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We present a sample of 16 likely strong gravitational lenses identified in the VST Optical Imaging of the CDFS and ES1 fields (VOICE survey) using Convolutional Neural Networks (CNNs). We train two different CNNs on composite images produced by superimposing simulated gravitational arcs on real Luminous Red Galaxies observed in VOICE. Specifically, the first CNN is trained on single-band images and more easily identifies systems with large Einstein radii, while the second one, trained on composite RGB images, is more accurate in retrieving systems with smaller Einstein radii. We apply both networks to real data from the VOICE survey, taking advantage of the high limiting magnitude (26.1 in the r-band) and low PSF FWHM (0.8" in the r-band) of this deep survey. We analyse $\sim21,200$ images with $mag_r, 15 pages, 12 figures, submitted to MNRAS

Age at portal vein thrombosis (PVT) in liver cirrhosis (LC) carriers of the methylene tetrahydrofolate reductase (MTHFR) rs1801133 (C → T667 transition) polymorphism has never been addressed; we compared age at PVT in LC patients genotyped for the MTHFR and explored the interrelated clinical and laboratory factors predicting age at PVT.Retrospective cross-sectional cohort study. PVT participants: MTHFR CC n = 36, MTHFR CT n = 53, MTHFR TT n = 19; age, sex, age at PVT, Child-Pugh score, rs1799963 PT polymorphisms (G → A 20,210 transition), plasma HC and natural anticoagulants available for all participants. Age at PVT was lower in MTHFR TT than CT and CC (56 ± 13 vs. 57 ± 13 vs. 64 ± 9 years, p = 0.001); median (IQR) plasma HC was higher in MTHFR TT than in the other groups [(17 (9.4, 23.3) vs 13 (8,14.7) vs 11 (8.9, 12.7) μmol/l, p = 0.03)]. MTHFR TT, male gender and protein C predicted age at PVT (p = 0.02, p = 0.04 and p = 0.08); MTHFR TT and Child-Pugh score predicted plasma HC (p = 0.005 and p = 0.01) as well as low plasma protein C (p 0.0001 and p = 0.0002). Plasma HC inversely related to protein C in the MTHFR TT group (p 0.0001). Compound MTHFR TT with PT GA had lower age at PVT compared to MTHFR TT alone (49 ± 18 vs 58 ± 12 years).MTHFR TT anticipates PVT associated with LC by an average of 8 years; MTHFR TT associates with severity of liver disease and to high plasma HC; the latter may contribute to the prematurity of PVT by interfering with the anticoagulant activity of protein C.

Thrombosis associated with thrombocytopenia is an apparent paradox that is present across a wide spectrum of disorders. While thrombocytopenia has been a controversial clinical classification criterion for antiphospholipid syndrome because initial reports failed to demonstrate a relation between low platelet count with other clinical or laboratory manifestations of the syndrome, recent data highlight the association between mild to moderate thrombocytopaenia and the risk of thrombosis. Although antiphospholipid antibodies may induce platelet activation in vitro, additional stimuli may contribute to their activation in vivo, amongst which reactive oxygen and nitrogen species and lipid peroxidation products, elevated in patients with the antiphospholipid syndrome: an excess of the same stimuli may induce megakaryocyte and platelet apoptosis that leads to decreased platelet production and increased destruction, exposure resulting ultimately in thrombocytopaenia. Herein we provide a novel plausible framework involving free radicals that could add to the understanding of the thrombocytopenia/thrombosis paradox in the antiphospholipid syndrome.

The unprecedented number of gravitational lenses expected from new-generation facilities such as the ESA Euclid telescope and the Vera Rubin Observatory makes it crucial to rethink our classical approach to lens-modelling. In this paper, we present LeMoN (Lens Modelling with Neural networks): a new machine-learning algorithm able to analyse hundreds of thousands of gravitational lenses in a reasonable amount of time. The algorithm is based on a Bayesian Neural Network: a new generation of neural networks able to associate a reliable confidence interval to each predicted parameter. We train the algorithm to predict the three main parameters of the Singular Isothermal Ellipsoid model (the Einstein radius and the two components of the ellipticity) by employing two simulated datasets built to resemble the imaging capabilities of the Hubble Space Telescope and the forthcoming Euclid satellite. In this work, we assess the accuracy of the algorithm and the reliability of the estimated uncertainties by applying the network to several simulated datasets of 10.000 images each. We obtain accuracies comparable to previous studies present in the current literature and an average modelling time of just 0.5s per lens. Finally, we apply the LeMoN algorithm to a pilot dataset of real lenses observed with HST during the SLACS program, obtaining unbiased estimates of their SIE parameters. The code is publicly available on GitHub (https://github.com/fab-gentile/LeMoN)., Submitted to MNRAS; The code will be available on GitHub upon acceptance of the paper

We evaluated the relevance of plasma homocysteine (HC) and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in sickle cell disease (SCD) and associated vaso-occlusive crisis (VOC) and ischemic stroke (IS). We identified in Embase and Medline 22 studies on plasma HC and 22 on MTHFR genotypes. Due to age-related HC differences, adult and paediatric SCD were separated: 879 adult SCD and 834 controls (CTR) yielded a neutral effect size; 427 paediatric SCD and 625 CTR favoured SCD (p = 0.001) with wide heterogeneity (I2 = 95.5%) and were sub-grouped by country: six studies (Dutch Antilles n = 1, USA n = 5) yielded a neutral effect size, four (India n = 1, Arab countries n = 3) favoured SCD (p < 0.0001). Moreover, 249 SCD in VOC and 419 out of VOC yielded a neutral effect size. The pooled prevalence of the MTHFR TT genotype in 267 SCD equalled that of 1199 CTR (4.26% vs. 2.86%, p = 0.45), and in 84 SCD with IS equalled that of 86 without IS (5.9% vs. 3.7%, p = 0.47); removal of one paediatric study yielded a significant effect size (p = 0.006). Plasma HC in paediatric SCD from Middle East and India was higher, possibly due to vitamin deficiencies. Despite its low prevalence in SCD, the MTHFR TT genotype relates to adult IS.

Objective: To compare age at occlusion and plasma homocysteine (HC) in patients with idiopathic portal vein thrombosis (PVT) genotyped for methylene tetrahydrofolate reductase (MTHFR) rs1801133 (C®T667 transition), to identify which clinical or laboratory variables influenced age at first PVT, including the prothrombin rs1799963 PT (G®A transition at position 20210) (PT) mutation. Methods: Retrospective cross-sectional cohort survey on 17 MTHFR TT, 45 MTHFR TC and 24 MTHFR CC participants with idiopathic PVT who contributed age, sex, age at PVT, smoking status, plasma HC and natural anticoagulant concentrations. Results: Age at PVT was lower in MTHFR TT than MTHFR TC and CC (31±8 vs. 46±16 vs. 52±14 years, respectively, p=0.001); median (IQR) plasma HC was higher in MTHFR TT than in the other groups [17 (12.6,25.0) vs. 10 (7.4,13.1) vs. 11.9 (8.1,5.8) μmol/l, respectively, p=0.002)]. MTHFR TT and protein C independently predicted age at PVT (pConclusions: MTHFR TT anticipates age at PVT by an average of 20 years compared to other MTHFR genotypes. PT GA had no age lowering effect combined with MTHFR TT. Smoking predicts cavernoma formation, suggesting that smoking may associate with recurrent subclinical PVT before the symptomatic presentation.

Aim To evaluate the clinical relevance of antiphospholipid antibodies (aPL) in patients with lower extremity peripheral artery disease (PAD). Data sources EMBASE and MEDLINE databases were searched from inception to March 2020 for clinical studies reporting on the association between of aPL [IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA)] and PAD. Methods We determined the pooled prevalence (PP) of patients positive for aPL in PAD or the PP of PAD in patients positive for aPL; we employed Peto's odds ratio with random effect for the meta-analysis. Results Twenty-one studies comprising 6,057 patients were evaluated: in patients with PAD, the PP of IgG aCL was 12% vs 4.1% in those without, IgM aCL was 13.2% vs 2.1%, and LA 13.3% vs 3.3%, respectively. The PP of patients with LA was greater in critical limb ischemia than in the control group (19.3% vs 4.2%). Also, the PP of patients with LA was greater in the failed than in the successful revascularisation group (35.8% vs 15.8%). The PP of post-procedural revascularisation failures was similar in the groups given or not given oral anticoagulation (59.2% vs 61.9%). Conclusion All the aPL related to PAD regardless of diagnostic definition used, whereas LA related also to critical limb ischaemia and failed revascularisation. Data expressed as percentage of participants positive for aPL limit the interpretation of these relationships.

To investigate whether age at first presentation of pure peripheral arterial thrombosis (PAT) in lower and upper limbs and in the splanchnic circulation occurs earlier in carriers of the methylenetetrahydrofolate reductase (MTHFR) T677T genotype compared to the heterozygous and wild type and to identify predictors of a possible earlier onset. Retrospective cohort study on 27 MTHFR TT, 29 MTHFR TC and 29 MTHFR CC participants; data regarding age, sex, age at PAT, clinical history (dyslipidaemia, hypertension, smoking, obesity) and homocysteine (HC) measured by immunoassay were collected. Age at PAT was lower in MTHFR TT than MTHFR TC and CC (43 ± 9 vs 47 ± 9 vs 51 ± 4 years, respectively, p = 0.02); plasma HC was higher in MTHFR TT than in the other groups (25 ± 19 vs 12.7 ± 6.7 vs 11.3 ± 3.3 μmol/l, respectively, p 0.001) while the activated partial thromboplastin ratio (aPTTr) was lower in MTHFR TT than in other genotypes (0.90 ± 0.10 vs 0.97 ± 0.12 vs 0.97 ± 0.08 μmol/L p 0.001). Among categorical variables, MTHFR TT and dyslipidaemia independently predicted age at AT (p = 0.01p = 0.03, respectively) whereas among the continuous variables HC independently predicted age at PAT (p = 0.02) as well as the aPTTr (p = 0.001); smoking predicted lower limb PAT (p = 0.005). MTHFR TT carriers develop their first PAT an average of 4 and 8 years earlier than MTHF CT and CC genotypes; MTHFR TT, dyslipidaemia and plasma HC contribute to the prematurity of the PAT while the interplay between elevated HC and smoking may affect type of arterial district occlusion.

To compare age at 1st ischaemic stroke (IS) in a cohort of juvenile ( 46 years of age) IS patients evaluated for the rs1801133 polymorphism (C → T677) of the methylene tetrahydrofolate reductase (MTHFR) gene; to identify predictors of age at IS and of type of cerebral vessel involvement, small vessel disease (SVD) vs large vessel disease (LVD) responsible for the IS; to evaluate possible associations between other clinical and laboratory variables. Retrospective cohort study on 82 MTHFR TT, 54 MTHFR TC and 34 MTHFR CC participants; data regarding age, sex, age at IS, history of dyslipidaemia, hypertension, smoking, migraine and homocysteine (HC) as well as neuroimaging were collected. Age at IS was lower in MTHFR TT than MTHFR TC and CC (35 ± 4 vs 38 ± 0 vs 40 ± 3 years, respectively, p = 0.002); plasma HC (median, interquartile range) was higher in MTHFR TT than in the other groups [16.7 (11.8, 28.6) vs 11.4 (8.2, 16.1) vs 9.8 (7.9, 1.3) respectively, p 0.0001)] and was higher in SVD than LVD [17.4 (12.4, 32.5) vs 11.4 (8.8, 16.4) p 0.0001]. MTHFR TT independently predicted age at IS (p = 0.0008) alongside smoking both as a categorical (p = 0.003) or continuous variable (p = 0.02), whereas HC independently predicted SVD as categorical (p = 0.01) and continuous variable (p 0.0001). Smoking positively predicted plasma HC (p = 0.005) and negatively the activated partial thromboplastin ratio (aPTTr) (p = 0.02). Juvenile IS carriers of the MTHFR TT genotype develop their 1st occlusion on average 5 years earlier compared to the CC genotype; smoking contributes to this prematurity adversely affecting plasma HC and coagulation whereas plasma HC predicts IS secondary to SVD. Public health campaigns against smoking should highlight the prematurity of IS in the juvenile population.

Aim To evaluate the relevance of plasma homocysteine (HC) in Behcet's disease (BD) and its clinical manifestations. Methods Systematic review of EMBASE and PubMed databases according to PRISMA guidelines from inception to July 2021; random-effects meta-analyses for continuous outcomes. Results The search strategy retrieved 48 case–control (2,669 BD and 2,245 control participants) and 5 cohort studies (708 BD participants). Plasma HC was higher in BD than in controls (p 1.5; some pooled ethnicities explained a small part of the heterogeneity (I2 = 16.3%). Active BD participants had higher HC than inactive ones (p Conclusion Although causality cannot be inferred, the consistency of the elevation of plasma HC in BD, particularly in patients with active disease, with vascular and ocular involvement suggests an intrinsic involvement of HC in these clinical manifestations.

Alzheimer’s disease is a neurodegenerative disorder whose pathological mechanisms, despite recent advances, are not fully understood. However, the deposition of beta amyloid -peptide and neuroinflammation, which is probably aggravated by dysbiotic microbiota, seem to play a key role. Anti-Gal are the most abundant xenoreactive natural antibodies. They are supposed to stem from immunization against the gut microbiota and have been implicated in the pathogenesis of several diseases, including multiple sclerosis. These antibodies target the alpha-Gal epitope, expressed on the terminal sugar units of glycoprotein or glycolipid of all mammals except apes, Old World monkeys and humans. The alpha-Gal is constitutively expressed in several bacteria constituting the brain microbiota, and alpha-Gal-like epitopes have been detected in gray matter, amyloid plaque, neurofibrillary tangles and corpora amylacea of the human brain, suggesting a potential link between anti-Gal and Alzheimer’s disease etiopathogenesis. For the first time, our study searched for possible alterations of anti-Gal immunoglobulin levels in Alzheimer’s disease patients. IgG and IgM blood levels were significantly lower, and IgA significantly higher in patients than in healthy subjects. These results suggest that such immunoglobulins might be implicated in Alzheimer’s disease pathogenesis and open new scenarios in the research for new biomarkers and therapeutic strategies.

The aim of the study was to compare age at first venous thromboembolism (VTE), plasma homocysteine and activated partial thromboplastin time ratio (aPTTr) amongst unprovoked VTE patients with the methylentetrahydrofolate reductase (MTHFR) C667T genotypes, and to identify predictors of age at first VTE, of plasma homocysteine and of the aPTTr; to evaluate whether heterozygous or homozygous prothrombin (PT) G20210A mutation lowered the age at first VTE when associated with MTHFR TT. Retrospective cohort study on 259 MTHFR TT, 76 MTHFR TC and 64 MTHFR CC participants with unprovoked VTE; each participant contributed age, sex, age at VTE, history of dyslipidaemia, hypertension, smoking, homocysteine (measured by enzyme immunoassay) and aPTTr (measured by standard coagulation assay). Age at first VTE was lower in MTHFR TT than MTHFR TC and CC (41 ± 14 vs. 50 ± 16 vs. 51 ± 12 years, respectively, P

The relationship between autoimmune haemolytic anaemia (AIHA) and antiphospholipid antibodies (aPL) has never been addressed via a meta-analysis in the paediatric age group. We evaluated the link between AIHA and aPL in childhood systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS).EMBASE and PubMed were screened from inception to May 2020 and Peto's odds ratio for rare events was employed for the between group comparisons.The meta-analysis included 11 articles for a total of 575 children: the pooled prevalence of AIHA was greater in (1) IgG aCL-positive than IgG aCL-negative children (39.7% vs 20.9%, p = 0.005); (2) in APS-positive than APS-negative SLE children (36.8% vs 13.2%, p = 0.01); and (3) in SLE-related APS than in primary APS children (53% vs 16.2%, p = 0.008).The pooled prevalence of AIHA is greatest in SLE with aPL/APS, low-moderate in SLE without aPL/APS, and lowest in primary APS. Key Points • Antiphospholipid antibodies strongly relate to autoimmune haemolytic anaemia. • Autoimmune haemolytic anaemia is more common in systemic lupus erythematosus with antiphospholipid antibodies.

This paper continues the series of the Fornax Deep Survey (FDS). Following the previous studies dedicated to extended Fornax cluster members, we present the catalogs of compact stellar systems in the Fornax cluster as well as extended background sources and point-like sources. We derive ugri photometry of ~1.7 million sources over the $\sim$21 sq. degree area of FDS centered on NGC1399. For a wider area, of $\sim$27 sq. degs extending in the direction of NGC1316, we provide gri data for ~3.1 million sources. To improve the morphological characterization of sources we generate multi-band image stacks by coadding the best seeing gri-band single exposures with a cut at FWHM, 25 pages, 18 figures, A&A accepted, tables 3-6 available on line

INTRODUCTION The relationship between autoimmune hemolytic anemia and antiphospholipid antibodies (aPL) and/or antiphospholipid syndrome has never been systematically addressed. METHODS Systematic review of EMBASE and PubMed databases performed according to PRISMA guidelines from inception to March 2020; meta-analysis performed by Peto's odds ratio for rare events. FINDINGS Forty-five studies with different outcomes met the inclusion/exclusion criteria. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) positivity was greater in end-stage renal disease (ESRD) than controls (20.2% vs. 2.6%, P = 0.001, I2 >80%; I2 = heterogeneity), particularly in hemodialysis patients (18.3% vs. 8%, I2 = 0%). The PP of lupus anticoagulant was greater in ESRD than controls (8.7% vs. 0.2%, P

The relationship between autoimmune haemolytic anaemia (AIHA) and antiphospholipid antibodies (aPL) has never been addressed via a meta-analysis in the paediatric age group. We evaluated the link between AIHA and aPL in childhood systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). EMBASE and PubMed were screened from inception to May 2020 and Peto’s odds ratio for rare events was employed for the between group comparisons. The meta-analysis included 11 articles for a total of 575 children: the pooled prevalence of AIHA was greater in (1) IgG aCL–positive than IgG aCL–negative children (39.7% vs 20.9%, p = 0.005); (2) in APS-positive than APS-negative SLE children (36.8% vs 13.2%, p = 0.01); and (3) in SLE-related APS than in primary APS children (53% vs 16.2%, p = 0.008). The pooled prevalence of AIHA is greatest in SLE with aPL/APS, low-moderate in SLE without aPL/APS, and lowest in primary APS.

Prothrombin fragment F1 + 2 (F1 + 2) and thrombin–antithrombin (TAT) have been assessed in antiphospholipid syndrome (APS) but without evaluating a direct relationship with antiphospholipid (aPL) antibody titers. This article aims to investigate a direct relationship between aPL and F1 + 2 and perform a systematic review and meta-analysis of F1 + 2 and TAT in APS. Systematic search was performed using EMBASE and PubMed databases from January 1982 to December 2018 and random effects meta-analyses for continuous outcomes. This is a cross-sectional case–control study; immunoglobulin G/immunoglobulin M (IgG/IgM) anticardiolipin (aCL) anti-β2-glycoprotein-I, antiprothrombin (aPT) antibodies, F1 + 2, and lupus anticoagulants (LA) were measured in 25 thrombotic primary APS (PAPS), 9 nonthrombotic carriers of aPL, and 18 controls. The significant effect size (ES) for F1 + 2 between aPL +ve and aPL −ve systemic lupus erythematosus (SLE) and between aPL +ve SLE and control displayed high heterogeneity. The significant ES for F1 + 2 between aPL −ve SLE and controls displayed no heterogeneity. The ES for TAT between aPL +ve and aPL −ve SLE patients and between aPL −ve SLE and controls was low, without heterogeneity. Mean F1 + 2 was greater in PAPS (p

The relationship between antiphospholipid antibodies (aPL) and sickle cell disease (SCD) has never been systematically addressed. Our aim was to evaluate potential links between SCD and aPL in all age groups. EMBASE/PubMed was screened from inception to May 2020 and Peto odds ratios for rare events were calculated. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) was higher in individuals with SCD than in controls (27.9% vs 8.7%, P < 0.0001), that of IgM aCL was similar in the two groups (2.9% vs 2.7%); only individuals with SCD were positive for lupus anticoagulant (LA) (7.7% vs 0%, P < 0.0001). The PP of leg ulcers was similar between aPL positive and negative individuals (44% vs 53%) and between patients in acute crisis and stable patients (5.6% vs 7.3%). Reporting of aPL as a binary outcome and not as a titer precluded further interpretation. The results indicate that a prospective case-control study with serial measurements of a panel of aPL in SCD patients might be warranted, in order to understand further the possible pathogenic role of aPL in SCD.

The relationship between antiphospholipid antibodies (aPL) and autoimmune haemolytic anaemia (AIHA) has never been systematically addressed. The aim of this study is to assess the link between aPL and AIHA in adult systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). This study performed an EMBASE/PubMed search from inception to June 2019 and meta-analysis using Peto’s odds ratios. The pooled prevalence (PP) of IgG/IgM anticardiolipin (aCL) and lupus anticoagulant (LA) was greater in AIHA +ve than AIHA –ve patients (34.7% vs. 27.6%, p = 0.03; 33.3% vs. 21.8%, p < 0.0001; 20.9% vs. 8.3%, p = 0.01). The PP of AIHA was greater in: (1) IgG and IgM aCL +ve than -ve patients (21.8% vs. 11.1%, p = 0.001 and 18.7% vs. 6.3%, p < 0.0001), (2) in SLE related APS than in primary APS patients (22.8% vs. 3.9% p < 0.0001), (3) in APS +ve than APS -ve SLE patients (23.2% vs. 8.4%, p = 0.01), and (4) in thrombotic APS than non-thrombotic APS/SLE patients (26.8% vs. 10%, p = 0.03). The PP of IgG/IgM aCL and LA was greater in DAT +ve than DAT -ve patients (42.4% vs. 12.8%, p < 0.0001; 26.2% vs. 12.8%, p = 0.03 and 29.2% vs. 15.7%, p = 0.004 respectively). It was found that AIHA prevalence is maximal in SLE with aPL/APS, low-moderate in SLE without aPL and minimal in PAPS. Moreover, AIHA is rightly included among the classification criteria for SLE but not for APS/aPL. The significance of an isolated DAT positivity remains unclear in this setting

Religion has always been an extraordinary element of social cohesion, despite the fact that over the centuries its structure and power of influence adjusted to the epochal changes that, especially during the 20th century, have affected societies in the world. Through research, we wanted to highlight the features that characterise the concept of religiosity among young university students, with a focus on the intensity of religious sentiment, the relationship with God and, contextually, the religious institution, attested by attendance to the rites. This research, that was carried out through a structured questionnaire with closed answers, involved a population consisting of students enrolled in master or postgraduate courses and others enrolled in the fourth and fifth year of single-cycle courses of the University of Bari Aldo Moro in the academic year 2017-2018. The results show that, despite the large part of the sample declares itself a Christian Catholic faith, only a small part constantly attends religious services; rather, the percentage of students declaring to pray often or daily is quite relevant. We are witnessing a change in the way young people enjoy religion: more individual, more emotional, syncretically directed to the individual, rather than to a uniformly defined category.

To evaluate the effect of antiphospholipid antibodies (aPL) on renal allograft outcome after kidney transplantation.A systematic search of EMBASE and PubMed databases from inception to July 2018 was run according to PRISMA guidelines; Peto's odds ratio (OR) for rare events was used for the meta-analysis.Our inclusion/exclusion criteria were met by 22 cohort studies having different outcomes: allograft thrombosis (n = 9) and thromboprophylaxis (n = 3), allograft loss from any cause (n = 9), allograft malfunction (n = 3), duration (n = 2), glomerular filtration rate at 1 year (n = 3) and allograft rejection (n = 5). The pooled prevalence of allograft thrombosis and of thrombotic microangiopathy was greater in aPL+ve than negative recipients (10.4% vs 1.7%, p 0.0001 and 10.2% vs 0%, p = 0.005, respectively). The pooled prevalence of allograft thrombosis was 75% in patients not taking anticoagulation whereas none of the anticoagulated recipients developed thrombosis (p 0.0001). The pooled prevalence of allograft loss was greater in aPL+ve recipients (28% vs 18% respectively, p 0.0001); the pooled prevalence of aPL was greater in allograft loss recipients compared to those who did not lose it (51% vs 33%, p 0.0001). The pooled prevalence of allograft malfunction and rejection was similar in aPL-ve and aPL+ve recipients (32.2% vs 40.3% and 14.9% vs 14.4%, respectively) but graft duration was shorter in aPL+ve than aPL-ve recipients (p = 0.001) and glomerular filtration rate at 1 year was lower in aPL + ve than aPL-ve recipients (p 0.0001).APL relate strongly to allograft thrombosis, loss and duration but not to allograft malfunction and rejection. Oral antivitamin K anticoagulants effectively prevent allograft thrombosis in aPL recipients. The debate on the role of aPL in renal transplant is limited by the expression of data as percentage of recipients positive for aPL rather than aPL titres in many studies.

Among the various mechanisms involved in aging, it was proposed long ago that a prominent role is played by oxidative stress. A major way by which the latter can provoke structural damage to biological macromolecules, such as DNA, lipids, and proteins, is by fueling the peroxidation of membrane lipids, leading to the production of several reactive aldehydes. Lipid peroxidation-derived aldehydes can not only modify biological macromolecules, by forming covalent electrophilic addition products with them, but also act as second messengers of oxidative stress, having relatively extended lifespans. Their effects might be further enhanced with aging, as their concentrations in cells and biological fluids increase with age. Since the involvement and the role of lipid peroxidation-derived aldehydes, particularly of 4-hydroxynonenal (HNE), in neurodegenerations, inflammation, and cancer, has been discussed in several excellent recent reviews, in the present one we focus on the involvement of reactive aldehydes in other age-related disorders: osteopenia, sarcopenia, immunosenescence and myelodysplastic syndromes. In these aging-related disorders, characterized by increases of oxidative stress, both HNE and malondialdehyde (MDA) play important pathogenic roles. These aldehydes, and HNE in particular, can form adducts with circulating or cellular proteins of critical functional importance, such as the proteins involved in apoptosis in muscle cells, thus leading to their functional decay and acceleration of their molecular turnover and functionality. We suggest that a major fraction of the toxic effects observed in age-related disorders could depend on the formation of aldehyde-protein adducts. New redox proteomic approaches, pinpointing the modifications of distinct cell proteins by the aldehydes generated in the course of oxidative stress, should be extended to these age-associated disorders, to pave the way to targeted therapeutic strategies, aiming to alleviate the burden of morbidity and mortality associated with these disturbances.

Systemic sclerosis (SSc) is a multisystem autoimmune disease: characterised from the clinical side by progressive vasculopathy and fibrosis of the skin and different organs and from the biochemical side by fibroblast deregulation with excessive production of collagen and increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). The latter contributes to an overproduction of reactive oxygen species that through an autocrine loop maintains NOX4 in a state of activation. Reactive oxygen and nitrogen species are implicated in the origin and perpetuation of several clinical manifestations of SSc having vascular damage in common; attempts to dampen oxidative and nitrative stress through different agents with antioxidant properties have not translated into a sustained clinical benefit. Objective of this narrative review is to describe the origin and clinical implications of oxidative and nitrative stress in SSc, with particular focus on the central role of NOX4 and its interactions, to re-evaluate the antioxidant approaches so far used to limit disease progression, to appraise the complexity of antioxidant treatment and to touch on novel pathways elements of which may represent specific treatment targets in the not so distant future. info:eu-repo/semantics/publishedVersion

To investigate possible abnormalities of vasoactive compounds, nitrative stress, and antioxidant activity of paraoxonase (PONa) in human hepatopulmonary syndrome (HPS), we determined endothelin-1 (ET), nitric oxide (NOx) metabolites, PONa alongside crude plasma nitrotyrosine (NT) as surrogate marker of nitrative stress.Liver cirrhosis (LC) patients with HPS (n = 12) were matched by age, sex, and Child-Pugh score to LC patients without HPS (n = 15) and to healthy controls (CTR) (n = 15); plasma NO2(-) (nitrite) (vascular metabolite), NO3(-) (nitrate) (inflammatory metabolite), and PONa were determined by a colorimetric assay, ET, and NT by immunoassays.HPS patients showed higher level of ET (p = 0.0002), NO2(-) (p = 0.002), NO3(-) (p = 0.0001), NT (p0.0001), and lower PONa (p = 0.0004) than CTR; post-hoc analysis revealed greater ET (p0.05) and NO3(-) (p0.005) in LC patients with HPS than in LC patients without HPS. NT correlated to Child-Pugh score within HPS (p = 0.04) and LC (p = 0.02).Our HPS patients are characterized by elevated plasma levels of ET and NOx metabolites and lower PONa. Reduced PONa alongside elevated NO3(-) and NT suggests that defective antioxidation may favor nitrative stress and both may be implicated in the pathogenesis of HPS.

Background The relationship between antiphospholipid antibodies (aPL) and multiple sclerosis (MS) is unclear. Objectives To evaluate a link between aPL and MS. Methods EMBASE and PubMed search to August 2016; Peto's odds ratio (OR) meta-analysis. Results The pooled prevalence of participants positive for IgG and IgM anticardiolipin (aCL) from 12 case–control studies was superior in MS than controls (6.8% vs 1.8%, p = 0.01 and 8.58% vs 2.18%, p = 0.001) with medium and high heterogeneities respectively ( I 2 = 48.55% and 68.13%). The pooled prevalence of participants positive for IgG anti-beta 2 glycoprotein-I (aβ 2 GPI) from seven case–control studies was lower in MS than controls (0.93% vs 4.02%) with high heterogeneity ( I 2 = 53.92%) though the pooled prevalence of participants positive for IgM aβ 2 GPI was similar (7.24% vs 6.13%) with high heterogeneity ( I 2 = 52.85%). Five cohorts compared IgG/IgM aCL and IgM aβ 2 GPI in stable/remission vs active/relapsing MS: the pooled prevalence of IgG aCL was similar in active/relapsing and stable/remission MS (19% vs 18.9%) but the pooled prevalence of IgM aCL was higher in active than in stable MS (36.9% vs 21%, p 2 GPI (40.5% vs 3.2%, p Conclusion Data from case–control studies do not support a link between IgG/IgM aPL and MS. Data from cohort studies comparing active vs stable MS indicate a strong link between aPL of IgM isotype and active/relapsing MS but in the absence of aPL titres to comment upon this may either represent an epiphenomenon of active neuro-inflammation or natural autoantibodies devoid of pathogenic potential. Data expressed as frequency of aPL positive participants rather than average titres preclude further assumptions.

Background Several autoimmune skin disorders are characterised by an increased risk of thrombosis, with bollous pemphigoid carrying a higher risk than pemphigus vulgaris (PV). We describe the case of a middle aged gentleman who developed recurrent venous thromboembolism despite adequate oral anticoagulation during very active PV that required escalation of treatment to bring the disease under control. Case presentation In May 2014 a 49 year gentleman was admitted for widespread mucocutaneous blistering diagnosed as PV by histology and immunofluorescence. After 6 weeks of treatment with systemic steroids and azathioprine the patient developed pulmonary emboli and started oral anticoagulation with warfarin. In late September, the patient re-presented with a severe flare of PV and a recurrent deep vein thrombosis despite oral anticoagulation within therapeutic range. Warfarin was changed to subcutaneous low molecular heparin in therapeutic dose while treatment for pemphigus was escalated: first azathioprine was switched to mycophenolate mofetil and the steroids dose increased; then due to poor response, intravenous immunoglobulins were given for three courses and finally he received four infusions of Rituximab that induced sustained remission. In April 2015 the dose of mycophenolate was decreased but anticoagulation was continued until the beginning of July 2015 to ensure that decreasing immune suppression did not allow the emergence of another flare with attendant thrombotic risk. Conclusion The case highlights the risk of thrombosis and re-thrombosis in aggressive PV and demands further clinical research in this area to assess the need for thromboprophylaxis in aggressive bollous skin disease.

Peripheral blood eosinophilia (PBE) may be associated with the development of thrombosis and this holds true also for transient PBE though in the latter case the likely hood of thrombosis may not be as high as for long standing PBE. The co-existence of transient PBE with other pro-coagulant factors may precipitate thrombosis in some patients. We report a young gentleman with PBE of unknown cause who developed thrombosis at the peak of his transient PBE and was later found to have antiphospholipid antibodies. We performed a systematic review to evaluate how often the two conditions co-existed, their clinical expression and their management.

In several human diseases, such as cancer and neurodegenerative diseases, the levels of reactive oxygen species (ROS), produced mainly by mitochondrial oxidative phosphorylation, is increased. In cancer cells, the increase of ROS production has been associated with mtDNA mutations that, in turn, seem to be functional in the alterations of the bioenergetics and the biosynthetic state of cancer cells. Moreover, ROS overproduction can enhance the peroxidation of fatty acids in mitochondrial membranes. In particular, the peroxidation of mitochondrial phospholipid cardiolipin leads to the formation of reactive aldehydes, such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA), which are able to react with proteins and DNA. Covalent modifications of mitochondrial proteins by the products of lipid peroxidation (LPO) in the course of oxidative cell stress are involved in the mitochondrial dysfunctions observed in cancer and neurodegenerative diseases. Such modifications appear to affect negatively mitochondrial integrity and function, in particular energy metabolism, adenosine triphosphate (ATP) production, antioxidant defenses and stress responses. In neurodegenerative diseases, indirect confirmation for the pathogenetic relevance of LPO-dependent modifications of mitochondrial proteins comes from the disease phenotypes associated with their genetic alterations.

Heat shock 60 kDa protein 1 (HSP60) is a chaperone and stress response protein responsible for protein folding and delivery of endogenous peptides to antigen-presenting cells and also a target of autoimmunity implicated in the pathogenesis of atherosclerosis. By two-dimensional electrophoresis and mass spectrometry, we found that exposure of human promyelocytic HL-60 cells to a nontoxic concentration (10 μM) of 4-hydroxy-2-nonenal (HNE) yielded a HSP60 modified with HNE. We also detected adducts of HNE with putative uncharacterized protein CXorf49, the product of an open reading frame identified in various cell and tissue proteomes. Moreover, exposure of human monocytic THP-1 cells differentiated with phorbol 12-myristate 13-acetate to 10 μM HNE, and to light density lipoprotein modified with HNE (HNE-LDL) or by copper-catalyzed oxidation (oxLDL), but not to native LDL, stimulated the formation of HNE adducts with HSP60, as detected by immunoprecipitation and western blot, well over basal levels. The identification of HNE-HSP60 adducts outlines a framework of mutually reinforcing interactions between endothelial cell stressors, like oxLDL and HSP60, whose possible outcomes, such as the amplification of endothelial dysfunction, the spreading of lipoxidative damage to other proteins, such as CXorf49, the activation of antigen-presenting cells, and the breaking of tolerance to HSP60 are discussed.

We localized the site of type D (chondroitin 6-sulfate) oligosaccharide unit addition to human thyroglobulin (hTg). hTg was chromatographically separated into chondroitin 6-sulfate-containing (hTg-CS) and chondroitin 6-sulfate-devoid (hTg-CS0) molecules on the basis of their d-glucuronic acid content. In an ample number of hTg preparations, the fraction of hTg-CS in total hTg ranged from 32.0 to 71.6%. By exploiting the electrophoretic mobility shift and metachromasia conferred by chondroitin 6-sulfate upon the products of limited proteolysis of hTg, chondroitin 6-sulfate was first restricted to a carboxyl-terminal region, starting at residue 2514. A single chondroitin 6-sulfate-containing nonapeptide was isolated in pure form from the products of digestion of hTg with endoproteinase Glu-C, and its sequence was determined as LTAGXGLRE (residues 2726-2734, X being Ser2730 linked to the oligosaccharide chain). In an in vitro assay of enzymatic iodination, hTg-CS produced higher yields of 3,5,5 ′-triiodothyronine (T3) (171%) and 3,5,3′,5′-tetraiodothyronine (T4) (134%) than hTg-CS0. Unfractionated hTg behaved as hTg-CS. Thus, chondroitin 6-sulfate addition to a subset of hTg molecules enhanced the overall level of T4 and, in particular, T3 formation. Furthermore, the chondroitin 6-sulfate oligosaccharide unit of hTg-CS protected peptide bond Lys2714-Gly2715 from proteolysis, during the limited digestion of hTg-CS with trypsin. These findings provide insights into the molecular mechanism of regulation of the hormonogenic efficiency and of the T4/T3 ratio in hTg. The potential implications in the ability of hTg to function as an autoantigen and into the pathogenesis of thyroidal and extra-thyroidal manifestations of autoimmune thyroid disease are discussed.

To explore whether antibodies against β2-glycoprotein I (β2GPI) complexed to 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and to oxidised low-density lipoproteins (oxLDL) relate to paraoxonase activity (PONa) and/or intima media thickness (IMT) of carotid arteries in primary antiphospholipid syndrome (PAPS). As many as 29 thrombotic patients with PAPS, 10 subjects with idiopathic antiphospholipid antibodies (aPL) without thrombosis, 17 thrombotic patients with inherited thrombophilia and 23 healthy controls were investigated. The following were measured in all participants: β2GPI-oxLDL complexes, IgG anti-β2GPI-oxLig-1, IgG anti-β2GPI-oxLDL antibodies (ELISA), PONa, (para-nitrophenol method), IMT of common carotid (CC) artery, carotid bifurcation (B), internal carotid (IC) by high resolution sonography. β2GPI-oxLDL complex was highest in the control group (p < 0.01), whereas, IgG anti-β2GPI-oxLig1 and IgG anti-β2GPI-oxLDL were highest in PAPS (p < 0.0001). In healthy controls, β2GPI- oxLDL complexes positively correlated to IMT of the IC (p = 0.007) and negatively to PONa after correction for age (p < 0.03). PONa inversely correlated with age (p = 0.008). In PAPS, IgG anti-β2GPI-oxLig-1 independently predicted PONa (p = 0.02) and IMT of B (p = 0.003), CC, (p = 0.03) and of IC (p = 0.04). In PAPS, PONa inversely correlated to the IMTof B, CC and IC (p = 0.01, 0.02 and 0.003, respectively). IgG anti- β2GPI-oxLig-1 may be involved in PAPS related atherogenesis via decreased PON activity. publishersversion published

Methylation in vivo is a post-translational modification observed in several organisms belonging to eucarya, bacteria, and archaea. Although important implications of this modification have been demonstrated in several eucaryotes, its biological role in hyperthermophilic archaea is far from being understood. The aim of this work is to clarify some effects of methylation on the properties of β-glycosidase from Sulfolobus solfataricus, by a structural comparison between the native, methylated protein and its unmethylated counterpart, recombinantly expressed in Escherichia coli. Analysis by Fourier transform infrared spectroscopy indicated similar secondary structure contents for the two forms of the protein. However, the study of temperature perturbation by Fourier transform infrared spectroscopy and turbidimetry evidenced denaturation and aggregation events more pronounced in recombinant than in native β-glycosidase. Red Nile fluorescence analysis revealed significant differences of surface hydrophobicity between the two forms of the protein. Unlike the native enzyme, which dissociated into SDS-resistant dimers upon exposure to the detergent, the recombinant enzyme partially dissociated into monomers. By electrospray mapping, the methylation sites of the native protein were identified. A computational analysis of β-glycosidase three-dimensional structure and comparisons with other proteins from S. solfataricus revealed analogies in the localization of methylation sites in terms of secondary structural elements and overall topology. These observations suggest a role for the methylation of lysyl residues, located in selected domains, in the thermal stabilization of β-glycosidase from S. solfataricus.

The perturbation induced by mono- and divalent cations on the thermophilicity and thermostability of Solfolobus solfataricus beta-glycosidase, a hyperthermophilic tetrameric enzyme, has been investigated by spectroscopic and computational simulation methods to ascertain the Hofmeister effects on two strategic protein regions identified previously. Specifically, (1). an extra segment (83-124), present only in the sequence of hyperthermophilic glycosidases and recognized as an important thermostability determinant for the enzyme structure; and (2). a restricted area of the subunit interface responsible for the quaternary structure maintenance. Mono- and divalent cations inhibit to a different extent the beta-glycosidase activity, whose kinetic constants show an apparent competitive inhibition of the catalytic process that reflects the Hofmeister order. The thermostability is also affected by the nature and charge of the cations, reaching maximal effects for the case of Mg(2+). Fourier transform infrared spectroscopy has revealed very small changes in the protein secondary structure in the presence of the investigated cations at 20 degrees C, while large effects on the protein melting temperatures are observed. Computational analysis of the enzyme structure has identified negative patches on the accessible surface of the two identified regions. Following the Hofmeister series, cations weaken the existing electrostatic network that links the extra segment to the remaining protein matrix. In particular, the perturbing action of cations could involve the ionic pair interactions E107-R245 and E109-R185, thus leading to a local destructuring of the extra segment as a possible starting event for thermal destabilization. A detailed investigation of the electrostatic network at the A-C intermolecular interface of Sbetagly after energy minimization suggests that cations could cause a strong attenuation of the ion pair interactions E474-K72 and D473-R402, with consequent partial dissociation of the tetrameric structure.