Intergenerational transmission of the positive effects of physical exercise on brain and cognition

Physical exercise has positive effects on cognition, but very little is known about the inheritance of these effects to sedentary offspring and the mechanisms involved. Here, we use a patrilineal design in mice to test the transmission of effects from the same father (before or after training) and from different fathers to compare sedentary- and runner-father progenies. Behavioral, stereological, and whole-genome sequence analyses reveal that paternal cognition improvement is inherited by the offspring, along with increased adult neurogenesis, greater mitochondrial citrate synthase activity, and modulation of the adult hippocampal gene expression profile. These results demonstrate the inheritance of exercise-induced cognition enhancement through the germline, pointing to paternal physical activity as a direct factor driving offspring’s brain physiology and cognitive behavior.We thank Cesar Cobaleda [Centre of Molecular Biology Severo Ochoa (CBMSO), Spanish National Research Council/Autonomous University of Madrid (CSIC/UAM), Madrid, Spain] and Alberto González-de la Vega (MegaLab, Madrid, Spain) for expert assistance and advice of the RNAseq, DAVID, and GSEA analysis; María Llorens-Martín (CBMSO, CSIC/UAM, Madrid, Spain) for useful discussions; Silvia Fernández (Cellular and Molecular Biology Unit, Cajal Institute, Madrid, Spain) and Laude Garmendia (Animal House, Cajal Institute, Madrid, Spain) for volunteer help and advice; the Image Analysis Unit of the Cajal Institute; Carmen Sandi (Brain Mind Institute, Lausanne, Switzerland) for helpful and useful advice and assistance; and all members of the National Centre for Biotechnology Mouse Embryo Cryopreservation Facility— María Jesús del Hierro, Marta Castrillo, and Lluís Montoliu—for their huge efforts and impressive involvement in the IVF experiments. This work was supported by the Spanish Ministry of Economy and Competitiveness Project Grants BFU2013-48907-R and BFU2016-77162-R (to J.L.T.), SAF2016-78845-R (to S.R.F.), RYC-2012-10193 and AGL2014-85739-R (to P.B.Á.), CP14/00105 and PI15/00134 (to A.M.-M.); by the Instituto de Salud Carlos III of the Spanish Ministry of Economy and Competitiveness; and by the European Regional Development Fund Grant PT17/0009/0019 (to A.E.-C). Á.F.-L. was funded by a CSIC JAE-Doc Programme grant and VPlan Propio US-Acceso Grant, I.L.-T. was funded by a predoctoral fellowship (FPI) grant, and K.R.M. was funded by a contract associated with the above-mentioned project grants awarded to J.L.T

Efficacy, safety and cost-efficiency of adalimumab 80 mg every other week in previously intensified IBD patients under treatment with adalimumab 40 mg every week

Background Dose escalation is often recommended for loss of response in patients with inflammatory bowel disease (IBD) under maintenance treatment with anti-TNF, but in normal conditions this strategy considerably increases the cost. A new presentation of Adalimumab (ADA) 80 mg has been approved in our hospital with the same price per unit as the ADA 40 mg presentation. The aim of this study was to evaluate the efficacy, safety and cost-efficiency of ADA 80 mg every other week (eow) in IBD patients under previously intensified treatment with ADA 40 mg every week. Methods A prospective and observational study was performed. Inclusion criteria were all IBD patients under intensified maintenance therapy with ADA 40 mg every week. Physicians informed all patients the reasons (cost and convenience) for changing to a ADA 80 mg eow dose and asked for their consent. So far we have evaluated a period of 1 month, although the complete follow-up period will be 12 months. The Harvey?Bradshaw index (HBI ?4) and the Mayo partial index (Mayo partial index ?2) were used to evaluate clinical remission in Crohn?s disease (CD) and ulcerative colitis (UC) patients, respectively. Adverse events were monitored. Faecal calprotectin (FC) and C reactive protein (CRP) were collected at baseline (week 0, before first dose of subcutaneous injection of ADA 80 mg) and after 1 month. Biological remission was defined as clinical remission and FC < 250 ?g/g and CRP < 5 mg/dl. A descriptive analysis was performed and data are shown as percentage, median and range. Cost efficiency analysis was also performed. Results We offered to 18 consecutive IBD patients the possibility of participating in the study, but only 16 agreed to participate. We included 15 CD and 1 extensive UC with a median age of 40. 56.3% were male, 37.5% non-smokers and 31.3% ex-smokers. In CD, 46.7% had ileal disease, 13.3% colonic disease and 40% ileocolonic disease. 46.7% CD patients presented fistulising behaviour. At baseline, 86.7% of patients were in clinical remission and 92.3% were in clinical remission after 1 month. Median FC concentration at inclusion was 210 (range 6?1900) and 1 month later 91 (range 10?3754). Median CRP concentration at inclusion was 0.14 (range 0?19) and 0.21 (range 0.01?2.94) at month 1. 60% of patients at month 0 and 53.3% at month 1 were in biological remission. No adverse events were registered. After 1 month in total we had saved more than 13.000 euros and if all patients complete 1 year of treatment we predict savings of more than 150.000 euros with our new schedule of treatment. Conclusions Changing to a single dose ADA 80 mg eow is an efficacy, safety and cost-efficient strategy in IBD patients under intensified maintenance therapy with ADA 40 mg every week

Intergenerational transmission of the positive effects of physical exercise on brain and cognition.

Physical exercise has positive effects on cognition, but very little is known about the inheritance of these effects to sedentary offspring and the mechanisms involved. Here, we use a patrilineal design in mice to test the transmission of effects from the same father (before or after training) and from different fathers to compare sedentary- and runner-father progenies. Behavioral, stereological, and whole-genome sequence analyses reveal that paternal cognition improvement is inherited by the offspring, along with increased adult neurogenesis, greater mitochondrial citrate synthase activity, and modulation of the adult hippocampal gene expression profile. These results demonstrate the inheritance of exercise-induced cognition enhancement through the germline, pointing to paternal physical activity as a direct factor driving offspring's brain physiology and cognitive behavior