Publications by authors named "Marina Sanchez"

50 Publications

Structural and Functional Brain Abnormalities in Mouse Models of Lafora Disease.

Int J Mol Sci 2020 Oct 20;21(20). Epub 2020 Oct 20.

Laboratory of Neurology, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain.

Mutations in the and genes, encoding laforin and malin proteins respectively, are responsible for Lafora disease, a fatal form of progressive myoclonus epilepsy with autosomal recessive inheritance. Neuroimaging studies of patients with Lafora disease have shown different degrees of brain atrophy, decreased glucose brain uptake and alterations on different brain metabolites mainly in the frontal cortex, basal ganglia and cerebellum. Mice deficient for laforin and malin present many features similar to those observed in patients, including cognitive, motor, histological and epileptic hallmarks. We describe the neuroimaging features found in two mouse models of Lafora disease. We found altered volumetric values in the cerebral cortex, hippocampus, basal ganglia and cerebellum using magnetic resonance imaging (MRI). Positron emission tomography (PET) of the cerebral cortex, hippocampus and cerebellum of mice revealed abnormal glucose uptake, although no alterations in mice were observed. Magnetic resonance spectroscopy (MRS) revealed significant changes in the concentration of several brain metabolites, including -acetylaspartate (NAA), in agreement with previously described findings in patients. These data may provide new insights into disease mechanisms that may be of value for developing new biomarkers for diagnosis, prevention and treatment of Lafora disease using animal models.
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http://dx.doi.org/10.3390/ijms21207771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589150PMC
October 2020

Pay for performance for specialised care in England: Strengths and weaknesses.

Health Policy 2019 11 17;123(11):1036-1041. Epub 2019 Jul 17.

School of Health Sciences, University of Manchester, M13 9PL, Manchester, UK.

Pay-for-Performance (P4P) schemes have become increasingly common internationally, yet evidence of their effectiveness remains ambiguous. P4P has been widely used in England for over a decade both in primary and secondary care. A prominent P4P programme in secondary care is the Commissioning for Quality and Innovation (CQUIN) framework. The most recent addition to this framework is Prescribed Specialised Services (PSS) CQUIN, introduced into the NHS in England in 2013. This study offers a review and critique of the PSS CQUIN scheme for specialised care. A key feature of PSS CQUIN is that whilst it is centrally developed, performance targets are agreed locally. This means that there is variation across providers in the schemes selected from the national menu, the achievement level needed to earn payment, and the proportion of the overall payment attached to each scheme. Specific schemes vary in terms of what is incentivised - structure, process and/or outcome - and how they are incentivised. Centralised versus decentralised decision making, the nature of the performance measures, the tiered payment structure and the dynamic nature of the schemes have created a sophisticated but complex P4P programme which requires evaluation to understand the effect of such incentives on specialised care.
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http://dx.doi.org/10.1016/j.healthpol.2019.07.007DOI Listing
November 2019

Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome.

Neurobiol Dis 2019 07 1;127:210-222. Epub 2019 Mar 1.

Instituto de Biología Molecular de Barcelona (IBMB), CSIC, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain. Electronic address:

Autism spectrum disorders are early onset neurodevelopmental disorders characterized by deficits in social communication and restricted repetitive behaviors, yet they are quite heterogeneous in terms of their genetic basis and phenotypic manifestations. Recently, de novo pathogenic mutations in DYRK1A, a chromosome 21 gene associated to neuropathological traits of Down syndrome, have been identified in patients presenting a recognizable syndrome included in the autism spectrum. These mutations produce DYRK1A kinases with partial or complete absence of the catalytic domain, or they represent missense mutations located within this domain. Here, we undertook an extensive biochemical characterization of the DYRK1A missense mutations reported to date and show that most of them, but not all, result in enzymatically dead DYRK1A proteins. We also show that haploinsufficient Dyrk1a mutant mice mirror the neurological traits associated with the human pathology, such as defective social interactions, stereotypic behaviors and epileptic activity. These mutant mice present altered proportions of excitatory and inhibitory neocortical neurons and synapses. Moreover, we provide evidence that alterations in the production of cortical excitatory neurons are contributing to these defects. Indeed, by the end of the neurogenic period, the expression of developmental regulated genes involved in neuron differentiation and/or activity is altered. Therefore, our data indicate that altered neocortical neurogenesis could critically affect the formation of cortical circuits, thereby contributing to the neuropathological changes in DYRK1A haploinsufficiency syndrome.
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http://dx.doi.org/10.1016/j.nbd.2019.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753933PMC
July 2019

A Novel Wearable Device for Continuous Ambulatory ECG Recording: Proof of Concept and Assessment of Signal Quality.

Biosensors (Basel) 2019 Jan 21;9(1). Epub 2019 Jan 21.

Electrophysiology Division, Institut Universitaire de cardiologie et de pneumologie de Québec, Québec, G1V 4G5, QC, Canada.

Diagnosis of arrhythmic disorders is challenging because of their short-lasting, intermittent character. Conventional technologies of noninvasive ambulatory rhythm monitoring are limited by modest sensitivity. We present a novel form of wearable electrocardiogram (ECG) sensors providing an alternative tool for long-term rhythm monitoring with the potential of increased sensitivity to detect intermittent or subclinical arrhythmia. The objective was to assess the signal quality and R-R coverage of a wearable ECG sensor system compared to a standard 3-lead Holter. In this phase-1 trial, healthy individuals underwent 24-h simultaneous rhythm monitoring using the OMsignal system together with a 3-lead Holter recording. The OMsignal system consists of a garment (bra or shirt) with integrated sensors recording a single-lead ECG and an acquisition module for data storage and processing. Head-to-head signal quality was assessed regarding adequate P-QRS-T distinction and was performed by three electrophysiologists blinded to the recording technology. The accuracy of signal coverage was assessed using Bland-Altman analysis. Fifteen individuals underwent simultaneous 24-h recording. Signal quality and accuracy of the OMgaments was equivalent to Holter-monitoring (84% vs 93% electrophysiologists rating, = 0.06). Signal coverage of R-R intervals showed a very close overlay between the OMsignal system and Holter signals, mean difference in heart rate of 2 5 bpm. The noise level of OMgarments was comparable to Holter recording. OMgarments provide high signal quality for adequate rhythm analysis, representing a promising novel technology for long-term non-invasive ECG monitoring.
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http://dx.doi.org/10.3390/bios9010017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468449PMC
January 2019

Amniotic ectoderm expansion in mouse occurs via distinct modes and requires SMAD5-mediated signalling.

Development 2018 07 2;145(13). Epub 2018 Jul 2.

VIB-KU Leuven Center for Brain and Disease Research, Leuven 3000, Belgium

Upon gastrulation, the mammalian conceptus transforms rapidly from a simple bilayer into a multilayered embryo enveloped by its extra-embryonic membranes. Impaired development of the amnion, the innermost membrane, causes major malformations. To clarify the origin of the mouse amnion, we used single-cell labelling and clonal analysis. We identified four clone types with distinct clonal growth patterns in amniotic ectoderm. Two main types have progenitors in extreme proximal-anterior epiblast. Early descendants initiate and expand amniotic ectoderm posteriorly, while descendants of cells remaining anteriorly later expand amniotic ectoderm from its anterior side. Amniogenesis is abnormal in embryos deficient in the bone morphogenetic protein (BMP) signalling effector SMAD5, with delayed closure of the proamniotic canal, and aberrant amnion and folding morphogenesis. Transcriptomics of individual mutant amnions isolated before visible malformations and tetraploid chimera analysis revealed two amnion defect sets. We attribute them to impairment of progenitors of the two main cell populations in amniotic ectoderm and to compromised cuboidal-to-squamous transition of anterior amniotic ectoderm. In both cases, SMAD5 is crucial for expanding amniotic ectoderm rapidly into a stretchable squamous sheet to accommodate exocoelom expansion, axial growth and folding morphogenesis.
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http://dx.doi.org/10.1242/dev.157222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053664PMC
July 2018

Tau-Induced Pathology in Epilepsy and Dementia: Notions from Patients and Animal Models.

Int J Mol Sci 2018 Apr 5;19(4). Epub 2018 Apr 5.

Laboratory of Neurology, IIS (Instituto Investigación Sanitaria/Health Research Institute)-Jiménez Díaz Foundation, UAM (Universidad Autonoma de Madrid/Autonomous University of Madrid) and Biomedical Research Network Center on Rare Diseases (CIBERER), 28045 Madrid, Spain.

Patients with dementia present epilepsy more frequently than the general population. Seizures are more common in patients with Alzheimer's disease (AD), dementia with Lewy bodies (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) than in other dementias. Missense mutations in the microtubule associated protein tau (MAPT) gene have been found to cause familial FTD and PSP, while the P301S mutation in MAPT has been associated with early-onset fast progressive dementia and the presence of seizures. Brains of patients with AD, LBD, FTD and PSP show hyperphosphorylated tau aggregates, amyloid-β plaques and neuropil threads. Increasing evidence suggests the existence of overlapping mechanisms related to the generation of network hyperexcitability and cognitive decline. Neuronal overexpression of tau with various mutations found in FTD with parkinsonism-linked to chromosome 17 (FTDP-17) in mice produces epileptic activity. On the other hand, the use of certain antiepileptic drugs in animal models with AD prevents cognitive impairment. Further efforts should be made to search for plausible common targets for both conditions. Moreover, attempts should also be made to evaluate the use of drugs targeting tau and amyloid-β as suitable pharmacological interventions in epileptic disorders. The diagnosis of dementia and epilepsy in early stages of those diseases may be helpful for the initiation of treatments that could prevent the generation of epileptic activity and cognitive deterioration.
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http://dx.doi.org/10.3390/ijms19041092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979593PMC
April 2018

A higher level of ketonaemia does not predict oral rehydration failure in vomiting paediatric patients and routine measurement is unnecessary.

Acta Paediatr 2018 Apr 22;107(4):714-717. Epub 2017 Dec 22.

Pediatric Emergency Unit, Pediatrics Department, Rio Hortega Universitary Hospital, Valladolid, Spain.

Aim: This study determined if blood levels of beta-hydroxybutyrate were associated with the rate of failure in oral rehydration in paediatric patients with vomiting.

Methods: This was a prospective observational study that was carried out from December 1, 2015 to November 30, 2016 in the Rio Hortega University Hospital, Valladolid, Spain. The study cohort were patients up to 14 years old who attended the emergency department with three or more vomiting episodes in the last four hours and glycaemia higher than 45 mg/dL. Blood was measured for beta-hydroxybutyrate levels prior to the administration of oral rehydration solution for 90 minutes. Two or more vomiting episodes during this period were considered failed oral rehydration.

Results: We analysed 248 patients, with a median age of four years and 7.5 months and 233 (94%) of the parents took part. The median number of vomiting episodes in the previous four hours was five and oral rehydration was successful in 183 (78.5%) patients. The multivariate analysis showed that the initial beta-hydroxybutyrate blood level was not associated with the failure of oral rehydration.

Conclusion: Blood levels of beta-hydroxybutyrate had no predictive value for oral rehydration failure in young patients with vomiting and this routine measurement is unnecessary.
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http://dx.doi.org/10.1111/apa.14173DOI Listing
April 2018

The impact of an innovative web-based school nutrition intervention to increase fruits and vegetables and milk and alternatives in adolescents: a clustered randomized trial.

Int J Behav Nutr Phys Act 2017 10 16;14(1):140. Epub 2017 Oct 16.

Département de l'éducation Physique, Faculté des Sciences de l'éducation, Université Laval, Québec City, QC, G1V 0A6, Canada.

Background: The increase in overweight and obesity in adolescents and its health-related consequences highlight the need to develop strategies, which could help them adopt healthy eating habits. The objective of this study was to evaluate the impact of an innovative web-based school nutrition intervention (Team Nutriathlon) aimed at promoting the consumption of vegetables and fruit (V/F) and milk and alternatives (M/A) in high school students and to identify facilitators and/or barriers influencing its success.

Methods: Ten classes of first and second year secondary students (grades 7 and 8) from the Québec City region were randomized into two groups (control n = 89 and intervention n = 193). Participants in the intervention (Team Nutriathlon) were to increase their consumption of V/F and M/A using an innovative web-based platform, developed for this study, over 6 weeks. The control group followed the regular school curriculum. The number of servings of V/F and M/A consumed by students per day was compared between the two groups before, during, immediately after and 10 weeks after the intervention using a web-based platform. Main outcome measures included V/F and M/A servings and facilitators and/or barriers of program success. Repeated measures linear fixed effects models were used to assess the impact of Team Nutriathlon on V/F and M/A consumption. A P-value of <0.05 was considered significant.

Results: Students in the intervention reported a significant increase of 3 servings and 1.8 servings per day of V/F and M/A, respectively, compared to the control group (P < 0.05); however, this was only observed in the short-term. Some factors contributing to the success of Team Nutriathlon included the team aspect of the program, use of the technology and recording results outside of classroom hours.

Conclusion: Team Nutriathlon represents an innovative web-based nutrition program which positively impacts V/F and M/A consumption among high school students. Using web-based or technological platforms may help youth adopt healthy eating habits that will have implications later in adulthood; however, further studies are needed to determine their long-term effects.

Trial Registration: NCT03117374 (retrospectively registered).
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http://dx.doi.org/10.1186/s12966-017-0595-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644089PMC
October 2017

Effects of a Diet-Based Weight-Reducing Program with Probiotic Supplementation on Satiety Efficiency, Eating Behaviour Traits, and Psychosocial Behaviours in Obese Individuals.

Nutrients 2017 Mar 15;9(3). Epub 2017 Mar 15.

Faculty of Medicine, Department of Kinesiology, Laval University, Quebec, QC G1V 0A6, Canada.

This study evaluated the impact of probiotic supplementation (Lactobacillus rhamnosus CGMCC1.3724 (LPR)) on appetite sensations and eating behaviors in the context of a weight-reducing program. Obese men ( = 45) and women ( = 60) participated in a double-blind, randomized, placebo-controlled trial that included a 12-week weight loss period (Phase 1) based on moderate energy restriction, followed by 12 weeks of weight maintenance (Phase 2). During the two phases of the program, each subject consumed two capsules per day of either a placebo or a LPR formulation (10 mg of LPR equivalent to 1.6 108 CFU/capsule, 210 mg of oligofructose, and 90 mg of inulin). The LPR supplementation increased weight loss in women that was associated with a greater increase in the fasting desire to eat ( = 0.03). On the other hand, satiety efficiency (satiety quotient for desire to eat) at lunch increased ( = 0.02), whereas disinhibition ( = 0.05) and hunger ( = 0.02) scores decreased more in the LPR-treated women, when compared with the female control group. Additionally, the LPR female group displayed a more pronounced decrease in food craving ( = 0.05), and a decrease in the Beck Depression Inventory score ( = 0.05) that was significantly different from the change noted in the placebo group ( = 0.02), as well as a higher score in the Body Esteem Scale questionnaire ( = 0.06). In men, significant benefits of LPR on fasting fullness and cognitive restraint were also observed. Taken together, these observations lend support to the hypothesis that the gut-brain axis may impact appetite control and related behaviors in obesity management.
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http://dx.doi.org/10.3390/nu9030284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372947PMC
March 2017

4-Phenylbutyric acid and metformin decrease sensitivity to pentylenetetrazol-induced seizures in a malin knockout model of Lafora disease.

Neuroreport 2017 Mar;28(5):268-271

aDepartment of Neuroscience, Laboratory of Neurology, IIS-Jiménez Díaz Foundation, UAM and Biomedical Research Network Center on Rare Diseases (CIBERER), Madrid bDepartment of Nutrient Signalling, Institute of Biomedicine of Valencia, CSIC, and CIBERER, Valencia, Spain.

Lafora disease (LD) is a rare adolescent-onset progressive myoclonic epilepsy caused by loss-of-function mutations either in the EPM2A gene encoding laforin or in the EPM2B gene encoding malin. Mouse models with deletion in the Epm2a or the Epm2b gene show intracellular aggregates of polyglucosans (Lafora bodies) and neurological complications that resemble those observed in patients with LD. In the absence of laforin or malin expression, mice also show different degrees of hyperexcitability, as reflected by an enhanced response to the convulsant drug pentylenetetrazol (PTZ). Malin knockout mice treated with 4-phenylbutyric acid (4-PBA) and metformin showed decreased amounts of Lafora bodies and polyubiquitin protein aggregates in the brain, diminished neurodegeneration, and amelioration of some neurological conditions. In this study, we analyzed the action of 4-PBA and metformin treatments on response to PTZ in a malin knockout model of LD. Both treatments decreased seizure susceptibility, bringing about a reduction in both seizure number and length, and eliminated the mortality induced by PTZ. These results show a neuroprotective role of 4-PBA and metformin and extend the beneficial effects reported in the malin knockout model of LD Video abstract: http://links.lww.com/WNR/A411.
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http://dx.doi.org/10.1097/WNR.0000000000000751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491969PMC
March 2017

Sodium selenate treatment improves symptoms and seizure susceptibility in a malin-deficient mouse model of Lafora disease.

Epilepsia 2017 03 18;58(3):467-475. Epub 2017 Jan 18.

Laboratory of Neurology, IIS-Jiménez Díaz Foundation, UAM, Madrid, Spain.

Objective: To search for new therapies aimed at ameliorating the neurologic symptoms and epilepsy developing in patients with Lafora disease.

Methods: Lafora disease is caused by loss-of-function mutations in either the EPM2A or EPM2B genes. Epm2a and Epm2b mice display neurologic and behavioral abnormalities similar to those found in patients. Selenium is a potent antioxidant and its deficiency has been related to the development of certain diseases, including epilepsy. In this study, we investigated whether sodium selenate treatment improved the neurologic alterations and the hyperexcitability present in the Epm2b mouse model.

Results: Sodium selenate ameliorates some of the motor and memory deficits and the sensitivity observed with pentylenetetrazol (PTZ) treatments in Epm2b mice. Neuronal degeneration and gliosis were also diminished after sodium selenate treatment.

Significance: Sodium selenate could be beneficial for ameliorating some symptoms that present in patients with Lafora disease.
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http://dx.doi.org/10.1111/epi.13656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495962PMC
March 2017

Spontaneous liver rupture as first sign of polyarteritis nodosa.

World J Hepatol 2016 Nov;8(32):1414-1418

Irene Gómez-Luque, General Surgery, Reina Sofía University Hospital, 14004 Córdoba, Spain.

Polyarteritis nodosa (PAN) is one of the systemic vasculitis that affects the media wall of arteries of small and medium diameter. Diagnosis proves difficult due to the unspecific symptoms that dominate the clinical profile. Liver involvement is very diverse, ranging from the development of cirrhotic liver disease to acute abdomen presentation that requires surgery because of liver rupture. The management of these patients requires an expert multidisciplinary team. There are several cases in the literature that describe a sudden liver rupture as the first manifestation of a PAN. In this paper we present the case of a 75 years old patient without any previous disease, who is subjected to major hepatic resection for spontaneous liver rupture.
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http://dx.doi.org/10.4254/wjh.v8.i32.1414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114477PMC
November 2016

[Multiple organ failure after spontaneous return of circulation in cardiac arrest in children].

An Pediatr (Barc) 2017 Jul 21;87(1):34-41. Epub 2016 Jul 21.

Servicio de Cuidados Intensivos Pediátricos, Hospital General Universitario Gregorio Marañón, Madrid, España; Instituto de Investigación Sanitaria, Hospital Gregorio Marañón, Madrid, España; Facultad de Medicina, Universidad Complutense de Madrid, Madrid, España.

Objective: To assess the frequency of the multiple organ failure and the prognostic value of multiple organ failure scores in children who have recovered from an in-hospital cardiac arrest.

Patients And Methods: A single centre, observational, and retrospective study was conducted on children between 1 month and 16 years old who suffered an in-hospital cardiac arrest and achieved return of spontaneous circulation (ROSC). In the first 24-48hours and between the fifth and the seventh day after ROSC, a record was made of the scores on paediatric severity (PRISM and PIM II) and multiple organ failure scales (PELOD and P-MODS), along with the clinical and analytical data, and including monitoring and treatment, mortality and cause of death.

Results: Of the total of 41 children studied, 70.7% male were male, and the median age was 38 months. The overall mortality during admission was 41.5%, with 14.6% dying in the first 48hours, and 7.6% in the following 3 to 5 days. In the first 48hours, clinical severity and multiple organ failure scores were higher in the patients that died than in survivors (PRISM 29 vs. 21) P=.125, PIM II (26.8% vs. 9.2%) P=.02, PELOD (21 vs. 12) P=.005, and P-MODS (9 vs. 6) P=.001. Between the fifth and seventh day, the scores on the four scales were also higher in patients who died, but only those of the PELOD (20.5 vs. 11) p=.002 and P-MODS (6.5 vs. 3) P=.003 reached statistical significance.

Conclusions: Mortality in children after return of spontaneous circulation after cardiac arrest is high. The multiple organ failure after return of spontaneous circulation after cardiac arrest in children is associated with increased mortality.
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http://dx.doi.org/10.1016/j.anpedi.2016.06.010DOI Listing
July 2017

Host sphingomyelin increases West Nile virus infection in vivo.

J Lipid Res 2016 Mar 13;57(3):422-32. Epub 2016 Jan 13.

Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA), Madrid 28040, Spain

Flaviviruses, such as the dengue virus and the West Nile virus (WNV), are arthropod-borne viruses that represent a global health problem. The flavivirus lifecycle is intimately connected to cellular lipids. Among the lipids co-opted by flaviviruses, we have focused on SM, an important component of cellular membranes particularly enriched in the nervous system. After infection with the neurotropic WNV, mice deficient in acid sphingomyelinase (ASM), which accumulate high levels of SM in their tissues, displayed exacerbated infection. In addition, WNV multiplication was enhanced in cells from human patients with Niemann-Pick type A, a disease caused by a deficiency of ASM activity resulting in SM accumulation. Furthermore, the addition of SM to cultured cells also increased WNV infection, whereas treatment with pharmacological inhibitors of SM synthesis reduced WNV infection. Confocal microscopy analyses confirmed the association of SM with viral replication sites within infected cells. Our results unveil that SM metabolism regulates flavivirus infection in vivo and propose SM as a suitable target for antiviral design against WNV.
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http://dx.doi.org/10.1194/jlr.M064212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766991PMC
March 2016

Impact of yogurt on appetite control, energy balance, and body composition.

Nutr Rev 2015 Aug;73 Suppl 1:23-7

A. Tremblay, C. Doyon, and M. Sanchez are with the Department of Kinesiology, Pavillon de l'éducation physique et des sports (PEPS), Laval University, Quebec City, Quebec, Canada.

Recent data support the idea that regular yogurt consumption promotes body weight stability. The simplest explanation is that regular consumption of healthful foods such as yogurt results in decreased intake of less healthful foods containing high amounts of fat and/or sugar. There is also evidence to suggest that the high calcium and protein contents of yogurt and other dairy foods influence appetite and energy intake. The existence of a calcium-specific appetite control mechanism has been proposed. Milk proteins differ in terms of absorption rate and post-absorptive responses, which can influence their satiating properties. Studies in humans have shown that consumption of milk and yogurt increases the circulating concentration of the anorectic peptides glucagon-like peptide (GLP)-1 and peptide YY (PYY). The food matrix can also affect appetite and satiety. Yogurt is a fermented milk that contains bacteria that enrich the microbiota of the host. It appears that lean vs obese humans differ in the composition of their gut microbiota. The available relevant literature suggests that yogurt is a food that facilitates the regulation of energy balance.
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http://dx.doi.org/10.1093/nutrit/nuv015DOI Listing
August 2015

Accelerometric assessment of different dimensions of natural walking during the first year after stroke: Recovery of amount, distribution, quality and speed of walking.

J Rehabil Med 2015 Sep;47(8):714-21

Physical Therapy, Seville University, 41009 Seville, Spain.

Objectives: To describe the course of walking behaviour over a period of 1 year after stroke, using accelerometry, and to compare 1-year data with those from a healthy group.

Design: One-year follow-up cohort study.

Subjects: Twenty-three stroke patients and 20 age-matched healthy subjects.

Methods: Accelerometer assessments were made in the participants' daily environment for 8 h/day during the 1st (T1), 12th (T2) and 48th (T3) weeks after stroke, and at one time-point in healthy subjects. Primary outcomes were: percentage of time walking and upright (amount); mean duration and number of walking periods (distribution); step regularity and gait symmetry (quality); and walking speed.

Results: Time walking, time upright, and number of walking bouts increased during T1 and T2 (p < 0.01) and then levelled off (p > 0.30). Mean duration of walking periods showed no significant improvements (p > 0.30) during all phases. Step regularity, gait symmetry and gait speed showed a tendency to increase consistently from T1 to T3. At T3, amount and distribution variables reached the level of the healthy group, but significant differences remained (p < 0.02) in step regularity and gait speed.

Conclusion: In this cohort, different outcomes of walking behaviour showed different patterns and levels of recovery, which supports the multi-dimensional character of gait.
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http://dx.doi.org/10.2340/16501977-1994DOI Listing
September 2015

The thermal unfolding of the ribosome-inactivating protein saporin-S6 characterized by infrared spectroscopy.

Biochim Biophys Acta 2015 Oct 19;1854(10 Pt A):1357-64. Epub 2015 Jun 19.

Prometeo Researcher, Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja (UTPL), Loja, Ecuador. Electronic address:

Saporin-S6 is a plant toxin belonging to the type 1 ribosome-inactivating protein (RIP) family. Since it was extracted and isolated from Saponaria officinalis for the first time almost thirty years ago, the protein has been widely studied mainly for its potential applications in anti-tumour and anti-viral infection therapy. Like other RIPs, saporin-S6 is particularly effective in the form of immunotoxin conjugated with monoclonal antibodies and its chemico-physical characteristics made the protein a perfect candidate for the synthesis, development and use of saporin-S6-based chimeric toxins. The high stability of the protein against different denaturing agents has been broadly demonstrated, however, its complete thermal unfolding characterization has not already been performed. In this work we analyse in detail structure, thermostability and unfolding features by means of infrared spectroscopy coupled with two-dimensional correlation spectroscopy. Our data showed that saporin-S6 in solution at neutral pH exhibits a secondary structure analogue to that of the crystal and confirmed its good stability at moderately high temperatures, with a temperature of melting of 58°C. Our results also demonstrated that the thermal unfolding process is non-cooperative and occurs in two steps, and revealed the sequence of the events that take place during the denaturation, showing a higher stability of the N-terminal domain of the protein.
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http://dx.doi.org/10.1016/j.bbapap.2015.06.006DOI Listing
October 2015

Pharmacological Interventions to Ameliorate Neuropathological Symptoms in a Mouse Model of Lafora Disease.

Mol Neurobiol 2016 Mar 28;53(2):1296-1309. Epub 2015 Jan 28.

Instituto de Biomedicina de Valencia (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain.

Lafora disease (LD, OMIM 254780) is a rare fatal neurodegenerative disorder that usually occurs during childhood with generalized tonic-clonic seizures, myoclonus, absences, drop attacks, or visual seizures. Unfortunately, at present, available treatments are only palliatives and no curative drugs are available yet. The hallmark of the disease is the accumulation of insoluble polyglucosan inclusions, called Lafora bodies (LBs), within the neurons but also in heart, muscle, and liver cells. Mouse models lacking functional EPM2A or EPM2B genes (the two major loci related to the disease) recapitulate the Lafora disease phenotype: they accumulate polyglucosan inclusions, show signs of neurodegeneration, and have a dysregulation of protein clearance and endoplasmic reticulum stress response. In this study, we have subjected a mouse model of LD (Epm2b-/-) to different pharmacological interventions aimed to alleviate protein clearance and endoplasmic reticulum stress. We have used two chemical chaperones, trehalose and 4-phenylbutyric acid. In addition, we have used metformin, an activator of AMP-activated protein kinase (AMPK), as it has a recognized neuroprotective role in other neurodegenerative diseases. Here, we show that treatment with 4-phenylbutyric acid or metformin decreases the accumulation of Lafora bodies and polyubiquitin protein aggregates in the brain of treated animals. 4-Phenylbutyric acid and metformin also diminish neurodegeneration (measured in terms of neuronal loss and reactive gliosis) and ameliorate neuropsychological tests of Epm2b-/- mice. As these compounds have good safety records and are already approved for clinical uses on different neurological pathologies, we think that the translation of our results to the clinical practice could be straightforward.
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http://dx.doi.org/10.1007/s12035-015-9091-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474477PMC
March 2016

Childhood obesity: a role for gut microbiota?

Int J Environ Res Public Health 2014 Dec 23;12(1):162-75. Epub 2014 Dec 23.

Department of Kinesiology, Faculty of Medicine, Laval University, Québec, QC G1V 0A6, Canada.

Obesity is a serious public health issue affecting both children and adults. Prevention and management of obesity is proposed to begin in childhood when environmental factors exert a long-term effect on the risk for obesity in adulthood. Thus, identifying modifiable factors may help to reduce this risk. Recent evidence suggests that gut microbiota is involved in the control of body weight, energy homeostasis and inflammation and thus, plays a role in the pathophysiology of obesity. Prebiotics and probiotics are of interest because they have been shown to alter the composition of gut microbiota and to affect food intake and appetite, body weight and composition and metabolic functions through gastrointestinal pathways and modulation of the gut bacterial community. As shown in this review, prebiotics and probiotics have physiologic functions that contribute to changes in the composition of gut microbiota, maintenance of a healthy body weight and control of factors associated with childhood obesity through their effects on mechanisms controlling food intake, fat storage and alterations in gut microbiota.
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http://dx.doi.org/10.3390/ijerph120100162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306855PMC
December 2014

Enhanced sensitivity of laforin- and malin-deficient mice to the convulsant agent pentylenetetrazole.

Front Neurosci 2014 12;8:291. Epub 2014 Sep 12.

Laboratory of Neurology, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid Madrid, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras Madrid, Spain.

Lafora disease is a rare form of inherited progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin, or in the EPM2B gene, which encodes malin. It is characterized by the presence of polyglucosan inclusion bodies (Lafora bodies) in brain and other tissues. Genetically engineered mice lacking expression of either the laforin (Epm2a(-/-) ) or malin (Epm2b(-/-) ) genes display a number of neurological and behavioral abnormalities that resemble those found in patients suffering from Lafora disease; of these, both Epm2a(-/-) and Epm2b(-/-) mice have shown altered motor activity, impaired motor coordination, episodic memory deficits, and different degrees of spontaneous epileptic activity. In this study, we analyze the sensitivity of Epm2a(-/-) and Epm2b(-/-) mice to the convulsant drug pentylenetetrazol (PTZ), an antagonist of the γ-aminobutyric acid type A (GABAA) receptor, commonly used to induce epileptic tonic-clonic seizures in laboratory animals. PTZ-induced epileptic activity, including myoclonic jerks and tonic-clonic seizures, was analyzed in 2 age groups of mice comprising representative samples of young adult and aged mice, after administration of PTZ at sub-convulsive and convulsive doses. Epm2a(-/-) and Epm2b(-/-) mice showed a lower convulsive threshold after PTZ injections at sub-convulsive doses. A lower convulsive threshold and shorter latencies to develop epileptic seizures were observed after PTZ injections at convulsive doses. Different patterns of generalized seizures and of discharges were observed in Epm2a(-/-) and Epm2b(-/-) mice. Epm2a(-/-) and Epm2b(-/-) mice present an increased sensitivity to the convulsant agent PTZ that may reflect different degrees of increased GABAA receptor-mediated hyperexcitability.
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http://dx.doi.org/10.3389/fnins.2014.00291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162417PMC
October 2014

Computational study of interactions and nuclear magnetic shielding constants in linear chains of formamide clusters.

J Mol Model 2014 Jul 20;20(7):2320. Epub 2014 Jun 20.

Instituto de Física Fundamental, IFF-CSIC, Serrano 123, 28006, Madrid, Spain.

We investigated the energetic, structural, dielectric, and nuclear magnetic shielding properties of linear n-formamide clusters, with n up to 6, to quantitatively characterize cooperative effects in model biological systems. The geometries of the complexes were optimized at the MP2 and DFT/B3LYP levels by using the pc-2 and pc-3 basis sets, while the nuclear magnetic shielding constants were calculated by employing pcS-n type basis sets, which have been optimized specifically for density functional calculations of these properties. The interaction energies show the cooperative effect, which favors the successive addition of monomers. In addition, by analyzing structural changes in the intermolecular C=O, C-N and hydrogen O⋯H bonds, as well as in the average dipole moments as cluster size increases, we found that the cooperative interaction far exceeds that expected for electrostatic interactions. Such non-pairwise-additive effects are also reflected in the changes of the nuclear magnetic shielding constants. In particular, the negativity of O shielding decreases around 23% from the monomer to the 6-formamide chain. It is possible to note the decrease in the shielding of H and in the deshielding of O as a result of their hydrogen bonding. However, the results obtained show that these variations in the extremes of formamide chains tend to zero, and the respective shielding values tend to stabilize as the number of monomers increases in the chain. Also, the cooperative effect increases in the middle of the chains, by decreasing the shielding for all atoms except that of O, which decreases its deshielding. These results could serve to guide improvements in current conventional models for simulating hydrogen bonded systems.
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http://dx.doi.org/10.1007/s00894-014-2320-7DOI Listing
July 2014

Association of C4d deposition with clinical outcomes in IgA nephropathy.

Clin J Am Soc Nephrol 2014 May 27;9(5):897-904. Epub 2014 Feb 27.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: Several studies have suggested that activation of the complement system is a contributing pathogenic mechanism in IgA nephropathy (IgAN). C4d staining is an inexpensive and easy-to-perform method for the analysis of renal biopsies. This study aimed to assess the clinical and prognostic implications of C4d staining in IgAN.

Design, Setting, Participants, & Measurements: This retrospective cohort study included 283 patients with IgAN in 11 hospitals in Spain who underwent a renal biopsy between 1979 and 2010. The primary predictor was mesangial C4d staining. Secondary predictors included demographic, clinical, and laboratory characteristics, and Oxford pathologic classification criteria. The primary end point was the cumulative percentage of patients who developed ESRD, defined as onset of chronic dialysis or renal transplantation. C4d was analyzed by immunohistochemical staining using a polyclonal antibody. Kaplan-Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d staining on renal survival.

Results: There were 109 patients (38.5%) and 174 patients (61.5%) who were classified as C4d positive and C4d negative, respectively. Renal survival at 20 years was 28% in C4d-positive patients versus 85% in C4d-negative patients (P<0.001). Independent risk factors associated with ESRD were as follows: proteinuria (hazard ratio [HR] per every 1 g/d increase. 1.16; 95% confidence interval [95% CI], 1.03 to 1.31; P=0.01), eGFR (HR per every 1 ml/min per 1.73 m(2) increase, 0.96; 95% CI, 0.94 to 0.97; P<0.001), T2 Oxford classification (tubular atrophy/interstitial fibrosis, >50%; HR, 4.42; 95% CI, 1.40 to 13.88; P=0.01), and C4d-positive staining (HR, 2.45; 95% CI, 1.30 to 4.64; P=0.01).

Conclusions: C4d-positive staining is an independent risk factor for the development of ESRD in IgAN. This finding is consistent with the possibility that complement activation is involved in the pathogenesis of this disease.
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http://dx.doi.org/10.2215/CJN.09710913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011455PMC
May 2014

Effect of Lactobacillus rhamnosus CGMCC1.3724 supplementation on weight loss and maintenance in obese men and women.

Br J Nutr 2014 Apr 3;111(8):1507-19. Epub 2013 Dec 3.

Department of Kinesiology, Faculty of Medicine, Laval University, Quebec, QC, Canada G1V 0A6.

The present study investigated the impact of a Lactobacillus rhamnosus CGMCC1.3724 (LPR) supplementation on weight loss and maintenance in obese men and women over 24 weeks. In a double-blind, placebo-controlled, randomised trial, each subject consumed two capsules per d of either a placebo or a LPR formulation (1.6 × 10(8) colony-forming units of LPR/capsule with oligofructose and inulin). Each group was submitted to moderate energy restriction for the first 12 weeks followed by 12 weeks of weight maintenance. Body weight and composition were measured at baseline, at week 12 and at week 24. The intention-to-treat analysis showed that after the first 12 weeks and after 24 weeks, mean weight loss was not significantly different between the LPR and placebo groups when all the subjects were considered. However, a significant treatment × sex interaction was observed. The mean weight loss in women in the LPR group was significantly higher than that in women in the placebo group (P = 0.02) after the first 12 weeks, whereas it was similar in men in the two groups (P= 0.53). Women in the LPR group continued to lose body weight and fat mass during the weight-maintenance period, whereas opposite changes were observed in the placebo group. Changes in body weight and fat mass during the weight-maintenance period were similar in men in both the groups. LPR-induced weight loss in women was associated not only with significant reductions in fat mass and circulating leptin concentrations but also with the relative abundance of bacteria of the Lachnospiraceae family in faeces. The present study shows that the Lactobacillus rhamnosus CGMCC1.3724 formulation helps obese women to achieve sustainable weight loss.
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http://dx.doi.org/10.1017/S0007114513003875DOI Listing
April 2014

Hyperexcitability and epileptic seizures in a model of frontotemporal dementia.

Neurobiol Dis 2013 Oct 14;58:200-8. Epub 2013 Jun 14.

Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.

Epileptic seizures are more common in patients with Alzheimer disease than in the general elderly population. Abnormal forms of hyperphosphorylated tau accumulate in Alzheimer disease and other tauopathies. Aggregates of tau are also found in patients with epilepsy and in experimental models of epilepsy. We report here the analysis of epileptic activity and neuropathological correlates of a transgenic line over-expressing human mutant tau, a model of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The FTDP-17 model displays spontaneous epileptic activity and seizures with spike-wave complexes in the EEG, and a higher sensitivity to the GABAA receptor antagonist pentylenetetrazol (PTZ) when compared to age-matched controls, showing a notably increased seizure length and a shorter latency to develop severe seizures. FTDP-17 human tau mutants also display lower convulsive thresholds and higher lethality after PTZ injections. Astrocytosis and activated microglia are prominent in the hippocampus and other brain regions of young FTDP-17 mice where the human mutant tau transgene is expressed, before the appearance of hyperphosphorylated tau aggregates in these structures. FTDP-17 human mutant tau over-expression produces epilepsy and increased GABAA receptor-mediated hyperexcitability in the absence of Aβ pathology. Although aggregates of hyperphosphorylated tau have been observed in patients with epilepsy and in different chemically and electrically generated models of epilepsy, the FTDP-17 tau mutant analyzed here is the first model of genetically modified tau that presents with epilepsy. This model may represent a valuable tool to assay novel treatments in order to reduce tau pathology, a potential factor which may be involved in the development of epileptic seizures in dementia and other neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.nbd.2013.06.005DOI Listing
October 2013

Laforin and malin deletions in mice produce similar neurologic impairments.

J Neuropathol Exp Neurol 2012 May;71(5):413-21

Laboratory of Neurology, Instituto Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.

Lafora disease is a progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin or in the EPM2B gene encoding malin. It is characterized by the presence of polyglucosan intracellular inclusion bodies (Lafora bodies) in brain and other tissues. Targeted disruption of Epm2a or Epm2b genes in mice produced widespread neuronal degeneration and accumulation of Lafora bodies in neuronal and nonneuronal tissues. Here we analyzed the neurologic alterations produced by disruption of the laforin gene in Epm2a mice and compared them to those in malin-deficient mice. Both Epm2a and Epm2b mice showed altered motor activity, impaired motor coordination, abnormal hind limb clasping, and episodic memory deficits. Epm2a mice also had tonic-clonic seizures, whereas both Epm2a and Epm2b mice had spontaneous single spikes, spike-wave, polyspikes, and polyspike-wave complexes with correlated myoclonic jerks. Neurologic alterations observed in the mutants were comparable and correlated with the accumulation of abundant Lafora bodies in the cerebral cortex, the hippocampus, the basal ganglia, the cerebellum, and the brainstem, suggesting that these inclusions could cause cognitive and behavioral deterioration. Thus, both Epm2a and Epm2b mice exhibit many pathologic aspects seen in patients with Lafora disease and may be valuable for the study of this disorder.
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http://dx.doi.org/10.1097/NEN.0b013e318253350fDOI Listing
May 2012

Malin knockout mice support a primary role of autophagy in the pathogenesis of Lafora disease.

Autophagy 2012 Apr 1;8(4):701-3. Epub 2012 Apr 1.

Laboratory of Cellular Biology, Centro de Investigación Príncipe Felipe, Valencia, Spain.

Lafora disease (LD), a fatal neurodegenerative disorder characterized by intracellular inclusions called Lafora bodies (LBs), is caused by recessive loss-of-function mutations in the genes encoding either laforin or malin. Previous studies suggested a role of these proteins in regulating glycogen biosynthesis, in glycogen dephosphorylation and in the modulation of intracellular proteolytic systems. However, the contribution of each of these processes to LD pathogenesis is unclear. Here we review our recent finding that dysfunction of autophagy is a common feature of both laforin- and malin-deficient mice, preceding other pathological manifestations. We propose that autophagy plays a primary role in LD pathogenesis and is a potential target for its treatment.
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http://dx.doi.org/10.4161/auto.19522DOI Listing
April 2012

Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy.

Hum Mol Genet 2012 Apr 20;21(7):1521-33. Epub 2011 Dec 20.

Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.

Lafora disease (LD), a fatal neurodegenerative disorder characterized by the presence of intracellular inclusions called Lafora bodies (LBs), is caused by loss-of-function mutations in laforin or malin. Previous studies suggested a role of these proteins in the regulation of glycogen biosynthesis, in glycogen dephosphorylation and in the modulation of the intracellular proteolytic systems. However, the contribution of each of these processes to LD pathogenesis is unclear. We have generated a malin-deficient (Epm2b-/-) mouse with a phenotype similar to that of LD patients. By 3-6 months of age, Epm2b-/- mice present neurological and behavioral abnormalities that correlate with a massive presence of LBs in the cortex, hippocampus and cerebellum. Sixteen-day-old Epm2b-/- mice, without detectable LBs, show an impairment of macroautophagy (hereafter called autophagy), which remains compromised in adult animals. These data demonstrate similarities between the Epm2a-/- and Epm2b-/- mice that provide further insights into LD pathogenesis. They illustrate that the dysfunction of autophagy is a consequence of the lack of laforin-malin complexes and a common feature of both mouse models of LD. Because this dysfunction precedes other pathological manifestations, we propose that decreased autophagy plays a primary role in the formation of LBs and it is critical in LD pathogenesis.
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http://dx.doi.org/10.1093/hmg/ddr590DOI Listing
April 2012

Using cisTargetX to predict transcriptional targets and networks in Drosophila.

Methods Mol Biol 2012 ;786:291-314

TAGC Inserm U928 and Université de la Mediterranée, Marseille, France.

Gene expression regulation is a fundamental biological process leading to complete organism development by controlling processes like cell type specification and differentiation. The accuracy of this process is -governed by transcription factors (TFs) acting within a complex gene regulatory network. CisTargetX has been developed to enable a user to predict TFs, enhancers, and target genes involved in the regulation of co-expressed genes. It uses a strategy that incorporates the genome-wide prediction of clusters of transcription factor binding sites (TFBSs), starting from a large, unbiased collection of position weight matrices (PWMs) and uses comparative genomics criteria to filter potential TFBS. We describe in this chapter, step-by-step, how to use cisTargetX starting from a set of genes or TF(s) to predict transcriptional targets with their putative binding sites and networks in Drosophila. Next, we illustrate this approach on a particular developmental system, namely, sensory organ development, and identify relevant TFs, DNA regions regulating gene expression, and TF/target gene interactions. CisTargetX is available at http://med.kuleuven.be/lcb/cisTargetX .
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http://dx.doi.org/10.1007/978-1-61779-292-2_18DOI Listing
February 2012