Distinct Expression of Inflammatory Features in T Helper 17 Cells from Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). T helper (Th) 17 lymphocytes play a role in the pathogenesis of MS. Indeed, Th17 cells are abundant in the cerebrospinal fluid and peripheral blood of MS patients and promote pathogenesis in the mouse model of MS. To gain insight into the function of Th17 cells in MS, we tested whether Th17 cells polarized from naïve CD4 T cells of healthy donors and MS patients display different features. To this end, we analysed several parameters that typify the Th17 profile during the differentiation process of naïve CD4 T cells obtained from relapsing-remitting (RR)-MS patients (n = 31) and healthy donors (HD) (n = 28). Analysis of an array of cytokines produced by Th17 cells revealed that expression of interleukin (IL)-21, tumour necrosis factor (TNF)-β, IL-2 and IL-1R1 is significantly increased in Th17 cells derived from MS patients compared to healthy donor-derived cells. Interestingly, IL-1R1 expression is also increased in Th17 cells circulating in the blood of MS patients compared to healthy donors. Since IL-2, IL-21, TNF-β, and IL-1R1 play a crucial role in the activation of immune cells, our data indicate that high expression of these molecules in Th17 cells from MS patients could be related to their high inflammatory status

Lamin A/C Missense Mutation R216C Pinpoints Overlapping Features Between Brugada Syndrome and Laminopathies

A 31-year-old man experienced at-rest cardiac arrest. After successful resuscitation, the baseline ECG demonstrated sinus rhythm with concave ST segment elevation in right precordial leads (V1–V3) followed by a negative and symmetrical T-wave. Neither coronary artery disease nor electrolytes’ imbalances were detected. In the following days, ECG showed a spontaneous type 1 Brugada ECG pattern (Figure [A1]), more evident with right precordial leads in II and III intercostal spaces. Transthoracic echocardiography (Figure [A2]) failed to show any cardiomyopathy. Cardiac MRI showed normal chambers dimension, wall thickness, volume, and function (left ventricular end diastolic volume, 67.7 mL/m2; IVS, 1 cm; left ventricular end fraction, 59.7%). Late gadolinium enhancement sequences were negative; adipose and fibrous tissue infiltration were excluded. The patient was implanted with a transvenous single chamber cardioverter defibrillator (Medtronic). Several appropriate ICD interventions on VT and ventricular fibrillation were recorded in the following years. Family history (Figure [B]) was positive for sudden cardiac death: the maternal grandfather died at age 45 years, aII degree maternal cousin died during sleep at age 40 years. The proband’s mother showed a first degree atrioventricular block (PR interval=280 ms) and right bundle branch block (Figure [A3]). A neurological examination in the index case and his mother was negative and creatine phosphokinase levels were normal in both. Informed written consent was obtained from all family members. Study was approved by the Local Ethics Committee (152/2013/O/Oss, June 1, 2013). Molecular genetic analysis was performed by next generation sequencing using PED MASTR Plus assay comprising 52 cardiac electrical disorders related genes, SCN5A included (www.agilent.com)

Identifying and predicting amyotrophic lateral sclerosis clinical subgroups: a population-based machine-learning study.

Background: Amyotrophic lateral sclerosis (ALS) is known to represent a collection of overlapping syndromes. Various classification systems based on empirical observations have been proposed, but it is unclear to what extent they reflect ALS population substructures. We aimed to use machine-learning techniques to identify the number and nature of ALS subtypes to obtain a better understanding of this heterogeneity, enhance our understanding of the disease, and improve clinical care. Methods: In this retrospective study, we applied unsupervised Uniform Manifold Approximation and Projection [UMAP]) modelling, semi-supervised (neural network UMAP) modelling, and supervised (ensemble learning based on LightGBM) modelling to a population-based discovery cohort of patients who were diagnosed with ALS while living in the Piedmont and Valle d'Aosta regions of Italy, for whom detailed clinical data, such as age at symptom onset, were available. We excluded patients with missing Revised ALS Functional Rating Scale (ALSFRS-R) feature values from the unsupervised and semi-supervised steps. We replicated our findings in an independent population-based cohort of patients who were diagnosed with ALS while living in the Emilia Romagna region of Italy. Findings: Between Jan 1, 1995, and Dec 31, 2015, 2858 patients were entered in the discovery cohort. After excluding 497 (17%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 2361 (83%) patients were available for the unsupervised and semi-supervised analysis. We found that semi-supervised machine learning produced the optimum clustering of the patients with ALS. These clusters roughly corresponded to the six clinical subtypes defined by the Chiò classification system (ie, bulbar, respiratory, flail arm, classical, pyramidal, and flail leg ALS). Between Jan 1, 2009, and March 1, 2018, 1097 patients were entered in the replication cohort. After excluding 108 (10%) patients with missing ALSFRS-R feature values, data for 42 clinical features across 989 patients were available for the unsupervised and semi-supervised analysis. All 1097 patients were included in the supervised analysis. The same clusters were identified in the replication cohort. By contrast, other ALS classification schemes, such as the El Escorial categories, Milano-Torino clinical staging, and King's clinical stages, did not adequately label the clusters. Supervised learning identified 11 clinical parameters that predicted ALS clinical subtypes with high accuracy (area under the curve 0·982 [95% CI 0·980-0·983]). Interpretation: Our data-driven study provides insight into the ALS population substructure and confirms that the Chiò classification system successfully identifies ALS subtypes. Additional validation is required to determine the accuracy and clinical use of these algorithms in assigning clinical subtypes. Nevertheless, our algorithms offer a broad insight into the clinical heterogeneity of ALS and help to determine the actual subtypes of disease that exist within this fatal neurodegenerative syndrome. The systematic identification of ALS subtypes will improve clinical care and clinical trial design. Funding: US National Institute on Aging, US National Institutes of Health, Italian Ministry of Health, European Commission, University of Torino Rita Levi Montalcini Department of Neurosciences, Emilia Romagna Regional Health Authority, and Italian Ministry of Education, University, and Research. Translations: For the Italian and German translations of the abstract see Supplementary Materials section

RING and ReCal GPS networks: two Italian geodetic infrastructures and their data management, sharing and dissemination

Geographic data sharing and collection are becoming key activities among geological and geophysical studies worldwide, and the recent increase of infrastructures is demanding to scientific and civil community an effort to manage and disseminate their products as efficiently as possible. With this effort in mind, INGV began some years ago to collaborate with civilian and commercial subjects in order to promote the integration and sharing of data from GNSS (Global Navigation Satellite System) networks existing in Italy. Since 2004, INGV deployed a permanent, integrated and real-time monitoring CGPS network (RING, Rete Integrata Nazionale GPS, http://ring.gm.ingv.it), which is now constituted by about 170 stations all over Italy (Selvaggi et al., 2006; Avallone et al, 2010). All stations have high quality GPS monuments (D’Ambrosio, 2007; Minichiello et al., 2010) and most of them are co-located with broadband or very broadband seismometers and strong motion sensors. This scientific network is aimed to monitor crustal deformation in Italy in order to study earthquake deformation processes, from interseismic strain accumulation to rupture processes, and is giving an effective contribute to Italian Civil Protection for seismic hazard monitoring. Moreover, in the last years, local Authorities, nation-wide industries and other scientific institutions started to establish GPS/GNSS networks all over the Italian territory mainly for cartographic and positioning purposes. More than 500 CGPS stations are actually operating in Italy. The INGV acquire and analyze most of these networks, promoting at the same time actions to integrate the RING with the ones managed by regional and national data providers (D’Anastasio et al., 2010). The Regione Calabria in 2009 planned and established a network of 17 CGPS stations for cartographic and civil protection purposes covering the Calabria region (hereafter ReCal network). The CGPS stations are good quality monument connected in real time and, in the next future, will start to furnish to the civil community a positioning service. In order to share the RING and ReCal data and relative products, a synergy between the CNT-INGV (Centro Nazionale Terremoti) and the Regione Calabria started in 2011. An official agreement between the two institutions state the sharing of CGPS data, the collaboration between CNT-INGV and Regione Calabria to test the efficiency and the positioning service of ReCal network, and the contribution of ReCal network to scientific monitoring of Calabria, one of the most seismically active region in Italy. Moreover, this agreement included also the commissioning of the ReCal network and of its positioning services performed by CNT-INGV. Figure 1 shows the GPS and GNSS stations currently operating in Italy. In the inset it could be noticed how the RING and ReCal networks are integrated in order to have the best spatial coverage of the Calabrian territory. We will present the first results of the agreement between INGV-CNT and Regione Calabria, and of the commissioning of ReCal network. Moreover, we will focus on the infrastructure already existing and developed by CNT-INGV to manage data acquisition, storage, distribution and access (Cecere, 2007; Cardinale et al., 2010; Falco, 2006; 2008; Memmolo et al., 2010; Pignone et al., 2009). INGV developed dedicated facilities including new softwares for data acquisition and a web-based collaborative environment for management of data and metadata. These facilities are used to manage data coming from the RING as well as from agreements with ReCal and other CGPS networks in Italy. We believe that this infrastructure represents an important reality in the framework of GNSS data sharing development in Italy

The role of the IRILD Consortium in the European DEDIPAC-KH project

The IRILD Consortium (partner in the DEDIPAC-KH joint Action) has been working in a few activities of Thematic Area1 and Thematic Area2 aimed at: -Developing a toolbox with state-of-the-art methods to assess dietary intake and their determinants based on their quality and suitability to be used in pan-European studies (task 1.1.1)- Identifying existing pan-European datasets including dietary intake to do secondary analysis according to variation in dietary intake by demographic (task 1.1.2)- Examining the validity and reliability of the measurement methods employed to assess physical activity and sedentary behaviours on children/adolescent and adults populations (task 1.2.4)-Identifying national state-of-the-art surveillance systems and infrastructures in Europe (task 1.3.3).-Mapping and defining life course determinants, correlates and key research challenges of dietary intake in old population (task 2.1.1)-Mapping and defining life course determinants, correlates and key research challenges of physical activity behaviour (task 2.2.1)Theoretical frameworks of determinants have been taken as the starting point for developing the frameworks and taxonomies. On-going/recently finished EU-funded projects on determinants has been consulted. Finally, SRLs have been conducted .The IRILD (Infrastructure to support Research In promoting active Lifestyles and healthy Diet) Consortium has been contributing to obtain the following results: Methodological assessment and measurements for evaluation of vitamin B12 and folate intake have been extracted. Information on the validity and reliability of assessment methods were collected and all essential data for a toolbox have been prepared (task 1.1.1);A report on variation of food consumption throughout Europe, concerning a secondary analysis to estimate food habits variation by food groups in different European age-gender population groups, has been prepared (task 1.1.2);Methodological effectiveness of measures of PA and SB on children/adolescent and adults populations have been examined (task 1.2.4);Information on nutritional surveillance in Italy have been delivered for sub-task 1.3.3.1 (task 1.3.3); Systematic Literature Review on determinants of dietary intake in community-dwelling older adults to get an overview is going to be concluded (task 2.1.1). The IRILD consortium was financially supported by the Italian Ministry of Agriculture Food and Forestry Policies (DM.14474/7303/13)

Withdrawal of mechanical ventilation in amyotrophic lateral sclerosis patients: a multicenter Italian survey

Background: Law 219/2017 was approved in Italy in December 2017, after a years-long debate on the autonomy of healthcare choices. This Law, for the first time in Italian legislation, guarantees the patient's right to request for withdrawal of life-sustaining treatments, including mechanical ventilation (MV). Objective: To investigate the current status of MV withdrawal in amyotrophic lateral sclerosis (ALS) patients in Italy and to assess the impact of Law 219/2017 on this practice. Methods: We conducted a Web-based survey, addressed to Italian neurologists with expertise in ALS care, and members of the Motor Neuron Disease Study Group of the Italian Society of Neurology. Results: Out of 40 ALS Italian centers, 34 (85.0%) responded to the survey. Law 219/2017 was followed by an increasing trend in MV withdrawals, and a significant increase of neurologists involved in this procedure (p 0.004). However, variations across Italian ALS centers were observed, regarding the inconsistent involvement of community health services and palliative care (PC) services, and the intervention and composition of the multidisciplinary team. Conclusions: Law 219/2017 has had a positive impact on the practice of MV withdrawal in ALS patients in Italy. The recent growing public attention on end-of-life care choices, along with the cultural and social changes in Italy, requires further regulatory frameworks that strengthen tools for self-determination, increased investment of resources in community and PC health services, and practical recommendations and guidelines for health workers involved

Impact of Marine Drugs on Animal Reproductive Processes

The discovery and description of bioactive substances from natural sources has been a research topic for the last 50 years. In this respect, marine animals have been used to extract many new compounds exerting different actions. Reproduction is a complex process whose main steps are the production and maturation of gametes, their activation, the fertilisation and the beginning of development. In the literature it has been shown that many substances extracted from marine organisms may have profound influence on the reproductive behaviour, function and reproductive strategies and survival of species. However, despite the central importance of reproduction and thus the maintenance of species, there are still few studies on how reproductive mechanisms are impacted by marine bioactive drugs. At present, studies in either marine and terrestrial animals have been particularly important in identifying what specific fine reproductive mechanisms are affected by marine-derived substances. In this review we describe the main steps of the biology of reproduction and the impact of substances from marine environment and organisms on the reproductive processes