Striatal pathways in dyskinesia and dystonia

Purposeful and well-coordinated movements depend on the control exerted by dopamine (DA) on the basal ganglia (BG) network. Accordingly, dysfunctions or lesions of the dopaminergic system in the BG can result in an overall poverty and slowness of movement, cardinal features of Parkinson´s disease (PD), or in dyskinesias, exaggerated and involuntary movements resulting from L-DOPA pharmacotherapy.The corpus striatum is the fulcrum of DA-dependent movement control. From this structure originate two pathways that are thought to modulate movement in opposite ways. The movement-promoting pathway (‘direct pathway’) originates from striatal projection neurons (dSPNs) expressing dopamine (DA) D1 receptors (D1Rs), whereas the movement-suppressing pathway (‘indirect pathway’) originates from striatal neurons (iSPNs) expressing D2 receptors (D2R).Classic theories attribute L-DOPA-induced dyskinesia (LID) to the overactivity of the movement-promoting pathway resulting from an aberrant activation of dSPN-D1R-mediated signalling in the DA-denervated striatum. However, these theories are inadequate to explain the complexity of LID, which cannot simply be equated with “more movement”, but instead consists of a mixture of fast hyperkinetic motions and dystonic postures in varying combinations. The overarching aim of this thesis is to parse the involvement of striatal output pathways and DA receptor subtypes in treatment-induced dyskinesia and dystonia using rodent models of clinically manifest PD.Using pathway-specific chemogenetic modulation, we demonstrate that selective iSPN stimulation promotes hypokinesia and inhibits the dyskinetic action of L-DOPA, while dSPN stimulation has opposite effects. Moreover, we prove that dSPN stimulation alone can induce mild dyskinesia, though not the full spectrum and severity of LID. In a second study, we show that D1Rs and metabotropic glutamate receptors type 5 form heteromers in the DA-denervated striatum, and that these receptor interactions are causally linked with dyskinesias mediated by D1R stimulation. Next, using a set of pharmacological tools and models of gene receptor ablation we show that D1R and D2R stimulation mediate different forms of dyskinesia. Specifically, D1R activation elicits mainly the hyperkinetic components of LID, whereas the D2R mediate mainly its dystonic features.Taken together, the results of this thesis present a refinement of the pathophysiological notions regarding the contribution of striatal pathways to the motor features of PD and LID, paving the way for more effective treatment options

A Spatial Analysis to evaluate the Farm's structure and the Geography of Rural Areas: The case study of Mugello Area

In order to promote rural development public agricultural policies need to constantly adapt to the continuous change of socio-economic conditions of rural areas, related to both farm and territorial dynamics. Hence beyond the zoning provided by the European Commission and developed by Member States [art. 11 Reg. Ce 1698/2005], policy makers should take into account geography, farms characteristics and farmers attitude to acquire a deeper knowledge of these rural areas. This paper aims at supporting the design of proper agricultural policies focusing on the case-study of Mugello territory, a rural area located in the North of Tuscany, which includes both: intermediate rural areas and areas with development problems. This purpose is firstly pursued by generating a geo-referenced database able to develop a deeper analysis on the existing interactions between socio - economic attributes of farms, land use and agricultural policies. The study combined several sources of data: the 2010 Italian Agriculture Census, the Tuscany Regional Agency for Payments in Agriculture (ARTEA) database, and cover land data from the database Corine Land Cover (CLC-06), as updated to 2007 by LaMMA (Laboratory for Environment Monitoring and Modeling). The resulting sample is composed by 821 farms operating in the Mugello area which are split in four different farm styles according to their level of multifunctionality and enterpreunership capacity. Results show that Mugello territory is characterized by an internal differentiation, that determines the prevalence of different farm structure according to the sub-areas characteristics. Especially analyzing the distribution of payments related to area with development problems we note that there are still margins of improvement

A spatial analysis of terrain features and farming styles in a disadvantaged area of Tuscany (Mugello): implications for the evaluation and the design of CAP payments

In recent times there has been a growing awareness of the role of agriculture in providing public goods and services, in particular in less favoured areas. However, since agriculture is an economic activity, its permanence implies that it should be able to generate a satisfactory income for farmers. Where this is not possible, due to natural constraints or adverse economic and market conditions, in order to maintain an adequate use of farmland it is necessary to provide public aid to farmers. In this framework, the design of proper interventions aimed to promote rural development in less favoured areas should be based on a deep knowledge at the farm and territorial level. As regards the territorial level, the RDP zoning [art. 11 Reg. Ce 1698/2005] developed by Member States on the base of the guidelines provided by the European Commission is very often not sufficient to adequately define the territorial characteristics of rural areas. The use of GIS techniques may help to handle this issue by providing a better and more detailed knowledge at the territorial level. Farm level is important insofar as aid effectiveness is usually strongly depending on the type of farm that is receiving it. Thus, a careful selection of beneficiaries could determine a more effective and efficient distribution of resources. This paper aims to provide a spatial analysis of natural constraints and types of farming style in Mugello area and to analyse their relations with CAP aid distribution. Both Single Payment Scheme (SPS) and Rural Development Programme (RDP) payments have been taken into account. The paper combines a GIS analysis of terrain features with the theoretical approach of farming styles. For this purpose, the study integrates several sources of data: the 2010 Italian Agriculture Census, the Tuscany Regional Agency for Payments in Agriculture (ARTEA) database, and land cover data from the database Corine Land Cover (CLC-06), as updated to 2007 by LAMMA (Laboratory for Environment Monitoring and Modelling). A geo-referenced database including socioeconomic attributes of farms, land use, and terrain characteristics has been generated in order to merge information at territorial and farm level. The results of this integrated analysis confirm that Mugello is a very heterogeneous area as regards terrain characteristics despite the fact that it is totally included in less favoured areas. On the other side, farm strategies and economic results seem to be related to entrepreneurial characteristics as much as to natural constraints. The analysis of Pillar I payments and RDP payments for farms located in this mountainous area shows a very complex situation where the strategies implemented by farmers of the strongest farming styles may successfully counteract natural constraints. Besides, in the Authors' opinion, the analyses performed highlight the importance of spatial analysis as a tool for evaluating how public resources are distributed on a territory, thus providing also useful information on the way this distribution could be improved, e.g. for ensuring a higher level of environmental services

Exosome-delivered microRNAs promote IFN-α secretion by human plasmacytoid DCs via TLR7

The excessive production of type I IFNs is a hallmark and a main pathogenic mechanism of many autoimmune diseases, including systemic lupus erythematosus (SLE). In these pathologies, the sustained secretion of type I IFNs is dependent on the improper activation of plasmacytoid DCs (pDCs) by self-nucleic acids. However, the nature and origin of pDC-activating self-nucleic acids is still incompletely characterized. Here, we report that exosomes isolated from the plasma of SLE patients can activate the secretion of IFN-α by human blood pDCs in vitro. This activation requires endosomal acidification and is recapitulated by microRNAs isolated from exosomes, suggesting that exosome-delivered microRNAs act as self-ligands of innate single-stranded endosomal RNA sensors. By using synthetic microRNAs, we identified an IFN induction motif that is responsible for the TLR7-dependent activation, maturation, and survival of human pDCs. These findings identify exosome-delivered microRNAs as potentially novel TLR7 endogenous ligands able to induce pDC activation in SLE patients. Therefore, microRNAs may represent novel pathogenic mediators in the onset of autoimmune reactions and potential therapeutic targets in the treatment of type I IFN-mediated diseases

Oligodendroglioma cells lack glutamine synthetase and are auxotrophic for glutamine, but do not depend on glutamine anaplerosis for growth

In cells derived from several types of cancer, a transcriptional program drives high consumption of glutamine (Gln), which is used for anaplerosis, leading to a metabolic addiction for the amino acid. Low or absent expression of Glutamine Synthetase (GS), the only enzyme that catalyzes de novo Gln synthesis, has been considered a marker of Gln-addicted cancers. In this study, two human cell lines derived from brain tumors with oligodendroglioma features, HOG and Hs683, have been shown to be GS-negative. Viability of both lines depends from extracellular Gln with EC of 0.175 ± 0.056 mM (Hs683) and 0.086 ± 0.043 mM (HOG), thus suggesting that small amounts of extracellular Gln are sufficient for OD cell growth. Gln starvation does not significantly affect the cell content of anaplerotic substrates, which, consistently, are not able to rescue cell growth, but causes hindrance of the Wnt/β-catenin pathway and protein synthesis attenuation, which is mitigated by transient GS expression. Gln transport inhibitors cause partial depletion of intracellular Gln and cell growth inhibition, but do not lower cell viability. Therefore, GS-negative human oligodendroglioma cells are Gln-auxotrophic but do not use the amino acid for anaplerosis and, hence, are not Gln addicted, exhibiting only limited Gln requirements for survival and growth

Renal function and physical fitness after 12-mo supervised training in kidney transplant recipients

To evaluate the effect of a 12-mo supervised aerobic and resistance training, on renal function and exercise capacity compared to usual care recommendations

Gender equity in academic rheumatology, current status and potential for improvement: a cross-sectional study to inform an EULAR task force

OBJECTIVES Evidence on the current status of gender equity in academic rheumatology in Europe and potential for its improvement is limited. The EULAR convened a task force to obtain empirical evidence on the potential unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology. METHODS This cross-sectional study comprised three web-based surveys conducted in 2020 among: (1) EULAR scientific member society leaders, (2) EULAR and Emerging EULAR Network (EMEUNET) members and (3) EULAR Council members. Statistics were descriptive with significance testing for male/female responses assessed by χ$^{2}$ test and t-test. RESULTS Data from EULAR scientific member societies in 13 countries indicated that there were disproportionately fewer women in academic rheumatology than in clinical rheumatology, and they tended to be under-represented in senior academic roles. From 324 responses of EULAR and EMEUNET members (24 countries), we detected no gender differences in leadership aspirations, self-efficacy in career advancement and work-life integration as well as the share of time spent on research, but there were gender differences in working hours and the levels of perceived gender discrimination and sexual harassment. There were gender differences in the ranking of 7 of 26 factors impacting career advancement and of 8 of 24 potential interventions to aid career advancement. CONCLUSIONS There are gender differences in career advancement in academic rheumatology. The study informs a EULAR task force developing a framework of potential interventions to accelerate gender-equitable career advancement in academic rheumatology

P72 Knowledge and use of contraceptive methods in portuguese women with systemic lupus erythematosus

n/

Improved pregnancy outcome in patients with Rheumatoid Arthritis who followed an ideal clinical pathway

Among women with rheumatoid arthritis (RA) we aimed to assess the effect of optimal management of pregnancy, on a composite outcome of miscarriage and complicated birth

Is cholecalciferol a potential disease modifying anti-rheumatic drug for the management of rheumatoid arthritis?

Vitamin D is a pleiotropic molecule with a well-characterised immunomodulatory activity in vitro; however, its potential clinical application in autoimmune conditions has yet to be clarified. Several authors have investigated the use of vitamin D as a disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA), obtaining divergent conclusions. This systematic review summarises and critically analyses the findings of papers assessing the impact of vitamin D supplementation on pain relief, disease activity, functional status and flare rate. We conclude that the correction of hypovitaminosis D may have a beneficial effect on pain perception; moreover, the achievement of an adequate plasma vitamin D concentration obtained with high-dose regimens might evoke immunomodulatory activities of vitamin D and favourably impact on disease control. Nevertheless, the current evidence is still not strong enough to support the use of cholecalciferol as a DMARD in RA, and further studies are required to clarify this issue