RESUMEN
One of the foremost targets in the advancement of biomaterials to engineer vascularized tissues is not only to replicate the composition of the intended tissue but also to create thicker structures incorporating a vascular network for adequate nutrients and oxygen supply. For the first time, to the best of current knowledge, a clinically relevant biomaterial is developed, demonstrating that hydrogels made from the human decellularized extracellular matrix can exhibit robust mechanical properties (in the kPa range) and angiogenic capabilities simultaneously. These properties enable the culture and organization of human umbilical vein endothelial cells into tubular structures, maintaining their integrity for 14 days in vitro without the need for additional polymers or angiogenesis-related factors. This is achieved by repurposing the placenta chorionic membrane (CM), a medical waste with an exceptional biochemical composition, into a valuable resource for bioengineering purposes. After decellularization, the CM underwent chemical modification with methacryloyl groups, giving rise to methacrylated CM (CMMA). CMMA preserved key proteins, as well as glycosaminoglycans. The resulting hydrogels rapidly photopolymerize and have enhanced strength and customizable mechanical properties. Furthermore, they demonstrate angio-vasculogenic competence in vitro and in vivo, holding significant promise as a humanized platform for the engineering of vascularized tissues.
RESUMEN
A better understanding of how age-related bone loss affects the fracture-prone regions of the proximal femur could lead to more informed fracture-prevention strategies. Therefore, the aim of this work was to assess the spatio-temporal distribution of bone deterioration in older men and women with aging. A subset of 305 men (74.87 ± 4.76 years; mean ± SD) and 371 age-matched women (74.84 ± 4.71 years) with no history of fracture were randomly selected from the Age, Gene/Environment Susceptibility-Reykjavik study. Quantitative computed tomography (QCT) scans of the left proximal femur obtained at baseline and at 5.2 ± 0.4 years follow-up were processed to assess local changes in volumetric bone mineral density (vBMD), cortical bone thickness (Ct.Th), and internal bone structure using voxel-based morphometry (VBM), surface-based statistical parametric mapping (surf-SPM), and tensor-based morphometry (TBM). Local parametric changes within each sex and sex differences in these changes were statistically assessed using linear mixed effects models allowing for baseline and time-varying covariates, yielding Student's t-test and P-value statistical maps of the proximal femur. The statistical maps indicated regions with significant parametric changes in each sex, and with significant different parametric changes between older men and older women with aging. Older women manifested significantly larger losses in vBMD, cortical bone thickness, and structure than older men, and they did so in regions where deficiency in these parameters has been associated with incident hip fracture. Using longitudinal QCT scans of the proximal femur and Computational Anatomy, we provided new insights into the higher fracture rates of the proximal femur in older women compared with men of similar age providing new information on the pathophysiology of osteoporosis.
RESUMEN
The few studies that have evaluated hygiene routines in farrowing accommodation to date have focused on pathogen elimination from pens, with little attention paid to pig growth and no information provided on pig health or medication usage. This study aimed to determine if implementation of an optimized farrowing accommodation hygiene routine could improve pig health and growth and reduce medication usage pre- and post-weaning (PW). Forty seven sows were blocked on parity, previous litter size and body weight and assigned to two treatments: T1) Basic hygiene: cold water washing only with minimal drying time; T2) Optimized hygiene: use of detergent and a chlorocresol-based disinfectant with a 6-d drying time. Total bacterial counts (TBC), Enterobacteriaceae counts and adenosine triphosphate (ATP) swabs were obtained from different areas within the farrowing pens. Pig growth and medication usage were monitored from birth to slaughter and carcass data were obtained at slaughter. On entry of sows to the farrowing pens, TBC and Enterobacteriaceae counts and ATP concentrations were lower on pen surfaces subjected to the optimized compared to the basic hygiene routine (Pâ <â 0.05). Pre-weaning diarrhea prevalence was lower in pigs born into optimal compared to basic hygiene pens (0 vs. 22%; Pâ <â 0.001). The number of clinical cases of disease and injections administered to piglets per litter was 75% and 79% less for the optimized compared to the basic hygiene routine, respectively (Pâ <â 0.001). This led to reductions of 77% (Pâ <â 0.001) and 75% (Pâ <â 0.01), respectively in the volume of antibiotics and anti-inflammatories administered per litter in the optimized hygiene group. Pigs from the optimized hygiene treatment were also heavier at weaning (Pâ <â 0.01) and their average daily gain (ADG) was higher from day 21 to weaning and days 22 to 49 PW (Pâ <â 0.05). However, these growth improvements did not carry through to the finisher period. In conclusion, implementation of an optimized hygiene routine reduced the bacterial load in farrowing pens, leading to a reduction in diarrhea and clinical cases of disease and therefore, medication usage, in suckling pigs. Pig growth was also improved during the suckling and early PW periods. Based on the results, an easily implementable farrowing room hygiene protocol with demonstrable benefits for pig health, growth, and welfare can be provided to farmers.
RESUMEN
Transposable elements (TEs) are mobile genetic modules of viral derivation that have been co-opted to become modulators of mammalian gene expression. TEs are a major source of endogenous dsRNAs, signaling molecules able to coordinate inflammatory responses in various physiological processes. Here, we provide evidence for a positive involvement of TEs in inflammation-driven bone repair and mineralization. In newly fractured mice bone, we observed an early transient upregulation of repeats occurring concurrently with the initiation of the inflammatory stage. In human bone biopsies, analysis revealed a significant correlation between repeats expression, mechanical stress and bone mineral density. We investigated a potential link between LINE-1 (L1) expression and bone mineralization by delivering a synthetic L1 RNA to osteoporotic patient-derived mesenchymal stem cells and observed a dsRNA-triggered protein kinase (PKR)-mediated stress response that led to strongly increased mineralization. This response was associated with a strong and transient inflammation, accompanied by a global translation attenuation induced by eIF2α phosphorylation. We demonstrated that L1 transfection reshaped the secretory profile of osteoblasts, triggering a paracrine activity that stimulated the mineralization of recipient cells.
RESUMEN
Background: Patients with complex congenital heart disease and Fontan palliation frequently develop extracardiac disease, including hematologic abnormalities, such as lymphopenia. However, the clinical implications of this finding are poorly understood and are therefore the topic of this investigation. Methods: Patients with Fontan physiology in our centre (1999-2018) were evaluated for the presence and impact of lymphopenia. The cohort was divided into a group with lymphopenia (L) (2 consecutive absolute lymphocyte counts ≤ 1∗103 K/ µL) and a group who had never had lymphopenia (NL). Clinical characteristics and hospital admissions (762 patient-years) were evaluated. Results: In 62 adult patients with Fontan physiology (aged 34 ± 9 years; 32 women [52%]), the patients who developed lymphopenia earliest did so 8 years after Fontan completion, with up to 60% of patients developing lymphopenia by 30 years. Lymphopenia was found to be associated with portal hypertension (varices, ascites, splenomegaly, and thrombocytopenia [VAST] score)-NL: 0 (0-2) vs L: 2 (0-4), P < 0.0001). A total of 76 heart failure and 81 arrhythmia-associated admissions occurred per 1000 patient-years. At 40 years post-Fontan, the probability of a heart failure admission was higher in the L group (L: 51 [86%] vs NL: 8 [14%], P < 0.01). Conclusions: Adult patients with Fontan physiology and lymphopenia demonstrated portal hypertension and lymphatic dysfunction more commonly, perhaps suggesting that this may be a marker of Fontan congestion and early Fontan failure. Further investigation into the relationship between lymphopenia, clinical outcomes, and Fontan function is needed.
Contexte: Chez les patients atteints d'une cardiopathie congénitale complexe ayant subi une intervention de Fontan, il est fréquent de voir apparaître des maladies extracardiaques, dont des anomalies hématologiques, comme la lymphopénie. Cependant, les implications cliniques de cette observation sont mal comprises et font donc l'objet de cette étude. Méthodologie: La présence et l'impact d'une lymphopénie ont été évalués chez des patients présentant une physiologie de Fontan dans notre centre (1999-2018). La cohorte a été divisée en un groupe composé de sujets atteints de lymphopénie (L) (2 mesures consécutives du nombre absolu de lymphocytes ≤ 1 x 103 K/µL) et un groupe de sujets n'ayant jamais présenté de lymphopénie (NL). Les caractéristiques initiales et les hospitalisations (762 années-patients) ont été évaluées. Résultats: Chez 62 adultes présentant une physiologie de Fontan (âgés de 34 ± 9 ans; 32 femmes [52 %]), la lymphopénie est apparue au plus tôt 8 ans après l'intervention de Fontan, avant 30 ans chez jusqu'à 60 % des patients. La lymphopénie a été associée à l'hypertension portale (score varices, ascite, splénomégalie et thrombocytopénie [VAST]) NL : 0 (0-2) vs L : 2 (0-4), p < 0,0001. Au total, il y a eu 76 hospitalisations pour insuffisance cardiaque et 81 pour arythmie pour 1000 années-patients. Quarante ans après l'intervention de Fontan, la probabilité d'une hospitalisation pour insuffisance cardiaque était plus élevée dans le groupe L que dans le groupe NL (L : 51 [86 %] vs NL : 8 [14 %], p < 0,01). Conclusions: L'hypertension portale et la dysfonction lymphatique étaient plus fréquentes chez les adultes présentant une physiologie de Fontan et une lymphopénie, ce qui laisse peut-être entendre que ce pourrait être un marqueur d'une congestion et d'une défaillance précoce du système Fontan. D'autres recherches sur le lien entre la lymphopénie, les issues cliniques et la fonction du système Fontan sont nécessaires.
RESUMEN
Activation of the transcription factor NF-κB in cardiomyocytes has been implicated in the development of cardiac function deficits caused by diabetes. NF-κB controls the expression of an array of pro-inflammatory cytokines and chemokines. We recently discovered that the stress response protein regulated in development and DNA damage response 1 (REDD1) was required for increased pro-inflammatory cytokine expression in the hearts of diabetic mice. The studies herein were designed to extend the prior report by investigating the role of REDD1 in NF-κB signaling in cardiomyocytes. REDD1 genetic deletion suppressed NF-κB signaling and nuclear localization of the transcription factor in human AC16 cardiomyocyte cultures exposed to TNFα or hyperglycemic conditions. A similar suppressive effect on NF-κB activation and pro-inflammatory cytokine expression was also seen in cardiomyocytes by knocking down the expression of GSK3ß. NF-κB activity was restored in REDD1-deficient cardiomyocytes exposed to hyperglycemic conditions by expression of a constitutively active GSK3ß variant. In the hearts of diabetic mice, REDD1 was required for reduced inhibitory phosphorylation of GSK3ß at S9 and upregulation of IL-1ß and CCL2. Diabetic REDD1+/+ mice developed systolic functional deficits evidenced by reduced ejection fraction. By contrast, REDD1-/- mice did not exhibit a diabetes-induced deficit in ejection fraction and left ventricular chamber dilatation was reduced in diabetic REDD1-/- mice, as compared to diabetic REDD1+/+ mice. Overall, the results support a role for REDD1 in promoting GSK3ß-dependent NF-κB signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice.
Asunto(s)
Diabetes Mellitus Experimental , Glucógeno Sintasa Quinasa 3 beta , Miocitos Cardíacos , FN-kappa B , Transducción de Señal , Factores de Transcripción , Animales , Miocitos Cardíacos/metabolismo , FN-kappa B/metabolismo , Ratones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Ratones Noqueados , Masculino , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Interleucina-1beta/metabolismo , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/metabolismo , Fosforilación , Eliminación de GenAsunto(s)
Leucemia Mieloide Aguda , Proteína Tumoral p73 , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Pronóstico , Proteína Tumoral p73/genética , Proteína Tumoral p73/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Anciano , Regulación Leucémica de la Expresión Génica , AdultoRESUMEN
Cellular therapies with cardiomyocytes produced from induced pluripotent stem cells (iPSC-CMs) offer a potential route to cardiac regeneration as a treatment for chronic ischemic heart disease. Here, we report successful long-term engraftment and in vivo maturation of autologous iPSC-CMs in two rhesus macaques with small, subclinical chronic myocardial infarctions, all without immunosuppression. Longitudinal positron emission tomography imaging using the sodium/iodide symporter (NIS) reporter gene revealed stable grafts for over 6 and 12 months, with no teratoma formation. Histological analyses suggested capability of the transplanted iPSC-CMs to mature and integrate with endogenous myocardium, with no sign of immune cell infiltration or rejection. By contrast, allogeneic iPSC-CMs were rejected within 8 weeks of transplantation. This study provides the longest-term safety and maturation data to date in any large animal model, addresses concerns regarding neoantigen immunoreactivity of autologous iPSC therapies, and suggests that autologous iPSC-CMs would similarly engraft and mature in human hearts.
Asunto(s)
Células Madre Pluripotentes Inducidas , Macaca mulatta , Miocitos Cardíacos , Animales , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/citología , Diferenciación Celular , Humanos , Trasplante Autólogo , Tomografía de Emisión de Positrones , Factores de Tiempo , Infarto del Miocardio/terapia , Infarto del Miocardio/patologíaRESUMEN
Human brain organoid models have emerged as a promising tool for studying human brain development and function. These models preserve human genetics and recapitulate some aspects of human brain development, while facilitating manipulation in an in vitro setting. Despite their potential to transform biology and medicine, concerns persist about their fidelity. To fully harness their potential, it is imperative to establish reliable analytic methods, ensuring rigor and reproducibility. Here, we review current analytical platforms used to characterize human forebrain cortical organoids, highlight challenges, and propose recommendations for future studies to achieve greater precision and uniformity across laboratories.
Asunto(s)
Encéfalo , Organoides , Humanos , Organoides/citología , Organoides/metabolismo , Encéfalo/citología , Reproducibilidad de los Resultados , Prosencéfalo/citologíaRESUMEN
Drug clearance in obese subjects varies widely among different drugs and across subjects with different severity of obesity. This study investigates correlations between plasma clearance (CLp) and drug- and patient-related characteristics in obese subjects, and evaluates the systematic accuracy of common weight-based dosing methods. A physiologically-based pharmacokinetic (PBPK) modeling approach that uses recent information on obesity-related changes in physiology was used to simulate CLp for a normal-weight subject (body mass index [BMI] = 20) and subjects with various severities of obesity (BMI 25-60) for hypothetical hepatically cleared drugs with a wide range of properties. Influential variables for CLp change were investigated. For each drug and obese subject, the exponent that yields perfect allometric scaling of CLp from normal-weight subjects was assessed. Among all variables, BMI and relative changes in enzyme activity resulting from obesity proved highly correlated with obesity-related CLp changes. Drugs bound to α1-acid glycoprotein (AAG) had lower CLp changes compared to drugs bound to human serum albumin (HSA). Lower extraction ratios (ER) corresponded to higher CLp changes compared to higher ER. The allometric exponent for perfect scaling ranged from -3.84 to 3.34 illustrating that none of the scaling methods performed well in all situations. While all three dosing methods are generally systematically accurate for drugs with unchanged or up to 50% increased enzyme activity in subjects with a BMI below 30 kg/m2, in any of the other cases, information on the different drug properties and severity of obesity is required to select an appropriate dosing method for individuals with obesity.
Asunto(s)
Índice de Masa Corporal , Modelos Biológicos , Obesidad , Humanos , Obesidad/metabolismo , Tasa de Depuración Metabólica/fisiología , Preparaciones Farmacéuticas/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Hígado/metabolismo , Orosomucoide/metabolismo , Albúmina Sérica Humana/metabolismo , Albúmina Sérica Humana/análisis , Masculino , AdultoRESUMEN
High utilizers of acute care in nonurban settings are at risk for poor health outcomes. Much of Massachusetts is nonurban, with many residents experiencing limited access to health care providers, fragmented health care services, inadequate housing, and low health literacy. This study examines patient perspectives on the Community Hospital Acceleration, Revitalization, and Transformation (CHART) investment program, a state-based grant program focused on advancing community hospitals toward value-based care. We found that CHART staff engaged patients in care coordination and patient advocacy, promoted patient agency and health literacy, and provided socioemotional support. These findings may help inform future program development around meeting the medical and social needs of high utilizers of health care services.
Asunto(s)
Hospitales Comunitarios , Humanos , Massachusetts , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Alfabetización en SaludRESUMEN
In certain situations, bones do not heal completely after fracturing. One of these situations is a critical-size bone defect where the bone cannot heal spontaneously. In such a case, complex fracture treatment over a long period of time is required, which carries a relevant risk of complications. The common methods used, such as autologous and allogeneic grafts, do not always lead to successful treatment results. Current approaches to increasing bone formation to bridge the gap include the application of stem cells on the fracture side. While most studies investigated the use of mesenchymal stromal cells, less evidence exists about induced pluripotent stem cells (iPSC). In this study, we investigated the potential of mouse iPSC-loaded scaffolds and decellularized scaffolds containing extracellular matrix from iPSCs for treating critical-size bone defects in a mouse model. In vitro differentiation followed by Alizarin Red staining and quantitative reverse transcription polymerase chain reaction confirmed the osteogenic differentiation potential of the iPSCs lines. Subsequently, an in vivo trial using a mouse model (n = 12) for critical-size bone defect was conducted, in which a PLGA/aCaP osteoconductive scaffold was transplanted into the bone defect for 9 weeks. Three groups (each n = 4) were defined as (1) osteoconductive scaffold only (control), (2) iPSC-derived extracellular matrix seeded on a scaffold and (3) iPSC seeded on a scaffold. Micro-CT and histological analysis show that iPSCs grafted onto an osteoconductive scaffold followed by induction of osteogenic differentiation resulted in significantly higher bone volume 9 weeks after implantation than an osteoconductive scaffold alone. Transplantation of iPSC-seeded PLGA/aCaP scaffolds may improve bone regeneration in critical-size bone defects in mice.
Asunto(s)
Regeneración Ósea , Diferenciación Celular , Células Madre Pluripotentes Inducidas , Osteogénesis , Andamios del Tejido , Animales , Células Madre Pluripotentes Inducidas/citología , Andamios del Tejido/química , Ratones , Ingeniería de Tejidos/métodos , Masculino , Modelos Animales de Enfermedad , Matriz ExtracelularRESUMEN
The aim of this study was to assess the effect of creep-feeding solid starter diet, liquid milk replacer, and a liquid mixture of starter diet and milk replacer to suckling pigs on their growth and medication usage up to target slaughter weight (approximately 120 kg). Ninety-one sows and their litters were randomly assigned to one of four post-farrowing treatments at day 107 of gestation; (1) no creep feed provided to weaning at day 28 of age (CONTROL; nâ =â 20), (2) dry pelleted starter diet provided as creep feed from day 10 of age to weaning (DPS; nâ =â 25), (3) liquid milk replacer provided as creep feed from day 3 of age to weaning (LMR; nâ =â 23), and (4) liquid milk replacer provided from days 3 to 6 of age followed by a mixture of liquid milk replacer with an increasing proportion of liquid starter diet to weaning provided as creep feed (LMRâ +â S; nâ =â 23). Pig weight and dry matter disappearance (DMd) were recorded during lactation and postweaning until pigs reached target slaughter weight (approximately 120 kg). At target slaughter weight, carcass weight and quality were recorded. Medication (antibiotic and anti-inflammatory) usage per pig on a litter basis, and number of injections and clinical cases of disease per litter were recorded from birth to slaughter. At day 5 postweaning, a subset of pigs (nâ =â 40) were sacrificed and intestinal samples were collected for histological analysis. Piglets supplemented with DPS had higher DMd of creep feed than those supplemented with LMR or LMRâ +â S (Pâ <â 0.001). Providing LMRâ +â S to suckling piglets reduced the coefficient of variation (CV) for within-litter piglet weaning weight (Pâ <â 0.01) compared to DPS and LMR, but the CV of LMRâ +â S was similar to that of CONTROL. Providing DPS or LMR to suckling piglets increased piglet weaning weight compared to CONTROL (Pâ <â 0.001) but pig weight was not significantly different from CONTROL at time points thereafter. Gain to feed ratio from weaning to day 6 postweaning was less for LMR pigs compared to all other treatments (Pâ <â 0.001). Providing DPS or LMRâ +â S to suckling piglets tended to increase postweaning ileal villus height (Pâ =â 0.07). Diarrhea incidence, as well as the number of clinical cases of disease and injections per litter and volume of antibiotic and anti-inflammatory administered per pig pre- and postweaning, were not affected by treatment (Pâ >â 0.05). In conclusion, supplementing suckling pigs with liquid milk replacer or dry pelleted starter diet improved growth at weaning, but the benefit did not persist to slaughter.
RESUMEN
BACKGROUND: Arterial calcification due to deficiency of CD73 (ACDC; OMIM 211800) is a rare genetic disease resulting in calcium deposits in arteries and small joints causing claudication, resting pain, severe joint pain, and deformities. Currently, there are no standard treatments for ACDC. Our previous work identified etidronate as a potential targeted ACDC treatment, using in vitro and in vivo disease models with patient-derived cells. In this study, we test the safety and effectiveness of etidronate in attenuating the progression of lower-extremity arterial calcification and vascular blood flow based on the computed tomography (CT) calcium score and ankle-brachial index (ABI). METHODS: Seven adult patients with a confirmed genetic diagnosis of ACDC were enrolled in an open-label, nonrandomized, single-arm pilot study for etidronate treatment. They took etidronate daily for 14 days every 3 months and were examined at the NIH Clinical Center bi-annually for 3 years. They received a baseline evaluation as well as yearly follow up after treatment. Study visits included imaging studies, exercise tolerance tests with ABIs, clinical blood and urine testing, and full dental exams. RESULTS: Etidronate treatment appeared to have slowed the progression of further vascular calcification in lower extremities as measured by CT but did not have an effect in reversing vascular and/or periarticular joint calcifications in our small ACDC cohort. CONCLUSIONS: Etidronate was found to be safe and well tolerated by our patients and, despite the small sample size, appeared to show an effect in slowing the progression of calcification in our ACDC patient cohort.(ClinicalTrials.gov Identifier NCT01585402).
Asunto(s)
5'-Nucleotidasa , Ácido Etidrónico , Proteínas Ligadas a GPI , Calcificación Vascular , Humanos , Proyectos Piloto , Calcificación Vascular/tratamiento farmacológico , Calcificación Vascular/diagnóstico por imagen , Ácido Etidrónico/uso terapéutico , Ácido Etidrónico/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/deficiencia , Factores de Tiempo , Proteínas Ligadas a GPI/sangre , Índice Tobillo Braquial , Adulto , Conservadores de la Densidad Ósea/uso terapéutico , Conservadores de la Densidad Ósea/efectos adversos , Progresión de la Enfermedad , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/fisiopatología , Anciano , Extremidad Inferior/irrigación sanguínea , Angiografía por Tomografía Computarizada , Predisposición Genética a la Enfermedad , Flujo Sanguíneo RegionalRESUMEN
Beckwith-Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the role of IGF2 upregulation in BWS, focusing on insulin-like growth factor pathways, which are poorly known in this syndrome. We examined the IGF2R, the primary receptor of IGF2, WNT, and autophagy/lysosomal pathways in BWS patient-derived lymphoblastoid cell lines, showing different genetic and epigenetic defects. The findings reveal a decreased expression and mislocalization of IGF2R protein, suggesting receptor dysfunction. Additionally, our results point to a dysregulation in the AKT/GSK-3/mTOR pathway, along with imbalances in autophagy and the WNT pathway. In conclusion, BWS cells, regardless of the genetic/epigenetic profiles, are characterized by alteration of the IGF2R pathway that is associated with the perturbation of the autophagy and lysosome processes. These alterations seem to be a key point of the molecular pathogenesis of BWS and potentially contribute to BWS's characteristic overgrowth and cancer susceptibility. Our study also uncovers alterations in the WNT pathway across all BWS cell lines, consistent with its role in growth regulation and cancer development.
Asunto(s)
Síndrome de Beckwith-Wiedemann , Neoplasias , Humanos , Autofagia/genética , Síndrome de Beckwith-Wiedemann/genética , Línea Celular , Glucógeno Sintasa Quinasa 3RESUMEN
Currently, coronary artery bypass and reperfusion therapies are considered the gold standard in long-term treatments to restore heart function after acute myocardial infarction. As a drawback of these restoring strategies, reperfusion after an ischemic insult and sudden oxygen exposure lead to the exacerbated synthesis of additional reactive oxidative species and the persistence of increased oxidation levels. Attempts based on antioxidant treatment have failed to achieve an effective therapy for cardiovascular disease patients. The controversial use of vitamin C as an antioxidant in clinical practice is comprehensively systematized and discussed in this review. The dose-dependent adsorption and release kinetics mechanism of vitamin C is complex; however, this review may provide a holistic perspective on its potential as a preventive supplement and/or for combined precise and targeted therapeutics in cardiovascular management therapy.
Asunto(s)
Ácido Ascórbico , Infarto del Miocardio , Humanos , Especies Reactivas de Oxígeno , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Vitamina E/uso terapéutico , Estrés Oxidativo , Vitaminas , Infarto del Miocardio/tratamiento farmacológicoRESUMEN
Background: Sudden cardiac death (SCD) is an important risk for adults with repaired coarctation of the aorta (rCoA). We aimed determine if there are clinical risk factors for SCD in adults with rCoA. Methods and results: SCD events and clinical data from all adults with rCoA at a tertiary care center (2007-2017) were evaluated. In 167 adults with rCoA (39 ± 11 years old, 75 (45%) female) SCD occurred in 8 (5%) (vs. age-matched adults 0.9%). Those with SCD demonstrated significant QTc prolongation (QTc: 479 ± 16 vs. 434 ± 30 msec, p < 0.001). Overall, adults with rCoA and a prolonged sex-normative QTc interval had a 12-fold increased risk of SCD (x2 (1) = 12.3, p < 0.001), with men sustaining SCD at younger ages (42 ± 13 years vs. women 60 ± 10 years, p < 0.05). Multiple logistic regression modeling demonstrated that prolonged QTc selectively advanced risk for SCD in men only (x2 QTc prolongation 8.46, p < 0.005 and x2 age 0.29, p = 0.587), whereas in women, age was associated with SCD risk (x2 QTc prolongation 2.84, p = 0.092 and x2 age 7.81, p = 0.005). Non-sustained ventricular tachycardia, ventricular dysfunction, and myocardial fibrosis did not significantly impact SCD risk. Conclusions: There is an unanticipated high burden of SCD in adults with rCoA, occurring in men at younger age than women, suspicious for primary electrophysiologic dysfunction. Future investigation of sex-specific SCD risk in rCoA is important to better understand this disease and its late phenotype.
RESUMEN
BACKGROUND: Commonly used endoscopic nasal polyp grading scales have been shown to correlate poorly with symptom scores and quality of life metrics. The recently described Postoperative Polyp Scale (POPS) is a grading system that more accurately characterizes polyp recurrence in postoperative sinus cavities by describing incremental recurrence in relation to the surgically opened sinus cavities. OBJECTIVE: The objective of this study was to determine if the POPS correlated with sinonasal symptoms. METHODS: CRSwNP patients were prospectively administered SNOT-22 questionnaires and graded according to the POPS starting at their 1-month postoperative appointments. Total POPS scores (sum of each side) and Max POPS score (larger value of left and right) were correlated with SNOT-22 total scores and subdomains using Kendall correlation testing. RESULTS: A total of 127 patients were enrolled in the study. Both Total POPS or Max POPS were significantly correlated to the SNOT-22 total score (P < .001, P < .001), Rhinologic (P < .001, P < .001), Extra-Nasal Rhinologic (P < .001, P < .001), Ear/Facial (P < .001, P < .001), and Psychologic (P = .028, P = .017) subdomains. Kendall's tau indicated strong correlation (≥0.3) with Rhinologic subdomain, moderate correlation (.21-.29) with Extra-Nasal Rhinologic and Ear/Facial subdomains, and weak correlation (.1-.19) with Psychologic subdomain. CONCLUSION: Previous endoscopic nasal polyp grading scales poorly correlate with symptoms and patient reported outcome measures. The new POPS moderately correlates with the total SNOT-22 score and strongly correlates with the Rhinologic subdomain, indicating that it may have good potential as a tool to evaluate postoperative CRSwNP patients.