Adrián Rodríguez

Health Research Institute of the Balearic Islands

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Inés Losada López

Health Research Institute of the Balearic Islands

F. Gráses

Research Institute of Health Sciences

Eugenia Cisneros‐Barroso

Health Research Institute of the Balearic Islands

Antonia Costa‐Bauzá

Research Institute of Health Sciences

Juan González‐Moreno

Hospital Son Llatzer

Tomás Ripoll‐Vera

Hospital Son Llatzer

Aina Gayà-Barroso

Health Research Institute of the Balearic Islands

Cristina Descals

Health Research Institute of the Balearic Islands

Mercedes García‐Gasalla

Health Research Institute of the Balearic Islands

Dolores Rodrigo

Instituto de Agroquímica y Tecnología de Alimentos

Cooperative Institutions

Health Research Institute of the Balearic Islands

Hospital Universitario Puerta de Hierro Majadahonda

Hospital Universitario Son Espases

Hospital Son Llatzer

Inserm

University College London

Instituto de Salud Carlos III

Assistance Publique – Hôpitaux de Paris

Centro de Investigación Biomédica en Red

Universitat de les Illes Balears

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On the origin of calcium oxalate monohydrate papillary renal stones

Urolithiasis (2014)

F. Gráses Antonia Costa‐Bauzá Carlo R. Bonarriba E. Pieras Rafael Alonso Fernández

10.1007/s00240-014-0697-5

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Citations (22)

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study

The Lancet Neurology (2020)

David Adams Michael Polydefkis Alejandra González‐Duarte Jonas Wixner Arnt V. Kristen

10.1016/s1474-4422(20)30368-9

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Citations (125)

Cross-sectional Neuromuscular Phenotyping Study of Patients With Arhinia With SMCHD1 Variants

Neurology (2022)

Payam Mohassel Ning Chang Kaoru Inoue Angela Delaney Ying Hu

Facioscapulohumeral muscular dystrophy type 2 (FSHD2) and arhinia are 2 distinct disorders caused by pathogenic variants in the same gene: SMCHD1. The mechanism underlying this phenotypic divergence remains unclear. In this study, we characterize the neuromuscular phenotype of individuals with arhinia caused by SMCHD1 variants and analyze their complex genetic and epigenetic criteria to assess their risk for FSHD2.Eleven individuals with congenital nasal anomalies, including arhinia, nasal hypoplasia, or anosmia, underwent a neuromuscular examination, genetic testing, muscle ultrasound, and muscle MRI. Risk for FSHD2 was determined by combined genetic and epigenetic analysis of 4q35 haplotype, D4Z4 repeat length, and methylation profile. We also compared expression levels of pathogenic DUX4 mRNA in primary myoblasts or dermal fibroblasts (upon myogenic differentiation or epigenetic transdifferentiation, respectively) in these individuals vs those with confirmed FSHD2.Among the 11 individuals with rare, pathogenic, heterozygous missense variants in exons 3-11 of SMCHD1, only a subset (n = 3/11; 1 male, 2 female; age 25-51 years) met the strict genetic and epigenetic criteria for FSHD2 (D4Z4 repeat unit length <21 in cis with a 4qA haplotype and D4Z4 methylation <30%). None of the 3 individuals had typical clinical manifestations or muscle imaging findings consistent with FSHD2. However, the patients with arhinia meeting the permissive genetic and epigenetic criteria for FSHD2 displayed some DUX4 expression in dermal fibroblasts under the epigenetic de-repression by drug treatment and in the primary myoblasts undergoing myogenic differentiation.In this cross-sectional study, we identified patients with arhinia who meet the full genetic and epigenetic criteria for FSHD2 and display the molecular hallmark of FSHD-DUX4 de-repression and expression in vitro-but who do not manifest with the typical clinicopathologic phenotype of FSHD2. The distinct dichotomy between FSHD2 and arhinia phenotypes despite an otherwise poised DUX4 locus implies the presence of novel disease-modifying factors that seem to operate as a switch, resulting in one phenotype and not the other. Identification and further understanding of these disease-modifying factors will provide valuable insight with therapeutic implications for both diseases.

Facioscapulohumeral muscular dystrophy

Muscle disorder

10.1212/wnl.0000000000200032

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Citations (6)

Val50Met hereditary transthyretin amyloidosis: not just a medical problem, but a psychosocial burden

Orphanet Journal of Rare Diseases (2021)

Juan González‐Moreno Aina Gayà-Barroso Inés Losada López Adrián Rodríguez Teresa Bosch-Rovira

Hereditary transthyretin (TTR) amyloidosis (ATTRv) is a heterogeneous disease with a clinical presentation that varies according to geographical area and TTR mutation. The symptoms of Val50Met-ATTRv are mainly neuropathic and progress to complete disability and death in most untreated patients within 10 to 15 years of diagnosis. The neurological effects may also be accompanied by gastrointestinal impairment, cardiomyopathy, nephropathy and/or ocular deposition. The disease is thus associated with a high degree of patient disability. Accordingly, we aimed to describe the psychosocial burden associated with ATTRv in a group of patients, asymptomatic Val50Met carriers, relatives and caregivers in the endemic focus of the disease in Majorca via a survey addressing various aspects related to psychosocial burden. We performed a an observational, descriptive, cross-sectional and multicentre study in order to analyze the prevalence of self-reported impact of ATTRv disease upon their daily life. In addition to the self-knowledge, fear and burden related to the disease. The survey was disseminated during the regular follow up at the outpatient clinic of the Hospital Universitario Son Llàtzer and during the meetings organized by the Andrade's Disease patients' advocacy group from the Balearic Islands. These meetings were attended also by subjects followed up by the Hospital Universitario Son Espases and their caregivers and relatives. Survey was self-administrated. No intervention was done by the investigators. 85 subjects completed the survey: 61 carrying the TTR-V50M variant and 24 caregivers or relatives.Our study revealed that, although most of the population studied had had prior contact with ATTRv through affected relatives, there was still a lack of information regarding disease diagnosis. Fear of the genetic test result and psychological issues were common in our population. Moreover, the disease had a stronger impact on the daily life of our patients than that of our asymptomatic carriers. Autonomic symptoms were the main source of burden for relatives and caregivers.Our survey results show high psychosocial burden associated with Val50Met-ATTRv in our area.

Outpatient clinic

10.1186/s13023-021-01910-5

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Citations (11)

Comparison of Supersaturation Outputs from Different Programs and Their Application in Testing Correspondence with Kidney Stone Composition

Journal of Endourology (2020)

Adrián Rodríguez Tamara da Silva Cunha Allen L. Rodgers Giovanni Gambaro Pietro Manuel Ferraro

Introduction: Relative supersaturation (SS) for calcium oxalate (CaOx), calcium phosphate (CaP), and uric acid (UA) has been used for assessing urinary crystallization and estimated by programs, including EQUIL, Joint Expert Speciation System (JESS), and Lithorisk. We compared outputs from these programs and their correspondence with stone composition. Materials and Methods: SS of CaOx, CaP, and UA, using EQUIL, JESS, and Lithorisk were calculated from stone-forming patients. Pearson correlation coefficients were used to ascertain the correspondence between the outputs. Fractional regression models evaluated the relationship between SS and the percentage of each compound in the stones. Results: Two hundred eleven patients were included. Pearson correlation coefficients for CaOx (r ≥ 0.96), CaP (r ≥ 0.99), and UA SS (r ≥ 0.99) showed a high correspondence between all programs. We observed a significant correspondence between CaOx SS and the percentage of CaOx dihydrate in the stone (p < 0.001), as well as between the percentage of brushite and apatite and CaP SS. UA SS showed the strongest correspondence with the percentage of UA in the stones (p < 0.001). Conclusions: Good correlation between EQUIL, JESS, and Lithorisk was observed and good correspondence with stone composition. The magnitude of the association demonstrated by fractional regression models supports evidence for applying SS in clinical practice.

Supersaturation

Brushite

10.1089/end.2020.0894

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Citations (5)

Anticipation on age at onset in kindreds with hereditary ATTRV30M amyloidosis from the Majorcan cluster

Amyloid (2020)

Eugenia Cisneros‐Barroso Juan González‐Moreno Adrián Rodríguez Tomás Ripoll‐Vera Jorge Santana Álvarez

Hereditary transthyretin amyloidosis (ATTRV30M) is a rare disease caused by amyloid deposition and characterized by a heterogeneous presentation. Anticipation (AC) is described as the decrease in age at onset (AO) within each generation. Our aim was to study AC in a large number of ATTRV30M kindred from Majorca (Spain), and gain further insight into parent-of-origin effects.In a cohort of 262 subjects with ATTRV30M amyloidosis belonging to 51 families, we found 37 affected pairs. AO is defined as the age at the first symptom and AC (parent's age at disease onset minus that of the offspring) were calculated. Chi-square test, independent t-test and paired t-test were used for comparisons between groups. Association between AO of parents and offsprings were assessed by Pearson's correlation coefficient.Offspring mean AO was 16 years lower than that of the parents (p < .001) regardless of the sex of the parents and the offspring. AC occurred in 31 out of the 37 pairs, with no differences related to the sex of parents or offspring. There was a moderate correlation (r = 0.49; p < .001) between AO of the parents and that of the offsprings.AC was no uncommon in our cohort, and AO tended to decrease in successive generations.

Anticipation (artificial intelligence)

10.1080/13506129.2020.1789580

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Citations (9)

BS69 Characterisation of in vivo and in vitro models for epigenomic investigations of cardiac hypertrophy

Diego M. Fernández‐Aroca Stephanie Frost Georgios Tikkas Adrián Rodríguez Andrew Tinker

Introduction

Pathological cardiac hypertrophy is widely linked to lifestyle and environmental factors, and is a risk factor for life-threatening conditions such as heart failure. GWAS population studies have clearly implicated non-coding regulatory genomic regions in the development of cardiac hypertrophy, and a number of mechanistic investigations suggest a role for epigenetic mechanisms in mediating hypertrophy. However, the identity and activity of epigenomic regions deployed during this pathological process have not been studied in detail, in particular cell-type specific epigenetic changes. In this ongoing project, we aim to study the epigenomic profiles associated to the development of cardiac hypertrophy, using in vivo and in vitro models we characterised here.

Methods

We have applied a cardiac hypertrophy induction protocol to a transgenic mouse reporter model (α-MHC-mCherry), chronically treated with Angiotensin II (1µg/kg/min) over 14 days. Induction of cardiac hypertrophy was measured by analysing heart weight; induction of hypertrophy-related gene markers by RT-qPCR; and cell size in histological sections by fluorescence microscopy with WGA in CellProfiler software. In this model, nuclei expressing mCherry were purified by FACS, allowing interrogation of epigenomic profiles (H3K27ac) in cardiomyocytes (CM) and non-cardiomyocytes (non-CM) by ChIP sequencing and differential binding analysis. As a complementary approach, we are employing an in vitro model in human iPSCs differentiated to cardiomyocytes (iPSC-CM) to study the impact of epigenomic elements in cardiac hypertrophy by using Endothelin-I and CRISPR/Cas9 perturbation approaches. Methods used in iPSC to analyse the induction of hypertrophy are the same as in the in vivo model.

Results

Mice treated with Angiotensin-II show a clear induction of hypertrophy-related gene markers as MYH7 and NPPA as well as an increase in cell size. Consistently, differential binding analysis showed 766 differentially bound sites in CMs and 2061 in non-CMs, most of them closely related to cardiac hypertrophy biological processes as shown in Gene Ontology enrichment analysis. In vitro, treatment with Endothelin-I (1-100nM) over 72h in iPSC-CM leads to a clear induction of hypertrophy-related gene markers (MYH7, NPPA, ACTA1) as well as to an increase in cell size. This system will allow investigations of epigenomic changes induced by endothelin-I in iPSC-CMs with similar approaches as used in vivo, and can be extended to investigation of other cardiac cell types.

Conclusions

Angiotensin-II-infused mice and Endothelin-I-treated iPSC are valid models for our purpose showing clear induction of cell hypertrophy at the molecular and cellular level. Induction of cardiac hypertrophy through Angiotensin-II induces broad epigenomic dysregulation in both CM and non-CM cells. Characterisation of these models will enable detailed investigation of global epigenomic changes occurring in vivo and in vitro, and assessment of selected candidate regions.

Conflict of Interest

None

Epigenomics

10.1136/heartjnl-2023-bcs.282

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Citations (0)

Factors Associated With the Lower Prevalence of Nephrolithiasis in Children Compared With Adults

Urology (2015)

F. Gráses Adrián Rodríguez Antonia Costa‐Bauzá Concepción Sáez-Torres Dolores Rodrigo

Urinary calcium

10.1016/j.urology.2015.06.028

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Citations (3)

1798 - MANIFESTACIONES NEUROPSIQUIÁTRICAS EN ATTR-PN V50M. EXPERIENCIA DE UN CENTRO DE FOCO ENDÉMICO

Revista Clínica Española (2023)

Ignasi Merino Esperalba Inés Losada López Eugenia Cisneros‐Barroso Adrián Rodríguez Guseppe Yuliano Razeto

10.1016/s0014-2565(23)00857-3

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Citations (0)

Modification to the AOAC Sporicidal Activity of Disinfectants Test (Method 966.04): Collaborative Study

Journal of AOAC International (2006)

Stephen F Tomasino Martin A. Hamilton H. Garza M Buen Histamine Myers

In an effort to improve AOAC Method 966.04, the Sporicidal Activity of Disinfectants Test, selected modifications to the procedure were evaluated in a collaborative study. Method 966.04 is used to generate efficacy data to support the product registration of sporicides and sterilants. The method is a carrier-based test that provides a qualitative measure of product efficacy against spores of Bacillus subtilis and Clostridium sporogenes. The use of garden soil extract and the lack of standard procedures for the enumeration of spores and neutralization of the test chemicals have been considered problematic for many years. The proposed modifications were limited to the B. subtilis and hard surface carrier (porcelain penicylinder) components of the method. The study included the evaluation of a replacement for soil extract nutrient broth and an establishment of a minimum spore titer per carrier, both considered crucial for the improvement and utilization of the method. Additionally, an alternative hard surface material and a neutralization confirmation procedure were evaluated. To determine the equivalence of the proposed alternatives to the standard method, 3 medium/carrier combinations, (1) soil extract nutrient broth/porcelain carrier (current method), (2) nutrient agar amended with 5 microg/mL manganese sulfate/porcelain carrier, and (3) nutrient agar amended with 5 microg/mL manganese sulfate/stainless steel carrier were analyzed for carrier counts, HCI resistance, efficacy, quantitative efficacy, and spore wash-off. The test chemicals used in the study represent 3 chemical classes and are commercially available antimicrobial liquid products: sodium hypochlorite (bleach), glutaraldehyde, and a combination of peracetic acid and hydrogen peroxide. Four laboratories participated in the study. The results of the spore titer per carrier, HCI resistance, efficacy, and wash-off studies demonstrate that amended nutrient agar in conjunction with the porcelain is comparable to the current method, soil extract nutrient broth/porcelain. The nutrient agar method is simple, inexpensive, reproducible, and provides an ample supply of high quality spores. Due to the current use of porcelain carriers for testing C. sporogenes, it is advisable to retain the use of porcelain carriers until stainless steel can be evaluated as a replacement carrier material for Clostridium. The evaluation of stainless steel for Clostridium has been initiated by the Study Director. Study Director recommendations for First Action revisions are provided in a modified method.

Clostridium sporogenes

Peracetic acid

Bleach

Nutrient agar

Glutaraldehyde

Hand sanitizer

Sodium hypochlorite

10.1093/jaoac/89.5.1373

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Citations (13)