A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis

[Abstract] Objectives: To identify mitochondrial DNA (mtDNA) genetic variants associated with the risk of rapid progression of knee osteoarthritis (OA) and to characterise their functional significance using a cellular model of transmitochondrial cybrids. Methods: Three prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 1095 subjects, the Cohort Hip and Cohort Knee included 373 and 326 came from the PROspective Cohort of Osteoarthritis from A Coruña. mtDNA variants were screened in an initial subset of 450 subjects from the OAI by in-depth sequencing of mtDNA. A meta-analysis of the three cohorts was performed. A model of cybrids was constructed to study the functional consequences of harbouring the risk mtDNA variant by assessing: mtDNA copy number, mitochondrial biosynthesis, mitochondrial fission and fusion, mitochondrial reactive oxygen species (ROS), oxidative stress, autophagy and a whole transcriptome analysis by RNA-sequencing. Results: mtDNA variant m.16519C is over-represented in rapid progressors (combined OR 1.546; 95% CI 1.163 to 2.054; p=0.0027). Cybrids with this variant show increased mtDNA copy number and decreased mitochondrial biosynthesis; they produce higher amounts of mitochondrial ROS, are less resistant to oxidative stress, show a lower expression of the mitochondrial fission-related gene fission mitochondrial 1 and an impairment of autophagic flux. In addition, its presence modulates the transcriptome of cybrids, especially in terms of inflammation, where interleukin 6 emerges as one of the most differentially expressed genes. Conclusions: The presence of the mtDNA variant m.16519C increases the risk of rapid progression of knee OA. Among the most modulated biological processes associated with this variant, inflammation and negative regulation of cellular process stand out. The design of therapies based on the maintenance of mitochondrial function is recommended

Bones pràctiques en atenció compartida: recomanacions per a una gestió òptima dels PIIC

Bones pràctiques; Presa decisions; Plans d’intervenció individualitzats i compartitsBuenas prácticas; Toma de decisiones; Planes de intervención individualizados i compartidosGood practices; Decision making; Individualized and shared intervention plansAquest document és un instrument per a professionals de l'atenció sanitària per posar al dia els criteris de bon ús dels PIIC respecte a la revisió que es va publicar l’abril de 2015

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

The emergence of non-state market-driven (NSMD) global environmental governance: A cross-sectoral assessment

Introduction The failure of states and intergovernmental processes to address some of the most important environmental problems facing the planet – explanations of which can often be traced back to “tragedy of the commons” or “collective action” dilemmas (see Delmas and Young in their Introduction to this volume) – has resulted in the proliferation of alternative nongovernmental approaches. Often grouped under the broad rubric of “corporate social responsibility” (CSR) these efforts comprise an array of initiatives including self-regulation (see King and Toffel, Chapter 4, this volume), voluntary environmental agreements (Khanna and Brouhle, Chapter 6, this volume), and public–private partnerships. Just how these innovations might become enduring and effective features of global environmental governance is arguably one of the most critical questions facing scholars and practitioners in the global era. This chapter focuses on one of the most unique nongovernmental institutional innovations that has attracted the attention of both practitioners and scholars: certification systems that attempt to reward environmentally responsible business practices through positive recognition and market incentives. That they do not appeal to the state for rule-making authority, but instead derive authority from evaluations of stakeholders who choose whether to demand such products, has led Cashore (2002) and Cashore, Auld, and Newsom (2004) to refer to them as “non-state market-driven” (NSMD). With certification institutions, firms are often coerced and cajoled by problem-focused environmental groups or, in some cases, mission-driven but incapacitated governmental officials or agencies

Can technological innovations improve private regulation in the global economy?

Those supplying private regulation in the global economy face two fundamental challenges if they are to ameliorate the problems for which they create these systems: targets must conform to, while demanders must have proof of, regulatory compliance. This paper explores an important area absent from assessments as to whether, when, and how, private regulatory bodies are successful in improving behavior and rewarding compliant firms: the role of technological innovations. Employing an inductive, comparative case study analysis, we offer an analytical framework that distinguishes technological innovations that improve tracking mechanisms from innovations that directly improve on-the-ground performance. We illustrate the utility of the analytical framework through an assessment of technological innovations in shaping "non-state market driven" global certification programs governing forestry, fisheries, coffee, e-waste, and climate

High accuracy of a blood ctDNA-based multimodal test to detect colorectal cancer

Background: Detection of circulating tumor DNA (ctDNA) is a minimally invasive and convenient blood-based screening strategy that may increase effectiveness of colorectal cancer (CRC) screening. Patients and methods: A novel multimodal ctDNA-based blood assay that integrates genomics, epigenomics and fragmentomics, as well as proteomics in a refined version, was tested in blood samples from two cohorts: (i) consecutive fecal immunochemical test (FIT)-positive individuals from the CRC Barcelona stool-based screening program; (ii) patients diagnosed with CRC. Primary endpoint was the performance of the test to detect CRC at different tumor-node-metastasis (TNM) stages. Secondary endpoint was the ability of the test to detect advanced precancerous lesions (advanced adenoma or advanced serrated lesion). Results: A total of 623 blood samples were analyzed in the primary analysis. Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection according to TNM stages was 84% for stage I, 94% for stage II and 96% for stage III (70/73) (P< 0.024). Sensitivity to detect advanced precancerous lesions was 23% with a refined version of the test (including protein and updating bioinformatic thresholding). Conclusion: A blood-based multimodal ctDNA assay detected CRC with high accuracy. This minimally invasive, accessible and convenient assay may help to increase the effectiveness of CRC screening

Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1-/- mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/- mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/- mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/- mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/- mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options. Keywords: Ceramide, Sphingolipids, Mitochondrial GSH, Cerebellum, Hepatosplenomegaly, Lysosomal disorder