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Purpose: This cross-sectional study investigates the utility of the quantitative ultrashort echo time (UTE) adiabatic T 1ρ (UTE-Adiab-T 1ρ ) magnetic resonance imaging (MRI) in detecting potential differences in Achilles tendons and entheses of patients with psoriatic arthritis disease (PsA) compared with asymptomatic volunteers., Material and Method: The Achilles tendons of forty-four PsA patients (59 ± 15 years old, 38 % female) and thirty-seven asymptomatic volunteers (32 ± 10 years old, 51 % female) were scanned on a 3 T clinical scanner in the sagittal plane using a 3-inch surface coil. The 3D UTE-Adiab-T 1ρ sequences with fat saturation (FS) were used to measure UTE-Adiab-T 1ρ . Tenderness of the tendons, the SF-12 health survey, and visual analog scale (VAS) were recorded for the patients. The Kruskal Wallis test was used to examine the differences in UTE-Adiab-T1 ρ values between asymptomatic volunteers and patients, as well as subgroups of patients with pain in the Achilles tendon region and those treated with Biologics. Spearman's correlation coefficients were calculated between UTE-Adiab-T 1ρ and patient evaluations. P values < 0.05 were considered significant., Results: UTE-Adiab-T 1ρ was significantly higher for the PsA group compared with the asymptomatic group in the enthesis (11.4 ± 2.6 ms vs. 10.4 ± 2.4 ms) and tensile tendon regions (9.8 ± 2.8 ms vs. 7.7 ± 1.7 ms). PsA patients with active Achilles pain showed significantly lower T1ρ in the entheses compared with other patients (10.7 ± 2.6 ms vs. 11.7 ± 2.5 ms). PsA patients treated with Biologics showed significantly lower T 1ρ values in the tendon compared with other patients (9.5 ± 2.5 ms vs. 10.3 ± 3.3 ms). The VAS score of patients showed a significant negative but weak correlation (R = -0.2) with UTE-Adiab-T1ρ of the enthesis. Correlations with SF-12 scores were not significant., Conclusion: This study highlighted the UTE-Adiab-T 1ρ sequence capability in evaluating tendons and entheses and their potential involvement in PsA disease or response to therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Adipose tissue has been associated with knee osteoarthritis (KOA) pathogenesis, but the longitudinal changes in adipose tissue with KOA progression have not been carefully evaluated. This study aimed to determine if longitudinal changes of systemic and local adipose tissue is associated with radiographic progression of KOA., Methods: This case-control study used data from the Osteoarthritis Initiative (OAI) and included 315 cases (all the right knees with a minimum of Kellgren-Lawrence score (KL) of 0 and an increase of ≥ 1 KL from baseline to 48 months) and 315 controls matched by age, sex, race, and baseline KL. Cross sectional area of IPFP (IPFP CSA) and subcutaneous adipose tissue around the distal thigh (SCATthigh) were measured using MRI images at baseline and 24 months. Conditional logistic regression models were fitted to estimate associations of obesity markers, IPFP CSA, and SCATthigh with radiographic KOA progression. Mediation analysis was used to assess whether IPFP CSA or SCATthigh mediates the relationships between baseline BMI and radiographic KOA progression., Results: 24-month changes of IPFP CSA (ΔIPFP CSA) and SCATthigh (ΔSCATthigh) were significantly greater in cases compared to controls, whereas Δ BMI and Δ abdominal circumference were similar in both groups during follow-up. Adjusted ORs for radiographic KOA progression were 9.299, 95% CI (5.357-16.141) per 1 SD increase of Δ IPFP CSA and 1.646, 95% CI (1.288-2.103) per 1 SD increase of Δ SCATthigh. ΔIPFP CSA mediated the association between baseline BMI and radiographic KOA progression (87%)., Conclusions: Subjects with radiographic progression of KOA, had significant increases in IPFP CSA and subcutaneous adipose tissue while BMI and abdominal circumference remained stable. Additional studies are needed to confirm these associations., (© 2024. The Author(s).)

Background: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities in patients, suggests that environmental, genetic, or biological factors act as disease modifiers. Still, the underlying mechanisms are not entirely understood. Here, we report that mild hypoxia accelerates CCM disease by promoting angiogenesis, neuroinflammation, and vascular thrombosis in the brains of CCM mouse models., Methods: We used genetic studies, RNA sequencing, spatial transcriptome, micro-computed tomography, fluorescence-activated cell sorting, multiplex immunofluorescence, coculture studies, and imaging techniques to reveal that sustained mild hypoxia via the CX3CR1-CX3CL1 (CX3C motif chemokine receptor 1/chemokine [CX3C motif] ligand 1) signaling pathway influences cell-specific neuroinflammatory interactions, contributing to heterogeneity in CCM severity., Results: Histological and expression profiles of CCM neurovascular lesions ( Slco1c1-iCreERT2;Pdcd10 fl/fl ; Pdcd10 BECKO ) in male and female mice found that sustained mild hypoxia (12% O 2 , 7 days) accelerates CCM disease. Our findings indicate that a small reduction in oxygen levels can significantly increase angiogenesis, neuroinflammation, and thrombosis in CCM disease by enhancing the interactions between endothelium, astrocytes, and immune cells. Our study indicates that the interactions between CX3CR1 and CX3CL1 are crucial in the maturation of CCM lesions and propensity to CCM immunothrombosis. In particular, this pathway regulates the recruitment and activation of microglia and other immune cells in CCM lesions, which leads to lesion growth and thrombosis. We found that human CX3CR1 variants are linked to lower lesion burden in familial CCMs, proving it is a genetic modifier in human disease and a potential marker for aggressiveness. Moreover, monoclonal blocking antibody against CX3CL1 or reducing 1 copy of the Cx3cr1 gene significantly reduces hypoxia-induced CCM immunothrombosis., Conclusions: Our study reveals that interactions between CX3CR1 and CX3CL1 can modify CCM neuropathology when lesions are accelerated by environmental hypoxia. Moreover, a hypoxic environment or hypoxia signaling caused by CCM disease influences the balance between neuroinflammation and neuroprotection mediated by CX3CR1-CX3CL1 signaling. These results establish CX3CR1 as a genetic marker for patient stratification and a potential predictor of CCM aggressiveness., Competing Interests: Disclosures None.

Recent evidence highlights the role of low-grade synovial inflammation in the progression of osteoarthritis (OA). Inflamed synovium of OA joints detected by imaging modalities are associated with subsequent progression of OA. In this sense, detecting and quantifying synovitis of OA by imaging modalities may be valuable in predicting OA progressors as well as in improving our understanding of OA progression. Of the several imaging modalities, molecular imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) has an advantage of visualizing the cellular or subcellular events of the tissues. Depending on the radiotracers used, molecular imaging method can potentially detect and visualize various aspects of synovial inflammation. This narrative review summarizes the recent progresses of imaging modalities in assessing inflammation and OA synovitis and focuses on novel radiotracers. Recent studies about imaging modalities including ultrasonography (US), magnetic resonance imaging (MRI), and molecular imaging that were used to detect and quantify inflammation and OA synovitis are summarized. Novel radiotracers specifically targeting the components of inflammation have been developed. These tracers may show promise in detecting inflamed synovium of OA and help in expanding our understanding of OA progression., (© 2024. The Author(s).)

Background: Synovial fibroblasts in rheumatoid arthritis (RAFLS) exhibit a pathological aberration of glycolysis and glutaminolysis. Henceforth, we aimed to investigate if dual inhibition of these pathways by phytobiological compound c28MS has the potential of synergistic therapy for arthritis by targeting both glucose and glutamine metabolism., Methods: The presence of HK2 and GLS across various cell types and associated gene expression in human synovial cells and a murine model of arthritis was evaluated by scRNA-seq. The metabolic profiling of RAFLS cells was done using H 1 -nuclear magnetic resonance spectroscopy under glycolytic and glutaminolytic inhibitory conditions by incubating with 3-bromopyruvate, CB839, or dual inhibitor c28MS. FLS functional analysis was conducted under similar conditions. ELISA was employed for the quantification of IL-6, CCL2, and MMP3. K/BxN sera was administered to mice to induce arthritis for in vivo arthritis experiments., Results: scRNA-seq analysis revealed that many fibroblasts expressed Hk2 along with Gls with several genes including Ptgs2, Hif1a, Timp1, Cxcl5, and Plod2 only associated with double-positive fibroblasts, suggesting that dual inhibition can be an attractive target for fibroblasts. Metabolomic and functional analysis revealed that c28MS decreased the aggressive behavior of RAFLS by targeting both upregulated glycolysis and glutaminolysis. c28MS administered in vivo significantly decreased the severity of arthritis in the K/BxN model., Conclusion: Our findings imply that dual inhibition of glycolysis and glutaminolysis could be an effective approach for the treatment of RA. It also suggests that targeting more than one metabolic pathway can be a novel treatment approach in non-cancer diseases., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Care of young adults with SLE (YA-SLE, 18-24 years) is challenging due to major life transitions co-occurring with chronic healthcare needs. Studies have demonstrated poorer outcomes in the post-transition period. Epidemiological studies focused on serious infection-related hospitalisation (SIH) in YA-SLE are lacking., Methods: We used National Inpatient Sample from 2010 to 2019 to study the epidemiology and outcomes of SIH for five common infections in SLE, namely sepsis, pneumonia, urinary tract infections, skin and soft tissue infections, and opportunistic infections. For time trends, we extended the dataset to cover 2000-2019. The primary outcome was the rate of SIH in YA-SLE compared with adults (25-44 years) with SLE and with young adults without SLE (YA-no SLE)., Results: From 2010 to 2019, we identified 1 720 883 hospital admissions with SLE in patients aged ≥18 years. Rates of SIH were similar in young adults and adults with SLE (15.0% vs 14.5%, p=0.12), but considerably higher than in the YA-no SLE group (4.2%, p<0.001). Among SLE with SIH, sepsis followed by pneumonia was the most common diagnosis. Significantly higher proportions of SIH among young adults than adults with SLE were comprised of non-white patients, belonged to the lowest income quartile and had Medicaid. However, only race/ethnicity was associated with SIH among YA-SLE. There was a higher prevalence of comorbid lupus nephritis and pleuritis among young adults compared with adults with SLE and SIH, and both comorbidities were associated with SIH in YA-SLE. Increasing rates of SIH, driven by sepsis, were seen over time., Discussion: YA- SLE had similar rates of SIH to adults with SLE. While hospitalised YA-SLE differed sociodemographically from SLE adults and YA-no SLE, only race/ethnicity was associated with SIH in the YA-SLE group. Lupus nephritis and pleuritis were associated with higher SIH in YA-SLE. Among SLE with SIH, increasing trends of sepsis deserve further study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Osteoarthritis is a common chronic degenerative disease that causes pain and disability with increasing incidence worldwide. The osteochondral junction is a dynamic region of the joint that is associated with the early development and progression of osteoarthritis. Despite the substantial advances achieved in the imaging of cartilage and application to osteoarthritis in recent years, the osteochondral junction has received limited attention. This is primarily related to technical limitations encountered with conventional MR sequences that are relatively insensitive to short T2 tissues and the rapid signal decay that characterizes these tissues. MR sequences with ultrashort echo time (UTE) are of great interest because they can provide images of high resolution and contrast in this region. Here, we briefly review the anatomy and function of cartilage, focusing on the osteochondral junction. We also review basic concepts and recent applications of UTE MR sequences focusing on the osteochondral junction., (© 2022 John Wiley & Sons Ltd.)

Human untargeted metabolomics studies annotate only ~10% of molecular features. We introduce reference-data-driven analysis to match metabolomics tandem mass spectrometry (MS/MS) data against metadata-annotated source data as a pseudo-MS/MS reference library. Applying this approach to food source data, we show that it increases MS/MS spectral usage 5.1-fold over conventional structural MS/MS library matches and allows empirical assessment of dietary patterns from untargeted data., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Linked metabolic and cardiovascular comorbidities are prevalent in hyperuricemia and gout. For mechanistic insight into impact on inflammatory processes and cardiometabolic risk factors of xanthine oxidase inhibitor urate-lowering therapy (ULT) titration to target, we performed a prospective study of gout serum metabolomes from a ULT trial., Methods: Sera of gout patients meeting the 2015 ACR/EULAR gout classification criteria (n = 20) and with hyperuricemia were studied at time zero and weeks 12 and 24 of febuxostat or allopurinol dose titration ULT. Ultrahigh performance liquid chromatography-tandem mass spectroscopy acquired the serum spectra. Data were assessed using the Metabolon and Metaboloanalyst software. Lipolysis validation assays were done in febuxostat and/or colchicine-treated 3T3-L1 differentiated adipocytes., Results: Serum urate decreased from time zero (8.21 ±1.139 SD) at weeks 12 (5.965 ± 1.734 SD) and 24 (5.655 ±1.763 SD). Top metabolites generated by changes in nucleotide and certain amino acid metabolism and polyamine pathways were enriched at 12 and 24 weeks ULT, respectively. Decreases in multiple fatty acid metabolites were observed at 24 weeks, linked with obesity. In cultured adipocytes, febuxostat significantly decreased while colchicine increased the lipolytic response to β-adrenergic-agonism or TNF., Conclusion: Metabolomic profiles linked xanthine oxidase inhibitor-based ULT titration to target with reduced serum free fatty acids. In vitro validation studies revealed that febuxostat, but not colchicine, reduced lipolysis in cultured adipocytes. Since soluble urate, xanthine oxidase inhibitor treatment, and free fatty acids modulate inflammation, our findings suggest that by suppressing lipolysis, ULT could regulate inflammation in gout and comorbid metabolic and cardiovascular disease., (© 2022. The Author(s).)

We engineered a machine learning approach, MSHub, to enable auto-deconvolution of gas chromatography-mass spectrometry (GC-MS) data. We then designed workflows to enable the community to store, process, share, annotate, compare and perform molecular networking of GC-MS data within the Global Natural Product Social (GNPS) Molecular Networking analysis platform. MSHub/GNPS performs auto-deconvolution of compound fragmentation patterns via unsupervised non-negative matrix factorization and quantifies the reproducibility of fragmentation patterns across samples.

Objectives: Dietary intake of choline has been linked to systemic inflammation through the microbial production of two metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO). Herein we explore the association between choline metabolites and inflammation in psoriatic arthritis (PsA) patients., Methods: Thirty-eight patients with PsA, all of whom satisfied the CASPAR classification criteria for PsA, were studied. Outcomes reflecting the activity of peripheral arthritis as well as skin psoriasis, Disease Activity Score (DAS)28, Clinical Disease Index (CDAI) and Body Surface Area (BSA) were assessed. Serum concentration of choline metabolites (choline, TMA, TMAO, betaine and carnitine) were determined by LC-MS, and metabolite levels associated with disease scores., Results: Among the 38 PsA patients included, the mean DAS28PCR was 2.74±1.29. Twenty-seven patients had active skin disease, with an average BSA of 7.2±16.22. TMAO, but not TMA or choline, significantly correlated with measures of disease activity for both skin and peripheral joints., Conclusions: In our cohort, only TMAO, but not TMA, choline, betaine or carnitine, was associated with inflammation in PsA patients, establishing a mechanistic link between TMAO and PsA phenotypes. Future studies will explore the modulation of TMAO and disease severity in PsA.

Nuclear factor kappa B (NF-κB) is a key transcription factor controlling inflammation, innate immunity, and tissue integrity. NF-κB is activated by IκB kinase (IKK) in response to pro-inflammatory stimuli but is also found to be chronically activated in many inflammatory diseases accompanied by tissue destruction. To study the effects of chronic NF-κB activation in intestinal epithelium, we generated IKKβ(EE)(IEC) transgenic mice which express constitutively active form of IKKβ in their intestinal epithelial cells (IEC). In this chapter, we describe three different methods that we applied for analysis of NF-κB activation in IEC of IKKβ(EE)(IEC) transgenic mice: immunohistochemistry (IHC), nuclear fractionation, and chromatin immunoprecipitation (ChIP). These methods can be also applied to analyze NF-κB activation in mouse intestinal tissue in general.