Toxicity and bioaccumulation of the fluorosurfactant cC6O4 in the earthworm Eisenia foetida (Savigny, 1826).

Cyclic C6O4 (cC6O4, CAS number 1190931-27-1) is a perfluoralkyl ether PFAS used as a polymerization aid in the synthesis of fluoropolymers and produced in Italy since 2011 as substitute of PFOA. To date, available ecotoxicological information on cC6O4 is related to regulatory requirements and limited to data on aquatic organisms, while the information on the effects for terrestrial organisms is completely lacking. This work reports the first ecotoxicological data of cC6O4 on terrestrial invertebrates: short- and long-term toxicity of cC6O4 on Eisenia foetida (Savigny, 1826), exposed to spiked soil under laboratory conditions, was investigated evaluating the earthworm survival and growth (observed after 7, 14 and 28 days of exposure), and reproduction (observed after an exposure period of 56 days). Furthermore, also bioaccumulation was investigated (28 days of exposure); overall results are discussed in comparison with literature data available for legacy PFAS. cC6O4 did not cause significant mortality on earthworms, for any of the tested concentrations and exposure periods (NOEC: > 1390 mg/kg d.w.), while the reproduction (measured as juveniles production) appears to be a more sensitive endpoint (EC50: 10.4 mg/kg d.w., EC10: 0.8 mg/kg d.w.). The observed adverse effects occur at levels significantly higher than realistic soil concentrations and cC6O4 appears to be less toxic than PFOA and PFOS. As for bioaccumulation, the results indicate a negligible bioaccumulation potential of cC6O4, whose Biota-Soil Bioaccumulation Factors (BSAF) are significantly lower than all other considered PFAS.

Imatinib-loaded gold nanoparticles inhibit proliferation of fibroblasts and macrophages from systemic sclerosis patients and ameliorate experimental bleomycin-induced lung fibrosis.

Interstitial lung involvement in Systemic Sclerosis (SSc-ILD) is a complication with high morbidity and mortality. Specifically, engineered gold nanoparticles (GNPs) are proposed as targeted delivery system increasing efficacy of drugs with antifibrotic effect, such as tyrosine kinases. We aimed to test in vitro and in vivo the activity of targeted Imatinib (Im)-loaded GNP on SSc-ILD patients derived cells and in experimental model of lung fibrosis. GNPs functionalized with anti-CD44 and loaded with Im (GNP-HCIm) were synthesized. Lung fibroblasts (LFs) and alveolar macrophages from bronchoalveolar lavage fluids of SSc-ILD patients were cultured in presence of nanoparticles. GNP-HCIm significantly inhibited proliferation and viability inducing apoptosis of LFs and effectively reduced IL-8 release, viability and M2 polarization in alveolar macrophages. Anti-fibrotic effect of tracheal instilled GNP-HCIm was evaluated on bleomycin lung fibrosis mouse model comparing effect with common route of Im administration. GNP-HCIm were able to reduce significantly lung fibrotic changes and collagen deposition. Finally, electron microscopy revealed the presence of GNPs inside alveolar macrophages. These data support the use of GNPs locally administered in the development of new therapeutic approaches to SSc-ILD.

First Report of the Italian Registry on Immune-Mediated Congenital Heart Block (Lu.Ne Registry).

Objective: Neonatal Lupus (NL) is a rare syndrome caused by placental transfer of maternal anti-SSA/Ro and anti-La/SSB autoantibodies to the fetus. The rarity of this condition requires the establishment of multidisciplinary registries in order to improve our knowledge. Method: Inclusion criteria in this retrospective study were the maternal confirmed positivity for anti-SSA/Ro and/or anti-SSB/La antibodies, and the presence of II or III degree congenital heart block (CHB) in utero or neonatal period (up to 27 days after birth). Result: Eighty-nine cases of CHB were observed in 85 women with 88 pregnancies that occurred between 1969 and 2017. CHB was mostly detected in utero (84 cases, 94.2%), while five cases were observed in the neonatal period. A permanent pacemaker was implanted in 51 of 73 children born alive (69.8), whereas global mortality rate was 25.8% (23 cases): 16 in utero, five perinatal, and two during childhood. By univariate analysis, factors associated with fetal death were pleural effusion (p = 0.005, OR > 100; CI 95% 2.88->100 and hydrops (p = 0.003, OR = 14.09; CI 95% 2.01-122). Fluorinated steroids (FS) were administered in 71.4% pregnancies, and its use was not associated with better survival. Some centers treated all cases with fluorinated steroids and some centers did not treat any case. CHB was initially incomplete in 24 fetuses, and of them five cases of II degree block reverted to a lower degree block after treatments. Recurrence rate in subsequent pregnancies was 17.6% (3 out of 17). A prophylactic treatment was introduced in 10 of these 16 subsequent (58.8%) pregnancies, mostly with FS or high dose intravenous immunoglobulins. Conclusion: This is the first report from the Italian Registry of neonatal lupus/CHB. The live birth rate was nearly 80%, with nearly two thirds of the children requiring the implantation of a pacemaker. The management of fetuses diagnosed with CHB was heterogeneous across Italian Centers. The registry at present is mainly rheumatological, but involvement of pediatric cardiologists and gynecologists is planned.

Pregnancy in systemic sclerosis.

This comprehensive review summarizes retrospective and prospective studies on pregnancy in systemic sclerosis in order to educate physicians on critical management issues. Fertility is normal in women with established systemic sclerosis. Their rates of spontaneous losses are comparable to the general population, except for patients with late diffuse systemic sclerosis and severe internal organ involvement who may have higher risks of abortion. Prematurity is clearly higher among systemic sclerosis women, similarly to other rheumatic diseases such as systemic lupus erythematosus and anti-phospholipid antibody syndrome. A placental vasculopathy has been observed in some women with systemic sclerosis. Overall, the disease generally remains stable in most pregnancies. Women with pulmonary hypertension should avoid pregnancy on account of the high maternal mortality risk. Management of systemic sclerosis patients before and during pregnancy includes evaluation of organ involvement and autoantibody analysis, preconceptional folic acid, and discontinuation of drugs with teratogenic potential (bosentan, mycophenolate mofetil, methotrexate, etc.). Management by high-risk pregnancy teams including neonatologists is very important to ensure the best outcomes.

Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis.

OBJECTIVES: Notch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice. METHODS: Notch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments. RESULTS: Notch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1. CONCLUSIONS: Inhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA.

Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologic treatment: Extending perspective from old to newer drugs.

Hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients undergoing biological therapy is not infrequent. This condition can occur in patients with chronic hepatitis B as well as in patients with resolved HBV infection. Current recommendations are mainly focused on prevention and management strategies of viral reactivation under tumor necrosis factor-α inhibitors or chimeric monoclonal antibody rituximab. In recent years, growing data concerning HBV reactivation in RA patients treated with newer biological drugs like tocilizumab and abatacept have cumulated. In this review, epidemiology, pathogenesis and natural history of HBV infection have been revised first, mainly focusing on the role that specific therapeutic targets of current biotechnological drugs play in HBV pathobiology; finally we have summarized current evidences from scientific literature, including either observational studies and case reports as well, concerning HBV reactivation under different classes of biological drugs in RA patients. Taking all these evidences into account, some practical guidelines for screening, vaccination, prophylaxis and treatment of HBV reactivation have been proposed.

Disease-related nutritional risk and mortality in systemic sclerosis.

BACKGROUND & AIMS: To evaluate the relationship between mortality and nutritional risk associated with disease activity in Systemic Sclerosis (SSc). METHODS: A single-centre prospective cohort study involving 160 SSc outpatients (median age, 62 years [25th-75th, 54-68]). Nutritional risk was assessed by the Malnutrition Universal Screening Tool (MUST), a screening tool that combines anthropometric parameters of nutritional status (body mass index [BMI] and percentage of unintentional weight loss [WL]) with the presence of an "acute disease" (as defined by a disease activity score ≥3 according to Valentini's criteria). RESULTS: Prevalence of high nutritional risk (MUST score ≥2) was 24.4% [95%CI, 17.4-31.3]. A low nutritional risk (MUST = 1) was detected in 30% of our study sample. In hazard analysis (median follow-up duration = 46 months [25th-75th percentile, 31-54]), high nutritional risk was significantly associated with mortality (HR = 8.3 [95%CI, 2.1-32.1]). The performance of the model based on nutritional risk including disease activity (Harrell's c = 0.74 [95%CI, 0.59-0.89]) was superior to that based on active disease alone (HR = 6.3 [95%CI, 1.8-21.7]; Harrell's c = 0.68 [95%CI, 0.53-0.84]). Risk scored only by anthropometric parameters (prevalence, 9.4% [95%CI, 4.6-14.2]) was not associated with mortality: HR = 2.8 [95%CI, 0.6-13.2]. CONCLUSIONS: In SSc outpatients MUST significantly predicts mortality. The combined assessment of nutritional parameters and disease activity significantly improves the evaluation of mortality risk. Disease-related nutritional risk screening should be systematically included in the clinical workup of every SSc patient.

Pulmonary hypertension in systemic sclerosis: prevalence, incidence and predictive factors in a large multicentric Italian cohort.

OBJECTIVES: This paper aims to investigate the prevalence, the incidence of pulmonary hypertension (PH) and its subtypes in Italian patients with systemic sclerosis (SSc) and to characterise features associated with and predictive of development of PH. METHODS: Eight-hundred and sixty-seven consecutive SSc patients recruited at 4 Italian centres were enrolled. At admission, all patients underwent a careful history, physical examination, EKG, lung high resolution computed tomography (HRCT), pulmonary function tests, B-mode echocardiography and right heart catheterisation (RHC), if indicated. Patients were then visited every 6-12 months. A RHC was performed in those patients in whom PH was suspected for the presence of pre-specified criteria. RESULTS: Among the 212 patients in whom it was suspected, PH was confirmed by RHC in 69 patients. On 31st December 2010, the point prevalence of P-arterial-H(PAH) and PH associated with interstitial lung disease (PH-ILD) was 3.7% and 1.4%, respectively; that of postcapillary PH was 1.3%. The estimated incidence rates of PH and PAH were respectively 1.85/100 patient-years and 1.02/100 patient-years. Multivariate analysis indicated that diffusing lung capacity for CO (DLCO) ≤55% (HR 4.45, 95%CI 2.24-8.83; p<0.001) and sPAP >40 mmHg (HR 18.03, 95%CI 9.01-36.06; p<0.001) were associated with an increased risk to develop PAH. SystolicPAP >40 mmHg resulted the only predictor of PH-ILD (HR 5.17, 95%CI 1.37-19.5; p=0.018) and post-capillary PH (HR 7.91, 95%CI 1.88-33.1; p=0.005) development. CONCLUSIONS: Our study confirms a lower prevalence of PH in Italy compared to Anglo-Saxon cohorts. We also identified patients at high risk, who should be carefully monitored.