Targeting CD20 in the treatment of interstitial lung diseases related to connective tissue diseases: A systematic review

INTRODUCTION: The effectiveness of CD20 targeting in connective tissue diseases (CTD) with lung involvement is controversial. This paper aims to review the current evidence about rituximab (RTX) use in CTD-related interstitial lung disease (ILD). METHODS: We performed a systematic review of papers published between January 2009 and May 2019. We included clinical trials, case/control studies and cohort studies. We excluded letters, case reports, case series, reviews, and full articles when not in English. The selected studies listed as primary or secondary outcome a variation in pulmonary function tests or in the scores used to radiologically stage lung involvement, in CTD-related ILD patients after RTX. RESULTS: Out of 1206 potentially eligible articles, 24 papers were selected: 3 retrospectively described cohorts of patients with different CTD, 14 dealt with systemic sclerosis (SSc)-related ILD, 5 with idiopathic inflammatory myopathies (IIMs)-related ILD, and 2 with Sjögren's Syndrome-related ILD. A direct comparison of the selected studies was hampered by their heterogeneity for outcomes, follow-up duration, the severity of lung involvement, and clinical features of study populations. However, an overall agreement existed concerning the effectiveness of RTX in the stabilization of lung disease, with some studies reporting an improvement of functional parameters from baseline. IIM-related ILD appeared more responsive than other CTD-related ILD to CD20 targeting. CONCLUSION: RTX is a promising therapeutic tool in CTD-related ILD. This systematic review remarks the unmet need of multicenter prospective studies aiming to evaluate the effectiveness of RTX with adequate sample size and study design

Community-based management induces rapid recovery of a high-value tropical freshwater fishery

Tropical wetlands are highly threatened socio-ecological systems, where local communities rely heavily on aquatic animal protein, such as fish, to meet food security. Here, we quantify how a ‘win-win’ community-based resource management program induced stock recovery of the world’s largest scaled freshwater fish (Arapaima gigas), providing both food and income. We analyzed stock assessment data over eight years and examined the effects of protected areas, community-based management, and landscape and limnological variables across 83 oxbow lakes monitored along a ~500-km section of the Juruá River of Western Brazilian Amazonia. Patterns of community management explained 71.8% of the variation in arapaima population sizes. Annual population counts showed that protected lakes on average contained 304.8 (±332.5) arapaimas, compared to only 9.2 (±9.8) in open-access lakes. Protected lakes have become analogous to a high-interest savings account, ensuring an average annual revenue of US$10,601 per community and US$1046.6 per household, greatly improving socioeconomic welfare. Arapaima management is a superb window of opportunity in harmonizing the co-delivery of sustainable resource management and poverty alleviation. We show that arapaima management deserves greater attention from policy makers across Amazonian countries, and highlight the need to include local stakeholders in conservation planning of Amazonian floodplains

Role of Gas6 and TAM Receptors in the Identification of Cardiopulmonary Involvement in Systemic Sclerosis and Scleroderma Spectrum Disorders

Background: Few biomarkers are available for early identification of pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) in systemic sclerosis (SS) and scleroderma spectrum disorders (SSD). Aims: To evaluate Gas6, sAxl, and sMer as biomarkers for cardiopulmonary complications of SS and SSD. Methods: In a cross-sectional observational study, we recruited 125 consecutive patients, affected by SS and SSD and referred to a tertiary-level pulmonary hypertension outpatient clinic. All patients underwent a comprehensive evaluation for identification of PAH and ILD. Gas6, sMer, and sAxl concentrations were measured with ELISA protocols, and concentrations were compared according to PAH or ILD. Results: Nineteen subjects had pulmonary hypertension (PH) (14 PAH), and 39 had ILD (6 severe). Plasma sMer was increased in PAH (18.6 ng/ml IQR [11.7-20.3]) with respect to the absence (12.4 [8.0-15.8]) or other form of pulmonary hypertension (9.6 [7.4-12.5]; K-W variance p < 0.04). Conversely, Gas6 and sAxl levels were slightly increased in mild ILD (25.8 ng/ml [19.5-32.1] and 24.6 [20.1-32.5]) and reduced in severe ILD (16.6 [15.0-22.1] and 15.5 [14.9-22.4]) in comparison to no evidence of ILD (23.4 [18.8-28.1] and 21.6 [18.1-28.4]; K-W, p 64 0.05). Plasma sMer 65 19 ng/ml has 50% sensitivity and 92% specificity in PAH identification (area under the ROC curve (AUC) 0.697, p < 0.03). Values of Gas6 64 24.5 ng/ml and of sAxl 64 15.5 ng/ml have 100% and 67% sensitivity and 47% and 86% specificity, respectively, in identifying severe ILD (Gas6 AUC 0.787, p < 0.001; sAxl AUC 0.705, p < 0.05). Conclusions: The assay of Gas6 sAxl and sMer may be useful to help in the identification of PAH and ILD in SS and SSD patients. The Gas6/TAM system seems to be relevant in cardiopulmonary complications of SS and SSD and merits further investigations

Decreased Gas6 and sAxl Plasma Levels Are Associated with Hair Loss in COVID-19 Survivors

: Post-acute conditions after coronavirus disease 2019 (COVID-19) are quite common, although the underlying pathogenetic mechanisms leading to these conditions are not yet completely understood. In this prospective observational study, we aimed to test the hypothesis that Growth Arrest-Specific 6 (Gas6) and its soluble receptors, Axl (sAxl) and MerTK (sMer), might be implicated. A total of 263 subjects underwent a structured clinical evaluation one year after their hospital discharge for COVID-19, and they consented to donate a blood sample to measure their circulating Gas6, sAxl, and sMer levels. A total of 98 (37.3%) post-COVID-19 subjects complained of at least one residual physical symptom one year after their hospital discharge. Univariate analysis revealed that sAxl was marginally associated with residual symptoms, but at the level of logistic regression analysis, only the diffusing capacity of the lungs for carbon monoxide (DLCO) (OR 0.98, CI 95%: 0.96-0.99; p = 0.007) and the female sex (OR 2.49, CI 95%: 1.45-4.28; p = 0.001) were independently associated with long-lasting symptoms. A total of 69 (26.2%) subjects had hair loss. At the level of univariate analysis, Gas6, sAxl, DLCO, and the female gender were associated with its development. In a logistic regression analysis model, Gas6 (OR 0.96, CI 95%: 0.92-0.99; p = 0.015) and sAxl (OR 0.98, CI 95%; 0.97-1.0; p = 0.014), along with the female sex (OR 6.58, CI 95%: 3.39-12.78; p = 0.0001), were independent predictors of hair loss. Decreased levels of Gas6 and sAxl were associated with a history of hair loss following COVID-19. This was resolved spontaneously in most patients, although 23.7% complained of persistent hair loss one year after hospital discharge

A Two-Stage Model for Lipid Modulation of the Activity of Integral Membrane Proteins

Lipid-protein interactions play an essential role in the regulation of biological function of integral membrane proteins; however, the underlying molecular mechanisms are not fully understood. Here we explore the modulation by phospholipids of the enzymatic activity of the plasma membrane calcium pump reconstituted in detergent-phospholipid mixed micelles of variable composition. The presence of increasing quantities of phospholipids in the micelles produced a cooperative increase in the ATPase activity of the enzyme. This activation effect was reversible and depended on the phospholipid/detergent ratio and not on the total lipid concentration. Enzyme activation was accompanied by a small structural change at the transmembrane domain reported by 1-aniline-8-naphtalenesulfonate fluorescence. In addition, the composition of the amphipilic environment sensed by the protein was evaluated by measuring the relative affinity of the assayed phospholipid for the transmembrane surface of the protein. The obtained results allow us to postulate a two-stage mechanistic model explaining the modulation of protein activity based on the exchange among non-structural amphiphiles at the hydrophobic transmembrane surface, and a lipid-induced conformational change. The model allowed to obtain a cooperativity coefficient reporting on the efficiency of the transduction step between lipid adsorption and catalytic site activation. This model can be easily applied to other phospholipid/detergent mixtures as well to other membrane proteins. The systematic quantitative evaluation of these systems could contribute to gain insight into the structure-activity relationships between proteins and lipids in biological membranes

Change over time of COVID-19 hospital presentation in Northern Italy

none40After the first autochthonous case described on February 19, also in Italy the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARSCoV-2) infection rapidly circulated, mainly in the Northern regions of the country. The earliest reports on Coronavirus disease-19 (COVID-19) have described worldwide a high prevalence of severe respiratory illness [1]. A suggestive feature of COVID-19 has been a rapid progression of the respiratory impairment, leading to acute respiratory distress syndrome (ARDS) and often requiring ventilation support [2]. To date, whether clinical features at hospital presentation and outcome of COVID-19 have changed over the outbreak course is unknown. We explored this issue in a multicenter cohort of patients hospitalized for COVID-19 in Northern Italy.mixedPatti G.; Mennuni M.; Della Corte F.; Spinoni E.; Sainaghi P. P.; COVID-UPO Clinical Team; Azzolina D; Hayden E; Rognon A; Grisafi L; Colombo C; Lio V; Pirisi M; Vaschetto R; Aimaretti G; Krengli M; Avanzi GC; Balbo PE; Capponi A; Castello LM; Bellan M; Malerba M; Garavelli PL; Zeppegno P; Savoia P; Chichino G; Olivieri C; Re R; Maconi A; Comi C; Roveta A; Bertolotti M; Carriero A; Betti M; Mussa M; Borrè S; Cantaluppi V; Cantello R; Bobbio F; GavellI F.Patti, G.; Mennuni, M.; Della Corte, F.; Spinoni, E.; Sainaghi, P. P.; COVID-UPO Clinical, Team; Azzolina, D; Hayden, E; Rognon, A; Grisafi, L; Colombo, C; Lio, V; Pirisi, M; Vaschetto, R; Aimaretti, G; Krengli, M; Avanzi, Gc; Balbo, Pe; Capponi, A; Castello, Lm; Bellan, M; Malerba, M; Garavelli, Pl; Zeppegno, P; Savoia, P; Chichino, G; Olivieri, C; Re, R; Maconi, A; Comi, C; Roveta, A; Bertolotti, M; Carriero, A; Betti, M; Mussa, M; Borrè, S; Cantaluppi, V; Cantello, R; Bobbio, F; Gavelli, F

Fructose Modulates Cardiomyocyte Excitation-Contraction Coupling and Ca2+ Handling In Vitro

BACKGROUND: High dietary fructose has structural and metabolic cardiac impact, but the potential for fructose to exert direct myocardial action is uncertain. Cardiomyocyte functional responsiveness to fructose, and capacity to transport fructose has not been previously demonstrated. OBJECTIVE: The aim of the present study was to seek evidence of fructose-induced modulation of cardiomyocyte excitation-contraction coupling in an acute, in vitro setting. METHODS AND RESULTS: The functional effects of fructose on isolated adult rat cardiomyocyte contractility and Ca²⁺ handling were evaluated under physiological conditions (37°C, 2 mM Ca²⁺, HEPES buffer, 4 Hz stimulation) using video edge detection and microfluorimetry (Fura2) methods. Compared with control glucose (11 mM) superfusate, 2-deoxyglucose (2 DG, 11 mM) substitution prolonged both the contraction and relaxation phases of the twitch (by 16 and 36% respectively, p<0.05) and this effect was completely abrogated with fructose supplementation (11 mM). Similarly, fructose prevented the Ca²⁺ transient delay induced by exposure to 2 DG (time to peak Ca²⁺ transient: 2 DG: 29.0±2.1 ms vs. glucose: 23.6±1.1 ms vs. fructose +2 DG: 23.7±1.0 ms; p<0.05). The presence of the fructose transporter, GLUT5 (Slc2a5) was demonstrated in ventricular cardiomyocytes using real time RT-PCR and this was confirmed by conventional RT-PCR. CONCLUSION: This is the first demonstration of an acute influence of fructose on cardiomyocyte excitation-contraction coupling. The findings indicate cardiomyocyte capacity to transport and functionally utilize exogenously supplied fructose. This study provides the impetus for future research directed towards characterizing myocardial fructose metabolism and understanding how long term high fructose intake may contribute to modulating cardiac function

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO