Chronic Inflammatory Conditions Research Articles

Host–Microbe Interactions in Healthy and CSOM-Affected Middle Ears

Chronic suppurative otitis media (CSOM) is a chronic middle ear inflammatory condition due to persistent polymicrobial middle ear infection. The interaction between local immune responses and microbial communities is not well understood, complicating the development of targeted therapies. This study aimed to characterise local immune cell responses and microbial composition in CSOM-affected middle ear mucosa, focusing on Pseudomonas aeruginosa and Staphylococcus aureus. A total of 24 CSOM patients and 22 controls undergoing tympanomastoid surgery participated in this prospective study. Middle ear and mastoid mucosa were collected for histological and microbiological analysis. Bacterial identification was performed using standard culture methods and Vitek MS, while immune cell populations were quantified via immunohistochemistry. Statistical analyses were performed using Kruskal–Wallis and Mann–Whitney tests. Microbiology results identified multiple pathogens in CSOM, including S. aureus and P. aeruginosa, with polymicrobial infections in 10 samples. CSOM patients exhibited significantly elevated immune cells, including CD3+, CD20+, and CD68+ cells, compared to controls. Histological analysis showed Gram-positive bacteria in three mastoid samples, with positive antibody staining for S. aureus (20.8%) and P. aeruginosa (12.5%) in CSOM patients. Controls had no bacterial staining. Intracellular bacteria may evade host defences and reduce antibiotic efficacy, contributing to CSOM persistence. Targeting intracellular pathogens in future treatments, along with studying polymicrobial communities, could improve management strategies.

Granulomatous vulvitis complicated by polymicrobial growth.

Granulomatous vulvitis (GV) is a rare chronic inflammatory condition presenting with persistent vulvar swelling and noncaseating granulomas, often mimicking Crohn's disease and sarcoidosis. We report a 21-year-old sexually inactive woman with a five-month history of painless vulvar swelling and occasional itching, complicated by secondary polymicrobial infection. A thorough evaluation excluded other granulomatous diseases, and histopathology revealed noncaseating granulomas, supporting the diagnosis of granulomatous vulvitis. Initial antibiotic therapy was followed by hydroxychloroquine, and intralesional triamcinolone, leading to marked symptom resolution. This case highlights intralesional corticosteroids as an effective first-line treatment and underscores the need for a multidisciplinary and personalized approach in managing GV, particularly in the presence of secondary infections.

Silajathu Rasayana in management of Ankylosing Spondylitis - A Case Report

Ankylosing Spondylitis is a chronic seronegative inflammatory condition that primarily impacts the sacroiliac joint and spine, potentially leading to the fusion of spinal bones. The exact cause of this condition remains unknown. A 50-year-ojoints andatient was admitted to the Kayachikitsa inpatient department of Vaidyaratnam Ayurveda College, Ollur, presenting with both knee pain and swelling, pain in both elbow joints, and generalized back pain. She was treated by following the Amavatha management protocol, which included internal administration of Ayurvedic formulations such as Amrithotharam Kashaya, Indukantham Kashaya, Yogaraja Guggulu, Punarnavasam, and Rasnapanchakam Kashaya. External therapies such as Churna Pinda Sweda, Snehapana, Sarvanga Taila Dhara and Virechana. Silajathu Rasayana were administered in the final stage of the treatment. After six weeks of treatment, the patient experienced significant relief from upper and lower back pain, reduced elbow pain, and noticeable improvement in knee joint swelling and discomfort. This case study emphasizes the efficacy of Ayurvedic management especially Rasayana chikitsa in achieving substantial symptom improvement within a short duration.

Transcription Factor Blimp-1: A Central Regulator of Oxidative Stress and Metabolic Reprogramming in Chronic Inflammatory Diseases

B-lymphocyte-induced maturation protein 1 (Blimp-1) is a transcription factor that, among other functions, modulates metabolism and helps to regulate antioxidant pathways, which is important in the context of chronic inflammatory diseases like diabetes, cardiovascular disease, and autoimmune disease. In immune cell function, Blimp-1 has a modulatory role in the orchestration of metabolic reprogramming and as a promoter of anti-inflammatory cytokines, including IL-10, responsible for modulating oxidative stress and immune homeostasis. Moreover, Blimp-1 also modulates key metabolic aspects, such as glycolysis and fatty acid oxidation, which regulate reactive oxygen species levels, as well as tissue protection. This review depicts Blimp-1 as an important regulator of antioxidant defenses and anti-inflammation and suggests that the protein could serve as a therapeutic target in chronic inflammatory and metabolic dysregulation conditions. The modulation of Blimp-1 in diseases such as diabetic coronary heart disease and atherosclerosis could alleviate oxidative stress, augment the protection of tissues, and improve disease outcomes. The therapeutic potential for the development of new treatments for these chronic conditions lies in the synergy between the regulation of Blimp-1 and antioxidant therapies, which are future directions that may be pursued. This review emphasizes Blimp-1’s emerging importance as a novel regulator in the pathogenesis of inflammatory diseases, providing new opportunities for therapeutic intervention.

Characteristic TARC/CCL17 expression in the salivary gland of IgG4-related disease: potential diagnostic utility and insights into pathogenesis

Immunoglobulin G4-related disease (IgG4-RD) is a chronic inflammatory condition of unknown etiology characterized by lymphocytic infiltration, fibrosis, and infiltration of IgG4-positive plasma cells. It affects various organs, including the pancreas and salivary glands. Immunological abnormalities are suspected to play a role in its pathogenesis, and there is an epidemiological link to allergic conditions and type 2 inflammation. This study focused on the expression of thymus and activation-regulated chemokine (TARC)/CCL17, which is involved in the migration of T helper 2 and/or regulatory T cells, in salivary gland tissues of patients with IgG4-RD. We analyzed 60 salivary gland biopsy samples obtained from patients at Sapporo Medical University Hospital between 2015 and 2020. Immunohistochemical analysis revealed TARC/CCL17 positivity in 87.2% of histologically confirmed IgG4-RD cases and negativity in 84.6% of histologically unconfirmed but clinically suspected IgG4-RD cases. There was a significant correlation between histologically confirmed IgG4-RD and TARC/CCL17 expression, suggesting its potential diagnostic utility and possible involvement in the pathogenesis of IgG4-RD.

Narrative Review of Genetic and Immunological Mechanisms Involved in the Pathogenesis of Kimura’s Disease: New Therapeutic Targets

Kimura’s disease (KD) is a rare, chronic inflammatory disorder that predominantly affects young men of East Asian descent. It is characterized by painless solid masses primarily localized to the deep subcutaneous tissues of the head and neck, eosinophilia, and elevated serum immunoglobulin E (IgE). While the exact cause remains unclear, the pathogenesis is thought to involve dysregulated immune responses, particularly those mediated by T-helper cells 2 (Th2), eosinophils, and IgE production. Advances in molecular biology have suggested that genetic factors play a significant role in the development and progression of this chronic inflammatory condition. Recent studies have implicated several genes and immune pathways in its development, and understanding these genetic components may provide insights into better diagnostic tools and therapeutic strategies for KD. In this regard, biological therapies, by targeting the immune mechanisms underlying KD, have been used to treat this challenging condition with promising results, contributing to a better understanding of the pathogenesis of this rare disorder. The aim of this study was to review the literature concerning the genetic factors and immune mechanisms that contribute to the pathogenesis of KD, with a special focus on the role of biological therapies.

Leveraging genotypes and phenotypes to implement precision medicine in hidradenitis suppurativa management.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition with many unmet needs. It is characterized by significant clinical heterogeneity, which suggests that a diagnosis of HS captures multiple distinct disease entities and that research aimed at identifying medically relevant HS subtypes will improve its management. Precision medicine is an approach to disease management that uses information encoded in a patient's genome, and operationalized in clinical presentations and drug responses, to identify disease subtypes. Prior research aimed at identifying HS subtypes has largely focused on phenotypic classifications derived from clinical features of cutaneous lesions. Limitations of existing HS taxonomies emphasize a need for a more nuanced understanding of disease subtypes. Evidence that has emerged from initial genetic studies of HS suggests the presence of at least three HS subtypes, each of which has different clinical implications in terms of disease risks and drug responses. These preliminary findings are instructive in terms of expanding our definitions of HS phenotypes to not only include characteristics of skin lesions, but also disease comorbidities and molecular and cellular phenotypes. Here we provide a comprehensive review of HS phenotype and genotype knowledge, and propose a strategic framework for implementing precision medicine in HS management. Future research should focus on expanding phenotype assessments to include data on multiple scales. Iterative research designs performed with phenotype and genotype data from large diverse cohorts are needed to rigorously define clinically relevant HS subtypes.

The relationship between involutional ectropion and inflammatory disorders of the eyelids and ocular surface: insights from a large-scale national study

This study investigated potential associations between ectropion and various chronic and systemic inflammatory diseases affecting the eyelids and ocular surface. This retrospective case-control study, spanning 2001–2022, used electronic medical records from Clalit Health Services (CHS) in Israel. Patients diagnosed with involutional ectropion served as the case group, while two control groups were used for comparison: one comprising patients diagnosed with senile cataract and the other with various ophthalmic diseases. Matching for the control groups was performed at a 1:3 ratio based on year of birth, sex, and ethnicity. A total of 17,292 patients with involutional ectropion and 51,876 matched controls in each group were included. The average age of the patients with involutional ectropion was 78 ± 10 years and 58% were men. Significant associations were found between involutional ectropion and several local inflammatory eyelid diseases: blepharitis (OR 4.66), chalazion (OR 2.94), hordeolum (OR 2.26), and dermatitis of the eyelid (OR 2.46). Ocular surface diseases associated with ectropion included chronic conjunctivitis (OR2.89 ) and pterygium (OR 2.48). Systemic diseases such as hypertension (OR 1.46), dyslipidemia (OR 1.45), and autoimmune rheumatic diseases (OR 1.43) were also associated with involutional ectropion. This study found that localized chronic inflammatory conditions affecting the periocular tissues and ocular surface are significantly associated with the development of involutional ectropion.

Immunotherapy strategy for treating inflammatory bowel disease based on a nanozyme/total glucosides of paeony hybrid materials

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory condition that has long plagued patients. Herein, an innovative oral treatment strategy for IBD is proposed, which utilizes calcium alginate hydrogel as a carrier to deliver Co3O4 nanocages loaded with total glucosides of paeony (TGP) into the body. This design ingeniously exploits the protective properties of the alginate outer layer to ensure that the enzyme is not prematurely degraded when passing through acidic gastric juice. However, upon reaching the inflamed intestinal site, the overexpressed H2O2 there mixes with a specific solution, causing the hydrogel to degrade and release Co3O4@TGP. These negatively charged nanozymes can precisely recognize and accumulate in the inflamed colonic tissue, achieving targeted therapy through their unique charge characteristics. More importantly, Co3O4 itself possesses excellent catalytic activity, effectively consuming excess H2O2 at the site of inflammation and degrading into 10 nm small particles in the process, while simultaneously releasing TGP. Together, they exert dual effects of scavenging reactive oxygen species (ROS) and anti-inflammation. Its therapeutic mechanism involves fine regulation of the expression of key proteins such as TLR7, MYD88, and GAPDH, as well as effective inhibition of the NF-κB signaling pathway. This series of actions not only reduces the release of various pro-inflammatory cytokines (such as TNF-α, IL-18, IL-1β, IL-6, and HMGB1) but also promotes the production of the anti-inflammatory cytokine IL-10, thereby effectively maintaining the integrity of the intestinal barrier. This research achievement opens up a novel path for the treatment of colitis.

Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients

A substantial portion of patients infected with SARS-CoV-2 experience prolonged complications, known as Long COVID (LC). A subset of these patients exhibits the most debilitating symptoms, similar to those defined in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We performed bulk RNA sequencing (RNAseq) on the whole blood of LC with ME/CFS, at least 12 months post-onset of the acute disease, and compared them with controls. We found that LC patients had a distinct transcriptional profile compared to controls. Key findings include the upregulation of genes involved in immune dysregulation and neuronal development, such as Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3, and RELN. These genes are linked to neuroinflammatory responses, cognitive impairments, and hematopoietic disturbances, suggesting ongoing neurological and immune disturbances in LC patients.RELN, encoding the Reelin protein, was notably elevated in LC patients, potentially serving as a biomarker for LC pathogenesis due to its role in inflammation and neuronal function. Immune cell analysis showed altered profiles in LC patients, with increased activated memory CD4 + T cells and neutrophils, and decreased regulatory T cells and NK cells, reflecting immune dysregulation. Changes in cytokine and chemokine expression further underscore the chronic inflammatory state in LC patients. Notably, a unique upregulation of olfactory receptors (ORs) suggest alternative roles for ORs in non-olfactory tissues.Pathway analysis revealed upregulation in ribosomal RNA processing, amino acid metabolism, protein synthesis, cell proliferation, DNA repair, and mitochondrial pathways, indicating heightened metabolic and immune demands. Conversely, downregulated pathways, such as VEGF signaling and TP53 activity, point to impaired tissue repair and cellular stress responses.Overall, our study underscores the complex interplay between immune and neuronal dysfunction in LC patients, providing insights into potential diagnostic biomarkers and therapeutic targets. Future research is needed to fully understand the roles and interactions of these genes in LC pathophysiology.

Smart biomaterial gels for periodontal therapy: A novel approach.

Periodontitis, a chronic inflammatory condition of the oral cavity, is characterized by the progressive destruction of the supporting structures of the teeth. The pathogenic effects of periodontopathogens extend beyond the local periodontal environment, contributing to systemic health complications, thereby underscoring the need for effective therapeutic strategies. Current standard treatments, which involve mechanical debridement coupled with systemic anti-inflammatory and antibiotic therapies, are often associated with limited efficacy, adverse effects, and the emergence of antibiotic resistance. Recent advancements in localized drug delivery systems present an innovative alternative, offering site-specific targeting with sustained therapeutic action. Smart drug delivery platforms, designed to respond to the unique microenvironment of periodontal pockets, undergo physicochemical transformations such as gelation or controlled drug release, enhancing treatment efficacy. This review comprehensively explores the etiological and prognostic factors of periodontitis, critical diagnostic biomarkers, and an in-depth analysis of stimuli-responsive biomacromolecule-based gels. These systems are evaluated for their structural properties, biological compatibility, and therapeutic potential while addressing their limitations and barriers to clinical translation. By integrating insights into the interplay between material properties and biological performance, this review highlights the future role of these advanced delivery systems in overcoming challenges in periodontal healthcare. Such approaches aim to bridge the gap between bench-side innovation and bedside application, offering the transformative potential to enhance therapeutic outcomes and improve patient quality of life in managing periodontal diseases.

The Multiple Roles of Heat Shock Proteins in the Development of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), a chronic inflammatory condition of the human intestine, comprises Crohn's Disease (CD) and Ulcerative Colitis (UC). IBD causes severe gastrointestinal symptoms and increases the risk of developing colorectal carcinoma. Although the etiology of IBD remains ambiguous, complex interactions between genetic predisposition, microbiota, epithelial barrier, and immune factors have been implicated. The disruption of intestinal homeostasis is a cardinal characteristic of IBD. Patients with IBD exhibit intestinal microbiota dysbiosis, impaired epithelial tight junctions, and immune dysregulation; however, the relationship between them is not completely understood. As the largest body surface is exposed to the external environment, the gastrointestinal tract epithelium is continuously subjected to environmental and endogenous stressors that can disrupt cellular homeostasis and survival. Heat shock proteins (HSPs) are endogenous factors that play crucial roles in various physiological processes, such as maintaining intestinal homeostasis and influencing IBD progression. Specifically, HSPs share an intricate association with microbes, intestinal epithelium, and the immune system. In this review, we aim to elucidate the impact of HSPs on IBD development by examining their involvement in the interactions between the intestinal microbiota, epithelial barrier, and immune system. The recent clinical and animal models and cellular research delineating the relationship between HSPs and IBD are summarized. Additionally, new perspectives on IBD treatment approaches have been proposed.

Hidradenitis Suppurativa Treatment During Pregnancy and Lactation: Navigating Challenges.

Hidradenitis suppurativa (HS), or acne inversa, is a chronic inflammatory skin condition primarily affecting skin folds such as the axilla, groins, and the inframammary, perineal, and perianal regions. It is characterized by painful abscesses, sinus tracts, and scarring. Predominantly affecting young adults, particularly females, HS often emerges during reproductive age, and flares are widely reported during pregnancy and postpartum, underscoring the need to consider management strategies tailored to pregnant or lactating individuals. Moreover, the chronic and relapsing nature of HS, along with challenges related to the safety and compliance of medication use during pregnancy and lactation, as well as various comorbidities and psychological distress, significantly complicate its management in pregnant or lactating women. Treatment options, including topical clindamycin, oral clindamycin-rifampicin, adalimumab, metformin, antiseptic washes, and certolizumab pegol, have accumulated evidence supporting their relative safety in pregnant and lactating women. While certolizumab pegol has shown promising safety data among biologics, it requires more efficacy data in HS. Conversely, while newly approved HS medications such as secukinumab and bimekizumab show promise for the general population, further research is necessary to evaluate their safety profiles in pregnant and breastfeeding individuals. The scant research available on HS in pregnant and lactating women, also shown by our systematic literature review, highlights the need for a comprehensive investigation into the safety, efficacy, and suitability of management strategies.

Tumor microenvironment regulation by reactive oxygen species-mediated inflammasome activation.

Tumor microenvironment (TME) is composed of diverse cell types whose interactions, both direct and indirect, significantly influence tumorigenesis and therapeutic outcomes. Within TME, reactive oxygen species (ROS) are produced by various cells and exhibit a dual role: moderate ROS levels promote tumor initiation and progression, whereas excessive levels induce cancer cell death, influencing the efficacy of anticancer therapies. Inflammasomes, cytosolic multiprotein complexes, are pivotal in multiple stages of tumorigenesis and play a crucial role in establishing the inflammatory TME. By releasing cytokines such as IL-1β and IL-18, inflammasomes contribute to immune cell recruitment and sustain a chronic inflammatory state that supports tumor growth. ROS are critical regulators of inflammasome activation, with the impact of ROS-mediated activation differing across cell types, leading to distinct influences on tumor progression and therapeutic responses. This review explores how ROS drive inflammasome activation in various TME-associated cells and the reciprocal ROS generation induced by inflammasomes, examining their multifaceted impact on tumorigenesis and therapeutic efficacy. By elucidating the complex interplay between ROS and inflammasomes in TME, we provide insights into potential therapeutic approaches that could modulate cancer progression and enhance treatment outcomes.

Breastfeeding and Non-Communicable Diseases: A Narrative Review

Introduction: Breastfeeding plays a fundamental role in newborns’ and infants’ health. Breast milk’s protective power against malnutrition and its positive effect on neurological and physical development are well established and are reflected in the policy statements of all major pediatric health entities. However, breastfeeding also plays an important role in the prevention of so-called non-communicable diseases, such as obesity, hypertension, dyslipidemia, and autoimmune diseases. Methods: This narrative review aims to analyze the effect of breastfeeding and breast milk on the development of non-communicable diseases, with a special focus on weight excess, dyslipidemia, allergy, and gastrointestinal diseases. This narrative review was carried out through three steps: executing the search, examining abstracts and full texts, and analyzing results. To achieve this, the databases PubMed, EMBASE, Scopus, ScienceDirect, Web of Science, and Google Scholar were explored to collect and select publications from 1990 to 2024 to find pertinent studies in line with this review’s development. The search included randomized placebo-controlled trials, controlled clinical trials, double-blind, randomized controlled studies, and systematic reviews. A total of 104 manuscripts were ultimately included in the analysis. Results: Breastfeeding is associated with a decreased vulnerability to early viral infections or chronic inflammatory conditions during preschool years, a reduced incidence of weight excess, and likely lower cholesterol concentration, besides having a small protective effect against systolic blood hypertension. Conclusions: Pediatricians must promote breastfeeding, support the mother–infant dyad, and consider breast milk as a real “health voucher” that can last lifelong. However, further studies are needed to better define the extent and duration of breastfeeding’s protective power in this context.

Effect of non-surgical periodontal therapy on the salivary levels of IL-18 and IL-35 in patients with periodontitis.

Periodontal disease is the most prevalent chronic inflammatory condition that can cause the destruction of supporting periodontal tissues. It has been hypothesized that while the synthesis of proinflammatory cytokines causes tissue destruction and disease progression, anti-inflammatory cytokine production can result in protective immunity. The balance of inflammatory cytokines is central to the immunoregulation of the disease. The aim of the study was to assess and compare the salivary levels of interleukin (IL)-18 and IL‑35 in subjects diagnosed with gingivitis, periodontitis, and healthy individuals. Additionally, the study sought to evaluate the difference in the concentration of IL‑18 and IL‑35 after non-surgical periodontal therapy (NSPT) in subjects diagnosed with periodontal disease. A total of 69 individuals were divided into 3 groups: healthy (group 1; n = 23); gingivitis (group 2; n = 23); and stage II periodontitis (group 3A; n = 23). Saliva samples were obtained from each participant at baseline and, in the periodontitis group, at baseline and 12 weeks after NSPT (group 3B; n = 23). Probing pocket depth (PD), bleeding on probing (BoP), gingival index (GI), and clinical attachment level (CAL) were recorded and IL‑18 and IL‑35 levels were analyzed using an enzyme-linked immunosorbent assay (ELISA). The mean salivary level of IL‑18 was significantly higher in the gingivitis group compared to the other groups (p < 0.05), whereas the mean IL‑35 level was significantly higher in the healthy group compared to the other groups (p < 0.05). Twelve weeks after NSPT, the periodontitis group demonstrated a statistically significant difference in cytokine levels, characterized by a decline in the IL‑18 concentration (229.63 ±49.35 pg/mL) and an increase in the concentration of IL‑35 (29.47 ±17.88 pg/mL). In the present study, a significant difference in the salivary levels of IL‑18 and IL‑35 before and after NSPT was observed. Therefore, these cytokines could serve as potential inflammatory biomarkers.

Exploring receptors for pro-resolving and non-pro-resolving mediators as therapeutic targets for sarcopenia.

Sarcopenia is defined by a reduction in both muscle strength and mass. Sarcopenia may be an inevitable component of the aging process, but it may also be accelerated by comorbidities and metabolic derangements. The underlying mechanisms contributing to these pathological changes remain poorly understood. We propose that chronic inflammation-mediated networks and metabolic defects that exacerbate muscle dysfunction are critical factors in sarcopenia and related diseases. Consequently, utilizing specialized pro-resolving mediators (SPMs) that function through specific G-protein coupled receptors (GPCRs) may offer effective therapeutic options for these disorders. However, challenges such as a limited understanding of SPM/receptor signaling pathways, rapid inactivation of SPMs, and the complexities of SPM synthesis impede their practical application. In this context, stable small-molecule SPM mimetics and receptor agonists present promising alternatives. Moreover, the aged adipose-skeletal axis may contribute to this process. Activating non-SPM GPCRs on adipocytes, immune cells, and muscle cells under conditions of systemic, chronic, low-grade inflammation (SCLGI) could help alleviate inflammation and metabolic dysfunction. Recent preclinical studies indicate that both SPM GPCRs and non-SPM GPCRs can mitigate symptoms of aging-related diseases such as obesity and diabetes, which are driven by chronic inflammation and metabolic disturbances. These findings suggest that targeting these receptors could provide a novel strategy for addressing various chronic inflammatory conditions, including sarcopenia.

P-1834. An Enteric Bacterial Infection Disrupts Brain Homeostasis and Induces Chronic Neuroinflammation by Breaching the Gut-Brain Axis in 3xTg-AD Transgenic Mice

Abstract Background In previous studies, we found that an enteric infection caused by Klebsiella pneumoniae (Kpn) not only disturbs the balance of gut microbiome but also translocates to the brain, leading to inflammation and impairments in neurobehavior. Methods Triple-transgenic (3xTg-AD) mice were split into three categories: those infected with Kpn (Kpn group), a subset of Kpn mice treated with antibiotics to induce dysbiosis (Kpn+Ab group), and a control group receiving no treatment (TgCt group). Metabolomic and inflammation profiles of gut, serum, and brain samples collected six weeks after infection were evaluated using NMR-based metabolomic analysis and transcriptomics analysis conducted with the NanoString nCounter system. Results Significant shifts were observed in gut metabolites, while serum metabolites showed minor changes, particularly with an upward trend in branched-chain amino acids in Kpn-treated mice. In the gut, an inflammatory response was evident, characterized by the increased expression of inflammatory genes such as Cd14, Ptgs2, and Il6st. Transcriptomic analysis of the brain revealed disrupted homeostasis, with heightened neuropathological processes, including oxidative stress and cytokines, and reduced structural and anti-pathological functions, particularly notable in the Kpn+Ab group. Specifically, genes associated with inflammation and neurodegeneration, such as Il1r1 and Ptgs2, were upregulated in the Kpn+Ab group, suggesting a chronic inflammatory state potentially worsening neuropathology. Indeed, elevated levels of total tau were observed in the brains of Kpn+Ab mice. Furthermore, dysregulation in redox signaling linked to the malate-aspartate shuttle was evident, as indicated by increased levels of aspartate and N-acetylaspartate alongside decreased serine concentrations. Conclusion The results indicate that Kpn enteric infection leads to persistent inflammation in both the gut and the brain, disrupting essential pathways for brain homeostasis. This disruption may contribute to the buildup of AD pathologies and impairments in neurobehavioral function. Disclosures All Authors: No reported disclosures

Cardiovascular disease, bone fracture, and all-cause mortality risks among postmenopausal women by arthritis and veteran status: A multistate Markov transition analysis.

Arthritis, a chronic inflammatory condition linked to cardiovascular disease (CVD) and bone fracture, is more frequent among military veterans and postmenopausal women. This study examined correlates of arthritis and relationships of arthritis with risks of developing CVD, bone fractures, and mortality among postmenopausal veteran and non-veteran women. We analyzed longitudinal data on 135,790 (3,436 veteran and 132,354 non-veteran) postmenopausal women from the Women's Health Initiative who were followed-up for an average of 16years between enrollment (1993-1998) and February 17, 2024. Regression and multistate Markov modeling were applied to meet study objectives. The prevalence of arthritis at enrollment (1993-1998) did not differ by veteran status in a fully adjusted logistic model. Variable selection yielded 5 key predictors of prevalent arthritis among veterans and 15 key predictors among non-veterans. In fully-adjusted Cox models, prevalent arthritis was associated with CVD (hazard ratio [HR] = 1.08, 95% confidence interval [CI]: 1.05, 1.10) and all-cause mortality (HR = 1.03, 95% CI: 1.01, 1.05) risks among non-veterans only, but was not associated with bone fracture risk irrespective of veteran status. Transition probabilities between health and CVD and between bone fracture and death were higher among women with vs. without arthritis. The latter transition was more strongly related to arthritis among non-veteran vs. veteran women. In conclusion, among postmenopausal women, prevalent arthritis was associated with greater probabilities of transitioning from a healthy state to CVD and from bone fracture to death, with worse prognosis after bone fracture among those who did not serve in the military.

Health improvements by Understanding Residual Risk In CAd and NEw targets for prevention/treatment: Rationale and Research Protocol of the HURRICANE project

Abstract Optimal medical treatment in patients with stable coronary artery disease reduced morbidity and mortality but left a substantial residual risk of disease progression and events. According to recent evidence, insulin resistance or pre-diabetes together with elevated levels of triglycerides, low levels and functionality of high-density lipoprotein cholesterol, often associated with a chronic inflammatory state, are deemed to be relevant components of cardiometabolic and vascular residual risk. In the present project we aim at discovering specific individual genetic/molecular profiles subtending emerging cardiometabolic and vascular risk patterns and associated with more severe stable coronary artery disease phenotypes. To this end we will analyse clinical data, blood samples and imaging data already gathered in a retrospective population of 561 patients with suspected stable coronary disease and will develop integrated predictive models of severity and extent of disease defined by qualitative and quantitative analysis of coronary plaques by cardiac computed tomography. The new predictive models, which will incorporate relevant clinical and genetic/molecular variables associated with more severe coronary atherosclerosis, will be validated in a similar prospective population of patients and extended to the prediction of progression (at 1-year follow-up) of coronary disease phenotypes, occurring despite optimal medical treatment. ClinicalTrials.gov ID: NCT06601153