The role of the meningeal lymphatic system in local meningeal inflammation and trigeminal nociception

A system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in 'cleaning' the brain via cerebral fluid drainage. As meninges are the origin site of migraine pain, we hypothesized that malfunctioning of the lymphatic system should affect the local trigeminal nociception. To test this hypothesis, we studied nociceptive and inflammatory mechanisms in the hemiskull preparations (containing the meninges) of K14-VEGFR3-Ig (K14) mice lacking the meningeal lymphatic system. We recorded the spiking activity of meningeal afferents and estimated the local mast cells population, calcitonin gene-related peptide (CGRP) and cytokine levels as well as the dural trigeminal innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). Spiking activity data have been confirmed in an acquired model of meningeal lymphatic dysfunction (AAV-mVEGFR3(1-4)Ig induced lymphatic ablation). We found that levels of the pro-inflammatory cytokine IL12-p70 and CGRP, implicated in migraine, were reduced in the meninges of K14 mice, while the levels of the mast cell activator MCP-1 were increased. The other migraine-related pro-inflammatory cytokines (basal and stimulated), did not differ between the two genotypes. The patterns of trigeminal innervation in meninges remained unchanged and we did not observe alterations in basal or ATP-induced nociceptive firing in the meningeal afferents associated with meningeal lymphatic dysfunction. In summary, the lack of meningeal lymphatic system is associated with a new balance between pro- and anti-migraine mediators but does not directly trigger meningeal nociceptive state.Peer reviewe

Improving access to community-based pulmonary rehabilitation: 3R protocol for real-world settings with cost-benefit analysis

Background: Pulmonary rehabilitation (PR) has demonstrated patients’ physiological and psychosocial improvements, symptoms reduction and health-economic benefits whilst enhances the ability of the whole family to adjust to illness. However, PR remains highly inaccessible due to lack of awareness of its benefits, poor referral and availability mostly in hospitals. Novel models of PR delivery are needed to enhance its implementation while maintaining cost-efficiency. We aim to implement an innovative community-based PR programme and assess its cost-benefit. Methods: A 12-week community-based PR will be implemented in primary healthcare centres where programmes are not available. Healthcare professionals will be trained. 73 patients with CRD and their caregivers (dyads patientcaregivers) will compose the experimental group. The control group will include dyads age- and disease-matched willing to collaborate in data collection but not in PR. Patients/family-centred outcomes will be dyspnoea (modified Medical Research Council Questionnaire), fatigue (Checklist of individual strength and Functional assessment of chronic illness therapy – fatigue), cough and sputum (Leicester cough questionnaire and Cough and sputum assessment questionnaire), impact of the disease (COPD Assessment Test), emotional state (The Hospital Anxiety and Depression Scale), number of exacerbations, healthcare utilisation, health-related quality of life and family adaptability/cohesion (Family Adaptation and Cohesion Scale). Other clinical outcomes will be peripheral (biceps and quadriceps-hand held dynamometer, 1 or 10 repetition-maximum) and respiratory (maximal inspiratory and expiratory pressures) muscle strength, muscle thickness and cross sectional area (biceps brachialis, rectus femoris and diaphragm-ultrasound imaging), exercise capacity (six-minute walk test and one-minute sit to stand test), balance (brief-balance evaluation systems test) and physical activity (accelerometer). Data will be collected at baseline, at 12 weeks, at 3- and 6-months post-PR. Changes in the outcome measures will be compared between groups, after multivariate adjustment for possible confounders, and effect sizes will be calculated. A cost-benefit analysis will be conducted.Discussion: This study will enhance patients access to PR, by training healthcare professionals in the local primary healthcare centres to conduct such programmes and actively involving caregivers. The cost-benefit analysis of this intervention will provide an evidence-based insight into the economic benefit of community-based PR in chronic respiratory diseases. Trial registration: The trial was registered in the ClinicalTrials.gov U.S. National Library of Medicine, on 10th January, 2019 (registration number: NCT03799666). Keywords: Exercise training, Education and psychosocial support, Chronic respiratory diseases, Primary healthcare, Cost-benefit.This work, was funded by Fundo Europeu de Desenvolvimento Regional (FEDER) - Comissão Diretiva do Programa Operacional Regional do Centro and by Fundação para a Ciência e Tecnologia - FCT (SAICT-POL/23926/2016), and partially funded by Programa Operacional Competitividade e Internacionalização (COMPETE), through COMPETE 2020 (POCI-01-0145- FEDER-016701 and POCI-01-0145-FEDER-007628) and FCT (UID/BIM/04501/ 2013 and UID/BIM/04501/2019). CJ has a post-doctoral grant (SFRH/BPD/ 115169/2016) funded by FCT, co-financed by the European Social Fund (POCH) and Portuguese national funds from MCTES (Ministério da Ciência, Tecnologia e Ensino Superior).publishe

Le piacevoli notti, a cura di Guiseppe Rua.

"Cenni bibliograflei": v. 2, p. [243]-244.Mode of access: Internet.