achieving clinical and imaging remission in patients with axSpA.