Artículos (Instituto de Biomedicina de Sevilla (IBIS))

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Family study of a novel mutation of mucopolysaccharidosis type VI with a severe phenotype and good response to enzymatic replacement therapy Case report
(Lippincott Williams & Wilkins, 2018-10) Ley-Martos, Myriam; Guerrero Montávez, Juan Miguel; Lucas-Javato, Marta; Remón-García, Cristina; Raul García-Lozano, J.; Colón, Cristóbal; Macher, Hada C.; Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Biomedicina de Sevilla (IBIS); Fundacion Publica Andaluza Progreso y Salud; Instituto de Salud Carlos III-Fondos FEDER; CTS160: Neuroinmunoendocrinología Molecular
Rationale: Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome is produced by the deficiency of the enzyme arylsulfatase B, responsible for the hydrolysis of N-acetyl-D-galactosamine, chondroitin sulfate, and dermatan sulfate. Patient concerns: A 3-year-old male with Moroccan origins is the index case. He had healthy consanguineous parents and 4 healthy brothers and sisters. The patient showed a wide spectrum of symptoms including skeletal dysplasia and short stature with elevated glycosaminoglycans (GAGs) in urine. Diagnoses, interventions, and outcomes: GAGs were quantified by spectrometry method with 1,9-dimethylen blue in 24-hour urine samples. The qualitative analysis of urine GAGs was obtained by thin-layer chromatography to determine the predominant presence of dermatan sulfate. The activities of both arylsulfatase B and beta-galactosidase as well as genetic studies were performed in dried blood spots. The genetic study was performed with deoxyribonucleic acid by massive sequencing a of lisosomal storage diseases. Results showed a new mutation c.263A > C with the severe phenotype in homozygous in the patient. The familiar study of ARSB and GLB1 genes presented some asymptomatic SNPs but with a discrete decrease in the activity of arylsulfatase B and beta-galactosidase. After an early detection by pediatricians, and both enzymatic and genetic confirmation, the patient had a good response to substitutive enzymatic treatment with galsulfase. Lessons: Mucoplysaccharidosis type VI is an autosomal recessive rare disease characterized by a lysosomal storage disorder. Although a number of mutations have been already associated to the disease, we have found a new mutation located in the arylsulfatase B enzyme gene. We have described that this mutation is the ultimate cause of a severe presentation of the disease.
IFNL4 ss469415590 Variant Shows Similar Performance to rs12979860 as Predictor of Response to Treatment against Hepatitis C Virus Genotype 1 or 4 in Caucasians
(Ed. Public Library of Science PLoS, 2014-04-18) Real Navarrete, Luis Miguel; Neukam, Karin; Herrero, Rocío; Guardiola, Josep M.; Reiberger, Thomas; Rivero-Juarez, Antonio; Macías Sánchez, Juan; Pineda, Juan A.; Caruz, Antonio; Bioquímica Médica y Biología Molecular e Inmunología; Fondo de Investigaciones Sanitarias; Fundación para la Investigación y la Prevención del Sida en España; Junta de Andalucía; Instituto de Salud Carlos III; Ministerio de Sanidad, Servicios Sociales e Igualdad. España; Red de Investigación en SIDA
Objectives: The rs12979860 variant, linked to IL28B gene, predicts sustained viral response (SVR) to pegylated-interferon/ ribavirin (pegIFN/RBV) therapy in Hepatitis C Virus genotype 1 or 4 (HCV-1/4)-infected patients. Recently, a functional variant, ss469415590, in linkage disequilibrium (LD) with rs12979860, has been discovered. Our objective was to assess the value of ss469415590 to predict SVR to pegIFN/RBV in Caucasian HCV-1/4-infected individuals and to compare its performance with that of rs12979860. Methods: 272 Caucasian HCV-1/4-infected patients who completed a course of pegIFN/RBV were genotyped for both rs12979860 and ss469415590 markers. Logistic regression models including factors with univariate association with SVR and each genetic marker were elaborated. The area under the receiver operating-characteristic curve (AUROC) was calculated for each model and both were compared. Results: Both markers were in LD (r2 = 0.82). For rs12979860, 66 (64.0%) CC versus 56 (33.1%) T allele carriers achieved SVR (Adjusted OR = 4.156, 95%CI = 2.388–7.232, p = 4.64761027 ). For ss469415590, 66 (66.0%) TT/TT versus 56 (32.5%) –G allele carriers (Adjusted OR = 4.783, 95%CI = 2.714–8.428, p = 6.15361028 ) achieved SVR. The AUROC of the model including rs12979860 was 0.742 (95%CI = 0.672–0.813) and of that based on ss469415590 was 0.756 (95%CI = 0.687–0.826) (p = 0.780). Conclusions: The ss469415590 variant shows an equivalent performance to predict SVR to pegIFN/RBV than the rs2979860 in Caucasian HCV-1/4-infected patients.
Circulating cell-free DNA is a predictor of short-term neurological outcome in stroke patients treated with intravenous thrombolysis
(Sage Journals, 2016) Bustamante, Alejandro; Mancha, Fernando; Macher, Hada C.; García-Berrocoso, Teresa; Giralt, Dolors; Ribó, Marc; Guerrero Montávez, Juan Miguel; Montaner, Joan; Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); CTS160: Neuroinmunoendocrinología Molecular
Circulating cell-free DNA (cfDNA) has been described as a prognostic marker for several diseases. Its prognostic value for short-term outcome in stroke patients treated with intravenous thrombolysis remains unexplored. cfDNA was measured on admission in 54 tissue plasminogen activator (tPA)-treated patients and 15 healthy controls using a real-time quantitative polymerase chain reaction assay. Neurological outcome was assessed at 48 h. Predictors of neurological improvement were evaluated by logistic regression analysis, and the additional predictive value of cfDNA over clinical variables was determined by integrated discrimination improvement (IDI). Stroke patients presented higher baseline cfDNA than healthy controls (408.5 (179–700.5) vs. 153.5 (66.9–700.5) kilogenome-equivalents/L, p ¼ 0.123). A trend towards lower cfDNA levels was found in patients who neurologically improved at 48 h (269.5 (143.3–680) vs. 504 (345.9–792.3) kilogenome-equivalents/L, p ¼ 0.130). In logistic regression analysis, recanalization at 1 h and cfDNA < 302.75 kilogenome-equivalents/L was independently associated with neurological improvement after adjustment by age, gender and baseline National Institutes of Health Stroke Scale score. The addition of cfDNA to the clinical predictive model improved its discrimination (IDI ¼ 21.2% (9.2–33.3%), p ¼ 0.009). These data suggest that cfDNA could be a surrogate marker for monitoring tPA efficacy by the prediction of short-term neurological outcome.
Biomechanical and clinical differences in muscle tone, stiffness, range of motion, and pain perception in children with cerebral palsy: a cross-sectional study
(Frontiers Media SA, 2025-04-15) González-Matilla, Ramón; Abuín-Porras, Vanesa; Mínguez-Esteban, Isabel; Heredia Rizo, Alberto Marcos; Fisioterapia; CTS1110: Understanding Movement & Self in Health from Science
Introduction: Spasticity and altered muscle tone are key features in children withneurodevelopmentaldisorders,particularlycerebralpalsy(CP).Theyimpact movement, range of motion (ROM), and pain perception, influencing functional abilities and quality of life. Understanding the intrinsic muscle differences in children with CP can help improve clinical assessment and therapeutic interventions. This study aims to evaluate differences in muscle tone, stiffness, ROM, and pain perception between children with CP and typically developing peers using objective biomechanical measures. Methods: An observational, cross-sectional study was conducted with 40 participants of both sexes (20 children with CP, 20 typically developing peers). Muscle tone and stiffness of the lower limb muscles were measured using the Myoton PRO device. ROM was assessed by goniometry, and pain perception was evaluated using the Visual Analog Scale during a Straight Leg Raise (SLR) test. A generalized linear mixed model was used to detect differences in myotonometry, ROM, and pain perception measurements. In participants with CP, the Pearson product-moment correlation coefficient analysis was used to explore possible associations between clinical features and muscle tone and stiffness. Results: Children with CP exhibited reduced ROM, with a significant group effect for hip flexion (P < 0.001; η2 = 0.843), knee extension (P < 0.001; η2 = 0.355), and ankle flexion (P < 0.001; η2 = 0.959) and higher pain perception during the SLR test (P < 0.001; η2 = 0.831), compared to controls. Myotonometry revealed significantly increased muscle stiffness of the rectus femoris (P = 0.004; η2 = 0.112) and adductor muscles (P = 0.019; η2 = 0.074) in the CP group, with no differences in muscle tone between the groups. Sex-related differences were found for muscle tone and stiffness, with males showing higher values. Correlation analyses indicated that adductor muscles stiffness was associated with CP severity. Conclusion: Children with CP demonstrate significant changes in ROM, pain perception, and muscle stiffness, emphasizing the need for targeted therapeutic interventions. These findings support the use of objective biomechanical tools for assessing muscle properties in clinical settings, contributing to better management strategies for spasticity-related impairments.
Short-term effects of visceral manual therapy on autonomic nervous system modulation in individuals with clinically based bruxism: a randomized controlled trial
(Mdpi, 2025-07-16) Navarro-rico, Cayetano; Fricke Comellas, Hermann Wolfgang; Heredia Rizo, Alberto Marcos; Díaz Mancha, Juan Antonio; Rosado-Portillo, Adolfo; Fernández Seguín, Lourdes María; Fisioterapia; CTS1110: Understanding Movement & Self in Health from Science; CTS1043: Salud, Fisioterapia y Actividad Física
Background/Objectives: Bruxism has been associated with dysregulation of the autonomic nervous system (ANS). Visceral manual therapy (VMT) has shown beneficial effects on the vagal tone and modulation of ANS activity. This study aimed to evaluate the immediate and short-term effects of VMT in individuals with clinically based bruxism. Methods: A single-blind randomized controlled trial was conducted including 24 individuals with clinically based bruxism. Participants received two sessions of either VMT or a sham placebo technique. Outcome measures included heart rate variability (HRV), both normal-to-normal intervals (HRV-SDNN), and the root mean square of successive normal-to-normal intervals (HRV-RMSSD), as well as muscle tone and stiffness and pressure pain thresholds (PPTs). Measurements were made at T1 (baseline), T2 (post-first intervention), T3 (pre-second intervention), T4 (post-second intervention), and T5 (4-week follow-up). Results: A significant time*group interaction was observed for HRV-SDNN (p = 0.04, η2 = 0.12). No significant changes were found for muscle tone or stiffness. PPTs significantly increased at C4 after the second session (p = 0.049, η2 = 0.16) and at the left temporalis muscle after the first session (p = 0.01, η2 = 0.07). Conclusions: The findings suggest that two sessions of VMT may lead to significant improvements in HRV-SDNN compared to the placebo, suggesting a modulatory effect on autonomic function. No consistent changes were observed for the viscoelastic properties of the masticatory muscles. Isolated improvements in pressure pain sensitivity were found at C4 and the left temporalis muscle. Further research with larger sample sizes and long-term follow-up is needed to determine the clinical relevance of VMT in the management of signs and symptoms in individuals with bruxism.
Prognostic and diagnostic value of eosinopenia, C-reactive protein, procalcitonin, and circulating cell-free DNA in critically ill patients admitted with suspicion of sepsis
(Current Science Ltd., 2014-06-05) Garnacho-Montero, Jose; Huici-Moreno, María J.; Gutiérrez-Pizarraya, Antonio; López, Isabel; Márquez-Vácaro, Juan A.; Macher, Hada; Guerrero Montávez, Juan Miguel; Puppo-Moreno, Antonio; Bioquímica Médica y Biología Molecular e Inmunología; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (MINECO). España; Spanish Network for the Research in Infectious Diseases
Introduction: The aims of this study were to assess the reliability of circulating cell-free DNA (cf-DNA) concentrations, compared with C-reactive protein (CRP), procalcitonin (PCT) and eosinophil count, in the diagnosis of infections in patients with systemic inflammatory response syndrome (SIRS) and their prognostic values in a cohort of critically ill patients. Methods: We conducted a prospective cohort study in a medical-surgical intensive care unit of a university hospital. Eosinophil count and concentrations of cf-DNA, CRP, and PCT were measured in patients who fulfilled SIRS criteria at admission to the intensive care unit (ICU) and a second determination 24 hours later. DNA levels were determined by a PCR method using primers for the human beta-haemoglobin gene. Results: One hundred and sixty consecutive patients were included: 43 SIRS without sepsis and 117 with sepsis. Levels of CRP and PCT, but not cf-DNA or eosinophil count, were significantly higher in patients with sepsis than in SIRS-no sepsis group on days 1 and 2. PCT on day 1 achieves the best area under the curve (AUC) for sepsis diagnosis (0.87; 95% confidence interval = 0.81-0.94). Levels of cf-DNA do not predict outcome and the accuracy of these biomarkers for mortality prediction was lower than that shown by APACHE II score. PCT decreases significantly from day 1 to day 2 in survivors in the entire cohort and in patients with sepsis without significant changes in the other biomarkers. Conclusions: Our data do not support the clinical utility of cf-DNA measurement in critical care patients with SIRS. PCT is of value especially for infection identification in patients with SIRS at admission to the ICU.
Melatonin: Buffering the Immune System
(MDPI, 2013-03-03) Carrillo Vico, Antonio; Lardone, Patricia Judith; Álvarez-Sánchez, Nuria; Rodríguez-Rodríguez, Ana; Guerrero Montávez, Juan Miguel; Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía; Regional Government Ministry of Health
Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed.
Cannabinoid effective targeting of atherosclerotic plaques by optimized-PLGA nanoparticles
(Elsevier, 2025-08-25) Martín Navarro, Lucía; Herrera González, María Dolores; Álvarez Fuentes, Josefa; Claro Cala, Carmen María; Martín Banderas, Lucía; Farmacia y Tecnología Farmacéutica; Farmacología; Junta de Andalucía; European Union (UE); Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Agencia Estatal de Investigación. España
Aim While selective CB2 receptor agonists hold significant promise for mitigating inflammation and atherosclerosis, their poor physicochemical properties have hampered clinical translation. To overcome this, we engineered a sophisticated, nanoparticle-based delivery system designed for precise cannabinoid deposition at atheromatous plaque sites. Our approach utilized PEGylated PLGA nanoparticles (NPs), functionalized with a peptide ligand specifically targeting vascular cell adhesion molecule-1 (VCAM-1), a well-established biomarker of atherosclerotic lesions. Methods PEGylated PLGA NPs were synthesized via nanoprecipitation using a blend of PLGA, PLGA-PEG, and PLGA-PEG-Mal polymers. Peptide conjugation was then achieved through a maleimide-click reaction. The resulting functionalized nanoparticles were characterized for their physicochemical properties and evaluated both in vitro (using human vascular endothelial cells), and in vivo (in apolipoprotein E-deficient, ApoE-/-, mice). Results Optimal NP functionalization with the VBP peptide was achieved using a 1:1 maleimide-to-ligand molar ratio in 10 mM HEPES / 0.4 mM EDTA buffer after a 2-hour incubation. In vitro assays demonstrated that these functionalized NPs significantly downregulated the expression of adhesion molecules, inflammatory cytokines, and chemokines, while also successfully restoring oxidative balance in human endothelial cells. Importantly, in vivo experiments demonstrated efficient and site-specific delivery of the functionalized NPs to atheroprone regions in ApoE⁻/⁻ mice, resulting in a significant reduction of atherosclerotic plaque formation in the aortic sinus. Conclusion These findings indicate that this developed nanosystem represents a highly promising strategy for targeted cannabinoid delivery. This breakthrough could significantly contribute to the advancement of novel anti-atherogenic therapies, offering a new avenue for treating atherosclerosis.
Toll-like receptor agonists enhance HIV-specific T cell response mediated by plasmacytoid dendritic cells in diverse HIV-1 disease progression phenotypes
(Elsevier, 2023-04-03) Jiménez-León, María R.; Gasca-Capote, Carmen; Tarancón-Díez, Laura; Domínguez-Molina, Beatriz; López-Verdugo, Macarena; Ritraj, Ryan; Gallego Jiménez, Isabel; Rafii-El-Idrissi Benhnia, Mohammed; López Cortés, Luis Fernando; Ruiz-Mateos, Ezequiel; Fisiología Médica y Biofísica; Bioquímica Médica y Biología Molecular e Inmunología; Medicina; Instituto de Biomedicina de Sevilla (IBIS); Fondo Europeo de Desarrollo Regional (FEDER), (Instituto de Salud Carlos III); Red Temática de Investigación Cooperativa en SIDA; Consejo Superior de Investigaciones Científicas (CSIC)
Background: Plasmacytoid dendritic cells (pDCs) sense viral and bacterial products through Toll-like receptor (TLR)-7 and -9 and translate this sensing into Interferon-α (IFN-α) production and T-cell activation. The understanding of the mechanisms involved in pDCs stimulation may contribute to HIV-cure immunotherapeutic strategies. The objective of the present study was to characterize the immunomodulatory effects of TLR agonist stimulations in several HIV-1 disease progression phenotypes and in non HIV-1 infected donors. Methods: pDCs, CD4 and CD8 T-cells were isolated from 450 ml of whole blood from non HIV-1 infected donors, immune responders (IR), immune non responders (INR), viremic (VIR) and elite controller (EC) participants. pDCs were stimulated overnight with AT-2, CpG-A, CpG-C and GS-9620 or no stimuli. After that, pDCs were co-cultured with autologous CD4 or CD8 T-cells and with/without HIV-1 (Gag peptide pool) or SEB (Staphylococcal Enterotoxin B). Cytokine array, gene expression and deep immunophenotyping were assayed. Findings: pDCs showed an increase of activation markers levels, interferon related genes, HIV-1 restriction factors and cytokines levels after TLR stimulation in the different HIV-disease progression phenotypes. This pDC activation was prominent with CpG-C and GS-9620 and induced an increase of HIV-specific T-cell response even in VIR and INR comparable with EC. This HIV-1 specific T-cell response was associated with the upregulation of HIV-1 restriction factors and IFN-α production by pDC. Interpretation: These results shed light on the mechanisms associated with TLR-specific pDCs stimulation associated with the induction of a T-cell mediated antiviral response which is essential for HIV-1 eradication strategies. Funding: This work was supported by Gilead fellowship program, the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, FEDER, "a way to make Europe") and the Red Temática de Investigación Cooperativa en SIDA and by the Spanish National Research Council (CSIC).
The Impressive Anti-Inflammatory Activity of Cerium Oxide Nanoparticles: More than Redox?
(MDPI, 2023-10-21) Corsi, Francesca; Deidda Tarquini, Greta; Urbani, Marta; Bejarano Hernando, Ignacio; Traversa, Enrico; Ghibelli, Lina; Bioquímica Médica y Biología Molecular e Inmunología; Instituto de Biomedicina de Sevilla (IBIS); CTS160: Neuroinmunoendocrinología Molecular
Cerium oxide nanoparticles (CNPs) are biocompatible nanozymes exerting multifunctional biomimetic activities, including superoxide dismutase (SOD), catalase, glutathione peroxidase, photolyase, and phosphatase. SOD- and catalase-mimesis depend on Ce3+/Ce4+ redox switch on nanoparticle surface, which allows scavenging the most noxious reactive oxygen species in a self-regenerating, energy-free manner. As oxidative stress plays pivotal roles in the pathogenesis of inflammatory disorders, CNPs have recently attracted attention as potential anti-inflammatory agents. A careful survey of the literature reveals that CNPs, alone or as constituents of implants and scaffolds, strongly contrast chronic inflammation (including neurodegenerative and autoimmune diseases, liver steatosis, gastrointestinal disorders), infections, and trauma, thereby ameliorating/restoring organ function. By general consensus, CNPs inhibit inflammation cues while boosting the pro-resolving anti-inflammatory signaling pathways. The mechanism of CNPs’ anti-inflammatory effects has hardly been investigated, being rather deductively attributed to CNP-induced ROS scavenging. However, CNPs are multi-functional nanozymes that exert additional bioactivities independent from the Ce3+/Ce4+ redox switch, such as phosphatase activity, which could conceivably mediate some of the anti-inflammatory effects reported, suggesting that CNPs fight inflammation via pleiotropic actions. Since CNP anti-inflammatory activity is potentially a pharmacological breakthrough, it is important to precisely attribute the described effects to one or another of their nanozyme functions, thus achieving therapeutic credibility.
Aztreonam-avibactam for the treatment of serious infections caused by metallo-β-lactamase-producing Gram-negative pathogens: a Phase 3 randomized trial (ASSEMBLE)
(Oxford University Press, 2025-07-28) Daikos, George L.; Cisneros, José Miguel; Carmeli, Yehuda; Wang, Mingyi; Leong, Chee Loon; Pontikis, Konstantinos; Chow, Joseph W.; Medicina
Background: The Phase 3 ASSEMBLE study investigated aztreonam–avibactam versus best available therapy (BAT) for treatment of complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), hospital-acquired/ventilator-associated pneumonia (HAP/VAP) or bloodstream infection (BSI) caused by confirmed MBL-producing multidrug-resistant pathogens. Methods: This prospective, multicentre, randomized, open-label, central assessor-blinded study randomized hospitalized adults 2:1 to aztreonam–avibactam [+ metronidazole (cIAI)] or BAT for 5–14 (cIAI, cUTI and BSI) or 7–14 (HAP/VAP) days. Primary endpoint was clinical cure at test-of-cure (TOC) visit on Day 28 ± 3 [microbio logical ITT (micro-ITT) analysis set]. Secondary endpoints included microbiological response at TOC, 28-day mor tality and safety. No formal hypothesis testing was planned. Results: Fifteen patients were randomized [aztreonam–avibactam, n = 12; BAT, n = 3 (ITT and micro-ITT analysis sets)]. Most frequent baseline pathogens were Enterobacterales; Klebsiella pneumoniae was most common [az treonam–avibactam, 6/12 (50%); BAT, 2/3 (67%)]. MBL subtypes/variants identified in the aztreonam–avibac tam group were NDM-1 (n = 7), NDM-5 (n = 3), VIM-2 (n = 2) and L1 (n = 3); and for BAT were NDM-1 (n = 2) and NDM-5 (n = 1). Clinical cure rates at TOC were 5/12 (42%) for aztreonam–avibactam and 0/3 (0%) for BAT. Per-patient microbiological responses were generally consistent with clinical responses. Twenty-eight- day all-cause mortality rates for aztreonam–avibactam and BAT were 1/12 (8%) and 1/3 (33%), respectively. Aztreonam–avibactam was generally well-tolerated, with no treatment-related serious adverse events. Conclusions: These Phase 3 data provide support for aztreonam–avibactam as a potential therapeutic option for difficult-to-treat infections caused by MBL-producing Gram-negative bacteria
Neuropilin-2 mediates VEGF-C–induced lymphatic sprouting together with VEGFR3
(Rockefeller University Press, 2010) Xu, Yunling; Yuan, Li; Mak, Judy; Pardanaud, Luc; Caunt, Maresa; Kasman, Ian; Toro Estévez, Raquel del; Bagri, Anil; Fisiología Médica y Biofísica; Agence Nationale de la Recherche (Neuroscience, blanc); European Community (EC); Institut de France (Cino del Duca); Institut National de la Sante et de la Recherche Medicale; Institut National du Cancer; Medical Research Council
Vascular sprouting is a key process-driving development of the vascular system. In this study, we show that neuropilin-2 (Nrp2), a transmembrane receptor for the lymphangiogenic vascular endothelial growth factor C (VEGF-C), plays an important role in lymphatic vessel sprouting. Blocking VEGF-C binding to Nrp2 using antibodies specifically inhibits sprouting of developing lymphatic endothelial tip cells in vivo. In vitro analyses show that Nrp2 modulates lymphatic endothelial tip cell extension and prevents tip cell stalling and retraction during vascular sprout formation. Genetic deletion of Nrp2 reproduces the sprouting defects seen after antibody treatment. To investigate whether this defect depends on Nrp2 interaction with VEGF receptor 2 (VEGFR2) and/or 3, we intercrossed heterozygous mice lacking one allele of these receptors. Double-heterozygous nrp2vegfr2 mice develop normally without detectable lymphatic sprouting defects. In contrast, double-heterozygote nrp2vegfr3 mice show a reduction of lymphatic vessel sprouting and decreased lymph vessel branching in adult organs. Thus, interaction between Nrp2 and VEGFR3 mediates proper lymphatic vessel sprouting in response to VEGF-C.
Development and validation of a predictive mortality scoring model for bloodstream infections due to Escherichia coli in the PROBAC cohort
(Springer ; Springer Heidelberg, 2025-07-23) Olivares Navarro, Paula; Pérez-Rodríguez, María Teresa; Goikoetxea Aguirre, Ane Josune; Reguera-Iglesias, José María; León, Eva; Mantecón, María Ángeles; Retamar Gentil, Pilar; López-Cortés, Luis E.; Rodríguez-Baño, Jesús; Medicina; Instituto de Salud Carlos III; Gobierno de España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Introduction Escherichia coli is the most frequent cause of bacteraemia and has a major impact on morbidity and mortality. The aim of this study is to define and internally validate a predictive risk score of 30-day all-cause mortality. Methods A prospective, multicentre, cohort study conducted in 26 Spanish hospitals between October 2016 and March 2017 was performed. All monomicrobial E. coli bloodstream infections (BSIs) were included. The primary outcome was 30-day all-cause mortality. Cases were randomized to a derivation cohort (DC) and a validation cohort (VC). The predictive score was calculated from a multivariable model performed by logistic regression in the DC and subsequently applied to the VC. The predictive ability of the model was estimated by calculating the area under the ROC curve (AUROC) and the goodness of fit by Hosmer–Lemeshow test and calibration plot. Results Overall, 1435 cases were included in the DC and 715 in the VC. The final multivariable model for mortality in DC included (adjusted OR; 95% CI) age over 55 years (2.10; 1.01–4.36), dementia (2.08; 1.24–3.50), liver disease (1.81; 0.99–3.28), healthcare-associated acquisition (2.29; 1.52–3.44), Pitt index > 3 (3.59; 2.30–5.61), SOFA ≥ 2 (1.66; 1.04–2.64), and urinary tract source (0.37; 0.24–0.56). The predictive score showed an AUROC of 0.78 (95% CI 0.74–0.83) in the DC and 0.78 (95% CI 0.73–0.84) in the VC. Conclusion We developed and internally validated a predictive scoring model to identify patients with E. coli bacteraemia at high and low risk of crude mortality on day 30 of BSI.
The role of mhealth applications in uro-oncology: a systematic review and future directions
(Mdpi Ag, 2025-08-09) Gómez-Luque, Miguel Ángel; Rivero Belenchón, Inés; Congregado-Ruíz, Carmen Belén; Escobar-Rodríguez, Germán Antonio; Delgado-Granados, Francisco Javier; Rivas-González, José Antonio; Medina López, Rafael; Cirugía
Purpose: This systematic review aims to evaluate the utility of mobile health (mHealth) applications in uro-oncology, hereafter referred to as mHealth apps, specifically examining their potential to improve patient care, symptom management, and communication in genitourinary cancer treatment. Methods: Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive systematic review was conducted focusing on mHealth applications for patients with genitourinary cancers. Results: The review analyzed 29 studies, which revealed that mHealth apps demonstrated potential in uro-oncology patient care. Key findings included effective symptom monitoring, enhanced decision support, and improved patient education. The applications were found to be feasible and well-accepted by patients. However, implemen tation challenges were identified, including technical barriers, variations in app quality, and unequal access to digital healthcare technologies. This review systematically categorized mHealth interventions into three functional domains—symptom management, decision support, and personalized care—and identified critical implementation barriers including digital inequity, high risk of bias, and app quality variability. Conclusions: Mobile health applications demonstrate promise in revolutionizing uro-oncology care. Future research should prioritize developing comprehensive applications that address a broader range of urological cancers, enhance patient–clinician communication, and undergo rigorous evaluation. Collaborative efforts among researchers, clinicians, and app developers are crucial to overcome existing limitations and maximize the potential of these innovative healthcare tools.
Outlook on the neuroprotective effect of estrogen
(Editorial Board of Neural Regeneration Research, 2017-11) D'Anglemont De Tassigny, Xavier; Fisiología Médica y Biofísica
Epidemiologic studies often consider gender differences in a particular pathology, and constantly observe variations between men and women. Indeed, a remarkable sexual dimorphism exists in the epidemiology of neurological conditions and brain diseases. Physiologically, males and females differ by their levels of circulating hormones that drive sexual behavioral, as well as endocrine functions. Estrogen is the primary female sex hormonal group that enwraps estradiol, estrone and estriol, and which are the major naturally occurring hormones prevalent in women. Their role in the reproductive function has long been established, although the ubiquitous expression of its receptors (alpha, beta and G protein-coupled, GPR30) presumes a broader spectrum of action. This short review will summarize the current knowledge in estrogen therapy with particular focus on some of the recent work that might lead to new neuroprotective treatments.
Clinical and Demographics Aspects of Foot Angioleiomyomas: Case Reports and Systematic Review
(MDPI, 2025-08-01) Córdoba Fernández, Antonio; Mir-Gil, Joaquín; Díaz-Baena, Carolina; Ballesteros-Mora, Marina; Córdoba-Jiménez, Victoria Eugenia; Castro Méndez, Aurora; Podología; Instituto de Biomedicina de Sevilla (IBIS); CTS589: Avances en Cirugía Podológica; CTS601: Hermes
Background and Clinical Significance: Angioleiomyoma (ALM) is a benign tumor that generally presents as a single lesion and, according to the updated WHO classification, includes the following three histological subtypes: solid (or capillary), cavernous, and venous. Typically, ALMs are described as well-defined nodules in the lower extremities but are unusually located in the acral locations and toes. We summarize two cases of ALM and perform a systematic review to provide foot surgeons with the most up-to-date and useful information on the epidemiological aspects, anatomical distribution, and specific histological subtypes of ALM in the foot. Materials and Methods: A systematic review was carried out according to the criteria of a PICO framework, and a systematic search and data processing were carried out according to the PRISMA guidelines. We analyzed patient demographics, clinical characteristics, diagnostic workup, treatment, and clinical outcomes. Each one of the included articles was independently assessed for methodological quality and risk of bias by an independent evaluator. The risk of bias of the included studies was assessed based on their characteristics. Results: This systematic review included 14 case series with 172 reported cases of ALM. One hundred and seventy-two (18.57%) were cases of ALM located on foot, excluding the ankle region. The female-to-male ratio was 1.48. The most common location was the hindfoot (41.5%), followed by the forefoot (20.2%) and the midfoot (8.9%). In 29.4% of cases, the location of the lesions could not be determined. The most frequent location of the lesions was subcutaneous (69%), followed by subaponeurotic (16.5%) and skin (14.5%) locations. The most frequent histological presentation was the solid histologic subtype (65%), followed by the venous subtype (21%) and the cavernous subtype (14%), respectively. Of the total reported cases of ALM located in foot, 63.1% presented as solid painful lesions. Calcified presentations occurred in 7% of cases, with more than half of the cases located in the hindfoot. Surgical excision was the treatment of choice in the two herein reported cases of solid ALM located in the hindfoot, one of them with a calcified presentation. No recurrence was observed in either case after two and five years of follow-up, respectively. All cases reviewed after surgical excision showed a low recurrence rate with a favorable prognosis regardless of the histological subtype and a very rare tendency toward malignancy. Conclusions: ALMs of the foot present as well-defined, painful nodules in the subcutaneous tissue of middle-aged women. Solid histological subtypes are the most prevalent. Histopathological analysis is usually essential for confirmation. Treatment consists primarily of direct excision, with remarkably low recurrence rates.
Diaphragmatic breathing for referred pain after total laparoscopic hysterectomy: a randomized clinical trial
(Springer, 2025-08-18) Partida Márquez Antonio Luis; Fernández Domínguez, Juan Carlos; Martínez Fernández, José Antonio; Pabón Carrasco, Manuel; Melero Cortes Lidia; Oliva Pascual-Vaca, Ángel; Fisioterapia; Enfermería; Universidad de Sevilla; CTS1050: Cuidados Complejos, Cronicidad y Resultados en Salud; CTS1043: Salud, Fisioterapia y Actividad Física
Background: Referred cervicoscapular pain is common after laparoscopic surgery. This pain has different characteristics from incisional pain and requires a different approach. Method: A blinded, randomized, controlled trial was conducted. Women reporting referred pain with an intensity of 7 points or higher on the visual analogue scale after total laparoscopic hysterectomy (TLH) were randomly assigned to a diaphragmatic breathing group (DBG) or a neck exercise group (NEG). Both groups performed the exercises three times daily, and the usual medical care was maintained. Pain intensity and location were assessed using the McGill questionnaire. Specific self-reported questionnaires were used to assess the evolution of functional disability in the head (HIT-6), shoulder and neck (NDI), or upper limbs (QuickDASH). Follow-up was conducted weekly for 4 weeks after surgery. Results: Seventy-four women (43.7 ± 9,5 years; 26.6 ± 4.9 body mass index) were recruited. The most common area of referred pain was the shoulder and neck (n = 55), followed by the head (n = 48) and upper limbs (n = 14), with four women showing pain in all three areas and thirty-five in two areas. Both groups showed improvement over time in pain intensity and functional disability in all the locations (p < 0,001). However, DBG demonstrated a faster recovery for pain intensity, NDI, and HIT-6 (p < 0,001), while no between-group difference was found for QuickDASH (p > 0,05). No adverse effects were reported for any of the tested interventions. Conclusions: Referred pain in TLH tends to become self-limiting over time, but diaphragmatic breathing exercises resulted in a faster reduction in pain intensity and craniocervical disability when compared with gentle cervical stretching exercises. Thus, abdominodiaphragmatic breathing might be a simple and safe complementary intervention to be taught to patients suffering from referred pain after TLH.
Expression of aquaporins in bronchial tissue and lung parenchyma of patients with chronic obstructive pulmonary disease
(BioMed Central, 2014-05-26) Calero-Acuña, Carmen; López-Campos Bodineau, José Luis; Izquierdo, Lourdes Gómez; Sánchez-Silva, Rocío; López-Villalobos, José Luis; Sáenz-Coronilla, Francisco J.; Echevarría Irusta, Miriam; Fisiología Médica y Biofísica; Cirugía; Medicina
Background Aquaporins AQP1 and AQP5 are highly expressed in the lung. Recent studies have shown that the expression of these proteins may be mechanistically involved in the airway inflammation and in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the expression of AQP1 and AQP5 in the bronchial tissue and the lung parenchyma of patients with COPD and COPD-resistant smokers. Methods Using a case–control design, we selected a group of 15 subjects with COPD and 15 resistant smokers (smokers without COPD) as a control, all of whom were undergoing lung resection surgery due to a lung neoplasm. We studied the expression of AQP1 and AQP5 in the bronchial tissue and the lung parenchyma by means of immunohistochemistry and reverse-transcription real-time polymerase chain reaction. Tissue expression of AQP1 and AQP5 was semi-quantitatively assessed in terms of intensity and expression by immunohistochemistry using a 4-point scale ranging from 0 (none) to 3 (maximum). Results There were no significant differences in gene expression between COPD patients and resistant smokers both in the bronchial tissue and in the lung parenchyma. However, AQP1 gene expression was 2.41-fold higher in the parenchyma of smokers with COPD compared to controls, whereas the AQP5 gene showed the opposite pattern, with a 7.75-fold higher expression in the bronchus of smokers with COPD compared with controls. AQP1 and AQP5 proteins were preferentially expressed in endothelial cells, showing a higher intensity for AQP1 (66.7% of cases with an intensity of 3, and 93.3% of subjects with an extension of 3 among patients with COPD). Subtle interstitial disease was associated with type II pneumocyte hyperplasia and an increased expression of AQP1. Conclusions This study provides pilot observations on the differences in AQP1 and AQP5 expression between COPD patients and COPD-resistant smokers. Our findings suggest a potential role for AQP1 in the pathogenesis of COPD.
Essential Role of Protein-tyrosine Phosphatase 1B in the Modulation of Insulin Signaling by Acetaminophen in Hepatocytes
(Ed. Lightbinders, Inc., 2014-09-09) Mobasher, Maysa Ahmed; Toro-Martín, Juan de; González-Rodríguez, Águeda; Ramos, Sonia; Letzig, Lynda G.; Muntané Relat, Jordi; Valverde, Ángela M.; Fisiología Médica y Biofísica; Centro de Investigacion Biomédica en Red de Enfermedades Hepáticas y Digestivas; Centro de Investigacion Biomédica en Red de Enfermedades Hepáticas y Digestivas; Comunidad Autónoma de Madrid; European Foundation for the Study of Diabetes; Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (MINECO). España
Many drugs are associated with the development of glucose intolerance or deterioration in glycemic control in patients with pre-existing diabetes. We have evaluated the cross-talk between signaling pathways activated by acetaminophen (APAP) and insulin signaling in hepatocytes with or without expression of the protein-tyrosine phosphatase 1B (PTP1B) and in wild-type and PTP1B-deficient mice chronically treated with APAP. Human primary hepatocytes, Huh7 hepatoma cells with silenced PTP1B, mouse hepatocytes from wild-type and PTP1B-deficient mice, and a mouse model of chronic APAP treatment were used to examine the mechanisms involving PTP1B in the effects of APAP on glucose homeostasis and hepatic insulin signaling. In APAP-treated human hepatocytes at concentrations that did not induce death, phosphorylation of JNK and PTP1B expression and enzymatic activity were increased. APAP pretreatment inhibited activation of the early steps of insulin signaling and decreased Akt phosphorylation. The effects of APAP in insulin signaling were prevented by suramin, a PTP1B inhibitor, or rosiglitazone that decreased PTP1B levels. Likewise, PTP1B deficiency in human or mouse hepatocytes protected against APAP-mediated impairment in insulin signaling. These signaling pathways were modulated in mice with chronic APAP treatment, resulting in protection against APAP-mediated hepatic insulin resistance and alterations in islet alpha/beta cell ratio in PTP1B−/− mice. Our results demonstrate negative cross-talk between signaling pathways triggered by APAP and insulin signaling in hepatocytes, which is in part mediated by PTP1B. Moreover, our in vivo data suggest that chronic use of APAP may be associated with insulin resistance in the liver.
TP5H/KCTD2 locus is associated with Alzheimer's disease risk
(Nature Pub. Group, 2014) Boada, M.; Antúnez, C.; Ramírez Lorca, Reposo; DeStefano, A. L.; González-Pérez, A.; Gayán, J.; Real Navarrete, Luis Miguel; Seshadri, S.; Ruiz, A.; Fisiología Médica y Biofísica; Bioquímica Médica y Biología Molecular e Inmunología; Agencia IDEA; Alzheimer\'s Association; Alzheimer\'s Disease Neuroimaging Initiative (ADNI); Alzheimer\'s Drug Discovery Foundation; CIBER de Diabetes y Enfermedades Metabolicas Asociadas; Corporación Tecnológica de Andalucía; Ministerio de Educación. España; Ministerio de Ciencia e Innovación; National Institutes of Health Grant; NIH
To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer’s disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10−6 were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10−7 in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10−9). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

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