Levator Ani Avulsion in Ultrasound Increases Recurrence in Sacrospinous Fixation.

IMPORTANCE: Pelvic floor translabial ultrasound (TLUS) can identify levator ani muscle (LAM) avulsion and ballooning, which some studies have shown to be possible risk factors for prolapse recurrence. Our group uses TLUS to counsel patients preoperatively. If any of these risk factors exist, we offer sacrocolpopexy over vaginal repair. However, some patients, even though they have these possible risk factors, prefer to undergo vaginal surgery. OBJECTIVE: The objective of this study was to determine if TLUS LAM avulsion and/or ballooning are risk factors for composite outcome recurrence in patients undergoing sacrospinous ligament fixation for pelvic organ prolapse. STUDY DESIGN: This was a retrospective observational study. All patients with vaginal apical repair with sacrospinous ligament fixation with preoperative TLUS were included. Demographics, clinical characteristics, and follow-up were analyzed. Multivariable logistic regression analysis was performed for composite outcome that included TLUS risk factors, age, Pelvic Organ Prolapse Quantification System measurements and stage, and variables with P < 0.1 in the univariate analysis. RESULTS: Eighty-two patients were included. All patients had symptomatic vaginal bulge; 65.4% had stage III prolapse. Concomitant hysterectomy was performed in 54.3%. Median follow-up was 20 months (interquartile range, 8-35 months); 19.8% had LAM avulsion, and 43.2% had ballooning. Anatomic recurrence rate was 23.5%, symptomatic was 22.2%, and reoperation was 1.2%. The composite recurrence rate was 29.6%. In the multivariable logistic regression analysis, unilateral/bilateral avulsion in TLUS was found to be a significant risk factor for composite outcome with an odds ratio of 4.33 (confidence interval, 1.219-15.398; P = 0.023). CONCLUSIONS: Composite outcome of recurrence in our study was 29.6%. Avulsion on TLUS increased the risk of recurrence of pelvic organ prolapse by fourfold.

Reparación quirúrgica por vía vaginal de fístulas vesicovaginales: una experiencia exitosa / Vaginal surgical repair of vesico-vaginal fistulas: a successful experience

OBJETIVO: Se presenta una serie de casos de reparación por vía vaginal de fístula vesicovaginal (FVV) de nuestro centro. MATERIAL Y MÉTODOS: Estudio observacional descriptivo. Se evaluaron todas las pacientes con reparación quirúrgica de FVV en el Centro de Innovación de Piso Pélvico del Hospital Sótero del Río entre 2016 y 2022. RESULTADOS: Se reportaron 16 casos, de los cuales el 81,3% fueron secundarios a cirugía ginecológica. En todos se realizó la reparación por vía vaginal, con cierre por planos. En el 94% (15/16) se logró una reparación exitosa en un primer intento. El tiempo de seguimiento poscirugía fue de 10 meses (rango: 3-29). No hubo casos de recidiva en el seguimiento. Una paciente presentó fístula de novo, la cual se reparó de manera exitosa en un segundo intento por vía vaginal. Se reportaron satisfechas con la cirugía 15 pacientes, con mejoría significativa de su calidad de vida. Una paciente reportó sentirse igual (6,3%), pero sus síntomas se debían a síndrome de vejiga hiperactiva que la paciente no lograba diferenciar de los síntomas previos a la cirugía. CONCLUSIÓN: Las FVV en los países desarrollados son secundarias a cirugía ginecológica benigna. La cirugía por vía vaginal en nuestra serie demostró una alta tasa de éxito, con mejora significativa en la calidad de vida de las pacientes.

OBJETIVE: We present a case series of vesico-vaginal fistulas (VVF) vaginal repair in our center. MATERIAL AND METHODS: Descriptive observational study. All patients with surgical repair of VVF at the Centro de Innovación en Piso Pélvico of Hospital Sótero del Río were evaluated between September 2016 and September 2022. RESULTS: 16 cases were reported. 81.3% were secondary to gynecological surgery. In all cases, a vaginal repair was performed, with a layered closure. 94% (15/16) had no contrast extravasation at the time of examination, confirming fistula closure. The follow-up time was 10 months (range: 3-29). There were no cases of recurrence during follow-up. 1 patient presented de novo fistula which was successfully repaired in a second attempt vaginally. 15/16 patients reported being satisfied with the surgery, with significant improvement in quality of life. 1 patient reported feeling the same (6.3%), but her symptoms were due to overactive bladder syndrome that the patient could not differentiate from the symptoms prior to surgery. CONCLUSION: VFV in developed countries are mainly secondary to benign gynecological surgery. Vaginal surgery in our series achieved a significant improvement in the quality of life of patients.

Brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss and decline in cognitive and motor function. Increasing evidence suggests that blood-brain barrier (BBB) dysfunction may contribute to progression of the disease. Studies in animal models, in vitro models, and post-mortem tissue find that disease progression is associated with increased microvascular density, altered cerebral blood flow, and loss of paracellular and transcellular barrier function. Here, we report on changes in BBB phenotype due to expansion of CAG repeats using an isogenic pair of induced pluripotent stem cells (iPSCs) differentiated into brain microvascular endothelial-like cells (iBMECs). We show that CAG expansion associated with juvenile HD alters the trajectory of iBMEC differentiation, producing cells with ~ two-fold lower percentage of adherent endothelial cells. CAG expansion is associated with diminished transendothelial electrical resistance and reduced tight junction protein expression, but no significant changes in paracellular permeability. While mutant huntingtin protein (mHTT) aggregates were not observed in HD iBMECs, widespread transcriptional dysregulation was observed in iBMECs compared to iPSCs. In addition, CAG expansion in iBMECs results in distinct responses to pathological and therapeutic perturbations including angiogenic factors, oxidative stress, and osmotic stress. In a tissue-engineered BBB model, iBMECs show subtle changes in phenotype, including differences in cell turnover and immune cell adhesion. Our results further support that CAG expansion in BMECs contributes to BBB dysfunction during HD.

Expanding the known structure space for RNA binding: a test of 2,5-diketopiperazine.

As the importance of RNA as a therapeutic target has become increasingly recognized, the need for new chemotypes able to bind RNA has grown in significance. We hypothesized that diketopiperazines (DKPs), common substructures in natural products and protein-targeting therapeutic agents, could serve as effective scaffolds for targeting RNA. To confirm this hypothesis, we designed and synthesized two analogs, one incorporating a DKP and one not, of compounds previously demonstrated to bind an RNA critical to the life cycle of HIV-1 with high affinity and specificity. Prior to compound synthesis, calculations employing density functional methods and molecular mechanics conformational searches were used to confirm that the DKP could present functionality in a similar (albeit not identical) orientation to the non DKP-containing compound. We found that both the DKP-containing and parent compound had similar affinities to the target RNA as measured by surface plasmon resonance (SPR). Both compounds were found to have modest but equal anti-HIV activity. These results establish the feasibility of using DKPs to target RNA.

Three-dimensional induced pluripotent stem-cell models of human brain angiogenesis.

During brain development, chemical cues released by developing neurons, cellular signaling with pericytes, and mechanical cues within the brain extracellular matrix (ECM) promote angiogenesis of brain microvascular endothelial cells (BMECs). Angiogenesis is also associated with diseases of the brain due to pathological chemical, cellular, and mechanical signaling. Existing in vitro and in vivo models of brain angiogenesis have key limitations. Here, we develop a high-throughput in vitro blood-brain barrier (BBB) bead assay of brain angiogenesis utilizing 150 µm diameter beads coated with induced pluripotent stem-cell (iPSC)-derived human BMECs (dhBMECs). After embedding the beads within a 3D matrix, we introduce various chemical cues and extracellular matrix components to explore their effects on angiogenic behavior. Based on the results from the bead assay, we generate a multi-scale model of the human cerebrovasculature within perfusable three-dimensional tissue-engineered blood-brain barrier microvessels. A sprouting phenotype is optimized in confluent monolayers of dhBMECs using chemical treatment with vascular endothelial growth factor (VEGF) and wnt ligands, and the inclusion of pro-angiogenic ECM components. As a proof-of-principle that the bead angiogenesis assay can be applied to study pathological angiogenesis, we show that oxidative stress can exert concentration-dependent effects on angiogenesis. Finally, we demonstrate the formation of a hierarchical microvascular model of the human blood-brain barrier displaying key structural hallmarks. We develop two in vitro models of brain angiogenesis: the BBB bead assay and the tissue-engineered BBB microvessel model. These platforms provide a tool kit for studies of physiological and pathological brain angiogenesis, with key advantages over existing two-dimensional models.

Meanings of physics mathematization in pre-service physics teachers / Significados de matematización de la física en docentes de física en formación / Significados da matemátização da física em professores de física en formação

Abstract Introduction. Physics teaching practice is permeated by the meaning that teachers constructed about the relationship between mathematics and physics, but this relationship often goes unnoticed by the teacher himself, because of their education where it is traditionally thoughtlessly assumed that "mathematics is the physics language." Objective. In this work, we contribute to the comprehension of how modifying this reality in teacher training. To this end, we conducted a study on how is understanding physics and mathematics relationships by pre-service teachers. Materials and methods. Data collection was done from observation of a non-participating classroom in two physics courses using an observation grid and a questionnaire. We made a content analysis. Results. We found that pre-service teachers consider the mastery of problem-solving equations as the primary medium for learning physics, but when they are asked to explain physics they usually opt for qualitative descriptions and pictorial representations not for equations. Conclusions. It means that they differentiate between a "mathematical part" of the phenomenon that is self-controlled as the basis of his physics learning and a "qualitative part" of the phenomenon that serves to explain physics. So, it seems that to teach physics they feel the need to explain conceptually without mathematics, while to learn physics they should concentrate on applying equations, which is paradoxical.

Resumen Introducción. El tipo de trabajo docente en la enseñanza de la física está influenciado por el significado que cada docente ha construido sobre la relación entre las matemáticas y la física, pero esta relación a menudo pasa desapercibida para el maestro mismo, ya que es tradición en su formación suponer irreflexivamente que "las matemáticas son el lenguaje de la física". Objetivo. En este trabajo, contribuimos a la comprensión de cómo modificar esta realidad en la formación del profesorado. Con este fin, llevamos a cabo un estudio sobre cómo es la comprensión de las relaciones de física y matemáticas por parte de los docentes en formación. Materiales y métodos. La recolección de datos se realizó a partir de la observación no participante en dos cursos de física utilizando una rejilla de observación y un cuestionario. El análisis se hizo a partir del análisis de contenido. Resultados. Descubrimos que los maestros en formación consideran el dominio de las ecuaciones en la resolución de problemas como el eje fundamental para aprender física, pero cuando se les pide que expliquen física, optan por descripciones cualitativas y representaciones pictóricas y no por ecuaciones. Conclusiones. Los docentes en formación diferencian entre la "parte matemática" del fenómeno al que atribuye la base de su aprendizaje de física y la "parte cualitativa" del fenómeno que sirve para explicar la física. Entonces, parece que para enseñar física sienten la necesidad de explicar conceptualmente sin matemáticas, mientras que para aprender física se concentran solamente en aplicar ecuaciones, lo cual resulta paradójico.

Resumo Introdução: O tipo de trabalho docente no ensino de física é influenciado pelo significado que cada professor construiu sobre a relação entre matemática e física, mas essa relação geralmente passa despercebida pelo próprio professor, uma vez que é uma tradição em sua formaçao supõe, sem pensar, que "a matemática é a linguagem da física". Objetivo. Neste trabalho, contribuímos para a compreensão de como modificar essa realidade na formação de professores. Para tanto, realizamos um estudo sobre como é a comprensao das relaçoes entre a física e a matemática na formação de professores de física. Materiais e métodos. A coleta de dados foi realizada a partir da observação mais não do participante em diferentes aulas de física, utilizando um roteiro de observação e um questionário. A análise foi feita a partir da análise de conteúdo. Resultados. Descobrimos que os professores em formação consideram o domínio das equações na solução de problemas como o eixo fundamental para aprender física, mas, quando solicitados a explicar física, optam por descrições qualitativas e representações pictóricas, e não por equações. Conclusões. Os professores em formação diferenciam entre a "parte matemática" do fenômeno à qual ele atribui a base de seu aprendizado da física e a "parte qualitativa" do fenômeno que serve para explicar a física. Parece que, para ensinar física, eles sentem a necessidade de explicar conceitualmente sem matemática, enquanto que para aprender física, eles se concentram apenas na aplicação de equações, o que é paradoxal.

Tissue-engineered blood-brain barrier models via directed differentiation of human induced pluripotent stem cells.

Three-dimensional (3D) tissue-engineered models of the blood-brain barrier (BBB) recapitulate in vivo shear stress, cylindrical geometry, and cell-ECM interactions. Here we address four issues associated with BBB models: cell source, barrier function, cryopreservation, and matrix stiffness. We reproduce a directed differentiation of brain microvascular endothelial cells (dhBMECs) from two fluorescently labeled human induced pluripotent stem cell lines (hiPSCs) and demonstrate physiological permeability of Lucifer yellow over six days. Microvessels formed from cryopreserved dhBMECs show expression of BBB markers and maintain physiological barrier function comparable to non-cryopreserved cells. Microvessels displaying physiological barrier function are formed in collagen I hydrogels with stiffness matching that of human brain. The dilation response of microvessels was linear with increasing transmural pressure and was dependent on matrix stiffness. Together these results advance capabilities for tissue-engineered BBB models.