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In secondary analyses of a randomised controlled trial of exercise during pregnancy, we examined associations between mid-pregnancy maternal body mass index (BMI) and excessive gestational weight gain (GWG) with offspring health. Follow-up data were available on 57 mother–child pairs at 1-year and 52 pairs at 7-year follow-ups. Clinical assessments included body composition and fasting blood tests. At age 1 year, increased maternal BMI in mid-gestation was associated with greater weight standard deviation scores (SDS) in the offspring (p = 0.035), with no observed associations for excessive GWG. At age 7 years, greater maternal BMI was associated with increased weight SDS (p < 0.001), BMI SDS (p = 0.005), and total body fat percentage (p = 0.037) in their children. Irrespective of maternal BMI, children born to mothers with excessive GWG had greater abdominal adiposity (p = 0.043) and less favourable lipid profile (lower HDL-C and higher triglycerides). At 7 years, maternal BMI and excessive GWG had compounded adverse associations with offspring adiposity. Compared to offspring of mothers with overweight/obesity plus excessive GWG, children of normal-weight mothers with adequate and excessive GWG were 0.97 and 0.64 SDS lighter (p = 0.002 and p = 0.014, respectively), and 0.98 and 0.63 SDS leaner (p = 0.001 and p = 0.014, respectively). Both greater maternal BMI in mid-pregnancy and excessive GWG were independently associated with increased adiposity in offspring at 7 years.

Systolic and diastolic dysfunction in diabetes have frequently been associated with abnormal calcium (Ca 2+ ) regulation. However, there is emerging evidence that Ca 2+ mishandling alone is insufficient to fully explain diabetic heart dysfunction, with focus shifting to the properties of the myofilament proteins. Our aim was to examine the effects of diabetes on myofilament Ca 2+ sensitivity and Ca 2+ handling in left ventricular tissues isolated from the same type 2 diabetic rat hearts. We measured the force-pCa relationship in skinned left ventricular cardiomyocytes isolated from 20-week-old type 2 diabetic and non-diabetic rats. Myofilament Ca 2+ sensitivity was greater in the diabetic relative to non-diabetic cardiomyocytes, and this corresponded with lower phosphorylation of cardiac troponin I (cTnI) at ser23/24 in the diabetic left ventricular tissues. Protein expression of sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA), phosphorylation of phospholamban (PLB) at Ser16, and SERCA/PLB ratio were lower in the diabetic left ventricular tissues. However, the maximum SERCA Ca 2+ uptake rate was not different between the diabetic and non-diabetic myocardium. Our data suggest that impaired contractility in the diabetic heart is not caused by SERCA Ca 2+ mishandling. This study highlights the important role of the cardiac myofilament and provides new insight on the pathophysiology of diabetic heart dysfunction.

Outer membrane vesicles (OMVs) released by some gram-negative bacteria have been shown to exert immunomodulatory effects that favor the establishment of the infection. The aim of the present study was to assess the interaction of OMVs from Brucella abortus with human epithelial cells (HeLa) and monocytes (THP-1), and the potential immunomodulatory effects they may exert. Using confocal microscopy and flow cytometry, FITC-labeled OMVs were shown to be internalized by both cell types. Internalization was shown to be partially mediated by clathrin-mediated endocytosis. Pretreatment of THP-1 cells with Brucella OMVs inhibited some cytokine responses (TNF-α and IL-8) to E. coli LPS, Pam3Cys or flagellin (TLR4, TLR2 and TLR5 agonists, respectively). Similarly, pretreatment with Brucella OMVs inhibited the cytokine response of THP-1 cells to B. abortus infection. Treatment of THP-1 cells with OMVs during IFN-γ stimulation reduced significantly the inducing effect of this cytokine on MHC-II expression. OMVs induced a dose-dependent increase of ICAM-1 expression on THP-1 cells and an increased adhesion of these cells to human endothelial cells. The addition of OMVs to THP-1 cultures before the incubation with live B. abortus resulted in increased numbers of adhered and internalized bacteria as compared to cells not treated with OMVs. Overall, these results suggest that OMVs from B. abortus exert cellular effects that promote the internalization of these bacteria by human monocytes, but also downregulate the innate immune response of these cells to Brucella infection. These effects may favor the persistence of Brucella within host cells.

[This corrects the article DOI: 10.3389/fimmu.2024.1501791.].

Brucella canis infection is an important cause of late-term abortion in pregnant bitches. The pathophysiological mechanisms leading to B. canis-induced abortion are unknown, but heavily infected trophoblasts are consistently observed. As trophoblasts responses to other pathogens contribute to placental inflammation leading to abortion, the aim of the present study was to characterize the cytokine response of canine trophoblasts to B. canis infection. To achieve this, trophoblasts isolated from term placenta of healthy female dogs were infected with B. canis, culture supernatants were harvested for cytokine determinations, and the load of intracellular viable B. canis was determined at different times post-infection. Additionally, cytokine responses were assessed in non-infected trophoblasts stimulated with conditioned media (CM) from B. canis-infected canine monocytes and neutrophils. Finally, cytokine response and bacteria replication were assessed in canine placental explants infected ex vivo. B. canis successfully infected and replicated in primary canine trophoblasts, eliciting an increase in IL-8 and RANTES (CCL5) secretion. Moreover, the stimulation of trophoblasts with CM from B. canis-infected monocytes and neutrophils induced a significant increase in IL-8, IL-6 and RANTES secretion. B. canis replication was confirmed in infected placental explants and the infection elicited an increased secretion of TNF-α, IL-8, IL-6 and RANTES. This study shows that canine trophoblasts produce proinflammatory cytokines in response to B. canis infection and/or to stimulation with factors produced by infected monocytes and neutrophils. These cytokines may contribute to placental inflammation leading to abortion in B. canis-infected pregnant bitches.

Swine brucellosis, caused by , is a worldwide infectious zoonotic disease. Currently, there are no available human or porcine vaccines to protect against infection, which is primarily acquired through the mucosa. We recently described MapB, the homologous protein of TamB, the inner membrane component of the TAM system. Our findings indicate that MapB is involved in bacterial cell envelope homeostasis. In this study, we characterize the outer membrane vesicles (OMVs) of 1330 (wt) and those of Δ (Δ ) mutant strain and evaluate their vaccine potential in mice. OMVs were isolated using the ultracentrifugation method and characterized through electron microscopy, Dynamic Light Scattering, SDS-PAGE and proteomics. Immunogenicity was assessed by intramuscular immunization of mice with wt OMVs or Δ OMVs, followed by the measurement of antigen-specific antibody levels and functional assays to evaluate the protective capacity of the antibodies. Cellular immunity was assessed by characterizing cytokine secretion through ELISA after stimulation of spleen cells with heat-killed . To determine the level of protection conferred by immunization, mice were challenged with virulent via intraperitoneal or intratracheal routes, and the bacterial load was quantified post-challenge. Dynamic Light Scattering of the OMVs from both strains revealed the presence of spherical structures of 90-130 nm. Proteomic analysis identified 94 and 95 proteins in the wt and Δ OMVs, respectively, including several known immunogens. Both OMVs showed immunoreactivity with sera from -infected pigs. Intramuscular immunization of mice with both OMVs induced antigen-specific IgG in serum, with the Δ OMVs group showing higher titers compared to the wt OMVs group. Serum antibodies from both OMVs groups reduced adherence and invasion of lung epithelial cells and enhanced its phagocytosis by macrophages. Upon antigen stimulation, spleen cells from mice immunized with Δ OMVs secreted higher levels of interleukin-17 and especially gamma interferon compared to cells from mice immunized with wt OMVs, suggesting the induction of a stronger T helper 1 response in the Δ OMVs group. While immunization with both wt and Δ OMVs achieved the same level of protection following intratracheal infection with (p<0.01), immunization with Δ OMVs provided higher levels of protection against intraperitoneal infection. Overall, these results demonstrate that the Δ OMVs are immunogenic and capable of inducing both cellular and humoral immune responses that protect against mucosal and systemic challenges.

Despite the importance of the respiratory route for Brucella transmission, the lung immune response to this pathogen is scarcely characterized. We investigated the role of the cGAS/STING pathway of microbial DNA recognition in the control of respiratory Brucella infection. After in vitro B. abortus infection, CFU numbers were significantly higher in alveolar macrophages (AM) and lung explants from STING KO mice than in samples from wild type (WT) mice, but no difference was observed for cGAS KO samples. CFU were also increased in WT AM and lung epithelial cells preincubated with the STING inhibitor H151. Several proinflammatory cytokines (TNF-α, IL-1β, IL-6, IP-10/CXCL10) were diminished in Brucella -infected lung explants and/or AM from STING KO mice and cGAS KO mice. These cytokines were also reduced in infected AM and lung epithelial cells pretreated with H151. After intratracheal infection with B. abortus , STING KO mice exhibited increased CFU in lungs, spleen and liver, a reduced expression of IFN-β mRNA in lungs and spleen, and reduced levels of proinflammatory cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and lung homogenates. Increased lung CFU and reduced BALF cytokines were also observed in cGAS KO mice. In summary, the cGAS/STING pathway induces the production of proinflammatory cytokines after respiratory Brucella infection, which may contribute to the STING-dependent control of airborne brucellosis.

No definite clinical, laboratory or imaging finding has been identified to predict prognosis and different clinical course of PMR, nor the risk of further relapses. Primary endpoint was to assess the rate of PMR patients who, during the follow-up, undergo a diagnosis of GCA and arthritis, as well as to assess which clinical, laboratory and US findings are associated to a diagnostic shift and predict the long-term evolution of PMR. Secondary endpoint was to assess the optimal use of US in PMR. All patients who were diagnosed with PMR in our Rheumatology Unit from January 2017 to January 2022 and followed-up for at least 12 months were retrospectively included. If performed at the time of diagnosis, musculoskeletal and temporal (TA) and axillary arteries (AxA) US findings were recorded, too. A total of 201 patients (mean age 73.4 ± 7.63, M/F 89/112) were included. According to the US performed at baseline, patients were subdivided in 4 subgroups: in 32 of them, the diagnosis was only clinical (A); 35 underwent shoulders, hips, wrists and knees US (B); 48 underwent shoulders, hips, TA and AxA US (C), while 86 shoulders, hips, wrists, knees, TA and AxA US (D). At baseline, 14/132 (10.6%) of patients from groups C and D displayed findings consistent with GCA. During the follow-up, 47%, 52.8% and 60% of PMR patients who were re-evaluated at 12, 24 and 36 months, respectively, had a change in diagnosis (figure 1). The multivariate logistic regression showed that bilateral LHBT tenosynovitis at onset was the variable that better defined the persistence in PMR diagnosis (p=0.05, OR 8.425), whereas GH synovitis (p=0.022, OR 0.074) and RF positivity (p=0.028, OR 0.993) were the variables associated to a diagnostic shift on the follow-up. The model that better described (AUROC 0.854) a patient with a PMR-onset with subsequent diagnostic shift comprised higher frequency of bilateral GH synovitis, bilateral shoulder PD, higher values of CRP, WBC, PLT and Hb and longer time to obtain remission. On the other hand, the ones maintaining diagnosis of PMR had bilateral exudative LHBT tenosynovitis (OR 8.425) and SA-SD bursitis (OR 2.619), higher values of ESR (OR 1.015), lower values of Hb (OR 0.428) and shorter time to remission (OR 1.076). Continuous variables were included in a hierarchical clustering analysis identifying two groups. Cluster 2 identified older patients, with lower systemic inflammation, lower levels of WBC, PLT and Hb, who had a higher persistence in PMR diagnosis at 12 (42.7% vs 29.3%), 24 (37.2% vs 25.6%) and 36 months (36.4% vs 21.2%). Cluster 2 had lower frequency of PD positivity (PD 0 in 39.1% on shoulders and 47.1% on wrists) or peripheral synovitis (absence of synovitis on knee and MCF in 43.9% and 50% respectively), more frequent flares, and were taking PDN at 12 (until 45.8%) and 24 months (until 30.8%). An environmental trigger before onset were more commonly reported (in 5,8% vaccinations before onset, vs 1.4% in cluster 1) The comparisons among the B, C and D and A showed significant differences in diagnosis at 12 (p=0.0145) and 24 months (p=0.0432) and dosage of GC at 12 months (p=0.0009). At 12 months the complete withdrawal of PDN was achieved in a significant (p=0.002) lower number of patients belonging to group A (6.4%) when compared to group B (28.1%), C (37,5%) and D (12.9%). A direct correlation was obtained between GC dosage at 12 and 24 months (Spearman rho 0.284, p=0.002). Finally, a longer time to remission correlated positively with CRP and negatively with Hb, while fever at disease onset positively with ESR. More than half patients fulfilling criteria for PMR have their diagnosis changed during follow-up. The early use of US is associated with a more accurate diagnosis at baseline, as well as to a lower cumulative dosage of PDN. The early diagnosis of GCA is possible only in case of AxA and TA US at diagnosis. On the other hand, the lack of US is associated to a prolonged PDN treatment. Patient with a definite subset of clinical (fever, short time to remission), laboratory (lower Hb and CRP, higher ESR) and US findings (lower PD signal, LHBT tenosynovitis) are more prone to maintain the diagnosis of PMR during the follow-up. NIL. NIL. None Declared. [Display omitted]

BackgroundPatients with RA experience a decline in health-related quality of life, which is associated with increased illness severity and impairment of work abilities. Central sensitization (CS) emerges as an accurate predictor and correlate of poor pain experience.ObjectivesThe purpose of this cross-sectional, multicentric study is to investigate the mediating role of CS in unfavorable relationships with disease activity levels, CS and work productivity loss due to presenteeism in women with RA, with the goal of identifying potential new targets for preventive interventions.MethodsThe study used a cross-sectional design and included 101 female workers with RA classified according to 2010American College of Rheumatology (ACR)/Europenan League Against Rhumatisms (EULAR) classification criteria. All patients filled out the italian version of the RAID, an assessment and evaluation tool that measures RA patient disease activity, progress, and outcomes. The Central sensitization Inventory (CSI) was used to measure CS, and the Work Productivity and Activity Impairment questionnaire-RA (WPAI-RA) was used to evaluate patients’ employment status. RA patients were grouped into categories, based on their RAID total score. Multiple regression analysis was used to find out which factors were most likely to presenteeism.ResultsThe patients’ age ranged from 25 to 65 years, with a disease duration of 5.4 (SD 6.1) years. The CSI score was ≥ 40 in 39/101 patients (38.6%). 70 patients (69.3%) worked full-time, while 31 (30.7%) worked part-time. The majority of respondents (64.5%) reported a high degree of presenteeism with an average level of 31.8%. On the other hand, absenteeism was uncommon, with just 7.3% of respondents reporting it. %. Presenteeism was associated with higher CSI score (0.049), increased disease activity (0.0007), disease duration (0.0072) and age (0.0019) (Table 1).ConclusionCS disease activity and age were the factor most significantly associated with presenteeism-related productivity loss in RA patients. our findings have implications for health policy and emphasize the significance of identifying high-risk RA patients by monitoring CS as an indicator of presenteeism and severe disease activity.References[1]Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics 1993;4:353–365.[2]Salaffi F, Di Carlo M, Vojinovic J, Tincani A, Sulli A, Soldano S, Andreoli L, Dall’Ara F, Ionescu R, Simić Pašalić K, Balčune I, Ferraz-Amaro I, Tlustochowicz M, Butrimienė I, Punceviciene E, Toroptsova N, Grazio S, Morović-Vergles J, Masaryk P, Otsa K, Bernardes M, Boyadzhieva V, Cutolo M. Validity of the rheumatoid arthritis impact of disease (RAID) score and definition of cut-off points for disease activity states in a population-based European cohort of patients with rheumatoid arthritis. Joint Bone Spine. 2018 May;85(3):317-322.[3]Sakai R, Tanaka E, Inoue E, Sato M, Tanaka M, Ikari K, Yamanaka H, Harigai M. Association between patient-reported outcomes and impairments in work and activity in patients with rheumatoid arthritis in clinical remission: a retrospective analysis using the IORRA database. Mod Rheumatol. 2022 Sep 12:roac105. doi: 10.1093/mr/roac105. Epub ahead of print. PMID: 36094815.Table 1.Multiple Regression Equation: Coefficients, Standard Errors and p valuesIndependent variablesCoefficientStd. ErrortP(Constant)39.8907mRDCI comorbidity score0.10490.16090.6520.5153DASS-210.069350.084910.8170.4151CSI score2.88301.26401.9940.0498ROAD score0.80981.38990.5830.5609RAID score4.47371.29033.4670.0007Kihon score-0.39210.5589-0.7020.4838Age, yrs-0.66240.2100-3.1550.0019Disease duration-0.035420.01303-2.7190.0072Acknowledgements:NIL.Disclosure of InterestsNone Declared.

BackgroundAffective distress (clinically significant depression, anxiety and stress) and central sensitization (CS) are consistently associated with the reported sensitivity and severity of pain, physical disability, poor treatment outcomes, and inflammatory disease activity, and potentially with early mortality in rheumatoid arthritis (RA).ObjectivesWe aimed to explore affective distress in patients with RA and determine how they connected to CS.MethodsUsed the CSI to measure CS and the Depression, Anxiety and Stress Scale - 21 Items (DASS-21) to evaluate the negative emotional states of depression, anxiety and stress. The total CSI score ranges from 0 to 100, and a score of 40 or greater has been established to indicate CS. Each of the three DASS-21 scales contains 7 items, divided into subscales with similar content. Multiple regression analysis was used to find out which factors were most likely to be linked to CS.ResultsOverall we included 192 RA patients (age ranging from 22 to 86 years) with a mean disease duration of 5.95 (SD 13.75) years. The CSI score was ≥ 40 in 70/192 patients (36.5%). In our RA cohort, the DASS-21 total score was 32.3 (SD29.8). The mean Anxiety score (Mean=10.68 and SD=8.92 was in the moderate range (10-14), whereas the mean Depression (Mean = 10.11 and SD = 11.66) and Stress (Mean = 15.8 and SD=12.05) scores were in the mild range (10-13 and 15-18, respectively). In the 70 patients with CSI score > 40, the mean Anxiety score (Mean=12.20 and SD=10.01) and the mean Depression (Mean = 14.01 and SD = 13.83) and Stress (Mean = 19.51 and SD=12.77) scores were all in the moderate range (10-14, 14-20 and 19-25, respectively).ConclusionAffective distress symptoms (clinically significant depression, anxiety and stress) and CS are common in RA patients. Screening and recognition of such psychosocial disorders may help patients achieve optimal disease control and a good outcome. Overall, our findings have implications for health policy and emphasize the significance of identifying high-risk fibromyalgia (FM) patients by monitoring CS as an indicator of severe disease.References[1]Bottesi G, Ghisi M, Altoè G, Conforti E, Melli G, Sica C. The Italian version of the Depression Anxiety Stress Scales-21: Factor structure and psychometric properties on community and clinical samples. Compr Psychiatry. 2015 Jul;60:170-81.[2]Ruhaila AR, Chong HC. Self-reported symptoms of depression, anxiety and stress among patients with Rheumatoid Arthritis in a Malaysian rheumatology centre - prevalence and correlates. Med J Malaysia. 2018 Aug;73(4):226-232.[3]Bacconnier L, Rincheval N, Flipo RM, Goupille P, Daures JP, Boulenger JP, Combe B. Psychological distress over time in early rheumatoid arthritis: results from a longitudinal study in an early arthritis cohort. Rheumatology (Oxford). 2015 Mar;54(3):520-7.Acknowledgements:NIL.Disclosure of InterestsNone Declared.