Publications by authors named "Manzanares"

766 Publications

Hydrothermal processing of 3D-printed calcium phosphate scaffolds enhances bone formation in vivo: a comparison with biomimetic treatment.

Acta Biomater 2021 Sep 5. Epub 2021 Sep 5.

Biomaterials, Biomechanics and Tissue Engineering Group, Department of Materials Science and Engineering, Universitat Politècnica de Catalunya (UPC), EEBE, Av. Eduard Maristany, 16, 08019 Barcelona, Spain.; Barcelona Research Centre for Multiscale Science and Engineering, Universitat Politècnica de Catalunya (UPC), EEBE, Av. Eduard Maristany, 10-14, 08019 Barcelona, Spain; Biomedical Engineering Research Center (CREB), Universitat Politècnica de Catalunya, Av. Diagonal, 647, 08028 Barcelona, Spain; Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology, Baldiri Reixac 10- 12, 08028 Barcelona, Spain. Electronic address:

Hydrothermal (H) processes accelerate the hydrolysis reaction of α-TCP compared to the long-established biomimetic (B) treatments. They are of special interest for patient-specific 3D-printed bone graft substitutes, where the manufacturing time represents a critical constraint. Altering the reaction conditions has implications for the physicochemical properties of the reaction product. However, the impact of the changes produced by the hydrothermal reaction on the in vivo performance was hitherto unknown. The present study compares the bone regeneration potential of 3D printed α-TCP scaffolds hardened using these two treatments in rabbit condyle monocortical defects. Although both consolidation processes resulted in biocompatible scaffolds with osseointegrative and osteoconductive properties, the amount of newly formed bone increased by one third in the hydrothermal vs the biomimetic samples. B and H scaffolds consisted mostly of high specific surface area calcium deficient hydroxyapatite (38 and 27 m/g respectively), with H samples containing also 10 wt. % β-TCP. The shrinkage produced during the consolidation process was shown to be very small in both cases, below 3%, and smaller for H than for B samples. The differences in the in vivo performance were mainly attributed to the distinct crystallisation nanostructures, which proved to have a major impact on permeability and protein adsorption capacity, using BSA as a model protein, with B samples being highly impermeable. Given the crucial role that soluble proteins play in osteogenesis, this is proposed to be a relevant factor behind the distinct in vivo performances observed for the two materials. STATEMENT OF SIGNIFICANCE: : The possibility to accelerate the consolidation of self-setting calcium phosphate inks through hydrothermal treatments has aroused great interest, due to the associated advantages for the development of 3D-printed personalised bone scaffolds. Understanding the implications of this approach on the in vivo performance of the scaffolds is of paramount importance. This study compares, for the first time, this treatment to the long-established biomimetic setting strategy in terms of osteogenic potential in vivo in a rabbit model, and relates the results obtained to the physicochemical properties of the 3D-printed scaffolds (composition, crystallinity, nanostructure, nanoporosity) and their interaction with soluble proteins.
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http://dx.doi.org/10.1016/j.actbio.2021.09.001DOI Listing
September 2021

Photoprotection of parenteral nutrition: an international perspective.

Nutr Clin Pract 2021 Sep 8. Epub 2021 Sep 8.

Biopharma Stability Testing Laboratory, BioCity Nottingham, Nottingham, UK.

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http://dx.doi.org/10.1002/ncp.10773DOI Listing
September 2021

Response to: Comment on "Meta-analysis of omega-3 polyunsaturated fatty acids in critically ill patients with acute respiratory distress syndrome".

Nutrition 2021 Jul 25:111432. Epub 2021 Jul 25.

Maisonneuve-Rosemont Hospital, University of Montreal, Quebec, Canada.

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http://dx.doi.org/10.1016/j.nut.2021.111432DOI Listing
July 2021

Frequency and Characterization of Movement Disorders in Anti-IgLON5 Disease.

Neurology 2021 Aug 11. Epub 2021 Aug 11.

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy.

Objective: Anti-IgLON5 disease is a recently described neurological disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are under-reported. Here we describe the frequency and types of movement disorders in a series of consecutive patients with this disease.

Methods: In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by three experts in movement disorders.

Results: Seventy two patients were included. In 41 (57%) the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least one movement disorder with a median of three per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients, 72%), chorea (24, 33%), bradykinesia (20, 28%), dystonia (19, 26%), abnormal body postures or rigidity (18, 25%), and tremor (15, 21%). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients, 32%) including dystonia (13), myorhythmia (6), chorea (4) or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31(43%) of patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only seven (13%) cases.

Conclusions: Movement disorders are a frequent and leading cause of initial neurological consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.
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http://dx.doi.org/10.1212/WNL.0000000000012639DOI Listing
August 2021

Non-viral delivery of CRISPR-Cas9 complexes for targeted gene editing via a polymer delivery system.

Gene Ther 2021 Aug 6. Epub 2021 Aug 6.

Charles Institute of Dermatology, University College Dublin, Dublin, Republic of Ireland.

Recent advances in molecular biology have led to the CRISPR revolution, but the lack of an efficient and safe delivery system into cells and tissues continues to hinder clinical translation of CRISPR approaches. Polymeric vectors offer an attractive alternative to viruses as delivery vectors due to their large packaging capacity and safety profile. In this paper, we have demonstrated the potential use of a highly branched poly(β-amino ester) polymer, HPAE-EB, to enable genomic editing via CRISPRCas9-targeted genomic excision of exon 80 in the COL7A1 gene, through a dual-guide RNA sequence system. The biophysical properties of HPAE-EB were screened in a human embryonic 293 cell line (HEK293), to elucidate optimal conditions for efficient and cytocompatible delivery of a DNA construct encoding Cas9 along with two RNA guides, obtaining 15-20% target genomic excision. When translated to human recessive dystrophic epidermolysis bullosa (RDEB) keratinocytes, transfection efficiency and targeted genomic excision dropped. However, upon delivery of CRISPR-Cas9 as a ribonucleoprotein complex, targeted genomic deletion of exon 80 was increased to over 40%. Our study provides renewed perspective for the further development of polymer delivery systems for application in the gene editing field in general, and specifically for the treatment of RDEB.
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http://dx.doi.org/10.1038/s41434-021-00282-6DOI Listing
August 2021

Understanding Experiences of Fibromyalgia Patients Involved in the Fimouv Study During COVID-19 Lockdown.

Front Psychol 2021 20;12:645092. Epub 2021 Jul 20.

Univ. Lyon, UJM-Saint-Etienne Autonomic Nervous System Research Laboratory, SAINBIOSE INSERM, U1059, Saint-Etienne, France.

The COVID-19 pandemic implied a period of lockdown for the general population, increasing the risk to develop some physical or mental disorders. In fibromyalgia patients, these disorders are part of the large clinical picture of the syndrome. Fibromyalgia management is especially based on a regular practice of physical activity. Lockdown imposed a break in rhythms, requiring a restructuring of scheduling. Thus, the present study aimed to investigate the experiences of fibromyalgia patients during COVID-19 lockdown using a qualitative analysis. 19 patients (52 ± 9 years old) who completed a 3-month therapeutic education and/or supervised physical activity program were invited to participate (Fimouv study, Trial registration: ClinicalTrials.gov NCT04107948). A sociologist collected data by means of semi-structured interviews and analyzed them using thematic content analysis. Lockdown exacerbated the main symptoms of fibromyalgia, but adjusting the rhythms of life to fluctuations of these symptoms allowed a better quality of life. Patients felt the lack of physical activity and 68% found alternatives to remain physically active. The reduction of social constraints allowed them to better contend with their pathology. Fibromyalgia stopped being a main priority. Lockdown was positively experienced by fibromyalgia patients. They linked the absence of physical activity with increased pain and fatigue. Nevertheless, reducing social constraints could be a key for fibromyalgia management, where symptoms seemed to take less space in everyday life. www.ClinicalTrials.gov, identifier: NCT04107948.
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http://dx.doi.org/10.3389/fpsyg.2021.645092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329548PMC
July 2021

Polyphenol intake and cardiovascular risk in the PREDIMED-Plus trial. A comparison of different risk equations.

Rev Esp Cardiol (Engl Ed) 2021 Jul 30. Epub 2021 Jul 30.

Departamento de Medicina Preventiva y Salud Pública, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad de Navarra, Pamplona, Spain.

Introduction And Objectives: Quantification of cardiovascular risk has been based on scores such as Framingham, Framingham-REGICOR, SCORE or Life's Simple 7 (LS7). In vitro, animal, and randomized clinical studies have shown that polyphenols may provide benefits to the vascular system and reduce the inflammatory response. However, some clinical-epidemiological studies have yielded inconsistent results. Our aim was to assess the possible association between intake of the various polyphenol classes and established cardiovascular scores.

Methods: This cross-sectional analysis involved 6633 PREDIMED-Plus study participants. Food polyphenol content was estimated by a semiquantitative food frequency questionnaire, adjusted for total energy intake according to the residual method. The association between polyphenol intake and cardiovascular risk was tested using linear regression analyses.

Results: Total polyphenol and flavonoid intake were directly and significantly associated only with the LS7 scale. Intake of lignans was directly and significantly associated with SCORE and LS7 scales, stilbene intake with SCORE, and phenolic acid intake with Framingham and Framingham-REGICOR scores. Other polyphenol classes were associated in a protective and significant manner in Framingham, SCORE and LS7 scores. In women, intake of all the polyphenol classes, except phenolic acids, showed a protective trend in the results of the Framingham, Framingham-REGICOR scores and LS7 scale.

Conclusions: An inverse association was found between consumption of the 'other polyphenols' class and, especially among women, with estimated cardiovascular risk. The results were similar to those of Framingham, Framingham-REGICOR and LS7 (after eliminating the diet component) and differed from those of SCORE, but the predictors included were limited in the latter case.
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http://dx.doi.org/10.1016/j.rec.2021.06.013DOI Listing
July 2021

Editorial: The Search for Biomarkers in Psychiatry.

Front Psychiatry 2021 12;12:720411. Epub 2021 Jul 12.

Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Alicante, Spain.

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http://dx.doi.org/10.3389/fpsyt.2021.720411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310944PMC
July 2021

Cannabidiol and Sertraline Regulate Behavioral and Brain Gene Expression Alterations in an Animal Model of PTSD.

Front Pharmacol 2021 28;12:694510. Epub 2021 Jun 28.

Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Alicante, Spain.

This study evaluated the effects of cannabidiol (CBD) and/or sertraline (STR) on behavioral and gene expression alterations induced by a new chronic animal model of post-traumatic stress disorder (PTSD). C57BL/6J male mice were repeatedly exposed to physical and psychogenic alternate stressful stimuli. Fear-related memory and anxiety-like behaviors were evaluated. The effects of the administration of CBD (20 mg/kg, i.p.) and/or STR (10 mg/kg, p.o.) were analyzed on behavioral and gene expression changes induced by the model of PTSD. Gene expression alterations of targets related with stress regulation, endocannabinoid and serotonergic systems were analyzed by real-time PCR. The results revealed an increased and long-lasting fear-related memory and anxiety-like behaviors in mice exposed to the animal model of PTSD. Treatment with CBD improved these behaviors in PTSD animals, effects that were significantly potentiated when combined with STR. Gene expression analyses revealed a long-term increase of corticotropin releasing factor () that was significantly normalized with the combination CBD plus STR. Cannabinoid receptors ( and ) were up regulated in PTSD mice whereas the serotonin transporter () was reduced. Interestingly, CBD and STR alone or combined induced a significant and marked increase of gene expression. These results point out the cooperative action of the combination CBD plus STR to enhance fear extinction and reduce anxiety-like behaviors, normalizing gene expression alterations in this animal model of PTSD and suggesting that the combination of CBD with STR deserves to be further explored for the treatment of patients with PTSD.
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http://dx.doi.org/10.3389/fphar.2021.694510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273267PMC
June 2021

Socio-Demographic Health Determinants Are Associated with Poor Prognosis in Spanish Patients Hospitalized with COVID-19.

J Gen Intern Med 2021 Jul 8. Epub 2021 Jul 8.

Department of Emergency, Hospital Clínico San Carlos, Calle Profesor Martín-Lagos s/n, 28040, Madrid, Spain.

Introduction: Social vulnerability is a known determinant of health in respiratory diseases. Our aim was to identify whether there are socio-demographic factors among COVID-19 patients hospitalized in Spain and their potential impact on health outcomes during the hospitalization.

Methods: A multicentric retrospective case series study based on administrative databases that included all COVID-19 cases admitted in 19 Spanish hospitals from 1 March to 15 April 2020. Socio-demographic data were collected. Outcomes were critical care admission and in-hospital mortality.

Results: We included 10,110 COVID-19 patients admitted to 18 Spanish hospitals (median age 68 (IQR 54-80) years old; 44.5% female; 14.8% were not born in Spain). Among these, 779 (7.7%) cases were admitted to critical care units and 1678 (16.6%) patients died during the hospitalization. Age, male gender, being immigrant, and low hospital saturation were independently associated with being admitted to an intensive care unit. Age, male gender, being immigrant, percentile of average per capita income, and hospital experience were independently associated with in-hospital mortality.

Conclusions: Social determinants such as residence in low-income areas and being born in Latin American countries were associated with increased odds of being admitted to an intensive care unit and of in-hospital mortality. There was considerable variation in outcomes between different Spanish centers.
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http://dx.doi.org/10.1007/s11606-020-06584-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266293PMC
July 2021

Potential of Antifungal Proteins (AFPs) to Control Postharvest Fruit Decay.

J Fungi (Basel) 2021 Jun 4;7(6). Epub 2021 Jun 4.

Food Biotechnology Department, Instituto de Agroquímica y Tecnología de Alimentos (IATA), Consejo Superior de Investigaciones Científicas (CSIC), Catedrático Agustín Escardino Benlloch 7, 46980 Valencia, Spain.

phytopathogenic species provoke severe postharvest disease and economic losses. is the main pome fruit phytopathogen while and cause citrus green and blue mold, respectively. Control strategies rely on the use of synthetic fungicides, but the appearance of resistant strains and safety concerns have led to the search for new antifungals. Here, the potential application of different antifungal proteins (AFPs) including the three proteins (PAF, PAFB and PAFC), as well as the NFAP2 protein to control decay, has been evaluated. PAFB was the most potent AFP against , and , PAFC and NFAP2 showed moderate antifungal activity, whereas PAF was the least active protein. In fruit protection assays, PAFB provoked a reduction of the incidence of infections caused by and in oranges and by in apples. A combination of AFPs did not result in an increase in the efficacy of disease control. In conclusion, this study expands the antifungal inhibition spectrum of the AFPs evaluated, and demonstrates that AFPs act in a species-specific manner. PAFB is a promising alternative compound to control postharvest fruit decay.
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http://dx.doi.org/10.3390/jof7060449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229795PMC
June 2021

Analytical Characterization of Water-Soluble Constituents in Olive-Derived By-Products.

Foods 2021 Jun 5;10(6). Epub 2021 Jun 5.

Advanced Biofuels and Bioproducts Unit, Department of Energy-CIEMAT, Avda. Complutense 40, 28040 Madrid, Spain.

Olive trees constitute one of the largest agroindustries in the Mediterranean area, and their cultivation generates a diverse pool of biomass by-products such as olive tree pruning (OTP), olive leaves (OL), olive stone (OS), and extracted olive pomace (EOP). These lignocellulosic materials have varying compositions and potential utilization strategies within a biorefinery context. The aim of this work was to carry out an integral analysis of the aqueous extractives fraction of these biomasses. Several analytical methods were applied in order to fully characterize this fraction to varying extents: a mass closure of >80% was reached for EOP, >76% for OTP, >65% for OS, and >52% for OL. Among the compounds detected, xylooligosaccharides, mannitol, 3,4-dihydroxyphenylglycol, and hydroxytyrosol were noted as potential enhancers of the valorization of said by-products. The extraction of these compounds is expected to be more favorable for OTP, OL, and EOP, given their high extractives content, and is compatible with other utilization strategies such as the bioconversion of the lignocellulosic fraction into biofuels and bioproducts.
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http://dx.doi.org/10.3390/foods10061299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229305PMC
June 2021

Efficiency of an Optimized Care Organization in Fibromyalgia Patients: The From Intent to Move (FIMOUV) Study Protocol of a Randomized Controlled Trial.

Front Public Health 2021 25;9:554291. Epub 2021 May 25.

University Lyon, UJM-Saint-Etienne Sainbiose Laboratory, INSERM U1059, Saint-Étienne, France.

Fibromyalgia (FM) is characterized by multiple symptoms including pain, fatigue, and sleep disorders, altering patient's quality of life. In the absence of effective pharmacological therapy, the last European guidelines recommend a multidisciplinary management based on exercise and education. Thus, our main objective was to measure the effectiveness of a healthcare organization offering a specific program of adapted physical activity combined with a therapeutic education program for FM patients. The From Intent To Move (FIMOUV) study will recruit 330 FM patients randomized into two groups: test and control. The test group will benefit from a 1-month mixed exercise training program supervised at the hospital, followed by 2 months in a community-based relay in a health-sport structure. In addition, each of the two groups will benefit from therapeutic patient education sessions. The main endpoint is the measurement of the level of physical activity by accelerometry at 1 year. The secondary endpoints concern adherence to the practice of physical activity, impact on lifestyle, state of health, and physical capacity, as well as an estimate of the budgetary impact of this management strategy. This interventional research will allow us to assess the evolution of behaviors in physical activity after an FM syndrome management based solely on patient education or based on a supervised and adapted practice of physical activity associated with this same therapeutic education program. It seems to be the first study evaluating the impact of its intervention on objective data for measuring physical activity and sedentary behavior accelerometry among FM patients. ClinicalTrials.gov NCT04107948.
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http://dx.doi.org/10.3389/fpubh.2021.554291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185292PMC
June 2021

Impact of the COVID-19 pandemic on stress, resilience and depression in health professionals: a cross-sectional study.

Int Nurs Rev 2021 Jun 7. Epub 2021 Jun 7.

Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS, Barcelona, Spain.

Aim: To describe the impact of the COVID-19 pandemic on stress, resilience and depression in health professionals from a public hospital in Barcelona, Spain after the first peak of pandemic.

Background: The COVID-19 pandemic in Spain has pushed boundaries in health systems and, especially, for health professionals. Analysis of resilience as an individual resource and it is essential to understand the mechanisms that make staff react unfavourably to stressors caused by the pandemic.

Design: A descriptive cross-sectional study was designed.

Participants: Health professionals supervised by the nursing department, including registered nurses, health care assistants, health technicians, final year nurse student nurses, foreign nurses, and other nurse-related health workers.

Methods: The study complies with the STROBE checklist for cross-sectional studies. An online survey was administered to all health professionals supervised by the nursing department between 6 and 27 May 2020. The survey included the ER-14 Resilience Scale, the widely-used PHQ-9 depression scale, the Spanish version of the Nursing Stress Scale, and an ad-hoc questionnaire to obtain sociodemographic and occupational variables.

Results: A total of 686 participants answered the survey. Resilience was high or very high in health professionals, with an inverse correlation with stress and depression scores. Personal on fixed shifts showed better resilience. The most stressed health professionals were full-time registered nurses, followed by health care assistants. Up to 25% of nursing professionals had depression.

Conclusion: Our study showed a high degree of resilience among nurse professionals despite the overwhelming nature of the COVID-19 pandemic. Relevant signs of depression and stress were detected among participants. Occupational factors heavily influenced nurses' resilience, stress and depression.

Implications For Nursing & Health Policy: Government policy shifts are needed in Spain to improve nurses' workforce conditions, enhance the ratio of nurses to patient numbers, and avoid workforce losses. Maintaining the resilience of health professionals would assist in improving their health and their capacity to possible future emergency situations.
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http://dx.doi.org/10.1111/inr.12693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242605PMC
June 2021

Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders.

Front Pharmacol 2021 20;12:626010. Epub 2021 May 20.

Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain.

Drug treatments available for the management of substance use disorders (SUD) present multiple limitations in efficacy, lack of approved treatments or alarming relapse rates. These facts hamper the clinical outcome and the quality of life of the patients supporting the importance to develop new pharmacological agents. Lately, several reports suggest that cannabidiol (CBD) presents beneficial effects relevant for the management of neurological disorders such as epilepsy, multiple sclerosis, Parkinson's, or Alzheimer's diseases. Furthermore, there is a large body of evidence pointing out that CBD improves cognition, neurogenesis and presents anxiolytic, antidepressant, antipsychotic, and neuroprotective effects suggesting potential usefulness for the treatment of neuropsychiatric diseases and SUD. Here we review preclinical and clinical reports regarding the effects of CBD on the regulation of the reinforcing, motivational and withdrawal-related effects of different drugs of abuse such as alcohol, opioids (morphine, heroin), cannabinoids, nicotine, and psychostimulants (cocaine, amphetamine). Furthermore, a special section of the review is focused on the neurobiological mechanisms that might be underlying the 'anti-addictive' action of CBD through the regulation of dopaminergic, opioidergic, serotonergic, and endocannabinoid systems as well as hippocampal neurogenesis. The multimodal pharmacological profile described for CBD and the specific regulation of addictive behavior-related targets explains, at least in part, its therapeutic effects on the regulation of the reinforcing and motivational properties of different drugs of abuse. Moreover, the remarkable safety profile of CBD, its lack of reinforcing properties and the existence of approved medications containing this compound (Sativex®, Epidiolex®) increased the number of studies suggesting the potential of CBD as a therapeutic intervention for SUD. The rising number of publications with substantial results on the valuable therapeutic innovation of CBD for treating SUD, the undeniable need of new therapeutic agents to improve the clinical outcome of patients with SUD, and the upcoming clinical trials involving CBD endorse the relevance of this review.
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http://dx.doi.org/10.3389/fphar.2021.626010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173061PMC
May 2021

Juvenile idiopathic arthritis and Turner's syndrome.

An Pediatr (Engl Ed) 2020 Oct 2;93(4):259-261. Epub 2020 Oct 2.

Unidad de Reumatología Pediátrica, Servicio de Pediatría, Hospital Universitario Doce de Octubre, Madrid, Spain; Departamento de Salud Pública y Materno-Infantil, Universidad Complutense de Madrid, Madrid, Spain.

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http://dx.doi.org/10.1016/j.anpede.2019.12.011DOI Listing
October 2020

Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice.

Int J Mol Sci 2021 May 17;22(10). Epub 2021 May 17.

Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez 21, 46010 Valencia, Spain.

Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.
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http://dx.doi.org/10.3390/ijms22105279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157004PMC
May 2021

A feasibility trial of gamma sensory flicker for patients with prodromal Alzheimer's disease.

Alzheimers Dement (N Y) 2021 13;7(1):e12178. Epub 2021 May 13.

Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory University Atlanta Georgia USA.

Introduction: We and collaborators discovered that flickering lights and sound at gamma frequency (40 Hz) reduce Alzheimer's disease (AD) pathology and alter immune cells and signaling in mice. To determine the feasibility of this intervention in humans we tested the safety, tolerability, and daily adherence to extended audiovisual gamma flicker stimulation.

Methods: Ten patients with mild cognitive impairment due to underlying AD received 1-hour daily gamma flicker using audiovisual stimulation for 4 or 8 weeks at home with a delayed start design.

Results: Gamma flicker was safe, tolerable, and adherable. Participants' neural activity entrained to stimulation. Magnetic resonance imaging and cerebral spinal fluid proteomics show preliminary evidence that prolonged flicker affects neural networks and immune factors in the nervous system.

Discussion: These findings show that prolonged gamma sensory flicker is safe, tolerable, and feasible with preliminary indications of immune and network effects, supporting further study of gamma stimulation in AD.
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http://dx.doi.org/10.1002/trc2.12178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118113PMC
May 2021

Volumetric and shape analysis of the hippocampus in temporal lobe epilepsy with GAD65 antibodies compared with non-immune epilepsy.

Sci Rep 2021 May 13;11(1):10199. Epub 2021 May 13.

Magnetic Resonance Imaging Core Facility, IDIBAPS, Barcelona, Spain.

Glutamic acid decarboxylase 65 antibodies (anti-GAD65) have been found in patients with late-onset chronic temporal lobe epilepsy (TLE). No prior neuroimaging studies have addressed how they affect hippocampal volume and shape and how they relate to cognitive abnormalities. We aimed to investigate both brain structure and function in patients with isolated TLE and high anti-GAD65 levels (RIA ≥ 2000 U/ml) compared to 8 non-immune mesial TLE (niTLE) and 8 healthy controls (HC). Hippocampal subfield volume properties were correlated with the duration of the disease and cognitive test scores. The affected hippocampus of GAD-TLE patients showed no volume changes to matched HC whereas niTLE volumes were significantly smaller. Epilepsy duration in GAD-TLE patients correlated negatively with volumes in the presubiculum, subiculum, CA1, CA2-3, CA4, molecular layer and granule cell-molecular layer of the dentate nucleus. We found differences by advanced vertex-wise shape analysis in the anterior hippocampus of the left GAD-TLE compared to HC whereas left niTLE showed bilateral posterior hippocampus deformation. Verbal deficits were similar in GAD-TLE and niTLE but did not correlate to volume changes. These data might suggest a distinct expression of hippocampal structural and functional abnormalities based on the immune response.
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http://dx.doi.org/10.1038/s41598-021-89010-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119423PMC
May 2021

Safety of perioperative hyperthermic intraperitoneal chemotherapy with gemcitabine in patients with resected pancreatic adenocarcinoma: a pilot study of the clinical trial EudraCT 2016-004298-41.

J Gastrointest Oncol 2021 Apr;12(Suppl 1):S80-S90

Department of Surgery, University General Hospital, Ciudad Real, Faculty of Medicine, Ciudad Real, University of Castilla-La Mancha, Castilla La Mancha, Spain.

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) with gemcitabine, after cytoreductive surgery, may reduce the tumor progression of pancreatic cancer through the reduction of the neoplastic volume and the subpopulation of residual pancreatic cancer stem cells, improving the survival of patients with pancreatic cancer and decreasing the recurrence of the disease.

Methods: A pilot study is performed with the first ten patients in the experimental group. A randomized study (phase II-III clinical trial) that requires a population of 42 patients, with 21 patients in each group. All patients have a diagnosis of ductal adenocarcinoma of the pancreas, which will be surgically resected with curative intention. (I) Group I: after an R0 resection, patients receive individualized adjuvant treatments. (II) Group II: after an R0 resection, HIPEC is performed with gemcitabine (120 mg/m for 30 min), and they also receive individualized adjuvant treatments. To analyze the safety of the procedure, the main variables measured were as follows: grades of complications by means of the Clavien-Dindo system: pancreas surgery complications (e.g., pancreatic fistula, perioperative hemorrhage, delayed gastric emptying, biliary fistula), operative mortality, and laboratory parameters to control system functions. Values were measured three times: preoperatively, twenty-four hours after surgery, and on the 7th postoperative day.

Results: From 2018 to 2019, 31 patients were recruited for our clinical trial. Fifteen patients were excluded because of intraoperative unresectability or a different intraoperative histologic diagnosis. Ten patients were included in the experimental group (resection plus HIPEC gemcitabine). The mean age was 65±7 years, and six patients were female (60%). We confirmed the histologic diagnosis of ductal pancreatic adenocarcinoma in all patients prior to HIPEC. Total pancreatectomy was performed in five patients. The surgical median time was 360 min, and the hospital stay was 11 days. Four patients showed complications classified as Clavien-Dindo type II and one showing type I. Six patients were classified as having stage III tumors. To date, no hospital mortality, locoregional recurrence, or differences between the two groups in terms of perioperative complications, biochemical and gasometric values, or Clavien-Dindo complication grades were observed.

Conclusions: Our clinical pilot study demonstrated a similar perioperative outcome that allows the trial until main objectives are achieved.
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http://dx.doi.org/10.21037/jgo-20-238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100727PMC
April 2021

Computed tomography and histological evaluation of xenogenic and biomimetic bone grafts in three-wall alveolar defects in minipigs.

Clin Oral Investig 2021 May 1. Epub 2021 May 1.

Mimetis Biomaterials S.L., Carrer de Cartagena, 245, 3F, 08025, Barcelona, Spain.

Objectives: This study aimed to compare the performance of a xenograft (XG) and a biomimetic synthetic graft (SG) in three-wall alveolar defects in minipigs by means of 3D computerised tomography and histology.

Materials And Methods: Eight minipigs were used. A total of eight defects were created in the jaw of each animal, three of which were grafted with XGs, three with SGs, and two were left empty as a negative control. The allocation of the different grafts was randomised. Four animals were euthanised at 6 weeks and four at 12 weeks. The grafted volume was then measured by spiral computed tomography to assess volume preservation. Additionally, a histological analysis was performed in undecalcified samples by backscattered scanning electron microscopy and optical microscopy after Masson's trichrome staining.

Results: A linear mixed-effects model was applied considering four fixed factors (bone graft type, regeneration time, anatomic position, and maxilla/mandible) and one random factor (animal). The SG exhibited significantly larger grafted volume (19%) than the XG. The anterior sites preserved better the grafted volume than the posterior ones. Finally, regeneration time had a positive effect on the grafted volume. Histological observations revealed excellent osseointegration and osteoconductive properties for both biomaterials. Some concavities found in the spheroidal morphologies of SGs were associated with osteoclastic resorption.

Conclusions: Both biomaterials met the requirements for bone grafting, i.e. biocompatibility, osseointegration, and osteoconduction. Granule morphology was identified as an important factor to ensure a good volume preservation.

Clinical Relevance: Whereas both biomaterials showed excellent osteoconduction, SGs resulted in better volume preservation.
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http://dx.doi.org/10.1007/s00784-021-03956-yDOI Listing
May 2021

Childhood-onset systemic lupus erythematosus in an 8-year-old girl with liver transplantation: an unusual association.

Int J Dermatol 2021 Apr 26. Epub 2021 Apr 26.

Department of Dermatology, Hospital Universitario 12 de Octubre, Madrid, Spain.

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http://dx.doi.org/10.1111/ijd.15620DOI Listing
April 2021

Ontogenetic development of the holocephalan dentition: Morphological transitions of dentine in the absence of teeth.

J Anat 2021 09 25;239(3):704-719. Epub 2021 Apr 25.

Department of Earth Sciences, Natural History Museum, London, UK.

Among the cartilaginous fishes (Chondrichthyes), the Holocephali are unique in that teeth are absent both in ontogeny and adult regenerative growth. Instead, the holocephalan dentition of ever-growing nonshedding dental plates is composed of dentine, trabecular in arrangement, forming spaces into which a novel hypermineralized dentine (whitlockin) is deposited. These tissue features form a variety of specific morphologies as the defining characters of dental plates in the three families of extant holocephalans. We demonstrate how this morphology changes through ontogenetic development with continuity between morphologies, through successive growth stages of the dentition represented by the dental plate. For example, rod-shaped whitlockin appears early, later transformed into the tritoral pad, including a regular arrangement of vascular canals and whitlockin forming with increasing mineralization (95%-98%). While the tritoral pads develop lingually, stacks of individual ovoids of whitlockin replace the rods in the more labial parts of the plate, again shaped by the forming trabecular dentine. The ability to make dentine into new, distinctive patterns is retained in the evolution of the Holocephali, despite the lack of teeth forming in development of the dentition. We propose that developmentally, odontogenic stem cells, retained through evolution, control the trabecular dentine formation within the dental plate, and transition to form whitlockin, throughout lifetime growth. Our model of cellular activity proposes a tight membrane of odontoblasts, having transformed to whitloblasts, that can control active influx of minerals to the rapidly mineralizing dentine, forming whitlockin. After the reduced whitloblast cells transition back to odontoblasts, they continue to monitor the levels of minerals (calcium, phosphate and magnesium) and at a slower rate of growth in the peritubate 'softer' dentine. This model explains the unique features of transitions within the holocephalan dental plate morphology.
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http://dx.doi.org/10.1111/joa.13445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349418PMC
September 2021

Functional genomics and epigenomics of atrial fibrillation.

J Mol Cell Cardiol 2021 08 19;157:45-55. Epub 2021 Apr 19.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain. Electronic address:

Atrial fibrillation is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. Despite years of study, we still do not have a full comprehension of the molecular mechanism responsible for the disease. The recent implementation of large-scale approaches in both patient samples, population studies and animal models has helped us to broaden our knowledge on the molecular drivers responsible for AF and on the mechanisms behind disease progression. Understanding genomic and epigenomic changes that take place during chronification of AF will prove essential to design novel treatments leading to improved patient care.
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http://dx.doi.org/10.1016/j.yjmcc.2021.04.003DOI Listing
August 2021

Psychotic symptoms in drug resistant epilepsy patients after cortical stimulation.

Epilepsy Res 2021 Jul 2;173:106630. Epub 2021 Apr 2.

Epilepsy Program, Neurology Department, Hospital Clinic of Barcelona, Barcelona, 08036, Spain; Clinical Institute of Neurosciences, Hospital Clinic of Barcelona, Barcelona, 08036, Spain; Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Barcelona, 08036, Spain.

Purpose: The use of invasive EEG (iEEG) recordings before epilepsy surgery has increased as more complex focal epilepsies are evaluated. Psychotic symptoms (PS) during iEEG have been scarcely reviewed. We aim to report our series of patients with psychotic symptoms (PS) brought about by cortical stimulation (CS) and to identify triggers.

Methods: Retrospective cohort of patients who underwent iEEG and CS. We report patients who developed delusional thinking and/or disorganized behaviour within 24 h after CS. Exclusion criteria were primary psychiatric disorders or absence of CS.

Results: We evaluated 32 (SEEG 23; subdural 9) patients with a median age of 38 years, 6 with PS. Patients underwent 2586 stimulations over 1130 contacts. Age at CS was significantly higher in patients with PS. Temporal lobe epilepsy was significantly more often documented in patients with PS (χ: 3.94; p< 0.05). We found no correlation between stimulation of the limbic system and development of psychosis. Four (66.7 %) patients were stimulated in the non-dominant limbic system and developed psychosis compared to 7 (27 %) who did not [χ2: 3.41; p= 0.06].Epilepsy duration was significantly higher in PS patients (p=0.002). Patients with history of postictal psychosis were twice more likely to experience PS(p=0.04).

Conclusions: PS may arise more frequently in patients with PIP history, older age and longer epilepsy duration. The neurobiology and physiology of psychosis, that may share common mechanisms with epilepsy, is yet to be identified but we hypothesize that it may be triggered by CS due to alteration of brain networks dynamics.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106630DOI Listing
July 2021

Effect of a semi-immersive virtual reality navigation therapy on quality of life in persons with spinal cord injury.

Disabil Rehabil Assist Technol 2021 Apr 10:1-6. Epub 2021 Apr 10.

Centre for Sport Studies, Rey Juan Carlos University, Fuenlabrada (Madrid), Spain.

Purpose: This study aims to develop a sailing simulation-based therapeutic rehabilitation program for individuals with Spinal Cord Injuries (SCI) during the subacute phase of the injury.

Methods: Participants were 11 patients, aged between 20-56 years ( = 42.36, =12.90), who were randomly assigned into experimental group and control group, within a pre-test/post-test quasi-experimental design. While both groups followed the rehabilitation programmed by the hospital, experimental group participants were enrolled in an interactive rehabilitation exercise (The vSail-Access®, Virtual Sailing Pty Ltd). For this intervention, each subject underwent a semi-immersive Virtual Reality (VR) navigation therapy for 30-40 min per day, three times per week for six weeks. Quality of life (QoL), functionality and balance variables were measured for both groups one week before and after the intervention. Data was generated based on patients' responses using validated questionnaires and tests. A 2 (groups) × 2 (test-time) MANOVA was performed to detect between-group and within-group differences.

Results: Significant improvements were obtained in the experimental group in the mobility and balance variables, and in the global result of QoL.

Conclusions: The sailing simulation program, included as a therapy within the rehabilitation process after a SCI, provides participants with an overall increase in QoL and functionality.IMPLICATIONS FOR REHABILIATIONVirtual reality is a therapy that can be part of the rehabilitation process of spinal cord injuries in the acute phase, improving functional capacity.The initiation to recreational sailing in a virtual way is a safe tool for the initiation to the practice of sports.The practice of a dynamic sport, such as sailing, helps to improve the quality of life in spinal cord injuries.
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http://dx.doi.org/10.1080/17483107.2021.1913520DOI Listing
April 2021

Prognostic value of patient-derived xenograft engraftment in pediatric sarcomas.

J Pathol Clin Res 2021 Jul 9;7(4):338-349. Epub 2021 Apr 9.

Institut de Recerca Sant Joan de Deu, Barcelona, Spain.

The goals of this work were to identify factors favoring patient-derived xenograft (PDX) engraftment and study the association between PDX engraftment and prognosis in pediatric patients with Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. We used immunodeficient mice to establish 30 subcutaneous PDX from patient tumor biopsies, with a successful engraftment rate of 44%. Age greater than 12 years and relapsed disease were patient factors associated with higher engraftment rate. Tumor type and biopsy location did not associate with engraftment. PDX models retained histology markers and most chromosomal aberrations of patient samples during successive passages in mice. Model treatment with irinotecan resulted in significant activity in 20 of the PDXs and replicated the response of rhabdomyosarcoma patients. Successive generations of PDXs responded similarly to irinotecan, demonstrating functional stability of these models. Importantly, out of 68 tumor samples from 51 patients with a median follow-up of 21.2 months, PDX engraftment from newly diagnosed patients was a prognostic factor significantly associated with poor outcome (p = 0.040). This association was not significant for relapsed patients. In the subgroup of patients with newly diagnosed Ewing sarcoma classified as standard risk, we found higher risk of relapse or refractory disease associated with those samples that produced stable PDX models (p = 0.0357). Overall, our study shows that PDX engraftment predicts worse outcome in newly diagnosed pediatric sarcoma patients.
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http://dx.doi.org/10.1002/cjp2.210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185364PMC
July 2021

The administration of sertraline plus naltrexone reduces ethanol consumption and motivation in a long-lasting animal model of post-traumatic stress disorder.

Neuropharmacology 2021 05 2;189:108552. Epub 2021 Apr 2.

Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal S/n, San Juan de Alicante, 03550, Alicante, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain. Electronic address:

This study was aimed to evaluate the effects of sertraline (STR) and/or naltrexone (NTX) on ethanol consumption and motivation in an animal model of post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD). Male C57BL/6J mice were submitted to an intermittent and progressively increasing stressful stimuli simulating PTSD behavioural features. Behavioural alterations were explored by the fear conditioning (FC), novelty suppressed feeding test (NSFT) and acoustic startle response (ASR) paradigms. Afterwards, mice were evaluated in the voluntary ethanol consumption (VC) and the oral ethanol self-administration (OEA) paradigms. The effects of STR (10 mg/kg) and/or NTX (0.7 mg/kg) on ethanol consumption and motivation were analysed in the OEA. Furthermore, relative gene expression analyses of tyrosine hydroxylase (Th), mu-opioid receptor (Oprm1) and 5-hydroxitryptamine transporter (Slc6a4) were performed in the ventral tegmental area (VTA), nucleus accumbens (NAcc) and dorsal raphe nucleus (DR), respectively. PTSD-like mice presented increased fear-related memory, anxiety-like behaviours, and startle response, as well as enhanced ethanol consumption and motivation in the VC and OEA paradigms. Interestingly, STR plus NTX combination significantly reduced ethanol intake and motivation in the OEA. Gene expression analyses revealed reduced Th and Oprm1 whereas Slc6a4 gene expression increased in PTSD-like mice. STR and/or NTX modulated Th and Slc6a4 gene expression changes in PTSD-like mice. Furthermore, NTX increased Oprm1 gene expression revealing a synergistic action when combined with STR. These results provide evidence about the efficacy of the STR plus NTX to attenuate ethanol reinforcement and motivation in an animal model of PTSD and AUD dual pathology.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108552DOI Listing
May 2021
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