Enteroscopic Balloon Dilation of Multiple Ileal Strictures in Suspected Crohn's Disease

AbstractWith the advent of small bowel enteroscopy, the limits to the endoscopic access to the small bowel have been further exceeded, allowing histology sampling and therapeutical maneuvers. This conquest is of crucial meaning in small bowel inflammatory diseases. In this setting, enteroscopy may lead to a definite diagnosis, overcoming the limits of the anatomic disease location and of other (radiological and endoscopic imaging) techniques. Furthermore, enteroscopy permits strictures visualization and dilation, reducing or postponing the need for surgery. In this article the authors demonstrate the technique of hydrostatic balloon dilation of small bowel strictures suggestive of Crohn's disease in a patient suffering from persistent obscure gastrointestinal bleeding. This article is part of an expert video encyclopedia

Targeting interleukin-1β protects from aortic aneurysms induced by disrupted transforming growth factor β signaling

Aortic aneurysms are life-threatening conditions with effective treatments mainly limited to emergency surgery or trans-arterial endovascular stent grafts, thus calling for the identification of specific molecular targets. Genetic studies have highlighted controversial roles of transforming growth factor β (TGF-β) signaling in aneurysm development. Here, we report on aneurysms developing in adult mice after smooth muscle cell (SMC)-specific inactivation of Smad4, an intracellular transducer of TGF-β. The results revealed that Smad4 inhibition activated interleukin-1β (IL-1β) in SMCs. This danger signal later recruited innate immunity in the adventitia through chemokine (C-C motif) ligand 2 (CCL2) and modified the mechanical properties of the aortic wall, thus favoring vessel dilation. SMC-specific Smad4 deletion in Il1r1- or Ccr2-null mice resulted in milder aortic pathology. A chronic treatment with anti-IL-1β antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-β signaling, such as those driven by SMAD4 mutations

Transapical off-pump echo-guided mitral valve repair with neochordae implantation mid-term outcomes

Background: The NeoChord echo-guided transapical beating heart repair is a promising early-stage minimally invasive surgical procedure for degenerative mitral valve (MV) regurgitation (DMR) correction. The technique has been improved since its inception following procedure standardization, patient selection optimization, and learning curve stabilization. We hereby present the mid-term clinical results through three years of our large single center experience. Methods: All consecutive patients with severe symptomatic DMR due to prolapse or flail of one or both mitral leaflets that underwent the NeoChord procedure between November 2013 and June 2019 were included. Patients were categorized according to MV anatomy; Type A isolated central posterior leaflet prolapse and/or flail, Type B posterior multi-segment prolapse and/or flail, Type C anterior and/or bi-leaflet prolapse or flail, Type D paracommissural prolapse and/or flail and/or significant leaflet and/or annular calcifications. Patients underwent clinical and echocardiographic follow-up at one, three, six, twelve months and yearly thereafter. Clinical outcomes and the composite primary endpoint (patient success) were defined according to Mitral Valve Academic Research Consortium (MVARC) criteria. Mitral regurgitation (MR) severity was graded as absent, mild, moderate and severe according to American Society of Echocardiography (ASE) and European Society of Cardiology (ESC) guidelines. Results: Two hundred and three patients were included; median follow-up was 24 months [interquartile range (IQR), 9–36]. Median age was 64 years (IQR, 54–74 years), median Society of Thoracic Surgeons (STS) Predicted Risk of Mortality (PROM) was 0.60% (IQR, 0.32–1.44%). There were 106 Type A patients (52.2%), 68 Type B (33.5%), 16 Type C (7.9%), and 13 Type D (6.4%). Kaplan-Meier estimate of survival was 99.0%±0.7% at one and two years and 94.0%±2.9% at three years. At one-year follow-up patient success was 91.2%±2.0% and 111 patients (74%) presented a residual MR mild or less (1+). At three-year follow-up patient success was 81.2%±3.8% and 32 patients (64%) had a residual MR mild or less (1+). Patient success was significantly different according to anatomical type (P=0.001). Echocardiographic analysis showed a significant acute left ventricle and left atrial reverse remodeling that was maintained up to three years. Conclusions: The NeoChord echo-guided transapical beating heart repair procedure demonstrated good clinical outcomes and echocardiographic results up to three-year follow-up

Eml1 loss impairs apical progenitor spindle length and soma shape in the developing cerebral cortex

The ventricular zone (VZ) of the developing cerebral cortex is a pseudostratified epithelium that contains progenitors undergoing precisely regulated divisions at its most apical side, the ventricular lining (VL). Mitotic perturbations can contribute to pathological mechanisms leading to cortical malformations. The HeCo mutant mouse exhibits subcortical band heterotopia (SBH), likely to be initiated by progenitor delamination from the VZ early during corticogenesis. The causes for this are however, currently unknown. Eml1, a microtubule (MT)-associated protein of the EMAP family, is impaired in these mice. We first show that MT dynamics are perturbed in mutant progenitor cells in vitro. These may influence interphase and mitotic MT mechanisms and indeed, centrosome and primary cilia were altered and spindles were found to be abnormally long in HeCo progenitors. Consistently, MT and spindle length regulators were identified in EML1 pulldowns from embryonic brain extracts. Finally, we found that mitotic cell shape is also abnormal in the mutant VZ. These previously unidentified VZ characteristics suggest altered cell constraints which may contribute to cell delamination

An early European experience with transapical off-pump mitral valve repair with NeoChord implantation

OBJECTIVES: Transapical off-pump NeoChord repair is a novel minimally invasive surgical procedure to treat degenerative mitral valve regurgitation. The aim was to evaluate 1-year clinical results of the NeoChord procedure in a consecutive cohort of patients. METHODS: Between February 2013 and July 2016, 213 patients were enrolled in the NeoChord Independent International Registry. All patients presented severe mitral regurgitation due to flail/prolapse of 1 or both leaflets, and they all completed postoperative echocardiographic assessment up to 1 year. We identified the primary end point as composed of procedural success, freedom from mortality, stroke, reintervention, recurrence of severe mitral regurgitation, rehospitalization and decrease of at least 1 New York Heart Association functional class at 1-year follow-up. We also compared outcomes according to the anatomical classification (Type A: isolated central posterior leaflet disease; Type B: posterior multisegment disease; Type C: anterior, bileaflet, paracommissural disease with/without leaflet/annular calcifications). RESULTS: The median age was 68 years (interquartile range 56-77), and the median EuroSCORE II was 1.05% (interquartile range 0.67-1.76). The number of Type A, B and C patients was 82 (38.5%), 98 (46%) and 33 (15.5%), respectively. Procedural success was achieved in 206 (96.7%) patients. At 1-year follow-up, overall survival was 98 ± 1%. Composite end point was achieved in 84 ± 2.5% for the overall population and 94 ± 2.6%, 82.6 ± 3.8% and 63.6 ± 8.4% in Type A, Type B and Type C patients, respectively (P < 0.0001). CONCLUSIONS: These results demonstrate that the NeoChord procedure is safe, effective and reproducible. Clinical and echocardiographic efficacy is maintained up to 1 year with significant differences among the anatomical groups. Specific anatomical selection criteria are necessary to achieve stable results

Fibroblast Growth Factor Receptor 1 Drives the Metastatic Progression of Prostate Cancer

BACKGROUND: No curative therapy is currently available for metastatic prostate cancer (PCa). The diverse mechanisms of progression include fibroblast growth factor (FGF) axis activation. OBJECTIVE: To investigate the molecular and clinical implications of fibroblast growth factor receptor 1 (FGFR1) and its isoforms (α/β) in the pathogenesis of PCa bone metastases. DESIGN, SETTING, AND PARTICIPANTS: In silico, in vitro, and in vivo preclinical approaches were used. RNA-sequencing and immunohistochemical (IHC) studies in human samples were conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In mice, bone metastases (chi-square/Fisher's test) and survival (Mantel-Cox) were assessed. In human samples, FGFR1 and ladinin 1 (LAD1) analysis associated with PCa progression were evaluated (IHC studies, Fisher's test). RESULTS AND LIMITATIONS: FGFR1 isoform expression varied among PCa subtypes. Intracardiac injection of mice with FGFR1-expressing PC3 cells reduced mouse survival (α, p < 0.0001; β, p = 0.032) and increased the incidence of bone metastases (α, p < 0.0001; β, p = 0.02). Accordingly, IHC studies of human castration-resistant PCa (CRPC) bone metastases revealed significant enrichment of FGFR1 expression compared with treatment-naïve, nonmetastatic primary tumors (p = 0.0007). Expression of anchoring filament protein LAD1 increased in FGFR1-expressing PC3 cells and was enriched in human CRPC bone metastases (p = 0.005). CONCLUSIONS: FGFR1 expression induces bone metastases experimentally and is significantly enriched in human CRPC bone metastases, supporting its prometastatic effect in PCa. LAD1 expression, found in the prometastatic PCa cells expressing FGFR1, was also enriched in CRPC bone metastases. Our studies support and provide a roadmap for the development of FGFR blockade for advanced PCa. PATIENT SUMMARY: We studied the role of fibroblast growth factor receptor 1 (FGFR1) in prostate cancer (PCa) progression. We found that PCa cells with high FGFR1 expression increase metastases and that FGFR1 expression is increased in human PCa bone metastases, and identified genes that could participate in the metastases induced by FGFR1. These studies will help pinpoint PCa patients who use fibroblast growth factor to progress and will benefit by the inhibition of this pathway.Fil: Labanca, Estefania. University of Texas; Estados UnidosFil: Yang, Jun. University of Texas; Estados UnidosFil: Shepherd, Peter D. A.. University of Texas; Estados UnidosFil: Wan, Xinhai. University of Texas; Estados UnidosFil: Starbuck, Michael W.. University of Texas; Estados UnidosFil: Guerra, Leah D.. University of Texas; Estados UnidosFil: Anselmino, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Bizzotto, Juan Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Dong, Jiabin. University of Texas; Estados UnidosFil: Chinnaiyan, Arul M.. University Of Michigan Medical School; Estados UnidosFil: Ravoori, Murali K.. University of Texas; Estados UnidosFil: Kundra, Vikas. University of Texas; Estados UnidosFil: Broom, Bradley M.. University of Texas; Estados UnidosFil: Corn, Paul G.. University of Texas; Estados UnidosFil: Troncoso, Patricia. University of Texas; Estados UnidosFil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Logothethis, Christopher J.. University of Texas; Estados UnidosFil: Navone, Nora. University of Texas; Estados Unido

Waking up to Sleep’s Role in Obesity and Blood Pressure Among Black Adolescent Girls in Low-Income, US Urban Communities: A Longitudinal Analysis

Objective To identify longitudinal bidirectional associations between unique sleep trajectories and obesity and hypertension among Black, adolescent girls. Design, setting, and participants Longitudinal data were from a randomized controlled trial (2009-2013) implemented in schools serving low-income communities aimed at preventing obesity among adolescent girls (mean age = 12.2 years (standard deviation ± 0.72). Measures Nocturnal sleep data were extracted from accelerometers at T1 (enrollment, n = 470), T2 (6-month, n = 348), and T3 (18-month follow-up, n = 277); height and weight were measured at T1-T3; and systolic/diastolic blood pressure at T1 and T3 using an oscillometric monitor. Multilevel models examined longitudinal associations. Finite mixture models identified sleep trajectory groups. Structural equation models examined whether T1 chronic disease risk predicted sleep profiles, and conversely, if sleep trajectories predicted T3 chronic disease risk. Data were analyzed in 2021. Results For each additional hour of sleep and 1% increase in efficiency there was a 7% lower risk of overweight/obesity at T1 and 6% lower risk at T2, but not at T3. Four sleep trajectories emerged: Worsened, Irregular, Improved, and Regular, with no demographic or metabolic differences between the trajectories. Improved sleep trajectory predicted lower diastolic percentile at T3 (b = −8.81 [95% confidence interval −16.23, −1.40]). Conclusions Group-based trajectories of sleep duration and quality provide information on modifiable factors that can be targeted in interventions to evaluate their impact on reducing chronic diseases and addressing disparities. Additional research is needed on samples beyond those recruited in the context of an intervention study

Emilin-1 controls arterial blood pressure by regulating contractility of vascular smooth muscle cells

Emilin-1 is a protein of the elastic extracellular matrix (ECM) expressed in interstitial connective tissue and in the cardiovascular system. Emilin1 null mice display hypotrophic remodeling of the wall of conductance arteries and increased blood pressure. The protein regulates the bioavailability of TGF-b by inhibiting proteolysis of the proTGF-b precursor to LAP/TGF-b, a complex from which the growth factor can be subsequently released for receptor binding. In the absence of Emilin-1, the amount of active TGF-b is increased. As Emilin-1 is expressed in blood vessels starting from early stages of embryonic development to adulthood, a key question concerning the function of the protein is whether the Emilin1-/- phenotype is the result of a developmental defect or the function of the protein is required for the regulation of blood pressure and arterial structure also in the adult. The conditional gene targeting procedure chosen to inactivate the Emilin1 gene in smooth muscle cells (SMCs) of adult mice included the use of floxed Emilin1 and CreERT2 (a tamoxifen inducible Cre recombinase) under the control of the smooth muscle myosin heavy chain (Smmhc) promoter. Tamoxifen administration induced activity of Cre specifically in vascular and visceral SMCs, as revealed by X-gal staining of tissues from animals with the Rosa26R mutation. When Emilin1flox/flox mice carrying the Smmhc-CreERT2 transgene were given tamoxifen for 7 days, Emilin-1 disappeared completely in 10-12 days from start of treatment. In the same time, blood pressure increased of about 20 mmHg, a level that was stably maintained thereafter. The myogenic response of second branch meseteric arteries, evaluated using a pressure myograph, was found to be increased in Emilin1-/- mice. Additional experiments with aorta and mesenteric artery SMC cultures from control and mutant mice showed that lack of Emilin-1  enhanced phosphorylation of myosin light chain 20 when cells were stimulated with the a1-adrenergic receptor agonists phenylephrine or with angiotensin II. Moreover, basal cytosolic Ca2+ levels and calcium transients induced by stimulation with phenylephrine and angiotensin II were increased in SMCs from Emilin1-/- mutants. The data suggest that Emilin-1 expression is continuously required for regulation of blood pressure and that the increase of TGF-b activity induced by diminished Emilin-1  stimulates, likely through alteration of intracellular calcium homeostasis, contractility of vascular SMC to mechanical and chemical stimuli with ensuing hypertension