Ciencias de la Salud

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1–42 b -Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death
(Nature Publishing Group, 2013) Manterola, L.; Hernando Rodríguez, M.; Ruiz, A.; Jiménez Muñoz, Sebastián; Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular
1–42 b -Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death L Manterola 1,12 , M Hernando-Rodr ı ́ guez 2,12 , A Ruiz 3,4 , A Apraiz 5 , O Arrizabalaga 5 , L Vello ́ n 6 , E Alberdi 3,4 , F Cavaliere 3,4 , HM Lacerda 7 , S Jimenez 8,9 , LA Parada 10 , C Matute 3,4 and JL Zugaza 4,5,11 1–42 b -Amyloid (A b 1–42 ) peptide is a key molecule involved in the development of Alzheimer’s disease. Some of its effects are manifested at the neuronal morphological level. These morphological changes involve loss of neurites due to cytoskeleton alterations. However, the mechanism of A b 1–42 peptide activation of the neurodegenerative program is still poorly understood. Here, A b 1–42 peptide-induced transduction of cellular death signals through the phosphatidylinositol 3-kinase (PI3K)/ phosphoinositol-dependent kinase (PDK)/novel protein kinase C (nPKC)/Rac 1 axis is described. Furthermore, pharmacological inhibition of PDK1 and nPKC activities blocks Rac 1 activation and neuronal cell death. Our results provide insights into an unsuspected connection between PDK1, nPKCs and Rac 1 in the same signal-transduction pathway and points out nPKCs and Rac 1 as potential therapeutic targets to block the toxic effects of A b 1–42 peptide in neurons.
100 años de historia de la Odontología Sevillana (del “curandero-sacamuelas” al médico estomatólogo)
(1974-02-04) García Perla, Álvaro; Sánchez de la Cuesta y Gutiérrez, Gabriel; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología
Hasta que en 1848 fueron originadas las Subdelegaciones de Sanidad Interior del Reino, con el fin primordial de evitar que cualquier persona ejerciese el todo o parte de la ciencia de curar sin el correspondiente título, el arte de dentista era ejercido en Sevilla, al igual que en todo el territorio nacional, por barberos y curanderos. Había algunos sangradores titulados que ejercían como dentistas, pero salvo estos, la mayoría eran barberos y curanderos a quienes popularmente se llamaba sacamuelas. Los textos quirúrgicos de la época dicen que los cirujanos hacían sangrías, aplicaban ventosas, vejigatorios, cauterios y sanguijuelas pero no hablan del cuidado o extracción de dientes, lo que se dejaba como ocupación de topiqueros y barberos. De todos modos como ya decíamos había algunos sangradores que se ocupaban del arte dental, por ello vamos a dedicarle el primer capítulo. CONCLUSIONES: 1. El enorme avance de la Odontología, que en menos de un siglo ha saltado de ser un oficio propio de personas incultas a ser una especialidad de la medicina con un plan de estudios que ha sido el primero claramente ordenado por la vigente ley de especialidades médicas. 2. La odontología sevillana, ya desde finales del XIX, ha gozado de gran prestigio dentro y fuera de España, que le ha sido reconocido al considerársela como cuna de la odontología española. 3. Fue un dentista sevillano el precursor de la moderna Estomatología como concepto superior al de Odontología, utilizando esta titulación mucho antes de ser reconocida oficialmente. Este dentista y médico fue Don Manuel Valenzuela Rincón. 4. Corresponden a los dentistas sevillanos los primeros intentos de crear asociaciones odontológicas en España, siendo en esta provincia donde se fundó el primer colegio de dentistas. 5. Don Manuel Valenzuela Rincón ha sido el primer dentista español que ha ocupado un sillón de Académico de Medicina. 6. En Sevilla se han publicado numerosas obras odontológicas. 7. El primer gabinete odontológico municipal se inauguró en Sevilla. 8. Una gran preocupación por acercar los beneficios de los tratamientos dentales a las clases humildes se aprecia a lo largo de estos cien años de Historia de la Odontología Sevillana. 9. Ya antes de que las leyes exigieran una formación universitaria, varios dentistas sevillanos se distinguieron por alcanzar un gran nivel cultural y social. 10. Sevilla ha ejercido una gran atracción sobre dentistas extranjeros lo mismo que sobre artistas, comerciantes y otros profesionales, siendo numerosos lo que la eligieron como lugar ideal para su actividad profesional.
104-week safety and effectiveness of dupilumab in the treatment of severe atopic dermatitis. The experience of 5 reference dermatology units in Spain
(Sociedade Brasileira de Dermatologia. Elsevier, 2021-11) Pereyra-Rodríguez, José-Juan; Domínguez Cruz, Javier; Armario Hita, José Carlos; Ruíz Villaverde, Ricardo; Universidad de Sevilla. Departamento de Medicina
Atopic Dermatitis (AD) is a multifactorial disease resulting from the interaction of genetic predisposition, environmental triggers, disruption of skin barrier function, and type 2 immune dysregulation. Management of mild forms of AD includes the use of emollients, topical corticosteroids or calcineurin inhibitors, and phototherapy, while systemic immunosuppressive agents such as oral corticosteroids and Cyclosporine A (CsA) are reserved for severe refractory cases.1 Nevertheless, severe cases are usually not adequately controlled with any of these therapies, requiring a further step to reach clinical control.2 Recently, FDA and EMA have authorized Dupilumab, a treatment targeting Th2 cytokines Il-4 and Il-13 which has shown to be effective to control the signs and symptoms of AD. Real-world experience with Dupilumab shows a similar effectivity as compared to randomized clinical trials, but it is yet to know how this drug will perform in the long term in routine medical practice
10Kin1day: A Bottom-Up Neuroimaging Initiative
(Frontiers Research Foundation, 2019-05-09) Heuvel, Martijn P. van den; Scholtens, Lianne H.; Burgh, Hannelore K. van der; Agosta, Federica; Alloza, Clara; Arango, Celso; Crespo Facorro, Benedicto; De Lange, Siemon C.; Universidad de Sevilla. Departamento de Psiquiatría
We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.
168 intervenciones de desprendimiento de retina: la exploración clínica en la indicación quirúrgica y en los resultados
(1972-05-10) Ortiz García, Ramón; Piñero Carrión, Antonio; Universidad de Sevilla. Departamento de Medicina
Históricamente, el tratamiento del Desprendimiento de Retina puede ser dividido en dos épocas: la anterior a Gonin y otra después de Gonin. En los años en que Gonin (1925-1928) hablo de una técnica operatoria para la oclusión de los desgarros y agujeros retinianos por la formación de una adhesión coriorretiniana, había poca o ninguna esperanza de tratamiento feliz. Como suele ocurrir en estas circunstacnias, un gran número de métodos ha sido propuesto; cada uno tenía su época de moda y todos pasaban por fases alternativas de entusiasmo y desilusión. Los métodos de tratamiento médico consistían fundamentalmente en el reposo. Después que fue invocado originalmente por Stellwag (1861) y Donders (1866) se sabe que esto era completamente esencial en el tratamiento del Desprendimiento de Retina, fuese o no acompañado de medidas quirúrgicas; y por reposo se entiende la inmovilidad tan completa como sea posible (de los ojos y del cuerpo), admitiendo que no es tarea fácil, especialmente cuando se prolonga durante un período dilatado de tiempo. La posición de decúbito era importante. Inmovilidad absoluta con la cabeza entre bolsas de arena era la posición favorita adoptada. Si era posible se elegía una posición adecuada en dependencia con la localización del desprendimiento: Si era inferior se adoptaba la posición de Fowler; si era lateral, el enfermo se tendía hacia ese lado; si era posterior, se tendía el paciente en posición de Trandelenburg. La inmovilidad de los ojos era considerada de mayor importancia que la inmovilidad del cuerpo, y se consideraba esencial mantener oclusión bilateral. Todo esto era favorecido manteniendo constantemente los ojos atropinizados. Oclusión Compresiva, durante varias semanas combinadas con reposo fue el tratamiento invocada por Samelsohn (1875), sugerencia que fue seguida por mucos clínicos con diversos grados de variaciones, y superando las dificultades mecánicas de aplicar una presión uniforme al globo, por el uso de un molde plástico que se adapta al ojo y los rebordes orbitarios, distintos para cada individuo. Algunas veces se añadía a esto una dieta que favoreciese la absorción del líquido subrretiniano; Marx habla en 1922 de una dieta exenta de sal. Diaforesis con baños de aire caliente. Todo esto se encuentra ahora en desuso. Métodos quirúrgicos de tratamiento. Mientras muchos cayeron en desuso por mucho tiempo, es significativo que otros muchos han sido últimamente actualizados por favorecer la formación de adherencias corio-rretinianas. 1) La evacuación de líquido subrretiniano era intentada para establecer un drenaje temporal o permanente. a) El drenaje temporal fue ensayado primero por James Ware (1805) que llevó a cabo una punctura escleral con un cuchillete; más tarde, von Graefe (1863) extendió esta intervención. El termo-cauterio como sistema de punctura fue introducido por G. Martín (1881) y por Wecker y Masselon. b) El drenaje permanente fue muy empleado especialmente en el periodo inicial por Wecker (1872). La introducción de la trepanación de Elliot para la operación de glaucoma renovó desterradas porque la consecuencia invariable era la infección que llevaba a la pérdida del ojo. c) Las inyecciones subconjuntivales han sido invocadas como un sistema de drenaje del líquido subrretiniano por efecto de la presión osmótica. A este propósito se sugirió por Grossmann (1883) y luego se popularizó por Mellinger (1896) el uso de soluciones salinas hipertónicas; numerosos autores han continuado el uso de estas soluciones variando la concentración desde el 1 al 30%; otros han efectuado las inyecciones debajo de la cápsula de Tenon. El cloruro sódico era combinado con oxicianuro de mercurio por Ramsay (1906) y con Dionina por Tristanio (1922) para hacer la reacción más intensa. 2) La formación de adhesión coriorretiniana sin especial referencia al cierre de un agujero retiniano como se practicaba originariamente, era igualmente ineficaz. Se han intentado todo tipo de “retinopexia”… cauterización superficial, punctura con el cauterio; aplicación del cauterio directamente sobre la coroides después de disecar un colgajo de esclera. 3) La ruptura de las bandas de tracción del vítreo fue intentada ya por Deutschmann (1895). 4) Una reducción de la capacidad del ojo con intención de aproximar la retina desprendida a la coroides fue ya intentada por Muller en 1903, basándose en la teoría de von Graefe de que la causa de un Desprendimiento de Retina era un aumento de volumen del ojo en la miopía. La operación es modificada por von Blaskovics (1912); Török (1920) escribe un trabajo de 50 operaciones de este tipo. 5) La elevación de la presión intraocular fue propuesta con la esperanza de que la retina por este sistema se reaplicaría, siendo la técnica más popular de este tipo la llevada a cabo por Lagrange en 1912: después de disecar un colgajo de conjuntiva junto al limbo, se hacia un triple fila de cauterizaciones; posteriormente se ponía una inyección en la cámara anterior de alguna substancia que saliese con dificultad (vítreo, glicerina, gelatina, etc…). 6) El aumento del volumen de vítreo con el fin de empujar directamente la retina hacia atrás sobre la coroides fue intentado con inyecciones de diversas substancias en la cavidad del vítreo (vítreo de conejo, líquido cerebro-espinal, líquido subrretianiano, parafina, gelatina, solución de proteínas, aire, etc…). 7) la técnica heroica de suturar la misma retina fue practicada por E. Meyer (1871), mientras que el intento de suturar la retina a la coroides fue hecho por Galezowski (1890). La demostración desde Gonin de que la causa de un Desprendimiento de Retina asociado con un agujero retiniano depende de la obliteración de la perforación por el “sellado” a la coroides, ha revolucionado las técnicas quirúrgicas por completo: 1) Obliteración del desgarro por transfixión, sugerida por Gonin (1919-1921). 2) Cauterización química de la coroides, utilizada por Guist (1931). Adopta la técnica de Schoeler (1889) y cauterizada la coroides por contacto con una barra de potasa caústica en algunas zonas que han sido previamente expuestas por trepanación de la esclera. 3) Diatermia: La cauterización de la superficie escleral sobre la región del agujero en la retina provoca una reacción exudativa coroidea con la subsiguiente evacuación del líquido subrretiniano. Es descrita y practicada con éxito por Weve (1930) y por Larsson (1930-1932). Safär (1932) en su técnica de puncturas múltiples simultáneas, rodea el desgarro de la retina con una barrera de aplicaciones diatérmicas. La técnica heroica de diatermia intraocular para cerrar un agujero de la retina muscular o próximo a ella, era practicada por Dellaporta (1954) introduciendo por la pars plana una aguja aislada excepto por su punta. 4) En un intento de conseguir una acción más delicada y menos traumática de “sellar” el agujero, se recurrió a la electrolisis. 5) La fotocoagulación de un agujerp retiniano fue intentada primero por la acción de la luz soplar produciendo una quemadura en la retina, cuanto la lesión estaba en el polo posterior (Morón Salas y Meyer Schwickerath). 6) La Criocirugía como medio de provocar una coroiditis adhesiva fue introducida por Deutshmann (1933) y por Bietti (1933-34). 7) El acortamiento de la esclera como medio de reducir el volumen del globo es sugerido inicialmente por L. Müller (1903) e impulsado por Lindner (1934-1949). 8) La identación o bucle escleral como una intervención de cerclaje en un intento de acercar la retina a la coroides en la región del desgarro, mientras que el cierre y adhesión se intentaba por otros medios (diatermia, fotocoagulación etc…) es introducida por Jess (1937). La idea fue satisfactoriamente explotada por Custodis (1951-56), quien suturó un implante de poliviol a la esclera con este propósito, siendo asegurada la adherencia coriorretiniana por la diatermia. Schepens (1953-54) en su “scleral bucklin” colocaba un tubo de polietileno en el surco de una esclerotomía lamelar. Posteriormente Schepens y sus colaboradores (1960) y Lincoff y sus colegas (1965) usan la esponja de silicona. El sistema más drástico introducido por Schepens (1957) es el de su tubo circular de polietileno en la región ecuatorial, que ha sido substituido últimamente por la goma de silicona por provocar menos infecciones. Esta operación de cerclaje estaba muy simplificada por Grignolo (1956) y Arruga (1957-1958), que utilizaban el Supramid alrededor del globo próximo al ecuador. 9) La aproximación de la coroides a la retina ha sido un nuevo intento técnico: R. Smith (1952) inyectaba aire en el espacio supracoroidea; Strampelli Bauer (1966) inyectaba fibrina coagulada por la adición de protombina. 10) Cibis (1965) cortaba las bridas y membranas de vítreo en casos de retracción masiva con pliegues fijos de la retina.
1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
(Springer Nature, 2021) Sønderby, Ida E.; van der Meer, Dennis; Moreau, Clara; Kaufmann, Tobias; Walters, G. Bragi; Ellegaard, Maria; Crespo Facorro, Benedicto; Ophoff, Roel A.; Universidad de Sevilla. Departamento de Psiquiatría; Universidad de Sevilla. CTS1086: Psiquiatría Traslacional
Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function
2-Alquiltioderivados de 1,1-Dimetoxietano: síntesis y análisis conformacional
(1986-06-26) Campos Ramos, Ángel Luis; Alcudia González, Felipe; Zorrilla Benítez, F.; Universidad de Sevilla. Departamento de Química Orgánica y Farmacéutica
2-hydroxyglutarate metabolism is altered in an in vivo model of LPS induced endotoxemia
(Frontiers Media, 2020) Fitzpatrick, S. F.; Lambden, S.; Macías, David; Puthucheary, Z.; Pietsch, S.; Mendil, L.; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Wellcome Trust
The metabolic response to endotoxemia closely mimics those seen in sepsis. Here, we show that the urinary excretion of the metabolite 2-hydroxyglutarate (2HG) is dramatically suppressed following lipopolysaccharide (LPS) administration in vivo, and in human septic patients. We further show that enhanced activation of the enzymes responsible for 2-HG degradation, D- and L-2-HGDH, underlie this effect. To determine the role of supplementation with 2HG, we carried out co-administration of LPS and 2HG. This co-administration in mice modulates a number of aspects of physiological responses to LPS, and in particular, protects against LPS-induced hypothermia. Our results identify a novel role for 2HG in endotoxemia pathophysiology, and suggest that this metabolite may be a critical diagnostic and therapeutic target for sepsis. © Copyright © 2020 Fitzpatrick, Lambden, Macias, Puthucheary, Pietsch, Mendil, McPhail and Johnson.
2-years retrospective observational case-control study on survival and marginal bone loss of implants in patients with hereditary coagulopathies
(Medicina oral S.L, 2023) Pérez Fierro, Manuel Luis; Castellanos Cosano, Lizett; Hueto-Madrid, Juan Antonio; López Jiménez, Julián; Núñez Vázquez, Ramiro José; Machuca-Portillo, Guillermo; Universidad de Sevilla. Departamento de Estomatología; Instituto de Biomedicina de Sevilla (IBIS)
Background: Evaluating 2-years implant loss and marginal bone loss in patients with hereditary coagulopathies, comparing with a healthy control group. Material and Methods: 37 implants in 13 patients (17 haemophilia A, 20 Von-Willebrand disease) versus 26 im plants in 13 healthy patients. Data measured through Lagervall-Jansson index (after surgery, at prosthetic loading, at 2 years). Statistics: Chi-square, Haberman’s, ANOVA, Mann-Whitney-U. Significance p<0.05. Results: Haemorrhagic accidents in 2 coagulopathies patients (non-statistical differences). Hereditary coagulopa thies patients suffered more hepatitis (p<0.05), HIV (p<0.05) and less previous periodontitis (p<0.01). Non-sta tistical differences in marginal bone loss among groups. 2 implants were lost in the hereditary coagulopathies and none in the control group (non-statistical differences). Hereditary coagulopathies patients had longer (p<0.001), and narrower implants (p<0.05) placed. 43.2% external prosthetic connection in hereditary coagulopathies pa tients (p<0.001); change of prosthetic platform more frequent in control group (p<0.05). 2 implants lost: external connection (p<0.05). Survival rate 96.8% (hereditary coagulopathies 94.6%, control group 100%). Conclusions: Implant and marginal bone loss at 2 years is similar in patients with hereditary coagulopathies and control group. Precautions should be taken on the treatment for hereditary coagulopathies patients, through prior haematological protocol. Implant loss only occurred in in a patient with Von-Willebrand´s disease.
2018 consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary
(Springer, 2018) Losa, F.; Iglesias, L.; Pane, M.; Sanz, J.; Nieto, B.; Fuste, V.; Cruz Merino, Luis de la; Concha, A.; Balana, C.; Matias-Guiu, X.; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. CTS151: Bioquímica médica.
Cancer of unknown primary (CUP) is defned as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They difer from other primary tumours in their biological features and how they spread, which means that they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, CUP can account for 2–9% of all cancer patients, mostly 60–75 years old. This article reviews the main clinical, pathological, and molecular studies conducted to analyse and determine the origin of CUP.The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed.
267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation
(Oxford University Press, 2016) Dopazo, Joaquín; Amadoz, Alicia; Bleda, Marta; Garcia Alonso, Luz; Daub, Josephine T.; Antiñolo Gil, Guillermo; Bhattacharya, Shomi S.; Universidad de Sevilla. Departamento de Cirugía; Ministerio de Economía y Competitividad (MINECO). España
Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalog of local variability motivated the whole-exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one-third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including ∼10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes, and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies to distinguish real disease associations from population-specific polymorphisms.
2D ultrasound diagnosis of middle compartment prolapse: a multicenter study
(AME PUBL CO, 2022) García Mejido, José Antonio; González-Diaz, Enrique; Ortega, Ismael; Borrero González, Carlota; Fernández Palacín, Ana; Sáinz Bueno, José Antonio; Universidad de Sevilla. Departamento de Cirugía; Universidad de Sevilla. Departamento de Medicina Preventiva y Salud Pública
Background: Recently, a specific methodology has been defined, using transperineal ultrasound, for the differential diagnosis of middle compartment prolapse [uterine prolapse (UP) or cervical elongation (CE) without UP] based on the difference in the pubis-uterine fundus distance at rest and with the Valsalva maneuver, with a cutoff point of 15 mm. The objective of this study was to validate the diagnostic utility of a ≥15 mm difference between the pubis-uterine fundus distance at rest and during the Valsalva maneuver to define UP in a multicenter study. Methods: This prospective multicenter observational study included 94 patients (UP =51; CE without UP =43). The clinical examination was based on the International Continence Society Pelvic Organ Prolapse Quantification (ICS POP-Q) system for assessing pelvic organ prolapse (POP) and patients were candidates for corrective surgery of the middle compartment of the pelvic floor (correction of UP or CE without UP). The ultrasound study was performed by transperineal ultrasound (B-mode) with the patient undergoing dorsal lithotomy. The distance evaluation was performed in relation to the posteroinferior pubic margin in the midsagittal plane, with reference to the uterine fundus (established as the most distal hyperechogenic) line from the pubis to the uterine fundus at rest and with the Valsalva maneuver. We defined UP detected using UP as a difference of ≥15 mm between the pubis-uterine fundus distance at rest and with the Valsalva maneuver. Agreement between the clinical and ultrasound diagnosis of UP was assessed using the Cohen kappa coefficient of agreement and its 95% CIs. Results: The ultrasound diagnosis of global UP at the three centers showed very good agreement, with a kappa index of 0.826 (0.71, 0.94). The agreement of ultrasound with the clinical diagnosis of UP using the ICS POP-Q system was very good for each of the hospitals [Hospital 1: 0.814 (0.64, 0.98), Hospital 2: 0.847 (0.64, 1) and Hospital 3: 0.824 (0.59, 1)]. Conclusions: A difference of ≥15 mm between the pubis-uterine fundus distance at rest and during the Valsalva maneuver for the diagnosis of UP presents very good agreement with the results of clinical evaluation with the ICS POP-Q system.
3D printed drug delivery systems based on natural products
(Multidisciplinary Digital Publishing Institute (MDPI), 2020) Aguilar de Leyva, Mercedes Ángela; Linares Blasco, Vicente; Casas Delgado, Marta; Caraballo Rodríguez, Isidoro; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica
In the last few years, the employment of 3D printing technologies in the manufacture of drug delivery systems has increased, due to the advantages that they offer for personalized medicine. Thus, the possibility of producing sophisticated and tailor-made structures loaded with drugs intended for tissue engineering and optimizing the drug dose is particularly interesting in the case of pediatric and geriatric population. Natural products provide a wide range of advantages for their application as pharmaceutical excipients, as well as in scaffolds purposed for tissue engineering prepared by 3D printing technologies. The ability of biopolymers to form hydrogels is exploited in pressure assisted microsyringe and inkjet techniques, resulting in suitable porous matrices for the printing of living cells, as well as thermolabile drugs. In this review, we analyze the 3D printing technologies employed for the preparation of drug delivery systems based on natural products. Moreover, the 3D printed drug delivery systems containing natural products are described, highlighting the advantages offered by these types of excipients.
3D Printed Fractal-like Structures with High Percentage of Drug for Zero-Order Colonic Release
(MDPI, 2022) Linares Blasco, Vicente; Aguilar de Leyva, Mercedes Ángela; Casas Delgado, Marta; Caraballo Rodríguez, Isidoro; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Ministerio de Ciencia e Innovación (MICIN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Junta de Andalucía
Colonic drug delivery of drugs is an area of great interest due to the need to treat high prevalence colonic local diseases as well as systemic conditions that may benefit from the advantages associated to this route of drug administration. In the last decade, the use of 3D printing technologies has expanded, offering the possibility of preparing personalized medicines in small batches directly at the point of care. The aim of this work is to design a high drug loaded 3D printed system prepared by a combination of Fused Deposition Modelling (FDM) and Injection Volume Filling (IVF) techniques intended for zero-order colonic drug release. For this purpose, different batches of binary and ternary filaments based on the thermoplastic polyurethane Tecoflex EG-72D (TPU), theophylline anhydrous (AT) as model drug, and magnesium stearate as lubricant have been developed and characterized. Filaments with the highest drug load and the best rheological properties were selected for the manufacture of a printed fractal-like structure based on multiple toroids. This design was proposed to provide high surface area, leading to increased drug release and water uptake in the colonic region. This structure was 3D printed by FDM and then coated in a unique step by IVF technology using the enteric polymer DrugCoat S 12.5. This way, an additional coating process is avoided, reducing costs and production time. Studies of drug release confirmed the ability of the structures to provide a five-hour period of constant drug delivery in the colonic region.
3D printed systems for colon-specific delivery of camptothecin-loaded chitosan micelles
(Elsevier, 2021-10) Almeida, Andreia; Linares Blasco, Vicente; Mora Castaño, Gloria; Casas Delgado, Marta; Caraballo Rodríguez, Isidoro; Sarmento, Bruno; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Ministério da Ciência, Tecnologia e Ensino Superior. Portugal; Plataforma Portuguesa de Bioimagem; Ministerio de Ciencia, Innovación y Universidades (MICINN). España
The use of 3D printing technology in the manufacturing of drug delivery systems has expanded and benefit of a customized care. The ability to create tailor-made structures filled with drugs/delivery systems with suitable drug dosage is especially appealing in the field of nanomedicine. In this work, chitosan-based polymeric micelles loaded with camptothecin (CPT) were incorporated into 3D printing systems (printfills) sealed with an enteric layer, aiming to protect the nanosystems from the harsh environment of the gastrointestinal tract (GIT). Polymeric micelles and printfills were fully characterized and, a simulated digestion of the 3D systems upon an oral administration was performed. The printfills maintained intact at the simulated gastric pH of the stomach and, only released the micelles at the colonic pH. From there, the dissolution media was used to recreate the intestinal absorption and, chitosan micelles showed a significant increase of the CPT permeability compared to the free drug, reaching an apparent permeability coefficient (Papp) of around 9×10-6 cm/s in a 3D intestinal cell-based model. The combination of 3D printing with nanotechnology appears to have great potential for the colon-specific release of polymeric micelles, thereby increasing intestinal absorption while protecting the system/drug from degradation throughout the GIT.
3D Printing DirePowder Extrusion in the Production of Drug Delivery Systems: State of the Art and Future Perspectives
(MDPI, 2024-03-22) Aguilar de Leyva, Mercedes Ángela; Casas Delgado, Marta; Ferrero Rodríguez, Carmen; Linares Blasco, Vicente; Caraballo Rodríguez, Isidoro; Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica; Junta de Andalucía; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
The production of tailored, on-demand drug delivery systems has gained attention in pharmaceutical development over the last few years, thanks to the application of 3D printing technology in the pharmaceutical field. Recently, direct powder extrusion (DPE) has emerged among the extrusion-based additive manufacturing techniques. It is a one-step procedure that allows the direct processing of powdered formulations. The aim of this systematic literature review is to analyze the production of drug delivery systems using DPE. A total of 27 articles have been identified through scientific databases (Scopus, PubMed, and ScienceDirect). The main characteristics of the three types of 3D printers based on DPE have been discussed. The selection of polymers and auxiliary excipients, as well as the flowability of the powder mixture, the rheological properties of the molten material, and the printing temperatures have been identified as the main critical parameters for successful printing. A wide range of drug delivery systems with varied geometries and different drug release profiles intended for oral, buccal, parenteral, and transdermal routes have been produced. The ability of this technique to manufacture personalized, on-demand drug delivery systems has been proven. For all these reasons, its implementation in hospital settings in the near future seems promising.
3D VMAT Verification Based on Monte Carlo Log File Simulation with Experimental Feedback from Film Dosimetry.
(Public Library Of Science., 2016-11-21) Pereira Barbeiro, Ana Rita; Ureba Sánchez, Ana María; Baeza, José Antonio; Linares, R.; Perucha, M.A; Jiménez Ortega, Elisa Eugenia; Mateos Pérez, Juan Carlos; Leal Plaza, Antonio; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica.; Universidad de Sevilla. BIO236: Biofísica celular.; Universidad de Sevilla. CTS233: Física médica.
A model based on a specific phantom, called QuAArC, has been designed for the evaluation of planning and verification systems of complex radiotherapy treatments, such as volumetric modulated arc therapy (VMAT). This model uses the high accuracy provided by the Monte Carlo (MC) simulation of log files and allows the experimental feedback from the high spatial resolution of films hosted in QuAArC. This cylindrical phantom was specifically designed to host films rolled at different radial distances able to take into account the entrance fluence and the 3D dose distribution. Ionization chamber measurements are also included in the feedback process for absolute dose considerations. In this way, automated MC simulation of treatment log files is implemented to calculate the actual delivery geometries, while the monitor units are experimentally adjusted to reconstruct the dose-volume histogram (DVH) on the patient CT. Prostate and head and neck clinical cases, previously planned with Monaco and Pinnacle treatment planning systems and verified with two different commercial systems (Delta4 and COMPASS), were selected in order to test operational feasibility of the proposed model. The proper operation of the feedback procedure was proved through the achieved high agreement between reconstructed dose distributions and the film measure- ments (global gamma passing rates > 90% for the 2%/2 mm criteria). The necessary discre- tization level of the log file for dose calculation and the potential mismatching between calculated control points and detection grid in the verification process were discussed. Besides the effect of dose calculation accuracy of the analytic algorithm implemented in treatment planning systems for a dynamic technique, it was discussed the importance of the detection density level and its location in VMAT specific phantom to obtain a more reliable DVH in the patient CT. The proposed model also showed enough robustness and efficiency to be considered as a pre-treatment VMAT verification system.
4-Nitrofenilhidrazonas de peridin-aldehidos como indicadores colorimétricos del pH
(1985) Cameán Fernández, Ana María; Guzmán Chozas, Matías; ; Universidad de Sevilla. Departamento de Nutrición y Bromatología, Toxicología y Medicina Legal
5-Aza-2'-deoxycytidine causes replication lesions that require Fanconi anemia-dependent homologous recombination for repair
(Oxford University Press, 2013) Orta Vázquez, Manuel Luis; Calderón Montaño, José Manuel; Domínguez García, Inmaculada; Pastor Carrillo, Nuria María; Burgos Morón, Estefanía; López Lázaro, Miguel; Cortés, Felipe; Mateos Cordero, Santiago; Helleday, Thomas; Universidad de Sevilla. Departamento de Biología Celular; Universidad de Sevilla. Departamento de Farmacología; Ministerio de Educación y Ciencia (MEC). España; Junta de Andalucía
5-Aza-2'-deoxycytidine (5-azadC) is a DNA methyltransferase (DNMT) inhibitor increasingly used in treatments of hematological diseases and works by being incorporated into DNA and trapping DNMT. It is unclear what DNA lesions are caused by 5-azadC and if such are substrates for DNA repair. Here, we identify that 5-azadC induces DNA damage as measured by γ-H2AX and 53BP1 foci. Furthermore, 5-azadC induces radial chromosomes and chromatid breaks that depend on active replication, which altogether suggest that trapped DNMT collapses oncoming replication forks into double-strand breaks. We demonstrate that RAD51-mediated homologous recombination (HR) is activated to repair 5-azadC collapsed replication forks. Fanconi anemia (FA) is a rare autosomal recessive disorder, and deaths are often associated with leukemia. Here, we show that FANCG-deficient cells fail to trigger HR-mediated repair of 5-azadC-induced lesions, leading to accumulation of chromatid breaks and inter-chromosomal radial fusions as well as hypersensitivity to the cytotoxic effects of 5-azadC. These data demonstrate that the FA pathway is important to protect from 5-azadC-induced toxicity. Altogether, our data demonstrate that cytotoxicity of the epigenetic drug 5-azadC can, at least in part, be explained by collapsed replication forks requiring FA-mediated HR for repair.
5-year outcomes with cobimetinib plus vemurafenib in BRAFV600 mutation⇓positive advanced melanoma: extended follow-up of the coBRIM study
(American Association for Cancer Research, 2021) Ascierto, Paolo Antonio; Dreno, Brigitte; Larkin, James; Ribas, Antoni; Cruz Merino, Luis de la; McArthur, Grant A.; Universidad de Sevilla. Departamento de Medicina
Purpose: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation–positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized. Patients and Methods: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1–21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily). Results: 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3–28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0–19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5–14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6–7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports. Conclusions: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation–positive advanced melanoma.

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