Publications by authors named "Montserrat Ruiz"

54 Publications

Household SARS-CoV-2 transmission and children: a network prospective study.

Clin Infect Dis 2021 Mar 12. Epub 2021 Mar 12.

Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Background: The role of children in household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains uncertain. Here, we describe the epidemiological and clinical characteristics of children with COVID-19 in Catalonia (Spain) and investigate the dynamics of household transmission.

Methods: Prospective, observational, multicenter study performed during summer and school periods (1 July-31 October, 2020), in which epidemiological and clinical features, and viral transmission dynamics were analyzed in COVID-19 patients <16 years. A pediatric index case was established when a child was the first individual infected within a household. Secondary cases were defined when another household member tested positive for SARS-CoV-2 before the child. The secondary attack rate (SAR) was calculated, and logistic regression was used to assess associations between transmission risk factors and SARS-CoV-2 infections.

Results: The study included 1040 COVID-19 patients <16 years. Almost half (47.2%) were asymptomatic, 10.8% had comorbidities, and 2.6% required hospitalization. No deaths were reported. Viral transmission was common among household members (62.3%). More than 70% (756/1040) of pediatric cases were secondary to an adult, whereas 7.7% (80/1040) were index cases. The SAR was significantly lower in households with COVID-19 pediatric index cases during the school period relative to summer (p=0.02), and when compared to adults (p=0.006). No individual or environmental risk factors associated with the SAR were identified.

Conclusions: Children are unlikely to cause household COVID-19 clusters or be major drivers of the pandemic even if attending school. Interventions aimed at children are expected to have a small impact on reducing SARS-CoV-2 transmission.
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http://dx.doi.org/10.1093/cid/ciab228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989526PMC
March 2021

A novel hypomorphic splice variant in EIF2B5 gene is associated with mild ovarioleukodystrophy.

Ann Clin Transl Neurol 2020 09 15;7(9):1574-1579. Epub 2020 Aug 15.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908, Spain.

Objective: To identify the genetic cause in an adult ovarioleukodystrophy patient resistant to diagnosis.

Methods: We applied whole-exome sequencing (WES) to a vanishing white matter disease patient associated with premature ovarian failure at 26 years of age. We functionally tested an intronic variant by RT-PCR on patient's peripheral blood mononuclear cells (PBMC) and by minigene splicing assay.

Results: WES analysis identified two novel variants in the EIF2B5 gene: c.725A > G (p.Tyr242Cys) and an intronic noncanonical mutation (c.1156 + 13G>A). This intronic mutation resulted into generation of various isoforms both in patient's PBMC and in the minigene splicing assay, showing that ~20% residual wild-type isoform is still expressed by the intronic-mutated allele alone, concordant with an hypomorphic effect of this variant.

Conclusion: We report two novel variants in EIF2B5, one of them a noncanonical intronic splice variant, located at a +13 intronic position. This position is mutated only in 0.05% of ClinVar intronic mutations described so far. Furthermore, we illustrate how minigene splicing assay may be advantageous when validating splice-altering variants, in this case highlighting the coexistence of wild-type and mutated forms, probably explaining this patient's milder, late-onset phenotype.
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http://dx.doi.org/10.1002/acn3.51131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480926PMC
September 2020

High-dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy.

Brain Pathol 2020 09 7;30(5):945-963. Epub 2020 Jul 7.

Neurometabolic Diseases Laboratory, IDIBELL, Barcelona, Spain.

Biotin is an essential cofactor for carboxylases that regulates the energy metabolism. Recently, high-dose pharmaceutical-grade biotin (MD1003) was shown to improve clinical parameters in a subset of patients with chronic progressive multiple sclerosis. To gain insight into the mechanisms of action, we investigated the efficacy of high-dose biotin in a genetic model of chronic axonopathy caused by oxidative damage and bioenergetic failure, the Abcd1 mouse model of adrenomyeloneuropathy. High-dose biotin restored redox homeostasis driven by NRF-2, mitochondria biogenesis and ATP levels, and reversed axonal demise and locomotor impairment. Moreover, we uncovered a concerted dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord likely driven by aberrant SREBP-1c/mTORC1signaling. This resulted in increased triglyceride levels and lipid droplets in motor neurons. High-dose biotin normalized the hyperactivation of mTORC1, thus restoring lipid homeostasis. These results shed light into the mechanism of action of high-dose biotin of relevance for neurodegenerative and metabolic disorders.
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http://dx.doi.org/10.1111/bpa.12869DOI Listing
September 2020

Response surface methodology based on central composite design for simultaneous adsorption of rare earth elements using nanoporous calcium alginate/carboxymethyl chitosan microbiocomposite powder containing NiZnFeO magnetic nanoparticles: Batch and column studies.

Int J Biol Macromol 2020 Jul 17;154:937-953. Epub 2020 Mar 17.

Department of Chemical Engineering, ETSEIB, Universitat Politècnica de Catalunya, Diagonal 647, 08028 Barcelona, Spain.

In this research paper, the utilization of the magnetic calcium alginate/carboxymethyl chitosan/NiZnFeO (CA/CMC/NiZnFeO) was investigated for the simultaneous aqueous adsorption of Nd (III), Tb (III), and Dy (III). The magnetic products were characterized by FE-SEM, EDX, XRD, FT-IR, TGA, and VSM techniques. The saturation magnetization value for NiZnFeO and CA/CMC/NiZnFeO was found to be 45.87 and 14.14 emu/g, respectively. Using RSM, a quadratic polynomial equation was obtained to predict the adsorption efficiency of each ion. Under the conditions of pH = 5.5, adsorbent dosage of 0.1 g, initial concentration of 30 mg/L, and contact time of 53 min predicted by RSM, the adsorption efficiencies of Nd (III), Tb (III), and Dy (III) were respectively 95.72, 96.17, and 99.44%. The isotherm and kinetic data were respectively fitted well with Freundlich and pseudo-second-order (PSO) models. The desorption of the loaded ions was effectively carried out by 0.2 M HNO, and the adsorbent was consecutively utilized with 2.54, 1.63, and 1.16% decrease in adsorption efficiency for Nd (III), Tb (III), and Dy (III), respectively, after the forth cycle. Additionally, the adsorption behavior of the CA/CMC/NiZnFeO towards Nd (III), Tb (III), and Dy (III) was studied by using a fixed-bed column technique.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.03.131DOI Listing
July 2020

The peroxisomal fatty acid transporter ABCD1/PMP-4 is required in the C. elegans hypodermis for axonal maintenance: A worm model for adrenoleukodystrophy.

Free Radic Biol Med 2020 05 1;152:797-809. Epub 2020 Feb 1.

Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Spain; CIBERER U759, Center for Biomedical Research on Rare Diseases, Spain; ICREA (Institució Catalana de Recerca i Estudis Avançats), Barcelona, Spain. Electronic address:

Adrenoleukodystrophy is a neurometabolic disorder caused by a defective peroxisomal ABCD1 transporter of very long-chain fatty acids (VLCFAs). Its pathogenesis is incompletely understood. Here we characterize a nematode model of X-ALD with loss of the pmp-4 gene, the worm orthologue of ABCD1. These mutants recapitulate the hallmarks of X-ALD: i) VLCFAs accumulation and impaired mitochondrial redox homeostasis and ii) axonal damage coupled to locomotor dysfunction. Furthermore, we identify a novel role for PMP-4 in modulating lipid droplet dynamics. Importantly, we show that the mitochondria targeted antioxidant MitoQ normalizes lipid droplets size, and prevents axonal degeneration and locomotor disability, highlighting its therapeutic potential. Moreover, PMP-4 acting solely in the hypodermis rescues axonal and locomotion abnormalities, suggesting a myelin-like role for the hypodermis in providing essential peroxisomal functions for the nematode nervous system.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.01.177DOI Listing
May 2020

A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases.

Ann Clin Transl Neurol 2020 01 18;7(1):105-111. Epub 2019 Dec 18.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

Objective: To identify causative mutations in a patient affected by ataxia and spastic paraplegia.

Methods: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) were performed using patient's DNA sample. RT-PCR and cDNA Sanger sequencing were performed on RNA extracted from patient's fibroblasts, as well as western blot.

Results: A novel missense variant in SPG7 (c.2195T> C; p.Leu732Pro) was first found by whole-exome sequencing (WES), while the second, also unreported, deep intronic variant (c.286 + 853A>G) was identified by whole-genome sequencing (WGS). RT-PCR confirmed the in silico predictions showing that this variant activated a cryptic splice site, inducing the inclusion of a pseudoexon into the mRNA sequence, which encoded a premature stop codon. Western blot showed decreased SPG7 levels in patient's fibroblasts.

Interpretation: Identification of a deep intronic variant in SPG7, which could only have been detected by performing WGS, led to a diagnosis in this HSP patient. This case challenges the notion of an autosomal dominant inheritance for SPG7, and illustrates the importance of performing WGS subsequently or alternatively to WES to find additional mutations, especially in patients carrying one variant in a gene causing a predominantly autosomal recessive disease.
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http://dx.doi.org/10.1002/acn3.50967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952318PMC
January 2020

Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia.

J Med Genet 2020 02 5;57(2):132-137. Epub 2019 Oct 5.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain

Background: Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in , encoding the voltage-gated K channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as events.

Methods: A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings.

Results: WES revealed a homozygous variant (p.Val368Leu) in , involving a conserved residue in the pore domain, close to the selectivity signature sequence for K ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures.

Conclusion: This newly identified variant is the first to be reported to act in a recessive mode of inheritance in . These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.
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http://dx.doi.org/10.1136/jmedgenet-2019-106373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029237PMC
February 2020

Boron Removal from Aqueous Solutions by Using a Novel Alginate-Based Sorbent: Comparison with AlO Particles.

Polymers (Basel) 2019 Sep 16;11(9). Epub 2019 Sep 16.

Department of Chemical Engineering, Universitat Politècnica de Catalunya, ETSEIB, Diagonal 647, 08028 Barcelona, Spain.

Boron removal was evaluated in the present work by using calcium alginate beads (CA) and a novel composite based on alginate-alumina (CAAl) as sorbents in a batch system. The effects of different parameters such as pH, temperature, contact time, and composition of alginate (at different concentrations of guluronic and mannuronic acids) on boron sorption were investigated. The results confirm that calcium alginate beads (CA) exhibited a better adsorption capacity in a slightly basic medium, and the composite alginate-alumina (CAAl) exhibited improved boron removal at neutral pH. Sorption isotherm studies were performed and the Langmuir isotherm model was found to fit the experimental data. The maximum sorption capacities were 4.5 mmol g and 5.2 mmol g, using CA and CAAl, respectively. Thermodynamic parameters such as change in free energy (ΔG), enthalpy (ΔH), and entropy (ΔS) were also determined. The pseudo-first-order and pseudo-second-order rate equations (PFORE and PSORE, respectively) were tested to fit the kinetic data; the experimental results can be better described with PSORE. The regeneration of the loaded sorbents was demonstrated by using dilute HCl solution (distilled water at pH 3) as eluent for metal recovery.
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http://dx.doi.org/10.3390/polym11091509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780931PMC
September 2019

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.

Mov Disord 2019 10 21;34(10):1547-1561. Epub 2019 Aug 21.

Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.

Background: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA.

Objectives: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients.

Methods: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction.

Results: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001).

Conclusions: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27812DOI Listing
October 2019

Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study.

Neurotherapeutics 2019 10;16(4):1167-1182

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute, Hospital Duran i Reynals, Gran Via de l'Hospitalet 199, 08908, L'Hospitalet de Llobregat, Barcelona, Spain.

X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260.
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http://dx.doi.org/10.1007/s13311-019-00735-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985062PMC
October 2019

A novel mutation in the gene expands the phenotype of Alexander disease.

J Med Genet 2019 12 19;56(12):846-849. Epub 2019 Apr 19.

Neurometabolic Diseases Laboratory, Institut d'Investigacio Biomedica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Catalonia, Spain

Background: Alexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in . Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist.

Methods: A family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by whole exome sequencing (WES). A candidate variant was functionally tested in an astrocytoma cell line.

Results: The novel variant in (Glial Fibrillary Acidic Protein) N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterised so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models.

Conclusion: We suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander disease type II, probably associated with alternative pathogenic mechanisms, that is, astrocyte enlargement. analysis should be considered in adult-onset neurological presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases.
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http://dx.doi.org/10.1136/jmedgenet-2018-105959DOI Listing
December 2019

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

J Clin Invest 2019 03 11;129(3):1240-1256. Epub 2019 Feb 11.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.
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http://dx.doi.org/10.1172/JCI123959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391109PMC
March 2019

Aberrant regulation of the GSK-3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy.

EMBO Mol Med 2018 08;10(8)

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat Barcelona, Spain

The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and the mouse model ( null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long-chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK-3β. We find that GSK-3β inhibitors can significantly reactivate the blunted NRF2 response in patients' fibroblasts. In the mouse models ( and / mice), oral administration of dimethyl fumarate (DMF/BG12/Tecfidera), an NRF2 activator in use for multiple sclerosis, normalized (i) mitochondrial depletion, (ii) bioenergetic failure, (iii) oxidative damage, and (iv) inflammation, highlighting an intricate cross-talk governing energetic and redox homeostasis in X-ALD Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF2 hold therapeutic potential for X-ALD and other axonopathies with impaired GSK-3β/NRF2 axis.
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http://dx.doi.org/10.15252/emmm.201708604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079538PMC
August 2018

Epigenomic signature of adrenoleukodystrophy predicts compromised oligodendrocyte differentiation.

Brain Pathol 2018 11 10;28(6):902-919. Epub 2018 Apr 10.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.

Epigenomic changes may either cause disease or modulate its expressivity, adding a layer of complexity to mendelian diseases. X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic condition exhibiting discordant phenotypes, ranging from a childhood cerebral inflammatory demyelination (cALD) to an adult-onset mild axonopathy in spinal cords (AMN). The AMN form may occur with superimposed inflammatory brain demyelination (cAMN). All patients harbor loss of function mutations in the ABCD1 peroxisomal transporter of very-long chain fatty acids. The factors that account for the lack of genotype-phenotype correlation, even within the same family, remain largely unknown. To gain insight into this matter, here we compared the genome-wide DNA methylation profiles of morphologically intact frontal white matter areas of children affected by cALD with adult cAMN patients, including male controls in the same age group. We identified a common methylomic signature between the two phenotypes, comprising (i) hypermethylation of genes harboring the H3K27me3 mark at promoter regions, (ii) hypermethylation of genes with major roles in oligodendrocyte differentiation such as MBP, CNP, MOG and PLP1 and (iii) hypomethylation of immune-associated genes such as IFITM1 and CD59. Moreover, we found increased hypermethylation in CpGs of genes involved in oligodendrocyte differentiation, and also in genes with H3K27me3 marks in their promoter regions in cALD compared with cAMN, correlating with transcriptional and translational changes. Further, using a penalized logistic regression model, we identified the combined methylation levels of SPG20, UNC45A and COL9A3 and also, the combined expression levels of ID4 and MYRF to be good markers capable of discriminating childhood from adult inflammatory phenotypes. We thus propose the hypothesis that an epigenetically controlled, altered transcriptional program may drive an impaired oligodendrocyte differentiation and aberrant immune activation in X-ALD patients. These results shed light into disease pathomechanisms and uncover putative biomarkers of interest for prognosis and phenotypic stratification.
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http://dx.doi.org/10.1111/bpa.12595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857458PMC
November 2018

Neodymium Recovery by Chitosan/Iron(III) Hydroxide [ChiFer(III)] Sorbent Material: Batch and Column Systems.

Polymers (Basel) 2018 Feb 19;10(2). Epub 2018 Feb 19.

Department of Chemical Engineering, Universitat Politècnica de Catalunya, ETSEIB, Diagonal 647, 08028 Barcelona, Spain.

A low cost composite material was synthesized for neodymium recovery from dilute aqueous solutions. The in-situ production of the composite containing chitosan and iron(III) hydroxide (ChiFer(III)) was improved and the results were compared with raw chitosan particles. The sorbent was characterized using Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy-energy dispersive X-ray analyses (SEM-EDX). The equilibrium studies were performed using firstly a batch system, and secondly a continuous system. The sorption isotherms were fitted with the Langmuir, Freundlich, and Sips models; experimental data was better described with the Langmuir equation and the maximum sorption capacity was 13.8 mg g-1 at pH 4. The introduction of iron into the biopolymer matrix increases by four times the sorption uptake of the chitosan; the individual sorption capacity of iron (into the composite) was calculated as 30.9 mg Nd/g Fe. The experimental results of the columns were fitted adequately using the Thomas model. As an approach to Nd-Fe-B permanent magnets effluents, a synthetic dilute effluent was simulated at pH 4, in order to evaluate the selectivity of the sorbent material; the overshooting of boron in the column system confirmed the higher selectivity toward neodymium ions. The elution step was carried out using MilliQ-water with the pH set to 3.5 (dilute HCl solution).
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http://dx.doi.org/10.3390/polym10020204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414884PMC
February 2018

Evaluation of afferent pain pathways in adrenomyeloneuropathic patients.

Clin Neurophysiol 2018 03 24;129(3):507-515. Epub 2017 Dec 24.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via 199, 08908 L'Hospitalet de Llobregat, Barcelona, Spain; Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain. Electronic address:

Objective: Patients with adrenomyeloneuropathy may have dysfunctions of visual, auditory, motor and somatosensory pathways. We thought on examining the nociceptive pathways by means of laser evoked potentials (LEPs), to obtain additional information on the pathophysiology of this condition.

Methods: In 13 adrenomyeloneuropathic patients we examined LEPs to leg, arm and face stimulation. Normative data were obtained from 10 healthy subjects examined in the same experimental conditions. We also examined brainstem auditory evoked potentials (BAEPs), pattern reversal full-field visual evoked potentials (VEPs), motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs).

Results: Upper and lower limb MEPs and SEPs, as well as BAEPs, were abnormal in all patients, while VEPs were abnormal in 3 of them (23.1%). LEPs revealed abnormalities to stimulation of the face in 4 patients (30.7%), the forearm in 4 patients (30.7%) and the leg in 10 patients (76.9%).

Conclusions: The pathologic process of adrenomyeloneuropathy is characterized by a preferential involvement of auditory, motor and somatosensory tracts and less severely of the visual and nociceptive pathways. This non-inflammatory distal axonopathy preferably damages large myelinated spinal tracts but there is also partial involvement of small myelinated fibres.

Significance: LEPs studies can provide relevant information about afferent pain pathways involvement in adrenomyeloneuropathic patients.
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http://dx.doi.org/10.1016/j.clinph.2017.12.011DOI Listing
March 2018

Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder.

Am J Hum Genet 2017 Dec;101(6):965-976

Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. Electronic address:

Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3' untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3' UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.
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http://dx.doi.org/10.1016/j.ajhg.2017.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812895PMC
December 2017

Oxidative stress and mitochondrial dynamics malfunction are linked in Pelizaeus-Merzbacher disease.

Brain Pathol 2018 09 26;28(5):611-630. Epub 2017 Dec 26.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.

Pelizaeus-Merzbacher disease (PMD) is a fatal hypomyelinating disorder characterized by early impairment of motor development, nystagmus, choreoathetotic movements, ataxia and progressive spasticity. PMD is caused by variations in the proteolipid protein gene PLP1, which encodes the two major myelin proteins of the central nervous system, PLP and its spliced isoform DM20, in oligodendrocytes. Large duplications including the entire PLP1 gene are the most frequent causative mutation leading to the classical form of PMD. The Plp1 overexpressing mouse model (PLP-tg ) develops a phenotype very similar to human PMD, with early and severe motor dysfunction and a dramatic decrease in lifespan. The sequence of cellular events that cause neurodegeneration and ultimately death is poorly understood. In this work, we analyzed patient-derived fibroblasts and spinal cords of the PLP-tg mouse model, and identified redox imbalance, with altered antioxidant defense and oxidative damage to several enzymes involved in ATP production, such as glycolytic enzymes, creatine kinase and mitochondrial proteins from the Krebs cycle and oxidative phosphorylation. We also evidenced malfunction of the mitochondria compartment with increased ROS production and depolarization in PMD patient's fibroblasts, which was prevented by the antioxidant N-acetyl-cysteine. Finally, we uncovered an impairment of mitochondrial dynamics in patient's fibroblasts which may help explain the ultrastructural abnormalities of mitochondria morphology detected in spinal cords from PLP-tg mice. Altogether, these results underscore the link between redox and metabolic homeostasis in myelin diseases, provide insight into the pathophysiology of PMD, and may bear implications for tailored pharmacological intervention.
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http://dx.doi.org/10.1111/bpa.12571DOI Listing
September 2018

Loss of SIRT2 leads to axonal degeneration and locomotor disability associated with redox and energy imbalance.

Aging Cell 2017 12 5;16(6):1404-1413. Epub 2017 Oct 5.

Neurometabolic Diseases Laboratory, Institute of Neuropathology, IDIBELL, Barcelona, Spain.

Sirtuin 2 (SIRT2) is a member of a family of NAD -dependent histone deacetylases (HDAC) that play diverse roles in cellular metabolism and especially for aging process. SIRT2 is located in the nucleus, cytoplasm, and mitochondria, is highly expressed in the central nervous system (CNS), and has been reported to regulate a variety of processes including oxidative stress, genome integrity, and myelination. However, little is known about the role of SIRT2 in the nervous system specifically during aging. Here, we show that middle-aged, 13-month-old mice lacking SIRT2 exhibit locomotor dysfunction due to axonal degeneration, which was not present in young SIRT2 mice. In addition, these Sirt2 mice exhibit mitochondrial depletion resulting in energy failure, and redox dyshomeostasis. Our results provide a novel link between SIRT2 and physiological aging impacting the axonal compartment of the central nervous system, while supporting a major role for SIRT2 in orchestrating its metabolic regulation. This underscores the value of SIRT2 as a therapeutic target in the most prevalent neurodegenerative diseases that undergo with axonal degeneration associated with redox and energetic dyshomeostasis.
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http://dx.doi.org/10.1111/acel.12682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676070PMC
December 2017

Fuzzy logic modeling of Pb (II) sorption onto mesoporous NiO/ZnCl-Rosa Canina-L seeds activated carbon nanocomposite prepared by ultrasound-assisted co-precipitation technique.

Ultrason Sonochem 2018 Jan 24;40(Pt A):748-762. Epub 2017 Aug 24.

Ayatollah Amoli Branch, Department of Chemical Engineering, Islamic Azad University, Amol, Iran.

In this study, NiO/Rosa Canina-L seeds activated carbon nanocomposite (NiO/ACNC) was prepared by adding dropwise NaOH solution (2mol/L) to raise the suspension pH to around 9 at room temperature under ultrasonic irradiation (200W) as an efficient method and characterized by FE-SEM, FTIR and N adsorption-desorption isotherm. The effect of different parameters such as contact time (0-120min), initial metal ion concentration (25-200mg/L), temperature (298, 318 and 333K), amount of adsorbent (0.002-0.007g) and the solution's initial pH (1-7) on the adsorption of Pb (II) was investigated in batch-scale experiments. The equilibrium data were well fitted by Langmuir model type 1 (R>0.99). The maximum monolayer adsorption capacity (q) of NiO/ACNC was 1428.57mg/L. Thermodynamic parameters (ΔG°, ΔH° and ΔS°) were also calculated. The results showed that the adsorption of Pb (II) onto NiO/ACNC was feasible, spontaneous and exothermic under studied conditions. In addition, a fuzzy-logic-based model including multiple inputs and one output was developed to predict the removal efficiency of Pb (II) from aqueous solution. Four input variables including pH, contact time (min), dosage (g) and initial concentration of Pb (II) were fuzzified using an artificial intelligence-based approach. The fuzzy subsets consisted of triangular membership functions with eight levels and a total of 26 rules in the IF-THEN approach which was implemented on a Mamdani-type of fuzzy inference system. Fuzzy data exhibited small deviation with satisfactory coefficient of determination (R>0.98) that clearly proved very good performance of fuzzy-logic-based model in prediction of removal efficiency of Pb (II). It was confirmed that NiO/ACNC had a great potential as a novel adsorbent to remove Pb (II) from aqueous solution.
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http://dx.doi.org/10.1016/j.ultsonch.2017.08.022DOI Listing
January 2018

Tauroursodeoxycholic bile acid arrests axonal degeneration by inhibiting the unfolded protein response in X-linked adrenoleukodystrophy.

Acta Neuropathol 2017 02 21;133(2):283-301. Epub 2016 Dec 21.

Neurometabolic Diseases Laboratory, Institut de Neuropatologia de Bellvitge, IDIBELL, Gran Via, 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.

The activation of the highly conserved unfolded protein response (UPR) is prominent in the pathogenesis of the most prevalent neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), which are classically characterized by an accumulation of aggregated or misfolded proteins. This activation is orchestrated by three endoplasmic reticulum (ER) stress sensors: PERK, ATF6 and IRE1. These sensors transduce signals that induce the expression of the UPR gene programme. Here, we first identified an early activator of the UPR and investigated the role of a chronically activated UPR in the pathogenesis of X-linked adrenoleukodystrophy (X-ALD), a neurometabolic disorder that is caused by ABCD1 malfunction; ABCD1 transports very long-chain fatty acids (VLCFA) into peroxisomes. The disease manifests as inflammatory demyelination in the brain or and/or degeneration of corticospinal tracts, thereby resulting in spastic paraplegia, with the accumulation of intracellular VLCFA instead of protein aggregates. Using X-ALD mouse model (Abcd1 and Abcd1 /Abcd2 mice) and X-ALD patient's fibroblasts and brain samples, we discovered an early engagement of the UPR. The response was characterized by the activation of the PERK and ATF6 pathways, but not the IRE1 pathway, showing a difference from the models of AD, PD or ALS. Inhibition of PERK leads to the disruption of homeostasis and increased apoptosis during ER stress induced in X-ALD fibroblasts. Redox imbalance appears to be the mechanism that initiates ER stress in X-ALD. Most importantly, we demonstrated that the bile acid tauroursodeoxycholate (TUDCA) abolishes UPR activation, which results in improvement of axonal degeneration and its associated locomotor impairment in Abcd1 /Abcd2 mice. Altogether, our preclinical data provide evidence for establishing the UPR as a key drug target in the pathogenesis cascade. Our study also highlights the potential role of TUDCA as a treatment for X-ALD and other axonopathies in which similar molecular mediators are implicated.
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http://dx.doi.org/10.1007/s00401-016-1655-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5250669PMC
February 2017

Uniparental disomy of chromosome 16 unmasks recessive mutations of FA2H/SPG35 in 4 families.

Neurology 2016 Jul 17;87(2):186-91. Epub 2016 Jun 17.

From the Institute of Medical Genetics and Applied Genomics (A.S.S., S.B.-W., K.S., O.R., P.B.) and Department of Neurology and Hertie Institute for Clinical Brain Research (T.W.R., R.S., L.S.), University of Tübingen; German Center of Neurodegenerative Diseases (DZNE) (T.W.R., R.S.), Tübingen, Germany; Imprinting and Cancer Group (D.M.), Cancer Epigenetic and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain; Department of Neuropediatrics (M.D.-N.), Tübingen University School of Medicine; CeGaT GmbH (K.H.), Tübingen, Germany; Neurometabolic Diseases Laboratory (A.S., M.R., A.P.), Institut d'Investigació Biomedica de Bellvitge IDIBELL, Hospital Duran i Reynals, Barcelona; Centre for Biomedical Research on Rare Diseases (CIBERER) (A.S., M.R., A.P.), Institute Carlos III, Madrid; Catalan Institution for Research and Advanced Studies (ICREA) (A.P.), Barcelona, Spain; and Hussman Institute for Human Genomics (S.Z., R.S.), University of Miami Miller School of Medicine, FL.

Objective: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias.

Method: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes.

Results: Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling.

Conclusion: UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families.
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http://dx.doi.org/10.1212/WNL.0000000000002843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940069PMC
July 2016

Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury.

Glia 2016 May 16;64(5):853-74. Epub 2016 Feb 16.

Institut De Neurociències and Unitat De Bioquímica, Facultat De Medicina, Universitat Autònoma De Barcelona, Bellaterra, Barcelona, 08193, Spain.

The clinical challenge in acute injury as in traumatic brain injury (TBI) is to halt the delayed neuronal loss that occurs hours and days after the insult. Here we report that the activation of CREB-dependent transcription in reactive astrocytes prevents secondary injury in cerebral cortex after experimental TBI. The study was performed in a novel bitransgenic mouse in which a constitutively active CREB, VP16-CREB, was targeted to astrocytes with the Tet-Off system. Using histochemistry, qPCR, and gene profiling we found less neuronal death and damage, reduced macrophage infiltration, preserved mitochondria, and rescued expression of genes related to mitochondrial metabolism in bitransgenic mice as compared to wild type littermates. Finally, with meta-analyses using publicly available databases we identified a core set of VP16-CREB candidate target genes that may account for the neuroprotective effect. Enhancing CREB activity in astrocytes thus emerges as a novel avenue in acute brain post-injury therapeutics.
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http://dx.doi.org/10.1002/glia.22969DOI Listing
May 2016

Altered glycolipid and glycerophospholipid signaling drive inflammatory cascades in adrenomyeloneuropathy.

Hum Mol Genet 2015 Dec 14;24(24):6861-76. Epub 2015 Sep 14.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Institute of Neuropathology, University of Barcelona, 08908 L'Hospitalet de Llobregat, Barcelona, Spain, Center for Biomedical Research on Rare Diseases (CIBERER), Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain

X-linked adrenomyeloneuropathy (AMN) is an inherited neurometabolic disorder caused by malfunction of the ABCD1 gene, characterized by slowly progressing spastic paraplegia affecting corticospinal tracts, and adrenal insufficiency. AMN is the most common phenotypic manifestation of adrenoleukodystrophy (X-ALD). In some cases, an inflammatory cerebral demyelination occurs associated to poor prognosis in cerebral AMN (cAMN). Though ABCD1 codes for a peroxisomal transporter of very long-chain fatty acids, the molecular mechanisms that govern disease onset and progression, or its transformation to a cerebral, inflammatory demyelinating form, remain largely unknown. Here we used an integrated -omics approach to identify novel biomarkers and altered network dynamic characteristic of, and possibly driving, the disease. We combined an untargeted metabolome assay of plasma and peripheral blood mononuclear cells (PBMC) of AMN patients, which used liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (LC-Q-TOF), with a functional genomics analysis of spinal cords of Abcd1(-) mouse. The results uncovered altered nodes in lipid-driven proinflammatory cascades, such as glycosphingolipid and glycerophospholipid synthesis, governed by the β-1,4-galactosyltransferase (B4GALT6), the phospholipase 2γ (PLA2G4C) and the choline/ethanolamine phosphotransferase (CEPT1) enzymes. Confirmatory investigations revealed a non-classic, inflammatory profile, consisting on the one hand of raised plasma levels of several eicosanoids derived from arachidonic acid through PLA2G4C activity, together with also the proinflammatory cytokines IL6, IL8, MCP-1 and tumor necrosis factor-α. In contrast, we detected a more protective, Th2-shifted response in PBMC. Thus, our findings illustrate a previously unreported connection between ABCD1 dysfunction, glyco- and glycerolipid-driven inflammatory signaling and a fine-tuned inflammatory response underlying a disease considered non-inflammatory.
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http://dx.doi.org/10.1093/hmg/ddv375DOI Listing
December 2015

Boron removal from aqueous solutions using alginate gel beads in fixed-bed systems.

J Chem Technol Biotechnol 2014 Jun 12;89(6):934-940. Epub 2014 May 12.

Universitat Politècnica de Catalunya, Department of Chemical Engineering, ETSEIB Diagonal 647, 08028, Barcelona, Spain.

Background:

Results:

Conclusion:
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http://dx.doi.org/10.1002/jctb.4361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368418PMC
June 2014

Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy.

Acta Neuropathol 2015 Mar 31;129(3):399-415. Epub 2014 Dec 31.

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L' Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain.

X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts. Furthermore, mTOR inhibition by a rapamycin derivative (temsirolimus) restored autophagic flux and inhibited the axonal degenerative process as well as the associated locomotor impairment in the Abcd1 (-) /Abcd2 (-/-) mouse model. This process was mediated through the restoration of proteasome function and redox as well as metabolic homeostasis. These findings provide the first evidence that links impaired autophagy to X-ALD, which may yield a therapy based on autophagy activators for adrenomyeloneuropathy patients.
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http://dx.doi.org/10.1007/s00401-014-1378-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331612PMC
March 2015

Transitory beneficial effects of professional continuous glucose monitoring on the metabolic control of patients with type 1 diabetes.

Diabetes Technol Ther 2014 Apr;16(4):219-23

Diabetes Unit, Endocrinology and Nutrition Department, August Pi i Sunyer Institute for Biomedical Investigations, University Hospital Clinic , Barcelona, Spain .

Background: The benefit of professional continuous glucose monitoring (PCGM) in the metabolic control of patients with type 1 diabetes mellitus (T1DM) is uncertain.

Subjects And Methods: This was a retrospective study of all consecutive T1DM patients who underwent a 6-day PCGM in our Diabetes Unit over the course of 17 months. According to the indication, two groups were arbitrarily defined: "hyperglycemic" and "hypoglycemic." Data from medical files and sensor reports were reviewed. Glycated hemoglobin (HbA1c) was evaluated 2-4 weeks prior to PCGM, as well as 3-5 and 12 months after PCGM. In the hypoglycemic group, the number of self-reported mild hypoglycemic episodes (as defined by the American Diabetes Association) was collected.

Results: Of the 67 patients reviewed, 43 were in the hyperglycemic group, and 24 were in the hypoglycemic group. In the hyperglycemic group, the HbA1c level dropped at 3-5 months post-intervention from 8.45 ± 0.72% to 8.04 ± 0.9%, with the decline being statistically significant (-0.4%; P = 0.001) and positively correlated with the initial HbA1c value (0.366; P=0.016). One year after the PCGM study, the HbA1c level tended to return to the initial values: 8.20 ± 1.05% (-0.24%; P = 0.081). In the hypoglycemic group, HbA1c did not change either 3-5 or 12 months after PCGM, although the percentage of patients in whom the number of mild hypoglycemic episodes was significantly reduced was 86% (P=0.001).

Conclusions: Although a transient phenomenon, PCGM can be useful in the short term in improving metabolic and clinical profile of suboptimally controlled T1DM subjects, including those with repeated hypoglycemia.
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http://dx.doi.org/10.1089/dia.2013.0266DOI Listing
April 2014

Sputum microbiota in moderate versus severe patients with COPD.

Eur Respir J 2014 Jun 5;43(6):1787-90. Epub 2013 Dec 5.

Section of Microbiology, Hospital General Universitario de Elche, Alicante, Spain Universidad Miguel Hernández, Elche, Alicante, Spain.

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http://dx.doi.org/10.1183/09031936.00191513DOI Listing
June 2014