Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing ...TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in
Fbn1
C1041G/+
aortas, a mouse model of MFS.
Vcan
haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.
Synopsis
Thoracic aortic aneurysms and dissections are common in Marfan syndrome (MFS), a disorder resulting from Fibrillin-1 gene mutations. This study investigates the factors associated with MFS-induced aortopathy in mice.
The glycoprotein Vcan accumulates in aortas of both MFS mice and patients.
Silencing
Vcan
, but not
Acan
, reverses aortic disease and restores aortic Nos2 expression in MFS mice.
Vcan activates Akt, and pharmacological inhibition of Akt regresses aortic dilatation and decreases Nos2 protein levels in MFS mice.
Elevated pAKT-S473 levels were detected in the aortas of MFS patients.
Thoracic aortic aneurysms and dissections are common in Marfan syndrome (MFS), a disorder resulting from Fibrillin-1 gene mutations. This study investigates the factors associated with MFS-induced aortopathy in mice.
Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that ...nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and ...adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph− adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph− adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance. This trial was registered at www.clinicaltrials.gov as # NCT01540812.
•Adults with HR, Ph− ALL, and good MRD clearance after induction and early consolidation show promising outcomes without allo-HSCT.•Early assignment to allo-HSCT might provide long-term response to a fraction of patients showing suboptimal response to induction-1.
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El título del libro es un resumido anticipo de sus componentes esenciales; esto es, las respuestas jurídicas a la corrupción política direccionadas hacia la doble dimensión de dicha corrupción que va ...desde la contabilidad irregular en procesos electorales a los delitos de financiación ilegal de los partidos políticos. Ello posibilita una puesta en escena de múltiples posibilidades. La corrupción en general, y la política en particular, en sus diversas manifestaciones, se muestran como una especie de monstruo de las mil cabezas adaptado perfectamente a las más heterogéneas formas y maneras de convivencia ciudadana; universal en cuanto a su presencia y desarrollo, aparece igual, sin atención a los regímenes políticos existentes en los diversos países obviamente sobre contestaciones muy diferentes; no está afecto o integrado en una determinada ideología, pero convive con la mayoría de ellas. Como fenómeno social negativo afecta a la propia credibilidad del sistema, en cuanto semejante corrupción es la muestra, posiblemente con mayor dimensión, de dañinas perturbaciones a los principios más básicos del orden constitucional democrático. En consecuencia, requiere de respuestas contundentes, imaginativas y solidariamente compartidas. En esta obra, desde una perspectiva realista y, fundamentalmente, jurídica, pluridisciplinar y valorativa, se plantean las cuestiones de mayor relevancia en relación a la corrupción política, tanto sobre ella desde un planteamiento general, como en lo concreto acerca de procesos electorales y corrupción, financiación ilegal de los partidos políticos, prevención, personas y consecuencias jurídicas, procedimiento procesal, fiscalidad, contratación y acceso a la función pública, delitos de carácter instrumental -cohecho, blanqueo de capitales, malversación propia, tráfico de influencias-, perspectiva comparada de política criminal. Todo esto concluye con un amplio epígrafe dedicado a resultados de la investigación y propuestas de lege ferenda, a manera de conclusiones. Se construye de tal forma un sólido armazón científico, dogmático, práctico y político criminal que ha de servir como oferta unificada de lucha contra la plaga corrupta.
En los últimos años tanto el consumo como la producción de emisiones de audio creadas para su consumo en internet ha aumentado, como puede observarse en las principales plataformas de difusión de ...audio. Los pódcast han alcanzado un nivel de popularidad y de producción técnica muy alto a partir de una narrativa cada día más especializada, debido a la madurez alcanzada por el formato, y a la diversidad del contenido ofrecido, que abarca desde producciones domésticas hasta programas de radio profesional. Nos encontramos, además, que estos formatos tienen cada día más espacios para ofrecer sus contenidos, bien sea de forma gratuita o de pago, a un número creciente de usuarios. Cuando parece que las temáticas de humanidades, ciencias sociales e historia no son los más atractivos para los ciudadanos, encontramos en el formato pódcast una tecnología y unas estructuras narrativas que hacen más cercanas estos contenidos, independientemente del nivel de especialización de la audiencia. En este trabajo abordamos los pódcasts de historia como una herramienta para la divulgación de contenidos muy especializados y a los que les costaba encontrar un hueco en los medios de comunicación. De esta forma, presentamos un estudio sobre la capacidad de los pódcast con temática de historia de transmitir contenidos especializados de forma divulgativa y amena. Para ello, realizamos un análisis cualitativo y cuantitativo de los pódcast de historia más escuchados en España, sus características y temáticas, de tal forma que se ha podido establecer un perfil de la producción de contenido en este formato.
Are the alterations observed in the endometriotic cells, such as progesterone resistance, already present in the eutopic endometrium or acquired in the ectopic location?
The response to ...decidualization with progesterone and cyclic AMP for up to 28 days was compared in different endometrial stromal cell (EnSC) lines established from samples of endometriomas (eEnSC), eutopic endometrium from women with endometriosis (eBEnSC), endometrial tissue from healthy women (BEnSC) and menstrual blood from healthy donors (mEnSC).
Usual features of decidualized cells, such as changes in cell morphology and expression of prolactin, were similarly observed in the three types of eutopic EnSC studied, but not in the ectopic cells upon decidualization. Among the phenotypic markers analysed, CD105 was down-regulated under decidualization in all cell types (mEnSC, P = 0.005; BEnSC, P = 0.029; eBEnSC, P = 0.022) except eEnSC. mEnSC and BEnSC underwent apoptosis during decidualization, whereas eBEnSC and eEnSC were resistant to the induction of cell death. Lastly, migration studies revealed that mEnSC secreted undetermined factors during decidualization that inhibited cell motility, whereas eEnSC showed a significantly lower ability to produce those migration-regulating factors (P < 0.0001, P < 0.001 and P = 0.0013 for the migration of mEnSC at 24, 48 and 72 h, respectively; P < 0.0001 for the migration of eEnSC at all times studied).
This study provides novel insights into the differences between endometriotic and eutopic endometrial cells and reinforces the idea that the microenvironment in the ectopic location plays additional roles in the acquisition of the alterations that characterize the cells of the endometriotic foci.
Introduction
Epidermolysis bullosa (EB) is a rare genetic disorder characterized by skin fragility and blister formation. The phenotypic presentation is broad with four major types, being Recessive ...Dystrophic EB (RDEB) the most severe, including oral anomalies such as severe microstomia, ankyloglossia, vestibule obliteration and occlusal anomalies, turning orthodontic treatment into a challenge.
Aim
This case report aims to present the comprehensive treatment of a patient with severe RDEB, including periodontal surgery, orthodontic fixed braces with mini‐screws and oral rehabilitation with anterior veneers.
Case Report
A 27‐year‐old female patient with severe RDEB received orthodontic treatment in the upper jaw to improve malalignment and anterior crossbite. After 13 months of treatment with fixed appliances, miniscrews were placed in the anterior segment to intrude and procline the upper incisors. Oral surgery was performed to increase the vestibule depth of the upper lip. Once edge‐to‐edge occlusion was obtained, anterior veneers were placed to improve aesthetic and stabilize occlusion, especially with the lack of posterior support.
Discussion
The multidisciplinary treatment approach, involving orthodontic treatment, periodontal surgery and oral rehabilitation, played a crucial role in achieving favorable results. This case highlights the successful use of miniscrews as a viable orthodontic approach for patients with severe RDEB.
Emotion recognition (ER) deficits have been extensively demonstrated in schizophrenia. These deficiencies are not only restricted to facial emotion recognition but also include emotional prosody ...(tone of the voice) recognition deficits. They have been significantly associated with symptom severity and poor social functioning. The aim of this study was to test the efficacy, in real clinical conditions, of an online self-training prosodic game included in the Social Cognition rehabilitation program e-Motional Training.
A randomized, single-blind multicenter clinical trial was conducted with 50 outpatients with schizophrenia or schizoaffective disorder. The control group was treated with Treatment-as-usual (TAU), based on drug therapy, case management and individual and group psychotherapy (not focused on Social Cognition). The intervention group was treated with TAU plus the employment of Voices, an online self-training program devised for prosodic rehabilitation.
Linear regression was used to evaluate the effectiveness of the intervention in emotion recognition measured with the Reading the Mind in the Voice-Spanish Version (RMV-SV).
There were statistically significant differences between the intervention and control group measured with RMV-SV (β = 3,6IC 95%, p<0.001), with a response variable in RMV post R2 = 0,617.
Voices, a prosodic rehabilitation game included in e-Motional Training, seems to be a promising tool for improving emotional voice recognition deficits in schizophrenia, filling the need for such interventions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
What is already known about this topic? Effectiveness of seasonal influenza vaccine varies by season and circulating virus type. What is added by this report? The 2023 Southern Hemisphere seasonal ...influenza vaccine reduced the risk for influenza-associated hospitalizations by 52%. Circulating influenza viruses were genetically similar to those targeted by the 2023–24 Northern Hemisphere influenza vaccine formulation. This vaccine might offer similar protection if these viruses predominate during the coming Northern Hemisphere influenza season. What are the implications for public health practice? Vaccination remains one of the most effective ways to protect against influenza-associated complications. In anticipation of Northern Hemisphere influenza virus circulation, CDC recommends that health authorities encourage U.S. health care providers to administer seasonal influenza vaccine to all eligible persons aged ≥6 months.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
10.
Resultados a manera de conclusiones Ignacio F. Benítez Ortúzar; María José Cruz Blanca; Antonio Garrido Rubia ...
Respuestas jurídicas frente a la corrupción política,
12/2020
Book Chapter
PDF
