Neurophysiological oscillatory markers of hypoalgesia in conditioned pain modulation

Introduction:Conditioned pain modulation (CPM) is an experimental procedure that consists of an ongoing noxious stimulus attenuating the pain perception caused by another noxious stimulus. A combination of the CPM paradigm with concurrent electrophysiological recordings can establish whether an association exists between experimentally modified pain perception and modulations of neural oscillations.Objectives:We aimed to characterize how CPM modifies pain perception and underlying neural oscillations. We also interrogated whether these perceptual and/or neurophysiological effects are distinct in patients affected by chronic pain.Methods:We presented noxious electrical stimuli to the right ankle before, during, and after CPM induced by an ice pack placed on the left forearm. Seventeen patients with chronic pain and 17 control participants rated the electrical pain in each experimental condition. We used magnetoencephalography to examine the anatomy-specific effects of CPM on the neural oscillatory responses to the electrical pain.Results:Regardless of the participant groups, CPM induced a reduction in subjective pain ratings and neural responses (beta-band [15-35 Hz] oscillations in the sensorimotor cortex) to electrical pain.Conclusion:Our findings of pain-induced beta-band activity may be associated with top-down modulations of pain, as reported in other perceptual modalities. Therefore, the reduced beta-band responses during CPM may indicate changes in top-down pain modulations.</p

Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells

Background/Aims: Blocking estrogen signaling with endocrine therapies (Tamoxifen or Fulverstrant) is an effective treatment for Estrogen Receptor-α positive (ER+) breast cancer tumours. Unfortunately, development of endocrine therapy resistance (ETR) is a frequent event resulting in disease relapse and decreased overall patient survival. The long noncoding RNA, H19, was previously shown to play a significant role in estrogen-induced proliferation of both normal and malignant ER+ breast epithelial cells. We hypothesized that H19 expression is also important for the proliferation and survival of ETR cells. Methods: Here we utilized established ETR cell models; the Tamoxifen (Tam)-resistant LCC2 and the Fulvestrant and Tam cross-resistant LCC9 cells. Gain and loss of H19 function were achieved through lentiviral transduction as well as pharmacological inhibitors of the Notch and c-Met receptor signaling pathways. The effects of altered H19 expression on cell viability and ETR were assessed using three-dimensional (3D) organoid cultures and 2D co-cultures with low passage tumour-associated fbroblasts (TAFs). Results: Here we report that treating ETR cells with Tam or Fulvestrant increases H19 expression and that it’s decreased expression overcomes resistance to Tam and Fulvestrant in these cells. Interestingly, H19 expression is regulated by Notch and HGF signaling in the ETR cells and pharmacological inhibitors of Notch and c-MET signaling together significantly reverse resistance to Tam and Fulvestrant in an H19-dependent manner in these cells. Lastly, we demonstrate that H19 regulates ERα expression at the transcript and protein levels in the ETR cells and that H19 protects ERα against Fulvestrant-mediated downregulation of ERα protein. We also observed that blocking Notch and the c-MET receptor signaling also overcomes Fulvestrant and Tam resistance in 3D organoid cultures by decreasing ERα and H19 expression in the ETR cells. Conclusion: In endocrine therapy resistant breast cancer cells Fulvestrant is ineffective in decreasing ERα levels. Our data suggest that in the ETR cells, H19 expression acts as an ER modulator and that its levels and subsequently ERα levels can be substantially decreased by blocking Notch and c-MET receptor signaling. Consequently, treating ETR cells with these pharmacological inhibitors helps overcome resistance to Fulvestrant and Tamoxifen

Global Access to Comprehensive Care for Paediatric and Congenital Heart Disease

Paediatric and congenital heart disease (PCHD) is common but remains forgotten on the global health agenda. Congenital heart disease is the most frequent major congenital anomaly, affecting approximately 1 in every 100 live births. In high-income countries, most children now live into adulthood, whereas in low- and middle-income countries, over 90% of patients do not get the care they need. Rheumatic heart disease is the most common acquired cardiovascular disease in children and adolescents. While almost completely eradicated in high-income countries, over 30-40 million people live with rheumatic heart disease in low- and middle-income countries. Challenges exist in the care for PCHD and, increasingly, adult congenital heart disease (ACHD) worldwide. In this review, we summarize the current status of PCHD and ACHD care through the health systems lens of workforce, infrastructure, financing, service delivery, information management and technology, and governance. We further highlight gaps in knowledge and opportunities moving forward to improve access to care for all those living with PCHD or ACHD worldwide. Résumé: Les cardiopathies pédiatriques et congénitales (CPC) sont fréquentes, mais demeurent dans l’angle mort des politiques de santé mondiale. La cardiopathie est l’anomalie congénitale majeure la plus fréquente; elle touche environ 1 naissance vivante sur 100. Dans les pays à revenus élevés, la plupart de ces enfants atteignent désormais l’âge adulte, tandis que dans ceux à revenus faibles ou moyens, plus de 90 % des patients n’obtiennent pas les soins dont ils ont besoin. La cardiopathie rhumatismale est la maladie cardiovasculaire acquise la plus fréquente chez les enfants et les adolescents. Alors qu’elle est pratiquement éradiquée dans les pays à revenus élevés, plus de 30 à 40 millions de personnes en sont atteintes dans les pays à revenus faibles et moyens. À l’échelle mondiale, il existe de nombreux obstacles aux soins des CPC et, de plus en plus, des cardiopathies congénitales chez l’adulte (CCA). Notre article de synthèse présente un résumé de l’état actuel des soins des CPC et des CCA en abordant plusieurs aspects des systèmes de santé : ressources humaines, infrastructures, financement, services offerts, gestion des renseignements, technologies de l’information et gouvernance. Nous mettons également en lumière des lacunes dans les connaissances et des avenues d’amélioration de l’accès aux soins pour les personnes atteintes de CPC et de CCA partout dans le monde

The human brain connectome weighted by the myelin content and total intra-axonal cross-sectional area of white matter tracts

A central goal in neuroscience is the development of a comprehensive mapping between structural and functional brain features, which facilitates mechanistic interpretation of brain function. However, the interpretability of structure-function brain models remains limited by a lack of biological detail. Here, we characterize human structural brain networks weighted by multiple white matter microstructural features including total intra-axonal cross-sectional area and myelin content. We report edge-weight-dependent spatial distributions, variance, small-worldness, rich club, hubs, as well as relationships with function, edge length, and myelin. Contrasting networks weighted by the total intra-axonal cross-sectional area and myelin content of white matter tracts, we find opposite relationships with functional connectivity, an edge-length-independent inverse relationship with each other, and the lack of a canonical rich club in myelin-weighted networks. When controlling for edge length, networks weighted by either fractional anisotropy, radial diffusivity, or neurite density show no relationship with whole-brain functional connectivity. We conclude that the co-utilization of structural networks weighted by total intra-axonal cross-sectional area and myelin content could improve our understanding of the mechanisms mediating the structure-function brain relationship