Retinal functional changes measured by frequency-doubling technology in patients treated with hydroxychloroquine.

BACKGROUND: Antimalarial drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) are mainly used in the treatment of rheumatologic diseases, and their use may be associated with irreversible retinal toxicity. Previous studies indicate early paracentral visual field loss (Humphrey 10-2) in patients taking HCQ". These paracentral defects appear before changes in other clinical parameters as visual acuity and fundoscopy. The mechanism of CQ toxicity remains unclear. It was reported that toxic doses of CQ administered for as long as 4.5 years to Rhesus monkeys caused an initial dramatic effect on ganglion cells, followed later by photoreceptors and RPE degeneration. The purpose of this study is to explore early retinal functional changes measured by frequency-doubling technology (FDT) in patients treated with hydroxychloroquine (HCQ). METHODS: Forty-eight eyes of 48 subjects treated with hydroxychloroquine (HCQ), with no signs of retinal toxicity, and 36 eyes of 36 age and sex-matched healthy subjects were enrolled in this cross-sectional, prospective, observational, case control study. Functional testing included frequency-doubling Humphrey-matrix perimetry (FDP), white-on-white Humphrey visual field perimetry (HFA), using the 24-2 and 10-2 threshold programs, multifocal electroretinogram (mfERG, Veris 4.9) and low contrast sensitivity (CS) measurement. RESULTS: FDP mean deviation (MD) was found to be significantly reduced in HCQ-treated patients compared to controls both in the 24-2 (-1.38 ± 2.41 dB vs 0.21 ± 1.83 dB, p < 0.01) and in the 10-2 program (-0.97 ± 2.88 dB vs 0.15 ± 1.72 dB, p < 0.01). FDP pattern standard deviation (PSD) was found to be significantly worse in HCQ-treated patients compared to controls both in the 24-2 (2.70 ± 0.65 dB vs 2.41 ± 0.31 dB, p < 0.01 and in the 10-2 program (2.86 ± 0.48 dB vs 2.48 ± 0.39 dB, p < 0.01). HFA PSD and CS was also significantly reduced in HCQ patients, while response amplitude densities (RAD) were similar between patients and controls. A statistically significant difference in the ratio of the 5°-10° RAD and the 0°-2.5° RAD (0.31 ± 0.08 vs 0.36 ± 0.07 respectively, p < 0.05) was found between groups. CONCLUSION: Frequency doubling perimetry could be useful to detect early retinal impairment in patients treated with hydroxychloroquine

The PON “Reti e mobilità” and the objectives of Sustainability: the role of the Environmental Monitoring Plan.

Il  PON Reti e mobilità 2007-2013 (PON) è stato approvato dalla Commissione Europea con decisione C(2007)6318 del 7 dicembre 2007.La strategia del Programma, rivolto alle Regioni “Obiettivo Convergenza” (Campania, Calabria, Sicilia, Puglia) si  concretizza con interventi tesi a sviluppare l’intermodalità, a migliorare la mobilità e l’accessibilità anche per controllare e attenuare i fenomeni di congestione e a garantire la riduzione degli impatti ambientali delle infrastrutture di trasporto, in particolare in termini di riduzione delle emissioni di sostanze inquinanti attraverso il miglioramento complessivo della qualità e dell’efficienza del sistema dei trasporti con specifico riferimento alle merci.Appare dunque evidente come il PON Reti e mobilità tenga fortemente in conto i principi di sostenibilità affermati a livello europeo, non ultimi, quelli sottesi nel Libro Bianco dei Trasporti pubblicato nel 2011 dalla Commissione Europea. A conferma di una strategia complessiva del Programma improntata sulla sostenibilità ambientale, il PON Reti e mobilità destina oltre il 70% delle risorse programmate (cfr. Decreto dell’Autorità di Gestione del 28 luglio 2011) alla realizzazione di interventi relativi a modalità di trasporto sostenibili così come individuate a livello europeo (ferrovie, porti, trasporti multimodali e sistemi di trasporto intelligente).Il PON Reti e mobilità è stato sottoposto a procedura di VAS in accordo a quanto previsto dalla Direttiva 2001/42/CE del 27 giugno 2001, recepita in Italia con D. Lgs 152/2006 “Norme in materia ambientale”, successivamente modificato con D. Lgs 4/2008 e D. Lgs 128/2010.Nel Rapporto Ambientale della VAS del PON grande attenzione è dedicata all’attività di monitoraggio, come dimostra la previsione di  “adeguate misure per il monitoraggio ambientale, anche al fine di apportare eventuali misure correttive nella fase di attuazione”. Un primo e rilevante passaggio in tal senso è rappresentato dall’elaborazione del Piano di Monitoraggio Ambientale (PMA), che costituisce il principale documento di riferimento per la successiva implementazione delle attività di monitoraggio.In questo articolo, a valle della presentazione del Programma e dell’indicazione degli obiettivi di sostenibilità ambientale che si intendono perseguire attraverso l’attuazione degli interventi finanziati, verrà dunque illustrato il PMA, adottato dal Ministero delle Infrastrutture e dei Trasporti (Autorità di Gestione del PON) nel  febbraio 2011 che si pone nel panorama italiano come esperienza pilota nel campo del monitoraggio soprattutto dal punto di vista metodologico.The National Operative Program (PON) “Reti e mobilità” has been approved by European Commission on the 7th of December 2007.The strategic  approach of the PON, exclusively devoted to the  so-called “convergence regions” of Italy (Campania, Calabria, Sicilia, Puglia), aims to:1.    improve the modal balance by an economic, social and environmental perspective;2.    develop the inter-modality in order to move towards the integration of convergence area into the network of the European transport system;3.    improve the mobility and the accessibility, also to reduce the traffic congestion;4.    increase the efficiency related to security standards, to management techniques and to the quality of transportation services in the sector of freight; 5.    guarantee the reduction of environmental impacts through a global improvement of the efficiency of the transport systems.In such a way it is clear that the PON “Reti e mobilità”  takes greatly into account the Sustainability principles recognized at European scale as attested by the budget, namely over the 70% of the entire fund, associated with low-impacts infrastructures (railways and harbors). The PON has been submitted to the SEA procedure, following what the 2001/42/CE Directive establishes.The Environmental Report of PON devotes  great attention to the monitoring activity as shown by the reported recommendation about the need for adequate measures for the environmental monitoring, also in order to apply corrective measures during the implementation of the program. By this point of view, a first and important step has been the elaboration of the “Environmental Monitoring Plan”  (EMP) that represents the main methodological  document for the following implementation of the monitoring activity.This paper, after a brief presentation of the program and of the objectives of Sustainability that the Programs aims to pursue through the realization of specific projects, is devoted to introduce the Environmental Monitoring Plan of the PON that has been approved by the Ministry of the Infrastructures and Transport -in charge as Management Authority of the PON- in February 2011. In detail, the PMA represents the tool through which, the Management Authority, that has specific responsibilities and functions in terms of monitoring and environmental assessment of the program, controls the significant impacts on the environment caused by the implementation of the PON and verify the level of achievement of the established objectives of environmental sustainability. The structure of EMP is based on three main aspects:1)  the adoption of the results of other interesting experiences carried out by experts institutions on the topic;2)  an approach favoring the creation of an “integrated” monitoring system with  the others Operative Programs activated at regional scale;3)  the implementation of a cooperation and shared process with all the directly-involved actors

Potential Role of Cytochrome c and Tryptase in Psoriasis and Psoriatic Arthritis Pathogenesis: Focus on Resistance to Apoptosis and Oxidative Stress

Psoriasis (PsO) is an autoimmune disease characterized by keratinocyte proliferation, chronic inflammation and mast cell activation. Up to 42% of patients with PsO may present psoriatic arthritis (PsA). PsO and PsA share common pathophysiological mechanisms: keratinocytes and fibroblast-like synoviocytes are resistant to apoptosis: this is one of the mechanism facilitating their hyperplasic growth, and at joint level, the destruction of articular cartilage, and bone erosion and/or proliferation. Several clinical studies regarding diseases characterized by impairment of cell death, either due to apoptosis or necrosis, reported cytochrome c release from the mitochondria into the extracellular space and finally into the circulation. The presence of elevated cytochrome c levels in serum has been demonstrated in diseases as inflammatory arthritis, myocardial infarction and stroke, and liver diseases. Cytochrome c is a signaling molecule essential for apoptotic cell death released from mitochondria to the cytosol allowing the interaction with protease, as the apoptosis protease activation factor, which lead to the activation of factor-1 and procaspase 9. It has been demonstrated that this efflux from the mitochondria is crucial to start the intracellular signaling responsible for apoptosis, then to the activation of the inflammatory process. Another inflammatory marker, the tryptase, a trypsin-like serine protease produced by mast cells, is released during inflammation, leading to the activation of several immune cells through proteinase-activated receptor-2. In this review, we aimed at discussing the role played by cytochrome c and tryptase in PsO and PsA pathogenesis. To this purpose, we searched pathogenetic mechanisms in PUBMED database and review on oxidative stress, cytochrome c and tryptase and their potential role during inflammation in PsO and PsA. To this regard, the cytochrome c release into the extracellular space and tryptase may have a role in skin and joint inflammation

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology

Bakground &amp; aims Although discrimination of the model for end stage liver disease (MELD) is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discrimination and calibration performance of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intra-hepatic portosystemic shunt (TIPS); classic MELD-Mayo; MELD-UNOS, used by United Network for Organ Sharing (UNOS). Recalibration and model updating were also explored. Methods 776 patients submitted to elective TIPS (TIPS cohort), and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. Results Major patient characteristics in TIPS/non-TIPS cohorts were: viral etiology 402/188, alcoholic 185/130, NASH 65/33; mean follow-up± SD 25±9/19±21months; 3-6-12 month mortality were respectively, 57-102-142/31-47-99. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post-hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used for a MELD updating. Conclusions In this validation study the MELD performance was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for a MELD updating are proposed. Lay summary While discrimination performance of the Model for End Stage Liver Disease (MELD) is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in two independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis and propose a validated model recalibration. Candidate variables for a MELD updating are proposed

HELLP syndrome: a complication or a new autoimmune syndrome?

The HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a pregnancy-specific disease characterized by hemolysis with elevated lactate dehydrogenase, elevated liver enzymes, and decreased platelet count. It is considered a severe variant of the hypertensive disorders that occur during pregnancy together with the pre-eclampsia (PE) and the eclampsia giving symptoms in the mother from 20 weeks’ gestation onward. All these conditions are multi-system pregnancy-related diseases associated with an increase in blood pressure and in both the perinatal and the maternal morbidity/mortality. Observational studies suggest that steroid treatment in HELLP syndrome may improve the hematological and biochemical features in the mother and the perinatal outcome. The present review aims to show that the HELLP syndrome may be considered as an autoimmune disorder itself. Biomarkers of the immune system can be a useful tool improving the diagnostic and therapeutic management of women with HELLP by delineating the underlying etiology of this syndrome

Intravenous Immunoglobulins at the Crossroad of Autoimmunity and Viral Infections

Intravenous immunoglobulins (IVIG) are blood preparations pooled from the plasma of donors that have been first employed as replacement therapy in immunodeficiency. IVIG interact at multiple levels with the different components of the immune system and exert their activity against infections. Passive immunotherapy includes convalescent plasma from subjects who have recovered from infection, hyperimmune globulin formulations with a high titer of neutralizing antibodies, and monoclonal antibodies (mAbs). IVIG are used for the prevention and treatment of several infections, especially in immunocompromised patients, or in case of a poorly responsive immune system. The evolution of IVIG from a source of passive immunity to a powerful immunomodulatory/anti-inflammatory agent results in extensive applications in autoimmune diseases. IVIG composition depends on the antibodies of the donor population and the alterations of protein structure due to the processing of plasma. The anti-viral and anti-inflammatory activity of IVIG has led us to think that they may represent a useful therapeutic tool even in COVID-19. The human origin of IVIG carries specific criticalities including risks of blood products, supply, and elevated costs. IVIG can be useful in critically ill patients, as well as early empirical treatment. To date, the need for further well-designed studies stating protocols and the efficacy/tolerability profile of IVIG and convalescent plasma in selected situations are awaited