Pain Treatment for patients with osteoarthritis and central sensitization

Osteoarthritis is one of the most frequent, disabling, and costly pathologies of modern society. Among the main aims of osteoarthritis management are pain control and functional ability improvement. The exact cause of osteoarthritis pain remains unclear. In addition to the pathological changes in articular structures, changes in central pain processing or central sensitization appear to be involved in osteoarthritis pain. The latter calls for a broader approach to the management of patients with osteoarthritis. Yet, the scientific literature offers scant information addressing the treatment of central sensitization, specifically in patients with osteoarthritis. Inter-ventions such as cognitive-behavioral therapy and neuroscience education potentially target cognitive-emotional sensitization (and descending facilitation), and centrally acting drugs and exercise therapy can improve endogenous analgesia (descending inhibition) in patients with osteoarthritis. Future studies should assess these new treatment avenues

Coenzyme Q10 Metabolism: A Review of Unresolved Issues.

The variable success in the outcome of randomised controlled trials supplementing coenzyme Q10 (CoQ10) may in turn be associated with a number of currently unresolved issues relating to CoQ10 metabolism. In this article, we have reviewed what is currently known about these factors and where gaps in knowledge exist that need to be further elucidated. Issues addressed include (i) whether the bioavailability of CoQ10 could be improved; (ii) whether CoQ10 could be administered intravenously; (iii) whether CoQ10 could be administered via alternative routes; (iv) whether CoQ10 can cross the blood-brain barrier; (v) how CoQ10 is transported into and within target cells; (vi) why some clinical trials supplementing CoQ10 may have been unsuccessful; and (vii) which is the most appropriate tissue for the clinical assessment of CoQ10 status

PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome

The mitochondrial intramembrane rhomboid protease PARL has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that ablation in mouse causes a necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with conditional PARL deficiency in the nervous system, but not in muscle, develop a similar phenotype as germline KOs, demonstrating the vital role of PARL in neurological homeostasis. Genetic modification of two major PARL substrates, PINK1 and PGAM5, do not modify this severe neurological phenotype. brain mitochondria are affected by progressive ultrastructural changes and by defects in Complex III (CIII) activity, coenzyme Q (CoQ) biosynthesis, and mitochondrial calcium metabolism. PARL is necessary for the stable expression of TTC19, which is required for CIII activity, and of COQ4, which is essential in CoQ biosynthesis. Thus, PARL plays a previously overlooked constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and structural abnormalities leading to neuronal necrosis and Leigh-like syndrome

El magnetómetro por gradiente alternante de campo: una nueva herramienta para la caracterización de nanopartículas magnéticas en biofluidos y tejidos biológicos

Las aplicaciones que ofrecen las nanopartículas magnéticas basadas en sus interacciones con los campos magnéticos estáticos o variantes en el tiempo, son uno de los principales y más prometedores focos de investigación biomédica en la actualidad. La caracterización magnética de las partículas y de su comportamiento en el interior de materiales biológicos es un aspecto susceptible de numerosas mejoras, siendo además uno de los pasos preliminares fundamentales a la realización de cualquiera de los experimentos que las empleen. En este artículo se presenta una nueva herramienta que facilitará esta tarea, además de presentar futuras líneas de acción que ofrecerán nuevas posibilidades en el mundo de la nanobioingeniería, partiendo de una breve introducción teórica en la que se presentarán los principios físicos que se encuentran en la base de las aplicaciones biomédicas de las nanopartículas. Las aplicaciones que ofrecen las nanopartículas magnéticas basadas en sus interacciones con los campos magnéticos estáticos o variantes en el tiempo, son uno de los principales y más prometedores focos de investigación biomédica en la actualidad. La caracterización magnética de las partículas y de su comportamiento en el interior de materiales biológicos es un aspecto susceptible de numerosas mejoras, siendo además uno de los pasos preliminares fundamentales a la realización de cualquiera de los experimentos que las empleen. En este artículo se presenta una nueva herramienta que facilitará esta tarea, además de presentar futuras líneas de acción que ofrecerán nuevas posibilidades en el mundo de la nanobioingeniería, partiendo de una breve introducción teórica en la que se presentarán los principios físicos que se encuentran en la base de las aplicaciones biomédicas de las nanopartículas

Viral and Cellular factors leading to the Loss of CD4 Homeostasis in HIV-1 Viremic Nonprogressors

Human immunodeficiency virus type 1 (HIV-1) viremic nonprogressors (VNPs) represent a very rare HIV-1 extreme phenotype. VNPs are characterized by persistent high plasma viremia and maintenance of CD41 T-cell counts in the absence of treatment. However, the causes of nonpathogenic HIV-1 infection in VNPs remain elusive. Here, we identified for the first time two VNPs who experienced the loss of CD41 homeostasis (LoH) after more than 13 years. We characterized in deep detail viral and host factors associated with the LoH and compared with standard VNPs and healthy controls. The viral factors determined included HIV-1 coreceptor usage and replicative capacity. Changes in CD41 and CD81 T-cell activation, maturational phenotype, and expression of CCR5 and CXCR6 in CD41 T-cells were also evaluated as host-related factors. Consistently, we determined a switch in HIV-1 coreceptor use to CXCR4 concomitant with an increase in replicative capacity at the LoH for the two VNPs. Moreover, we delineated an increase in the frequency of HLA-DR1CD381 CD41 and CD81 T cells and traced the augment of naive T-cells upon polyclonal activation with LoH. Remarkably, very low and stable levels of CCR5 and CXCR6 expression in CD41 T-cells were measured over time. Overall, our results demonstrated HIV-1 evolution toward highly pathogenic CXCR4 strains in the context of very limited and stable expression of CCR5 and CXCR6 in CD41 T cells as potential drivers of LoH in VNPs. These data bring novel insights into the correlates of nonpathogenic HIV1 infection. Importance: The mechanism behind nonpathogenic human immunodeficiency virus type 1 (HIV-1) infection remains poorly understood, mainly because of the very low frequency of viremic nonprogressors (VNPs). Here, we report two cases of VNPs who experienced the loss of CD41 T-cell homeostasis (LoH) after more than 13 years of HIV-1 infection. The deep characterization of viral and host factors supports the contribution of viral and host factors to the LoH in VNPs. Thus, HIV-1 evolution toward highly replicative CXCR4 strains together with changes in T-cell activation and maturational phenotypes were found. Moreover, we measured very low and stable levels of CCR5 and CXCR6 in CD41 T-cells over time. These findings support viral evolution toward X4 strains limited by coreceptor expression to control HIV-1 pathogenesis and demonstrate the potential of host-dependent factors, yet to be fully elucidated in VNPs, to control HIV-1 pathogenesis.This research was supported by a Gilead Fellowship (grant GLD15/0298) and La Caixa Foundation (grant LCF/PR/PR16/11110026). M.C.-L. is a Beatriu de Pinós postdoctoral fellow (grant BP 00075) supported by the Government of Catalonia’s Secretariat for Universities and Research of the Ministry of Economy and Knowledge. J.G.P. was supported by the ISCIII (grant CP15/00014). E.J.-M. was funded by Redes Temáticas de Investigación en SIDA (ISCIII RETIC RD16/0025/0041); Acción Estratégica en Salud; Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008–2011; and Instituto de Salud Carlos III. E.J.-M. was cofunded by European Regional Development Fund/European Social Fund (FEDER) “Investing in your future.” J.M.-P. is supported by the Spanish Ministry of Science and Innovation (grant PID2019-109870RB-I00). J.G.P. and M.C.-L. designed the study, supervised experiments and data. J.G.P., M.C.-L., and A.K. contributed to data interpretation. M.C.-L., R.P., E.J.-M., M.P., and C.C. performed experiments, analyzed, and interpreted the data. J.D. carried out the clinical follow-up and patient identification. M.C.-L., D.O., M.P., and C.C. performed data analysis. M.C.-L., A.K., M.P., C.L.-G., B.C., J.M.-P., and J.G.P. performed manuscript writing, critical revision, and discussion. We declare no conflict of interest.S

Promotion of IL-4- and IL-5-dependent differentiation of anti-μ-primed B cells by ascorbic acid 2-glucoside

The stable ascorbic acid derivative 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G) was used to investigate the role of ascorbic acid (AA) in B cell differentiation in vitro. AA-2G is stable in a solution unlike AA but is hydrolyzed by cellular alpha-glucosidase to release AA. Mouse spleen B cells were primed for 2 days with an anti-mu antibody in the presence of interleukin (IL)-4 and IL-5 and then washed and recultured with AA-2G in the presence of IL-4 and IL-5. AA-2G, but not AA, dose-dependently increased IgM production, the greatest enhancement being 150% at concentrations of more than 0.5 mM. In the absence of IL-4 and IL-5, primed B cells produced a negligible amount of IgM, and AA-2G had no effect. AA-2G-induced IgM production in the presence of IL-4 and IL-5 was inhibited by the alpha-glucosidase inhibitor castanospermine. Intracellular AA content, depleted during the priming period, increased by adding AA-2G at the start of reculture. Treatment of B cells with AA-2G resulted in an increase in the number of IgM-secreting cells, CD138-positive cells and CD45R/B220-negative cells. The number of viable cells in untreated cultures decreased gradually, but the decrease was significantly attenuated by AA-2G, resulting in about 70% more viable cells in AA-2G-treated cultures. AA-2G caused a slight but reproducible enhancement of DNA synthesis and a slight decrease in the number of cells with a sub-G1 DNA content. These results demonstrated that AA released from AA-2G enhanced cytokine-dependent IgM production in anti-mu-primed B cells and suggest that its effect is caused through promoting the differentiation of B cells to plasma cells and attenuating the gradual decrease in the number of viable cells

Dynamic regulation of PGC-1α localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response

There is increasing evidence that longevity and stress resistance are connected, but the mechanism is unclear. We report that mitochondria are regulated in response to oxidative stress and calorie restriction through a shared mechanism involving peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α). We demonstrate that PGC-1α subcellular distribution is regulated, and its transcriptional activity is promoted through SIRT1-dependent nuclear accumulation. In addition, the duration of PGC-1α activity is regulated by glycogen synthase kinase beta (GSK3β), which targets PGC-1α for intranuclear proteasomal degradation. This mechanism of regulation permits the rapidity and persistence of PGC-1α activation to be independently controlled. We provide evidence that this pathway of PGC-1α regulation occurs in vivo in mice, both in the oxidative stress response and with calorie restriction. Our data show how mitochondrial function may be adapted in response to external stimuli, and support the concept that such adaptation is critically involved in cellular survival and in lifespan extension by calorie restriction

The A-to-Z factors associated with cognitive impairment. Results of the DeCo study

IntroductionCognitive impairment (CI) is known to be mediated by several risk and protective factors, many of which are potentially modifiable. Therefore, it is important to have up-to-date studies that address a standard assessment of psychosocial, clinical and lifestyle variables.Materials and methodsWe conducted a cross-sectional observational study, with a 24-month timeframe, to estimate the relationship between risk and protective factors associated with dementia, according to the A-to-Z Dementia Knowledge. Participants were considered at CI risk if they tested positive for at least one of three validated CI screening tests: The Memory Impairment Screening, Short Portable Mental State Questionnaire, and Semantic Verbal Fluency. The A-to-Z data Collection included Mediterranean Diet Adherence Screener and Geriatric Depression Scale.ResultsThe estimated prevalence of CI was 22.6% in a sample of 709 patients with an average of 69.3±10.3 years. The risk factors gradually associated with cognitive decline were hypertension, loneliness, and depression. In contrast, the protective factors gradually associated with less cognitive decline were internet use, reading, and intellectually stimulating jobs. Finally, living alone, having diabetes, taking benzodiazepines, and sleeping more than 9 h were statistically significant associated with CI, whereas to do memory training or a family history of dementia was characteristic of patients without CI.ConclusionA joint assessment of the influence of psychosocial, clinical, and lifestyle-related factors is needed to develop dementia prevention strategies

Individuals With SARS-CoV-2 Infection During the First and Second Waves in Catalonia, Spain: Retrospective Observational Study Using Daily Updated Data

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Epidemiologia; ComparacióCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Epidemiología; ComparaciónCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Epidemiology; ComparisonA description of individuals with SARS-CoV-2 infection comparing the first and second waves could help adapt health services to manage this highly transmissible infection.Objective: We aimed to describe the epidemiology of individuals with suspected SARS-CoV-2 infection, and the characteristics of patients with a positive test comparing the first and second waves in Catalonia, Spain. Methods: This study had 2 stages. First, we analyzed daily updated data on SARS-CoV-2 infection in individuals from Girona (Catalonia). Second, we compared 2 retrospective cohorts of patients with a positive reverse-transcription polymerase chain reaction or rapid antigen test for SARS-CoV-2. The severity of patients with a positive test was defined by their admission to hospital, admission to intermediate respiratory care, admission to the intensive care unit, or death. The first wave was from March 1, 2020, to June 24, 2020, and the second wave was from June 25, 2020, to December 8, 2020.Results: The numbers of tests and cases were lower in the first wave than in the second wave (26,096 tests and 3140 cases in the first wave versus 140,332 tests and 11,800 cases in the second wave), but the percentage of positive results was higher in the first wave than in the second wave (12.0% versus 8.4%). Among individuals with a positive diagnostic test, 818 needed hospitalization in the first wave and 680 in the second; however, the percentage of hospitalized individuals was higher in the first wave than in the second wave (26.1% versus 5.8%). The group that was not admitted to hospital included older people and those with a higher percentage of comorbidities in the first wave, whereas the characteristics of the groups admitted to hospital were more alike.This work was supported by grants from the European Union ERDF funds (Network for Prevention and Health Promotion in Primary Care, RedIAPP–CARDIOCAT; RD16/0007/0004) and from the Agency for Management of University and Research Grants (AGAUR; 2017-SGR 1146). We thank Eric Tornabell for his technical support. We also thank all health care professionals for their ceaseless work to care for COVID-19 patients in this pandemic

Calorie Restriction Increases Muscle Mitochondrial Biogenesis in Healthy Humans

BACKGROUND: Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood. METHODS AND FINDINGS: The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 ± 1.0 y), overweight (body mass index, 27.8 ± 0.7 kg/m(2)) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, −135 ± 42 kcal/d, p = 0.002 and CREX, −117 ± 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% ± 5% in the CR group (p = 0.005) and 21% ± 4% in the CREX group (p < 0.004), with no change in the control group (2% ± 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (−0.56 ± 0.11 arbitrary units, p = 0.003) and CREX (−0.45 ± 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR. CONCLUSIONS: The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults