Fatty acid metabolism and T cells in multiple sclerosis.

Cellular metabolic remodeling is intrinsically linked to the development, activation, differentiation, function, and survival of T cells. T cells transition from a catabolic, naïve state to an anabolic effector state upon T cell activation. Subsequently, specialization of T cells into T helper (Th) subsets, including regulatory T cells (Treg), requires fine-tuning of metabolic programs that better support and optimize T cell functions for that particular environment. Increasingly, studies have shown that changes in nutrient availability at both the cellular and organismal level during disease states can alter T cell function, highlighting the importance of better characterizing metabolic-immune axes in both physiological and disease settings. In support of these data, a growing body of evidence is emerging that shows specific lipid species are capable of altering the inflammatory functional phenotypes of T cells. In this review we summarize the metabolic programs shown to support naïve and effector T cells, and those driving Th subsets. We then discuss changes to lipid profiles in patients with multiple sclerosis, and focus on how the presence of specific lipid species can alter cellular metabolism and function of T cells

The effect of visitors in a touristic cave and the resulting constraints on natural thermal conditions for palaeoclimate studies (Eagle Cave, central Spain)

Temperature in Eagle Cave, central Spain, was measured over a year to determine the effect of tourists on the natural environ­ment. The mean cave temperature was 15.6°C in 2009, witha seasonal amplitude of <0.4°C. Access of tourists to the cavern produces thermal anomalies of <0.15°C, whichare recovered overnight in most cases. During days withhighvisitor num­bers, cumulative thermal anomalies may persist from one day to the next, causing an increase of cave temperature for longer periods. However, this anthropogenic effect disappears soon after the number of tourists reduces, lasting less than a week in most cases. Cumulative thermal anomalies are <0.02°C dur­ing most of the year and <0.1°C in periods withlarge number of visitors. The anthropogenic effect on cave temperature is non-persistent and has a small magnitude in comparison withnatural oscillations. Thus, long-term absolute temperatures ob­tained from Eagle Cave are not affected by visitors. The input of thermal energy caused by tourists is absorbed as latent heat by the cave (causing evaporation), whichprevents the increase of baseline temperatures in the environment. A condensation process occurs over cave walls and speleothems. This is the re­sult of cooling the atmosphere during the thermal equilibra­tion withcave walls once visitors leave. Althoughcondensation is found in Eagle Cave, the magnitude of the process is not enoughto cause any significant condensation corrosion that could damage speleothems as a result of the tourist visits. The cave is in thermal equilibrium withsurface temperatures, and calibration studies will produce suitable results for palaeocli­mate studies despite being a tourist cavern.

Preservation of NOM-metal complexes in a modern hyperalkaline stalagmite: Implications for speleothem trace element geochemistry

AbstractWe report the first quantitative study of the capture of colloidal natural organic matter (NOM) and NOM-complexed trace metals (V, Co, Cu, Ni) in speleothems. This study combines published NOM–metal dripwater speciation measurements with high-resolution laser ablation ICPMS (LA-ICPMS) and sub-annual stable isotope ratio (δ18O and δ13C), fluorescence and total organic carbon (TOC) analyses of a fast-growing hyperalkaline stalagmite (pH ∼11) from Poole’s Cavern, Derbyshire UK, which formed between 1997 and 2008 AD. We suggest that the findings reported here elucidate trace element variations arising from colloidal transport and calcite precipitation rate changes observed in multiple, natural speleothems deposited at ca. pH 7–8. We find that NOM–metal(aq) complexes on the boundary between colloidal and dissolved (∼1nm diameter) show an annual cyclicity which is inversely correlated with the alkaline earth metals and is explained by calcite precipitation rate changes (as recorded by kinetically-fractionated stable isotopes). This relates to the strength of the NOM–metal complexation reaction, resulting in very strongly bound metals (Co in this system) essentially recording NOM co-precipitation (ternary complexation). More specifically, empirical partition coefficient (Kd) values between surface-reactive metals (V, Co, Cu, Ni) [expressed as ratio of trace element to Ca ratios in calcite and in solution] arise from variations in the ‘free’ fraction of total metal in aqueous solution (fm). Hence, differences in the preservation of each metal in calcite can be explained quantitatively by their complexation behaviour with aqueous NOM. Differences between inorganic Kd values and field measurements for metal partitioning into calcite occur where [free metal]≪[total metal] due to complexation reactions between metals and organic ligands (and potentially inorganic colloids). It follows that where fm≈0, apparent inorganic Kd app values are also ≈0, but the true partition coefficient (Kd actual) is significantly higher. Importantly, the Kd of NOM–metal complexes [organic carbon–metal ratio) approaches 1 for the most stable aqueous complexes, as is shown here for Co, but has values of 24–150 for V, Ni and Cu. This implies that ternary surface complexation (metal–ligand co-adsorption) can occur (as for NOM–Co), but is the exception rather than the rule. We also demonstrate the potential for trace metals to record information on NOM composition as expressed through changing NOM–metal complexation patterns in dripwaters. Therefore, a suite of trace metals in stalagmites show variations clearly attributable to changes in organic ligand concentration and composition, and which potentially reflect the state of overlying surface ecosystems

Teriflunomide and Epstein–Barr virus in a Spanish multiple sclerosis cohort: in vivo antiviral activity and clinical response

Biomarker; Multiple sclerosis; TeriflunomideBiomarcador; Esclerosi múltiple; TeriflunomidaBiomarcador; Esclerosis múltiple; TeriflunomidaBackground: Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been associated with multiple sclerosis (MS). Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing forms of MS. In the preclinical Theiler’s murine encephalitis virus model of MS, the drug demonstrated an increased rate of viral clearance versus the vehicle placebo. Furthermore, teriflunomide inhibits lytic EBV infection in vitro. Objective: 1. To evaluate the humoral response against EBV and HHV-6 prior to teriflunomide treatment and 6 months later. 2. To correlate the variation in the humoral response against EBV and HHV-6 with the clinical and radiological response after 24 months of treatment with teriflunomide. 3. To analyze the utility of different demographic, clinical, radiological, and environmental data to identify early biomarkers of response to teriflunomide. Methods: A total of 101 MS patients (62 women; mean age: 43.4 years) with one serum prior to teriflunomide onset and another serum sample 6 months later were recruited. A total of 80 had been treated for at least 24 months, 13 had stopped teriflunomide before 24 months, and 8 were currently under teriflunomide therapy but with less than 24 months of follow-up. We analyzed the levels of the viral antibodies titers abovementioned in serum samples with ELISA commercial kits, and the levels of serum neurofilament light chain (Nf-L). Results: Antiviral antibody titers decreased for EBNA-1 IgG (74.3%), VCA IgG (69%), HHV-6 IgG (60.4%), and HHV-6 IgM (73.3%) after 6 months of teriflunomide. VCA IgG titers at baseline correlated with Nf-L levels measured at the same time (r = 0.221; p = 0.028) and 6 months later (r = 0.240; p = 0.017). We found that higher EBNA-1 titers (p = 0.001) and a higher age (p = 0.04) at baseline were associated with NEDA-3 conditions. Thus, 77.8% of patients with EBNA-1 >23.0 AU and >42.8 years (P50 values) were NEDA-3. Conclusion: Treatment with teriflunomide was associated with a reduction of the levels of IgG antibody titers against EBV and HHV-6. Furthermore, higher EBNA-1 IgG titers prior to teriflunomide initiation were associated with a better clinical response.AM has a technician contract from “REI: Red de Enfermedades Inflamatorias” (RD21/0002/0038). This work was financially supported by Ministerio de Ciencia e Innovación (Proyectos de generación de conocimiento)-Fondo Europeo de Desarrollo Regional (Feder) (PID2021-126041OB-I00) and “Fundación LAIR”

Virtual reality exercise intradialysis to improve physical function: A feasibility randomized trial

[EN] Objective The main objective of this investigation was to assess feasibility of conducting a future RCT with an intradialysis non-immersive virtual reality exercise intervention. The secondary aim was to explore the impact of either conventional or VR exercise on physical function. Design Feasibility randomized trial. Participants Eighteen subjects who participated in a 16-week intradialysis combined exercise program. Interventions The program lasted four additional weeks of either combined exercise or virtual reality exercise. Main outcome measures Physical function was measured through several reliable tests (sit-to-stand-to-sit tests 10 and 60, gait speed, one-leg heel-rise tests, and 6-minute walk test) at baseline, after 16 weeks of intradialysis combined exercise and by the end of four additional weeks of exercise. Adherence to the exercise programs was registered. Results There was a significant time effect, so that physical function improved in both groups. By the end of the 20 weeks, function improved as measured through the sit-to-stand-to-sit tests 10 and 60, gait speed, one-leg heel-rise left leg, and the 6-minute walk test. Changes that did not occur due to error in the test were seen after 20 weeks were achieved in the sit-to-stand-to-sit test 60, gait speed, one-leg heel-rise test for the left leg, and 6-minute walking test. Conclusion Virtual reality was a feasible intervention. Both interventions improved physical function. Adherence was not significantly different between groups.Universidad Cardenal Herrera-CEU, CEU Universities, Valencia, Spain, Grant/Award Number: Consolidacion de Indicadores CEU-UCH 2016-2017/ISegura-Orti, E.; Perez-Dominguez, B.; Ortega-Pérez De Villar, L.; Melendez-Oliva, E.; Martínez-Gramaje, J.; García-Maset, R.; Gil-Gómez, J. (2019). Virtual reality exercise intradialysis to improve physical function: A feasibility randomized trial. Scandinavian Journal of Medicine and Science in Sports. 29(1):89-94. https://doi.org/10.1111/sms.13304S8994291Segura-Ortí, E., Gordon, P. L., Doyle, J. W., & Johansen, K. L. (2017). Correlates of Physical Functioning and Performance Across the Spectrum of Kidney Function. Clinical Nursing Research, 27(5), 579-596. doi:10.1177/1054773816689282Segura-Orti, E., & Johansen, K. L. (2010). Exercise in End-Stage Renal Disease. Seminars in Dialysis, 23(4), 422-430. doi:10.1111/j.1525-139x.2010.00766.xDelgado, C., & Johansen, K. L. (2011). Barriers to exercise participation among dialysis patients. Nephrology Dialysis Transplantation, 27(3), 1152-1157. doi:10.1093/ndt/gfr404Heiwe, S., & Tollin, H. (2012). Patients’ perspectives on the implementation of intra-dialytic cycling—a phenomenographic study. Implementation Science, 7(1). doi:10.1186/1748-5908-7-68Konstantinidou, E., Koukouvou, G., Kouidi, E., Deligiannis, A., & Tourkantonis, A. (2002). Exercise training in patients with end-stage renal disease on hemodialysis: Comparison of three rehabilitation programs. Journal of Rehabilitation Medicine, 34(1), 40-45. doi:10.1080/165019702317242695Corbetta, D., Imeri, F., & Gatti, R. (2015). Rehabilitation that incorporates virtual reality is more effective than standard rehabilitation for improving walking speed, balance and mobility after stroke: a systematic review. Journal of Physiotherapy, 61(3), 117-124. doi:10.1016/j.jphys.2015.05.017Peruzzi, A., Cereatti, A., Della Croce, U., & Mirelman, A. (2016). Effects of a virtual reality and treadmill training on gait of subjects with multiple sclerosis: a pilot study. Multiple Sclerosis and Related Disorders, 5, 91-96. doi:10.1016/j.msard.2015.11.002Brien, M., & Sveistrup, H. (2011). An Intensive Virtual Reality Program Improves Functional Balance and Mobility of Adolescents With Cerebral Palsy. Pediatric Physical Therapy, 23(3), 258-266. doi:10.1097/pep.0b013e318227ca0fOrtega‐Pérez de VillarL Pérez‐ DomínguezB Segura‐OrtíE et al.Use of virtual reality game as part of exercise program for chronic kidney disease patients undergoing haemodialysis.2015.Cho, H., & Sohng, K.-Y. (2014). The Effect of a Virtual Reality Exercise Program on Physical Fitness, Body Composition, and Fatigue in Hemodialysis Patients. Journal of Physical Therapy Science, 26(10), 1661-1665. doi:10.1589/jpts.26.1661OrtegaL.Comparison of two exercise programs for hemodialysis patients intradialysis vs home based program. absolute and relative reliability of physical performance[tesis doctoral]. Universidad CEU Cardenal Herrera. Facultad de Ciencias de la Salud;2017.Guralnik, J. M., Ferrucci, L., Simonsick, E. M., Salive, M. E., & Wallace, R. B. (1995). Lower-Extremity Function in Persons over the Age of 70 Years as a Predictor of Subsequent Disability. New England Journal of Medicine, 332(9), 556-562. doi:10.1056/nejm199503023320902Segura-Ortí, E., & Martínez-Olmos, F. J. (2011). Test-Retest Reliability and Minimal Detectable Change Scores for Sit-to-Stand-to-Sit Tests, the Six-Minute Walk Test, the One-Leg Heel-Rise Test, and Handgrip Strength in People Undergoing Hemodialysis. Physical Therapy, 91(8), 1244-1252. doi:10.2522/ptj.20100141Segura-Ortí, E. (2017). Fisioterapia sobre ejercicio en pacientes en hemodiálisis. Fisioterapia, 39(4), 137-139. doi:10.1016/j.ft.2017.05.003Bohm, C., Stewart, K., Onyskie-Marcus, J., Esliger, D., Kriellaars, D., & Rigatto, C. (2014). Effects of intradialytic cycling compared with pedometry on physical function in chronic outpatient hemodialysis: a prospective randomized trial. Nephrology Dialysis Transplantation, 29(10), 1947-1955. doi:10.1093/ndt/gfu248KOUFAKI, P., NASH, P. F., & MERCER, T. H. (2002). Assessing the efficacy of exercise training in patients with chronic disease. Medicine & Science in Sports & Exercise, 34(8), 1234-1241. doi:10.1097/00005768-200208000-00002Cappy, C. S., Jablonka, J., & Schroeder, E. T. (1999). The effects of exercise during hemodialysis on physical performance and nutrition assessment. Journal of Renal Nutrition, 9(2), 63-70. doi:10.1016/s1051-2276(99)90002-xHeadley, S., Germain, M., Mailloux, P., Mulhern, J., Ashworth, B., Burris, J., … Jones, M. (2002). Resistance training improves strength and functional measures in patients with end-stage renal disease. American Journal of Kidney Diseases, 40(2), 355-364. doi:10.1053/ajkd.2002.34520Painter, P., Carlson, L., Carey, S., Paul, S. M., & Myll, J. (2000). Low-functioning hemodialysis patients improve with exercise training. American Journal of Kidney Diseases, 36(3), 600-608. doi:10.1053/ajkd.2000.16200Segura-Ortí, E., Kouidi, E., & Lisón, J. F. (2009). Effect of resistance exercise during hemodialysis on physical function and quality of life: randomized controlled trial. Clinical Nephrology, 71(05), 527-537. doi:10.5414/cnp71527Esteve Simó, V., Junqué, A., Fulquet, M., Duarte, V., Saurina, A., Pou, M., … Ramírez de Arellano, M. (2014). Complete Low-Intensity Endurance Training Programme in Haemodialysis Patients: Improving the Care of Renal Patients. Nephron Clinical Practice, 128(3-4), 387-393. doi:10.1159/000369253Johansen, K. L., Painter, P. L., Sakkas, G. K., Gordon, P., Doyle, J., & Shubert, T. (2006). Effects of Resistance Exercise Training and Nandrolone Decanoate on Body Composition and Muscle Function among Patients Who Receive Hemodialysis: A Randomized, Controlled Trial. Journal of the American Society of Nephrology, 17(8), 2307-2314. doi:10.1681/asn.2006010034Tao, X., Chow, S. K. Y., & Wong, F. K. (2017). The effects of a nurse-supervised home exercise programme on improving patients’ perceptions of the benefits and barriers to exercise: A randomised controlled trial. Journal of Clinical Nursing, 26(17-18), 2765-2775. doi:10.1111/jocn.13798Rossi, A. P., Burris, D. D., Lucas, F. L., Crocker, G. A., & Wasserman, J. C. (2014). Effects of a Renal Rehabilitation Exercise Program in Patients with CKD: A Randomized, Controlled Trial. Clinical Journal of the American Society of Nephrology, 9(12), 2052-2058. doi:10.2215/cjn.11791113Boone, A. E., Foreman, M. H., & Engsberg, J. R. (2017). Development of a novel virtual reality gait intervention. Gait & Posture, 52, 202-204. doi:10.1016/j.gaitpost.2016.11.025Orcy, R. B., Dias, P. S., Seus, T. L., Barcellos, F. C., & Bohlke, M. (2012). Combined Resistance and Aerobic Exercise is Better than Resistance Training Alone to Improve Functional Performance of Haemodialysis Patients - Results of a Randomized Controlled Trial. Physiotherapy Research International, 17(4), 235-243. doi:10.1002/pri.1526Oliveros R, M. S., Avendaño, M., Bunout, D., Hirsch, S., De La Maza, M. P., Pedreros, C., & Müller, H. (2011). Estudio piloto sobre entrenamiento físico durante hemodiálisis. Revista médica de Chile, 139(8), 1046-1053. doi:10.4067/s0034-98872011000800010Silva, S. F. da, Pereira, A. A., Silva, W. A. H. da, Simôes, R., & Barros Neto, J. de R. (2013). Physical therapy during hemodialyse in patients with chronic kidney disease. Jornal Brasileiro de Nefrologia, 35(3), 170-176. doi:10.5935/0101-2800.20130028Bulckaen, M., Capitanini, A., Lange, S., Caciula, A., Giuntoli, F., & Cupisti, A. (2011). Implementation of exercise training programs in a hemodialysis unit: effects on physical performance. Journal of Nephrology, 24(6), 790-797. doi:10.5301/jn.2011.6386Cook, S. A., MacLaughlin, H., & Macdougall, I. C. (2007). A structured weight management programme can achieve improved functional ability and significant weight loss in obese patients with chronic kidney disease. Nephrology Dialysis Transplantation, 23(1), 263-268. doi:10.1093/ndt/gfm511PérezDF.Comparación de los efectos de un programa de ejercicio intradiálisis frente a un programa de ejercicio domiciliario[tesis doctoral]. Universidad CEU Cardenal Herrera Facultad de Ciencias de la Salud;2017.Wilkinson, T. J., Shur, N. F., & Smith, A. C. (2016). «Exercise as medicine» in chronic kidney disease. Scandinavian Journal of Medicine & Science in Sports, 26(8), 985-988. doi:10.1111/sms.1271

Distorted TCR repertoires define multisystem inflammatory syndrome in children

While the majority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) display mild or no symptoms, rare individuals develop severe disease presenting with multisystem inflammatory syndrome (MIS-C). The reason for variable clinical manifestations is not understood. Here, we carried out TCR sequencing and conducted comparative analyses of TCR repertoires between children with MIS-C (n = 12) and mild (n = 8) COVID-19. We compared these repertoires with unexposed individuals (samples collected pre-COVID-19 pandemic: n = 8) and with the Adaptive Biotechnologies MIRA dataset, which includes over 135,000 high-confidence SARS-CoV-2-specific TCRs. We show that the repertoires of children with MIS-C are characterised by the expansion of TRBV11-2 chains with high junctional and CDR3 diversity. Moreover, the CDR3 sequences of TRBV11-2 clones shift away from SARS-CoV-2 specific T cell clones, resulting in distorted TCR repertoires. In conclusion, our study reports that CDR3-independent expansion of TRBV11-2+ cells, lacking SARS-CoV-2 specificity, defines MIS-C in children

Corrección a: Nifurtimox versus benznidazol o placebo para la infección asintomática por Trypanosoma cruzi (Equivalencia de intervenciones habituales para tripanosomiasis - EQUITY): protocolo de estudio para un ensayo controlado aleatorio (vol 20, 431, 2019)

Background: Either benznidazole (BZN) or nifurtimox (NFX) is recommended as equivalent to treat Trypanosoma cruzi infection. Nonetheless, supportive data from randomised trials is limited to individuals treated with BZN in southern cone countries of Latin America. Methods: The goal of this randomised, concealed, blind, parallel-group trial is to inform the trypanocidal efficacy and safety of NFX and its equivalence to BZN among individuals with T. cruzi positive serology (TC+). Eligible individuals are TC+, 20–65 years old, with no apparent symptoms/signs or uncontrolled risk factors for cardiomyopathy and at negligible risk of re-infection. Consenting individuals (adherent to a 10-day placebo run-in phase) receive a 120-day BID blinded treatment with NFX, BZN or matching placebo (2:2:1 ratio). The four active medication arms include (1) a randomly allocated sequence of 60-day, conventional-dose (60CD) regimes (BZN 300 mg/day or NFX 480 mg/day, ratio 1:1), followed or preceded by a 60-day placebo treatment, or (2) 120-day half-dose (120HD) regimes (BZN 150 mg/day or NFX 240 mg/day, ratio 1:1). The primary efficacy outcome is the proportion of participants testing positive at least once for up to three polymerase chain reaction (PCR) assays (1 + PCR) 12–18 months after randomisation. A composite safety outcome includes moderate to severe adverse reactions, consistent blood marker abnormalities or treatment abandons. The trial outside Colombia (expected to recruit at least 60% of participants) is pragmatic; it may be open-label and not include all treatment groups, but it must adhere to the randomisation and data administration system and guarantee a blinded efficacy outcome evaluation. Our main comparisons include NFX groups with placebo (for superiority), NFX versus BZN groups and 60CD versus 120HD groups (for non-inferiority) and testing for the agent-dose and group-region interactions. Assuming a 1 + PCR ? 75% in the placebo group, up to 25% among BZN-treated and an absolute difference of up to ? 25% with NFX to claim its trypanocidal effect, 60–80 participants per group (at least 300 from Colombia) are needed to test our hypotheses (80–90% power; one-sided alpha level 1%)