Chronic Inflammatory Conditions Research Articles

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

Optimized nanostructured lipid carriers from aceh traditional coconut (Pliek) oil: a promising topical formulations for atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by dry skin, severe itching, redness, and inflammation. Its complex etiology, involving genetic, immunological, and environmental factors, necessitates innovative therapeutic approaches. This study investigates nanostructured lipid carriers (NLCs) formulated with traditional fermented coconut (Cocos nucifera L.) oil from Aceh (pliek oil). The NLC was optimized using Box-Behnken Design and prepared through high shear homogenization and ultrasonication. The optimized formula consisted of 8% w/w lipid phase, 2min sonication time, and 6% Tween 80, resulting in a particle size of 207.1 ± 0.93nm, a polydispersity index of 0.275 ± 0.005, and a zeta potential of - 30.2 ± 0.78mV. A 1:1 ratio of Tween 80 and Span 20 ensured stable NLC. The NLC of Pliek oil (NLC-PL) gel met EuroGuiDerm standards for AD treatment, with a pH of 5.62 ± 0.06, indicating skin compatibility. Histological analysis demonstrated that the NLC-PL gel (2.5% w/w pliek oil) significantly reduced MC903-induced ear thickness and inflammation compared to the negative control (p < 0.05), and suppressed mast cell numbers, comparable to the positive control (p > 0.05). Enzyme-Linked Immunosorbent Assay (ELISA) confirmed its role as a c-jun N-terminal kinase 1 (JNK1) inhibitor, supporting its potential as targeted topical therapy for AD. This study aligns with the study's objective to develop innovative treatments for AD.

A current review on animal models of anti-asthmatic drugs screening

Asthma is a chronic inflammatory respiratory condition characterised by airway constriction, smooth muscle spasm, and severe morbidity. It affects around 300 million people globally, with children being especially vulnerable. Despite its worldwide effect, the invention of innovative asthma medicines has been slow over the last 5 decades, leaving significant unmet requirements in asthma care. Although intriguing medicines have demonstrated efficacy in animal models, many fail to fulfil safety and effectiveness requirements in human trials, highlighting the critical need for more predictive models that better transfer to human results. This comprehensive review investigates the mechanisms and efficacy of anti-asthmatic drugs using both genetic and conventional animal models. Both genetic and traditional models of anti-asthmatic agents, their characteristics, and their significance are summarized as: In-Vitro Animal Models: Histamine receptor assay, Cell Culture Method, WST Assay, Spasmolytic Activity of the Lungs of Guinea Pigs, Airway and Vascular Responses to an Isolated Lung, The Isolated Perfused Guinea Pig Trachea’s Reactivity. In-Vivo Models: In vivo small animal models, Broncho Spasmolytic Activity in anaesthetized Guinea Pigs, Guinea Pigs Respiratory and Vascular Dysfunction Caused by Arachidonic Acid or platelet-activated factor (PAF), Guinea Pig Asphyxia Induced by Serotonin Aerosol and Anaphylactic Microshock, Guinea Pigs Under Anaesthesia: Histamine-Induced Bronchoconstriction, Microshock in Rabbits and Pneumotachography in Guinea Pigs, Guinea Pig Bronchial Hyperactivity, Guinea Pig Airway Microvascular Leakage, Mice With Inflammatory Airways. Conclusion: This review focusses on the benefits and limitations of current animal models in asthma research, emphasising the need for more sophisticated, predictive models to decrease translational failures. By critically evaluating these models, the review emphasises their importance in directing anti-asthmatic drug development and highlights the urgent need for innovation to bridge the gap between preclinical success and clinical efficacy.

Vitamins and Celiac Disease: Beyond Vitamin D

Celiac disease is a chronic inflammatory condition of the small bowel caused, in genetically predisposed subjects, by the ingestion of gluten and characterised by a broad clinical polymorphism, ranging from patients with an asymptomatic or paucisymptomatic disease. The clinical presentation ranges from the presence of minor, apparently unrelated symptoms or first-degree kinship with known patients to severe intestinal malabsorption and all its clinical consequences and complications. Even if a large body of research improved our understanding of the molecular basis of celiac disease pathophysiology, enhancing the identification of new targets for future new treatments, an accurate gluten-free diet remains the mainstay of the therapy for this condition, restoring a normal absorptive mucosa. It is very rare, nowadays, to deal with patients with severe malabsorption syndrome secondary to celiac disease. Consequently, physicians are currently less prone to search for nutritional deficiencies in celiac disease. To pinpoint the possibility of both a disease-related and a diet-induced vitamin deficiency, we reviewed the literature on vitamin deficiency in this condition and reported the impact both in untreated and treated patients with celiac disease. A gluten-free diet must be tailored for each patient to meet nutritional targets: the pre-existence or diet-induced intake inadequacies should be carefully considered for an effective management of celiac disease.

From Evidence to Practice: A Narrative Framework for Integrating the Mediterranean Diet into Inflammatory Bowel Disease Management

Emerging evidence underscores the pivotal role of diet in preventing and managing inflammatory bowel disease (IBD). As our comprehension of the microbiome’s role in IBD expands, dietary modifications are increasingly recognized as potential adjuncts or primary therapeutic strategies. Key components of the Mediterranean diet (MD)—including microbiota-accessible carbohydrates, omega-3 fatty acids, polyphenols, and antioxidants—have demonstrated promise in enhancing gut microbiota diversity and reducing intestinal inflammation, making it a practical approach for managing IBD. Moreover, the MD offers additional benefits considering the rising prevalence of comorbid chronic inflammatory conditions such as diabetes, cardiovascular disease, and obesity in IBD patients. The purpose of this narrative review was to provide an overview of the feasibility and clinical outcomes of the MD and offer evidence-based guidance for researchers and practitioners on how to adapt the MD to patients with IBD. According to several cross-sectional and interventional studies, the MD is feasible for patients with IBD and confers several benefits, such as reduced inflammation, improved disease activity, and enhanced quality of life, with a strong adherence rate and minimal adverse effects. To facilitate knowledge translation, we provide a practical framework for integrating the MD as a nutritional therapy for IBD, including specific recommendations and messaging that researchers, practitioners, and patients can use. By synthesizing current evidence and offering actionable insights, the aim is to facilitate the integration of the MD into IBD management, with the potential to improve patient outcomes.

Identification of DDR1 Inhibitors from Marine Compound Library Based on Pharmacophore Model and Scaffold Hopping

Ulcerative colitis (UC) is a chronic inflammatory condition that affects the intestines. Research has shown that reducing the activity of DDR1 can help maintain intestinal barrier function in UC, making DDR1 a promising target for treatment. However, the development of DDR1 inhibitors as drugs has been hindered by issues such as toxicity and poor binding stability. As a result, there are currently no DDR1-targeting drugs available for clinical use, highlighting the need for new inhibitors. In a recent study, a dataset of 85 DDR1 inhibitors was analyzed to identify key characteristics for effective inhibition. A pharmacophore model was constructed and validated to screen a library of marine natural products for potential DDR1 inhibitors. Through high-throughput virtual screening and precise docking, 17 promising compounds were identified from a pool of over 52,000 molecules in the marine database. To improve binding affinity and reduce potential toxicity, scaffold hopping was employed to modify the 17 compounds, resulting in the generation of 1070 new compounds. These new compounds were further evaluated through docking and ADMET analysis, leading to the identification of three compounds—39713a, 34346a, and 34419a—with superior predicted activity and drug-like properties compared to the original 17 compounds. Further analysis showed that the binding free energy values of the three candidate compounds were less than −12.200 kcal/mol, which was similar to or better than −12.377 kcal/mol of the known positive compound VU6015929, and the drug-like properties were better than those of the positive compounds. Molecular dynamics simulations were then conducted on these three candidate compounds, confirming their stable interactions with the target protein. In conclusion, compounds 39713a, 34346a, and 34419a show promise as potential DDR1 inhibitors for the treatment of ulcerative colitis.

Kurarinone Mitigates LPS-Induced Inflammatory Osteolysis by Inhibiting Osteoclastogenesis Through the Reduction of ROS Levels and Suppression of the PI3K/AKT Signaling Pathway.

Inflammatory bone resorption represents a pathological condition marked by an increase in bone loss, commonly associated with chronic inflammatory conditions such as rheumatoid arthritis and periodontitis. Current therapies primarilyfocuson anti-inflammatory drugs and bisphosphonates; however, these treatments are limited due to side effects, inadequate efficacy, and unpredictable long-term complications. Kurarinone (KR), a bioactive compound isolated from the traditional Chinese herb Sophora flavescens, exhibits a range of biological activities, including anti-inflammatory, anticancer, and cardiovascular protective effects. To address the limitations of existing therapies and enhance drug utilization, this study explores the potential of KR as a therapeutic agent for inflammatory bone resorption and delineates its underlying mechanisms. In vitro experiments reveal that KR notably inhibits osteoclastogenesis and reduces the expression of osteoclastic markers. Additionally, KR decreases the levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, while downregulating NADPH oxidase 1 (NOX1) and Kelch-like ECH-associated protein 1 (Keap1) to diminish ROS production. Furthermore, KR activates the nuclear factor erythroid 2-related factor 2 (Nrf2), which enhances the activity of heme oxygenase-1 (HO-1) and catalase (CAT), facilitating the clearance of excess ROS. The compound also hinders osteoclast formation and functionality by inhibiting the PI3K/AKT/GSK-3β signaling pathway. Lentiviral knockdown of CAT can partially reverse these effects of KR. Meanwhile, in vivo experiments indicate that KR effectively mitigates bone loss in an LPS-induced inflammatory bone resorption model. In summary, KR is a promising new star in breaking through the limitations of previous drugs and treating inflammatory bone resorption.

Comparative Efficacy of Nonsteroid Immunosuppressive Medications in Childhood Nephrotic Syndrome

Cyclophosphamide and calcineurin inhibitors are the most used nonsteroid immunosuppressive medications globally for children with various chronic inflammatory conditions. Their comparative effectiveness remains uncertain, leading to worldwide practice variation. Nephrotic syndrome is the most common kidney disease managed by pediatricians globally and suboptimal treatment is associated with high morbidity. To evaluate the comparative effectiveness of cyclophosphamide vs calcineurin inhibitors (tacrolimus or cyclosporine) for childhood nephrotic syndrome relapse prevention. Using target trial emulation methods, the study team emulated a pragmatic, open-label clinical trial using available data from the Insight Into Nephrotic Syndrome: Investigating Genes, Health, and Therapeutics (INSIGHT) study. INSIGHT is a multicenter, prospective cohort study in the Greater Toronto Area, Canada. Participants included children (1 to 18 years) with steroid-sensitive nephrotic syndrome diagnosed between 1996 and 2019 from the Greater Toronto Area, who initiated cyclophosphamide or a calcineurin inhibitor treatment. Data analysis was performed in 2024. Incident cyclophosphamide or calcineurin inhibitor treatment. Randomization was emulated by overlap weighting of propensity scores for treatment assignment. The primary outcome was time to relapse, analyzed by weighted Kaplan-Meier and Cox proportional hazards models. Secondary outcomes included relapse rates, subsequent immunosuppression, kidney function, hypertension, adverse events, and quality of life. Of 578 children (median age at diagnosis, 3.7 [IQR, 2.8-6.0] years; 371 male [64%] and 207 female [36%]), 252 initiated cyclophosphamide, 131 initiated calcineurin inhibitors, and 87 sequentially initiated both medications. Baseline characteristics were well balanced after propensity score weighting. During median 5.5-year (quarter 1 to quarter 3, 2.5-9.2) follow-up, there was no significant difference in time to relapse between calcineurin inhibitor vs cyclophosphamide treatment (hazard ratio [HR], 1.25; 95% CI, 0.84-1.87). Relapses were more common after calcineurin inhibitor treatment than cyclophosphamide (85% vs 73%) in the weighted cohorts, but not statistically significant. There were also no significant differences in subsequent relapse rates, nonsteroid immunosuppression use, or kidney function between medications. Calcineurin inhibitor treatment was associated with more hospitalizations (HR, 1.83; 95% CI, 1.14-2.92) and intravenous albumin use (HR, 2.81; 95% CI, 1.65-4.81). In this study, there was no evidence of difference in time to relapse after cyclophosphamide and calcineurin inhibitor treatment in children with nephrotic syndrome. Cyclophosphamide treatment is shorter in duration and more accessible globally than calcineurin inhibitors.

Involvement of TGF-β, mTOR, and inflammatory mediators in aging alterations during myxomatous mitral valve disease in a canine model.

Inflammaging, a state of chronic low-grade inflammation associated with aging, has been linked to the development and progression of various disorders. Cellular senescence, a state of irreversible growth arrest, is another characteristic of aging that contributes to the pathogenesis of cardiovascular pathology. Senescent cells accumulate in tissues over time and secrete many inflammatory mediators, further exacerbating the inflammatory environment. This senescence-associated secretory phenotype can promote tissue dysfunction and remodeling, ultimately leading to the development of age-related cardiovascular pathologies, such as mitral valve myxomatous degeneration. The species-specific form of canine myxomatous mitral valve disease (MMVD) provides a unique opportunity to investigate the early causes of induction of ECM remodeling in mitral valve leaflets in the human form of MMVD. Studies have shown that in both humans and dogs, the microenvironment of the altered leaflets is inflammatory. More recently, the focus has been on the mechanisms leading to the transformation of resting VICs (qVICs) to myofibroblast-like VICs (aVICs). Cells affected by stress fall into a state of cell cycle arrest and become senescent cells. aVICs, under the influence of TGF-β signaling pathways and the mTOR complex, enhance ECM alteration and accumulation of systemic inflammation. This review aims to create a fresh new view of the complex interaction between aging, inflammation, immunosenescence, and MMVD in a canine model, as the domestic dog is a promising model of human aging and age-related diseases.

Prevalence of Comorbidities and Racial Disparities in Anterior Uveitis Risk Among Ankylosing Spondylitis Patients

Introduction: Ankylosing spondylitis (AS) is a chronic inflammatory condition primarily affecting the axial spine, commonly associated with extra-articular manifestations such as anterior uveitis (AU). Racial disparities have been observed in the prevalence of AU among AS patients, with African American individuals often experiencing higher frequencies compared to their white counterparts. Moreover, AS is linked with various comorbidities, contributing to increased morbidity and mortality. This study aims to investigate the prevalence of AU and associated comorbidities among AS patients, with a focus on racial differences. Methods: This retrospective study utilised data from the 2020 National Inpatient Sample (NIS) database, identifying adult patients with AS admitted to hospitals in the United States. Descriptive statistics were employed to analyse demographic characteristics and comorbidity prevalence. Multivariate analysis assessed the association between AU, race, comorbidities, and inpatient outcomes. Results: Our analysis revealed significant racial disparities in the prevalence of AU among AS patients. Patients with AU tended to be younger, with a mean age of 48 years versus a mean age of 60 in patients with AS without AU. Among patients with AS without AU, 82% were Caucasians and African Americans represented 6%. Among patients with AS with AU, Caucasians represented 71% and African Americans represented 18%. In terms of outcomes, patients with a history of AU exhibited similar inpatient mortality rates (less than 1%) compared to those without (3%). Acute kidney injury (AKI) was more prevalent among patients with AU (24%) versus those without (16%) but was not statistically significant. The comorbidities commonly associated with AS include hypertension, both complicated (23%) and uncomplicated (40%), along with diabetes presenting with and without chronic complications at rates of 17% and 11%, respectively. Conclusion: Our study underscores the need for further research to elucidate the relationships between AS, AU, and comorbidities, particularly in the context of racial disparities. Improved risk assessment and early detection strategies tailored to the African American population are crucial for facilitating timely diagnosis and targeted treatment interventions for AS. Addressing these disparities and advocating for proactive management approaches can help mitigate healthcare inequities and enhance overall health outcomes for African American AS patients.

Concerns and Considerations Regarding Azithromycin Use by Physicians

Dear Editor, Azithromycin is a macrolide antibiotic that targets a wide range of bacteria. It inhibits the growth of many Gram-positive and Gram-negative bacteria, as well as other pathogens like Mycoplasma pneumoniae and Mycobacterium avium complex. Azithromycin is also used to treat bacterial enteritis, cholera, traveller's diarrhoea, as well as complicated enteric fever. It works by decreasing protein synthesis within the bacteria. Azithromycin is commonly prescribed for respiratory and genitourinary infections because of its long half-life and optimal tissue penetration. Ideal for its function, it is often preferred for some specific sexually transmitted infections like non-gonococcal urethritis and cervicitis. Besides its antibacterial properties, azithromycin also exhibits immunomodulatory effects, which can be beneficial in managing chronic respiratory inflammatory conditions. Potential adverse events include cardiovascular arrhythmias and hearing impairment. [1,2] Due to its broad-spectrum coverage, there is a rising concern about azithromycin being misused for minor ailments and not being reserved for severe life-threatening conditions. According to a 2020 review article, 5,274 cases of XDR typhoid fever were documented in Pakistan. Azithromycin remains the only feasible oral antibiotic to which XDR typhoid remains susceptible, emphasizing that only three antimicrobial drugs including azithromycin (oral), carbapenems, and tigecycline (parenteral) remain effective against extensively drug-resistant strains. [3] In a study conducted by Khan et al. in Pakistan during the COVID-19 pandemic, researchers analysed 562 blood samples of typhoid patients, out of which 71 contained Salmonella typhi. Among these, majority were MDR. The isolates exhibited complete resistance to antibiotics from the fluoroquinolone, chloramphenicol, cephalosporin, and penicillin classes. This underscores the efficacy of azithromycin and carbapenems in treating every MDR or XDR Salmonella Typhi isolate.[4] This emphasizes the urgent need to preserve and carefully manage azithromycin for treating XDR typhoid infections. In a recent systematic review conducted by Kuitunen et al., azithromycin significantly reduced the risk of sepsis in the postpartum period in mothers who received azithromycin before delivery. [5] These findings once again raise the question of whether we are using and prescribing azithromycin appropriately, as bronchitis and unspecified upper respiratory tract infections are the most common conditions for which azithromycin is prescribed in primary care. In Pakistan, this drug continues to be used as first-line management for upper respiratory tract infections in primary care settings. Physicians must exercise caution when prescribing azithromycin, considering its critical role as a potential life-saving treatment for severe conditions. ---Continue

Gastroenteropancreatic Neuroendocrine Neoplasms and Celiac Disease: Rare or Neglected Association?

Background: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare tumors originating from neuroendocrine cells in the gastroenteropancreatic system. They are increasingly recognized as being potentially associated with chronic intestinal inflammatory conditions, namely Crohn’s disease and ulcerative colitis. Celiac disease (CD) is an immune-mediated chronic gastrointestinal inflammation triggered by gluten in genetically predisposed individuals. This study aimed to explore the relationship between GEP-NENs and CD, providing a detailed review of the existing literature and addressing the (possible) gaps in current knowledge. Methods: We conducted an extensive search of international databases using relevant keywords, with the last update on 1 November 2024. A total of 19 studies, published between 1983 and 2024, were included: two prospective studies, five retrospective studies, and 12 case reports. Results: Overall, we included 107 GEP-NENs in our analysis. Among the 94 GEP-NENs identified in prospective and retrospective studies, the small intestine was the most common site (88.3%). The small intestine was also the most frequently reported site in the case report series (46.2%), accounting for 13 GEP-NENs in 12 patients with CD. Conclusions: Although most studies on the association between CD and GEP-NENs are heterogeneous, and while some lack crucial data, emerging evidence suggests that screening GEP-NEN patients for CD could offer valuable insights. Testing for the presence of CD might reveal whether the observed association is more than coincidental and possibly pave the way for exploring and understanding the role of chronic inflammation in the tumorigenesis of GEP-NENs in CD.

Glucocorticoids on bone remodeling in systemic lupus erythematosus mice.

Systemic lupus erythematosus requires glucocorticoids for management. This study investigates how glucocorticoids influence bone in a SLE mouse model, focusing on bone mineral density (BMD), microstructure, and remodeling markers. MRL/lpr and C57BL/6 mice were administered dexamethasone or saline as a control for 4-weeks. Bone assessments included analyses of BMD, bone structure, and serum levels of RANKL and OPG. Dexamethasone decreased BMD and altered cortical and trabecular bone thickness in both MRL/lpr and C57BL/6 mice. In C57BL/6 mice, cortical bone exhibited increased catabolism while trabecular bone showed signs of increased anabolism, whereas MRL/lpr mice did not show significant changes in bone turnover. Both strains experienced weight loss, with a significant decrease in femur length observed only in C57BL/6 mice. Dexamethasone exacerbated BMD reduction in MRL/lpr mice and halted its increase in C57BL/6 mice. C57BL/6 mice exhibited notable changes in cortical and trabecular bone structure, while MRL/lpr mice didn't. After receiving dexamethasone, both strains showed higher serum RANKL levels, especially in C57BL/6 mice. OPG decreased in both strains. Both glucocorticoids and SLE contribute to abnormal bone remodeling through RANKL/OPG pathway. Glucocorticoid (GC) treatment in a mouse model of systemic lupus erythematosus (SLE) leads to significant changes in bone parameters, including decreased bone mineral density (BMD) and alterations in bone structure. Those change are associated with the modulation of RANKL and OPG expression. Both GC and inflammation in SLE contribute to BMD reduction, and GC may have a certain protective effect on bone in the early stage of chronic inflammation. GC can upregulate RANKL expression and downregulate OPG expression in vivo. During a state of chronic inflammation, RANKL expression increases. However, OPG may not exert a significant influence on inflammatory stimulation.