Innate Immunity and Sex: Distinct Inflammatory Profiles Associated with Murine Pain in Acute Synovitis.

Joint pain severity in arthritic diseases differs between sexes and is often more pronounced in women. This disparity is thought to stem from biological mechanisms, particularly innate immunity, yet the understanding of sex-specific differences in arthritic pain remains incomplete. This study aims to investigate these disparities using an innate immunity-driven inflammation model induced by intra-articular injections of Streptococcus Cell Wall fragments to mimic both acute and pre-sensitized joint conditions. Nociceptive behavior was evaluated via gait analysis and static weight-bearing, and inflammation was evaluated via joint histology and the synovial gene expression involved in immune response. Although acute inflammation and pain severity were comparable between sexes, distinct associations between synovial inflammatory gene expression and static nociceptive behavior emerged. These associations delineated sex-specific relationships with pain, highlighting differential gene interactions (Il6 versus Cybb on day 1 and Cyba/Gas6 versus Nos2 on day 8) between sexes. In conclusion, our study found that, despite similar pain severity between sexes, the association of inflammatory synovial genes revealed sex-specific differences in the molecular inflammatory mechanisms underlying pain. These findings suggest a path towards more personalized treatment strategies for pain management in arthritis and other inflammatory joint diseases.

A genderful research world: rapid review, design, and pilot study of an interactive platform for curated sex and gender health research resources.

BACKGROUND: Integration of sex and gender into health research is best practice for designing and conducting equitable, rigorous scientific research. Many evidence-based resources exist to support researchers in this endeavour, but such resources often remain underutilized as they are difficult to find, are not publicly accessible, or are specific to a particular research phase, context, or population. The development and evaluation of a repository of resources was deemed important to create an accessible platform for promoting sex- and gender-integration in health research. METHODS: A rapid review was conducted of critical resources for conducting sex and gender health research. These were integrated into a prototype website design (the Genderful Research World; GRW) that provided an interactive digital landscape for researchers to access these resources. A pilot study evaluated the GRW website for applicability, desirability, and usability with an international sample of 31 health researchers from various disciplines and career stages. Quantitative data from the pilot study was summarized with descriptive statistics. Qualitative data was summarized narratively and used to identify concrete elements for improvement in a second design iteration. RESULTS: Results of the pilot study revealed that the GRW was considered user friendly and desirable by health researchers and helped them access relevant information. Feedback suggested that providing these resources in a playful way may enhance the experience of the user, particularly given the high 'desirability' scores and that users emphasized the interactive layout as being key to their intention to integrate it into their teaching endeavors. Key feedback from the pilot study (e.g., addition of resources specific to research with transgender populations, revision of website layout) was integrated into the current version of the website: www.genderfulresearchworld.com . CONCLUSIONS: The present research suggests a utility for a repository of resources for integrating sex and gender considerations into research, and that providing a logical, intuitive means of cataloguing and navigating such resources is critical for usability. The results of this study may inform the development of other novel researcher-directed resource curation efforts to address health equity issues and encourage and support health researchers to integrate a sex and gender perspective in their work.

Early pain in females is linked to late pathological features in murine experimental osteoarthritis.

Background: Osteoarthritis (OA) is a progressive joint disease and a major cause of chronic pain in adults. The prevalence of OA is higher in female patients, who tend to have worse OA outcomes, partially due to pain. The association between joint pain and OA pathology is often inconclusive. Preclinical research studies have largely overlooked sex as a potential determinant in joint pain during OA. This study aimed to investigate the role of sex in joint pain in the collagenase-induced OA (CiOA) model and its link with joint pathology. Methods: Multiple aspects of pain were evaluated during identically executed experiments of CiOA in male and female C57BL/6J mice. Cartilage damage, osteophyte formation, synovial thickness, and cellularity were assessed by histology on day 56. The association between pain and pathology was investigated, disaggregated by sex. Results: Differences in pain behavior between sexes were found in the majority of the evaluated pain methods. Females displayed lower weight bearing ability in the affected leg compared to males during the early phase of the disease, however, the pathology at the end stage was comparable between sexes. In the second cohort, males displayed increased mechanical sensitivity in the affected joint compared to females but also showed more cartilage damage at the end stage of the model. Within this cohort, gait analysis showed varied results. Males used the affected paw less often and displayed dynamic weight-bearing compensation in the early phase of the model. These differences were not observed in females. Other evaluated parameters displayed comparable gait behavior between males and females. A detailed analysis of individual mice revealed that seven out of 10 pain measurements highly correlated with OA histopathology in females (Pearson r range: 0.642-0.934), whereas in males this measurement was only two (Pearson r range: 0.645-0.748). Conclusion: Our data show that sex is a determinant in the link between pain-related behavior with OA features. Therefore, to accurately interpret pain data it is crucial to segregate data analysis by sex to draw the correct mechanistic conclusion.

Gas6/Axl Axis Activation Dampens the Inflammatory Response in Osteoarthritic Fibroblast-like Synoviocytes and Synovial Explants.

Osteoarthritis (OA) is the most prevalent joint disease, and it is characterized by cartilage degeneration, synovitis, and bone sclerosis, resulting in swelling, stiffness, and joint pain. TAM receptors (Tyro3, Axl, and Mer) play an important role in regulating immune responses, clearing apoptotic cells, and promoting tissue repair. Here, we investigated the anti-inflammatory effects of a TAM receptor ligand, i.e., growth arrest-specific gene 6 (Gas6), in synovial fibroblasts from OA patients. TAM receptor expression was determined in synovial tissue. Soluble Axl (sAxl), a decoy receptor for the ligand Gas6, showed concentrations 4.6 times higher than Gas6 in synovial fluid of OA patients. In OA fibroblast-like synoviocytes (OAFLS) exposed to inflammatory stimuli, the levels of sAxl in the supernatants were increased, while the expression of Gas6 was downregulated. In OAFLS under TLR4 stimulation by LPS (Escherichia coli lipopolysaccharide), the addition of exogenous Gas6 by Gas6-conditioned medium (Gas6-CM) reduced pro-inflammatory markers including IL-6, TNF-α, IL-1ß, CCL2, and CXCL8. Moreover, Gas6-CM downregulated IL-6, CCL2, and IL-1ß in LPS-stimulated OA synovial explants. Pharmacological inhibition of TAM receptors by a pan inhibitor (RU301) or by a selective Axl inhibitor (RU428) similarly abrogated Gas6-CM anti-inflammatory effects. Mechanistically, Gas6 effects were dependent on Axl activation, determined by Axl, STAT1, and STAT3 phosphorylation, and by the downstream induction of the suppressors of the cytokine signaling family (SOCS1 and SOCS3). Taken together, our results showed that Gas6 treatment dampens inflammatory markers of OAFLS and synovial explants derived from OA patients associated with SOCS1/3 production.

Innate Immunity at the Core of Sex Differences in Osteoarthritic Pain?

Osteoarthritis (OA) is a progressive whole-joint disease; no disease-modifying drugs are currently available to stop or slow its process. Symptoms alleviation is the only treatment option. OA is the major cause of chronic pain in adults, with pain being the main symptom driving patients to seek medical help. OA pathophysiology is closely associated with the innate immune system, which is also closely linked to pain mediators leading to joint pain. Pain research has shown sex differences in the biology of pain, including sexually dimorphic responses from key cell types in the innate immune system. Not only is OA more prevalent in women than in men, but women patients also show worse OA outcomes, partially due to experiencing more pain symptoms despite having similar levels of structural damage. The cause of sex differences in OA and OA pain is poorly understood. This review provides an overview of the involvement of innate immunity in OA pain in joints and in the dorsal root ganglion. We summarize the emerging evidence of sex differences regarding innate immunity in OA pain. Our main goal with this review was to provide a scientific foundation for future research leading to alternative pain relief therapies targeting innate immunity that consider sex differences. This will ultimately lead to a more effective treatment of pain in both women and men.

Visual impairment and blindness in the Xingu Indigenous Park - Brazil.

BACKGROUND: Most estimates of visual impairment and blindness worldwide do not include data from specific minority groups as indigenous populations. We aimed to evaluate frequencies and causes of visual impairment and blindness in a large population sample from the Xingu Indigenous Park. METHODS: Cross-sectional study performed at Xingu Indigenous Park, Brazil, from 2016 to 2017. Residents from 16 selected villages were invited to participate and underwent a detailed ocular examination, including uncorrected (UVA) and best-corrected visual acuity (BCVA). The main cause of UVA < 20/32 per eye was determined. RESULTS: A total of 2,099 individuals were evaluated. Overall, the frequency of visual impairment and blindness was 10.00% (95% CI: 8.72-11.29%) when considering UVA, decreasing to 7.15% (95% CI: 6.04-8.25%) when considering BCVA. For each increasing year on age, the risk  of being in the visually impaired or blind category increased by 9% (p < 0.001). Cataracts (39.1%) and uncorrected refractive errors (29.1%) were the most frequent causes of visual impairment and blindness in this population. The main causes among those aged 45 years and more were cataracts (54.5%) while refractive errors were the main cause in adults aged 18 to 45 years (50.0%) and children up to 18 years old (37.1%). CONCLUSIONS: A higher frequency of visual impairment and blindness was observed in the indigenous population when compared to worldwide estimates with most of the causes being preventable and/or treatable. Blindness prevention programs should focus on accessibility to eye exam, cataract surgeries and eyeglass distribution.

Cicatricial ectropion secondary to psoriatic arthritis.

Ectropion is characterized by the eversion of the eyelid margin and the consequent exposure of the conjunctiva and cornea. The shortening of the anterior lamella of the lid causes cicatricial ectropion. We described a case of skin pathology causing cicatricial ectropion. The case is about a 68-year-old woman with a 2-year history of psoriatic arthritis. She complained of eyelid tearing and redness for two years. Due to the psoriasis, she presented a very dry skin, also in the periocular region, resulting in cicatricial ectropion. A skin graft was indicated to correct the eyelid malposition. Careful investigation should be performed in patients who have a skin disease that can lead to cicatricial ectropion.

Prevalence of temporomandibular disorders in obstructive sleep apnea patients referred for oral appliance therapy.

AIMS: To evaluate the prevalence of pain associated with temporomandibular disorders (TMD) in obstructive sleep apnea syndrome (OSAS) patients referred for oral appliance therapy. METHODS: Eighty-seven patients (46 men and 41 women), between 18 and 65 years of age, with an apnea-hypopnea index (AHI) of > 5 and < 30 (events by sleep hour), and body mass index (BMI) of =or< 30 Kg/m(2) were evaluated according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) to determine the presence of signs and symptoms of TMD. Statistical analyses included correlations assessed by Pearson's test. RESULTS: Fifty-two percent of patients presented symptoms of TMD. Thirty-two patients (average age 47 +/- 11 years, AHI 17.3 +/- 8.7, BMI 25.9 +/- 3.8 kg/m(2)) completed the study. According to the Scoring Protocol for Graded Chronic Pain (Axis II-RDC/TMD), 75% of the patients presented chronic pain related to TMD, categorized as low disability grade I (< 50 points for pain intensity, and < 3 disability points). The most common TMD diagnosis was myofascial pain with and without limited mouth opening and arthralgia (50%). CONCLUSION: The high prevalence of TMD in the current study indicates that patients with OSAS referred for oral appliance therapy require specific evaluation related to TMD.