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The narrative ecosystem spawned by the manga Berusaiyu no Bara (henceforth referred to by its English title The Rose of Versailles) (Riyoko Ikeda, 1972-1973) and its renowned protagonist, Lady Oscar, presents itself as a paradigmatic case study in the sphere of digital television seriality. It offers significant insights for the analysis of production and distribution, inter/transmedia dynamics, and the intercultural processes of fandom. This ecosystem stands out for its ability to permeate various media formats, thereby creating a rich transmedia universe. A prime example of its success is the 12-episode anime series, which first aired in Japan in 1979. This series delineates a path reflecting the metamorphosis of media consumption and practices in contemporary mediascape. Furthermore, Lady Oscar (the name given to the anime in France and Italy, where it achieved considerable success) (1979-1980, Nippon Television) assumes a pivotal role in discussions on gender representation in popular culture. The series challenges the tenets of heterosexual romanticism and traditional gender roles, with the protagonist serving as an icon of resistance against gender norms. She offers an alternative model of identity and relationships, resonating with contemporary issues of gender and sexuality. This analysis encompasses the intercultural and transnational processes, focusing on how The Rose of Versailles has captivated an international fandom, particularly in France and Italy. The series becomes a medium for exploring universal themes such as gender identity, social conflicts, and political dynamics, illustrating how a narrative can transcend cultural and geographical boundaries, influencing the perception and discussion of social issues in various contexts. Lady Oscar exemplifies how a television series can act as a crucial medium in narrating social and cultural transformations. Through its transmedia evolution, challenging gender roles, and intercultural resonance, the series provides a unique glimpse into the interaction between production, distribution, consumption, and participation in the contemporary media landscape.

In 1938, the Italian Fascist regime enacted legislation banning foreign comics, specifically targeting the children’s press. As a result, publishers like Nerbini had to radically alter their magazines’ contents to align with the regime’s aim of using the children’s press as a tool for indoctrinating Italian youth with Fascist values. This article takes L’Avventuroso as a case study to investigate how Fascist policies influenced children’s media between 1938 and 1940 – from the ban on foreign comics to Italy’s intervention in World War II – focusing on the transition from American-inspired contents to nationalist propaganda. Through content analysis of Italian-made comics and short novels, combined with socio-historical contextualisation, the article explores the extent to which Fascist rhetoric permeated the children’s press. The analysis examines recurring themes, character archetypes, and iconography to assess the role of comics as a vehicle for propaganda. The study also employs qualitative discourse analysis to trace the alignment of narrative structures with Fascist ideology. By examining nationalistic and propaganda contents in L’Avventuroso, the article provides a nuanced understanding of how Fascist policies at the onset of World War II influenced the publishing of comics, offering insights into the regime’s use of children’s media as a tool for propaganda.

Red blood cells (RBCs) are recognized to be important pathogenetic determinants in several human cardiovascular diseases (CVD). Undergoing to functional alterations when submitted to risk factors, RBCs modify their own intracellular signaling and the redox balance, shift their status from antioxidant defense to pro-oxidant agents, become a potent atherogenic stimulus playing a key role in the dysregulation of the vascular homeostasis favoring the developing and progression of CVD. Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a significantly increased risk of cardiovascular mortality with a prevalence from two to five more likely in woman, mainly attributed to accelerated atherosclerosis. The purpose of this study was to correlate the RA disease activity and the RBCs functional characteristics. Thirty-two women (aged more than 18 years) with RA, and 25 age-matched healthy women were included in this study. The disease activity, measured as the number of swollen and painful joints (DAS-28), was correlated with 1) the expression of RBCs estrogen receptors, which modulate the RBC intracellular signaling, 2) the activation of the estrogen-linked kinase ERK½, which is a key regulator of RBC adhesion and survival, and 3) the levels of inflammatory- and oxidative stress-related biomarkers, such as the acute-phase reactants, the antioxidant capacity of plasma, the reactive oxidizing species formation and 3-nitrotyrosine. All the biomarkers were evaluated in RA patients at baseline and 6 months after treatment with disease-modifying anti-rheumatic drugs (DMARDs). We found, for the first times, that in RA patients 1) the DAS-28 correlated with RBC ER-α expression, and did not correlate with total antioxidant capacity of plasma; 2) the RBC ER-α expression correlated with systemic inflammatory biomarkers and oxidative stress parameters, as well as ERK½ phosphorylation; and 3) the DMARDs treatments improved the clinical condition measured by DAS-28 score decrease, although the RBCs appeared to be more prone to pro-oxidant status associated to the expression of survival molecules. These findings represent an important advance in the study of RA determinants favoring the developing of CVD, because strongly suggest that RBCs could also participate in the vascular homeostasis through fine modulation of an intracellular signal linked to the ER-α.

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease. Modifications of gut microbiota seem to be associated with the disease, but the impact of gut microbiota on therapies’ outcome remains unclear. A role of T cells in RA pathogenesis has been addressed, particularly on the Th17/Treg cells balance. Our study aimed to evaluate in early RA (ERA) patients compared to a control group, fecal gut microbiota composition, short-chain fatty acids concentrations, and the levels of circulating Th17/Treg and their own cytokines, before and after 3 months of standard treatment (Methotrexate (MTX) plus glucocorticoids). Fecal microbiota characterization was carried out on 19 ERA patients and 20 controls matched for sex and age. Significant decreased biodiversity levels, and a partition on the base of the microbiota composition, between the ERA patients at baseline compared to controls, were observed. The co-occurrent analysis of interactions revealed a characteristic clustered structure of the microbial network in controls that is lost in ERA patients where an altered connection between microbes and clinical parameters/metabolites has been reported. Microbial markers such as Acetanaerobacterium elongatum, Cristiansella massiliensis, and Gracilibacter thermotolerans resulted significantly enriched in control group while the species Blautia gnavus emerged to be more abundant in ERA patients. Our results showed an alteration in Th17/Treg balance with higher Th17 levels and lower Treg levels in ERA group respect to control at baseline, those data improved after therapy. Treatment administration and the achievement of a low disease activity/remission appear to exert a positive pressure on the structure of intestinal microbiota with the consequent restoration of biodiversity, of the structure of microbial network, and of the abundance of taxa that became closer to those presented by the subject without the disease. We also found an association between Blautia gnavus and ERA patients characterized by a significant reduction of propionic acid level. Furthermore significant differences highlighted at baseline among controls and ERA patients are no more evident after treatment. These data corroborate the role played by gut microbiota in the disease and suggest that therapy aimed to restore gut microbiota would improve treatment outcome.

Abstract The aim of the study was to investigate the presence of subclinical vascular damage in polymyalgia rheumatica (PMR). We enrolled PMR patients having major cardiovascular risk factors (MCVRF) and, as controls, patients with MCVRF. All underwent: color Doppler ultrasound to evaluate the common carotid intima-media thickness (IMT), the anterior–posterior abdominal aortic diameter (APAD), and the prevalence of carotid artery stenosis; the cardio-ankle vascular index (CAVI) to measure arterial stiffness together with the ankle-brachial index (ABI) to investigate the presence of lower-extremity peripheral arterial disease. Finally, we measured the serum levels of adipocytokines implicated in vascular dysfunction. As a result, 48 PMR and 56 MCVRF patients were included. An increase of IMT (1.07/0.8–1.2 vs 0.8/0.8–1.05; p = 0.0001), CAVI (8.7/7.8–9.3 vs 7.6/6.9–7.8; p

The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. Here, we investigate the role of MLM on natural killer (NK) cells in the same patients. Twenty-nine FM and twelve OA patients were analyzed, and twenty-three pain-free subjects were considered as the control group. Blood samples were collected to perform immunophenotyping and Western blot analysis. Biological and clinical data were statistically analyzed. The final results showed that the percentage of NK cells expressing Mu was statistically lower in FM and OA patients than in pain-free subjects, as already demonstrated for B cells. A Western blot analysis was performed in order to detect NK cells’ functional status. Moreover, the correlation analysis of MLM expression with pharmacological therapy did not show any significant results. In conclusion, here, we confirm the role of MLM as a suitable marker for chronic pain and underline NK cells as a new possible immune cell type involved in the “Mu opioid receptor reserve theory”.

BackgroundScreening for latent tuberculosis infection is recommended in patients with rheumatoid arthritis (RA) starting Janus kinase inhibitors (Jaki). Interferon (IFN)-gamma release assays (IGRAs) are increasingly used for this purpose. Jaki tend to decrease the levels of IFNs, questioning the reliability of IGRAs during treatment with these drugs.ObjectivesTo compare the performance of QuantiFERON-TB Gold Plus (QFT-P) and QFT Gold In-tube (QFT-GIT) in RA patients treated with Jaki.MethodsRA patients underwent QFT-P and QFT-GIT at baseline (T0), and after 3 (T3) and 12 months (T12) of treatment with Jaki. The agreement between the two tests was calculated. The agreement between IGRAs and tuberculin skin test (TST) or chest radiography at baseline was also determined. The variability of QTF-P results was longitudinally assessed.ResultsTwenty-nine RA patients (F/M 23/6; median age/IQR 63/15.5 years; median disease duration/IQR 174/216 months) were enrolled. A perfect agreement was found between QFT-P and QFT-GIT at all times (κ = 1). At T0, no agreement was recorded between IGRAs and TST (κ = -0.08) and between TST and chest radiography (κ = -0.07), a low agreement was found between QFT-P and chest radiography (κ = 0.17). A variation of 33.3% in the results of QFT-P was recorded at T3 vs T0, of 29.4% at T12 vs T0, and of 11.8% at T12 vs T3. The median levels of IFN-γ produced by lymphocytes in response to the mitogen of QFT-P decreased after 3 months followed by an increase after 12 months (not significant). No change in the median number of circulating lymphocytes was documented. Glucocorticoids intake was associated with a higher probability of negative or indeterminate IGRA results at T0 (pConclusionA response to IGRAs is detectable during treatment with Jaki. However, fluctuations in the results of IGRAs have been observed in the absence of correlation with clinical outcomes, thus challenging their interpretation.

Background Screening for latent tuberculosis infection is recommended in patients with rheumatoid arthritis (RA) starting Janus kinase inhibitors (Jaki). Interferon (IFN)-gamma release assays (IGRAs) are increasingly used for this purpose. Jaki tend to decrease the levels of IFNs, questioning the reliability of IGRAs during treatment with these drugs. Objectives To compare the performance of QuantiFERON-TB Gold Plus (QFT-P) and QFT Gold In-tube (QFT-GIT) in RA patients treated with Jaki. Methods RA patients underwent QFT-P and QFT-GIT at baseline (T0), and after 3 (T3) and 12 months (T12) of treatment with Jaki. The agreement between the two tests was calculated. The agreement between IGRAs and tuberculin skin test (TST) or chest radiography at baseline was also determined. The variability of QTF-P results was longitudinally assessed. Results Twenty-nine RA patients (F/M 23/6; median age/IQR 63/15.5 years; median disease duration/IQR 174/216 months) were enrolled. A perfect agreement was found between QFT-P and QFT-GIT at all times (κ = 1). At T0, no agreement was recorded between IGRAs and TST (κ = -0.08) and between TST and chest radiography (κ = -0.07), a low agreement was found between QFT-P and chest radiography (κ = 0.17). A variation of 33.3% in the results of QFT-P was recorded at T3 vs T0, of 29.4% at T12 vs T0, and of 11.8% at T12 vs T3. The median levels of IFN-γ produced by lymphocytes in response to the mitogen of QFT-P decreased after 3 months followed by an increase after 12 months (not significant). No change in the median number of circulating lymphocytes was documented. Glucocorticoids intake was associated with a higher probability of negative or indeterminate IGRA results at T0 (pConclusion A response to IGRAs is detectable during treatment with Jaki. However, fluctuations in the results of IGRAs have been observed in the absence of correlation with clinical outcomes, thus challenging their interpretation.

Background Fibromyalgia is a chronic pain syndrome which occurs in the absence of an organic damage, whom causes is still unclear. Aims of this pilot study were to investigate the neural correlates of fibromyalgia in response to pain-related visual stimuli and explore the psychological differences among fibromyalgia, chronic low back pain (CLBP) and healthy conditions. Methods After a clinical assessment, electrophysiological responses to pain-related visual stimuli were recorded using a 256-Hydrocel Geodesic-Sensor-Net. Event-related potentials (ERPs), standardised low-resolution electromagnetic tomography (sLORETA), and psychological (Symptom Checklist-90-Revised) data were analysed for a total sample of 23 women (5 healthy volunteers, 12 fibromyalgia patients, 6 CLBP patients). Results The main finding was that fibromyalgia women reported a different brain response to pain-related visual stimuli on the frontal montage compared to women with CLBP ( p = .028). Moreover, fibromyalgia women showed an increased activity mainly on the hippocampus ( p = .003) and the posterior cingulate cortex ( p ≤ .001) in response to algic stimuli compared to not algic ones. Lastly, these women presented higher scores on the somatization ( p = .002), obsession-compulsion ( p = .045), depression ( p = .043) and positive symptom distress ( p = .023) dimensions compared to the healthy women. Conclusions These preliminary results suggest that although the painful symptoms are similar, the central elaboration of pain could be different between women with fibromyalgia and those with CLBP. Moreover, these findings provide preliminary evidences about the great alert and the central sensitivity to pain-related information regarding fibromyalgia patients.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with increased risk of cardiovascular events and mortality that can be attributed to accelerated atherosclerosis. This pilot study aimed to investigate if changes in blood parameters were compatible with atherosclerotic events in RA patients. To this aim, 45 RA women (aged more than 18 years), and 25 age and gender‐matched healthy donors (HD) were included. Biomarkers of oxidative stress, platelet activation and platelet aggregation were analysed in RA patients at baseline and after six months of treatment with disease modifying anti‐rheumatic drugs (DMARDs). Flow cytometry analysis revealed that ca. 4% of platelets was in activated state (evaluated in term of Annexin V and PAC‐1 positivity) in RA patients at baseline, and that the 76% of platelets displayed mitochondrial hyperpolarization. Moreover, platelets from RA patients at baseline aggregated more than those from HD after whole blood treatment with adenosine diphosphate. Interestingly, platelet aggregation in patients at baseline positively correlated with disease activity measured by DAS28 score. After six months of treatment with DMARDs, platelet activation and platelet aggregation reached values comparable to those of HD. Our preliminary data suggest that platelets might play an active role in the atherosclerosis occurring in RA patients.

Abstract Background Rheumatoid arthritis (RA) patients carry a high risk of cardiovascular morbidity and mortality. The excess of cardiovascular disease cannot be entirely explained by traditional risk factors and the immune system contributes to the development of atherosclerosis. Moreover, post-translational modifications such as citrullination and carbamylation have been linked to inflammation and atherosclerosis. Anti-carbamylated proteins antibodies (anti-CarP) are a new subset of autoantibodies identified in RA patients. This study aimed to investigate a possible association between anti-CarP and subclinical atherosclerosis in RA patients. Methods We enrolled RA patients and normal healthy controls (NHS) without known cardiovascular risk factors or heart disease. Cardiovascular risk was assessed using the Modified Systemic Coronary Risk Evaluation (mSCORE). Anti-CarP were investigated by a solid phase “home-made” ELISA. Anti-citrullinated protein antibodies (ACPA) and Rheumatoid Factor (RF) were investigated by ELISA assays. Subclinical atherosclerosis was evaluated by brachial artery Flow-Mediated Dilatation (FMD) and Carotid Intima-Media Thickness (c-IMT) while arterial stiffness by Ankle-Brachial Index (ABI) and Cardio-Ankle Vascular Index (CAVI). Results We enrolled 50 RA patients (34 F and 16 M, mean age 58.4 ± 13.1 years, mean disease duration 127 ± 96.7 months) and 30 age and sex matched NHS. According to the mSCORE, 58% of patients had a low risk, 32% a moderate and 8% a high risk for cardiovascular disease. FMD was significantly lower in RA patients than in NHS (5.6 ± 3.2 vs 10.7 ± 8.1%; p

Autophagy is a degradation mechanism by which cells recycle cytoplasmic components to generate energy. By influencing lymphocyte development, survival, and proliferation, autophagy regulates the immune responses against self and non-self antigens. Deregulation of autophagic pathway has recently been implicated in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis (RA). Indeed, autophagy seems to be involved in the generation of citrullinated peptides, and also in apoptosis resistance in RA. In this review, we summarize the current knowledge on the role of autophagy in RA and discuss the possibility of a clinical application of autophagy modulation in this disease.

Cardiovascular disease is the main cause of morbidity and mortality in rheumatoid arthritis (RA). Despite the advent on new drugs targeting the articular manifestations, the burden of cardiovascular disease is still an unmet need in the management of RA. The pathophysiology of accelerated atherosclerosis associated to RA is not yet fully understood, and reliable and specific markers of early cardiovascular involvement are still lacking. Asymmetric dimethylarginine is gaining attention for its implication in the pathogenesis of endothelial dysfunction and as biomarkers of subclinical atherosclerosis. Moreover, the metabolic pathway of methylarginines offers possible targets for therapeutic interventions to decrease the cardiovascular risk. The purpose of this review is to describe the main causes of increased methylarginine levels in RA, their implication in accelerated atherosclerosis, the possible role as biomarkers of cardiovascular risk, and finally the available data on current pharmacological treatment.

Mucosal surfaces play a central role in the pathogenesis of rheumatoid arthritis (RA). Several risk factors, such as cigarette smoking, environmental pollution, and periodontitis interact with the host at the mucosal level, triggering immune system activation. Moreover, the alteration of microbiota homeostasis is gaining increased attention for its involvement in the disease pathogenesis, modulating the immune cell response at a local and subsequently at a systemic level. Currently, the onset of the clinical manifest arthritis is thought to be the last step of a series of pathogenic events lasting years. The positivity for anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), in absence of symptoms, characterizes a preclinical phase of RA—namely systemic autoimmune phase- which is at high risk for disease progression. Several immune abnormalities, such as local ACPA production, increased T cell polarization towards a pro-inflammatory phenotype, and innate immune cell activation can be documented in at-risk subjects. Many of these abnormalities are direct consequences of the interaction between the environment and the host, which takes place at the mucosal level. The purpose of this review is to describe the humoral and cellular immune abnormalities detected in subjects at risk of RA, highlighting their origin from the mucosa−environment interaction.

Atherosclerosis is accelerated in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We investigated a possible association of oxidized low-density lipoproteins (ox-LDLs), nitric oxide (NO), 3-nitrotyrosine, vitamin A, vitamin E, and β-carotene serum levels with subclinical atherosclerosis in RA and PsA. By the use of ELISA, we observed higher ox-LDL levels in patients with intima-media thickness (IMT) > 1 than in patients with IMT ≤ 1 and a negative correlation between NO levels and IMT values. By the use of high-performance liquid chromatography, we determined higher levels of vitamin A in patients with PsA and IMT ≤ 1 than in controls and lower levels of β-carotene in patients with RA and PsA than in controls. β-carotene concentrations were negatively correlated to the duration of disease in RA. Our study confirms that ox-LDLs and NO may be markers of accelerated atherosclerosis in RA and PsA whereas vitamins seem to be associated only to the presence of the autoimmune disorders.

Objectives. Impaired endothelial function represents the early stage of atherosclerosis, which is typically associated with systemic inflammatory diseases like rheumatoid arthritis (RA). As modulators of endothelial nitric oxide synthase expression, asymmetric-dimethylarginine (ADMA) and apelin might be measured in the blood of RA patients to detect early atherosclerotic changes. We conducted a prospective, case-control study to investigate serum ADMA and apelin profiles of patients with early-stage RA (ERA) before and after disease-modifying antirheumatic drug (DMARD) therapy. Methods. We enrolled 20 consecutively diagnosed, treatment-naïve patients with ERA and 20 matched healthy controls. Serum ADMA and apelin levels and the 28-joint disease activity scores (DAS28) were assessed before and after 12 months of DMARDs treatment. All patients underwent ultrasonographic assessment for intima-media tickness (IMT) evaluation. Results. In the ERA group, ADMA serum levels were significantly higher than controls at baseline (P=0.007) and significantly decreased after treatment (P=0.012 versus controls). Baseline serum apelin levels were significantly decreased in this group (P=0.0001 versus controls), but they were not significantly altered by treatment. IMT did not show significant changes. Conclusions. ERA is associated with alterations of serum ADMA and apelin levels, which might be used as biomarkers to detect early endothelial dysfunction in these patients.