RESUMEN

Dilated cardiomyopathy (DCM) is the leading cause of heart transplantation. By microRNA (miRNA) array, a Kaposi's sarcoma-associated herpes virus (KSHV)-encoded miRNA, kshv-miR-K12-1-5p, was detected in patients with DCM. The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up. Increased KSHV seropositivity and quantitative titers were found in the patients with DCM compared with the non-DCM group (22.0% versus 9.1%, p < 0.05; 168 versus 14 copies/mL plasma, p < 0.05). The risk of the individual end point of death from cardiovascular causes or heart transplantation was increased among DCM patients with the KSHV DNA seropositivity during follow-up (adjusted hazard ratio 1.38, 95% confidence interval 1.01-1.90; p < 0.05). In heart tissues, the KSHV DNA load was also increased in the heart from patients with DCM in comparison with healthy donors (1016 versus 29 copies/105 cells, p < 0.05). The KSHV and kshv-miR-K12-1-5p in DCM hearts were detected using immunofluorescence and fluorescence staining in situ hybridization. KSHV itself was exclusively detectable in CD31-positive endothelium, while kshv-miR-K12-1-5p could be detected in both endothelium and cardiomyocytes. Moreover, kshv-miR-K12-1-5p released by KSHV-infected cardiac endothelium could disrupt the type I interferon signaling pathway in cardiomyocytes. Two models of kshv-miR-K12-1-5p overexpression (agomiR and recombinant adeno-associated virus) were used to explore the roles of KSHV-encoded miRNA in vivo. The kshv-miR-K12-1-5p aggravated known cardiotropic viruses-induced cardiac dysfunction and inflammatory infiltration. In conclusion, KSHV infection was a risk factor for DCM, providing developmental insights of DCM involving virus and its miRNA ( https://clinicaltrials.gov . Unique identifier: NCT03461107).

Asunto(s)

Cardiomiopatía Dilatada , Herpesvirus Humano 8 , MicroARNs , Sarcoma de Kaposi , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/metabolismo , Cardiomiopatía Dilatada/genética , Transducción de Señal

RESUMEN

OBJECTIVE: To evaluate the safety and exploratory efficacy of intratympanic administration of OTO-313 in patients with tinnitus. STUDY DESIGN: Single intratympanic injection of OTO-313 evaluated in a randomized, double-blind, placebo-controlled Phase 1/2 clinical study. SETTING: Tertiary referral centers. PATIENTS: Patients with unilateral tinnitus (moderate-severe) with tinnitus duration 1 to 6 months. INTERVENTIONS: Intratympanic OTO-313. MAIN OUTCOME MEASURES: Safety and change from baseline in tinnitus functional index (TFI), daily ratings of tinnitus loudness and annoyance, and patient global impression of change (PGIC). RESULTS: OTO-313 was well-tolerated with lower incidence of adverse events than placebo. Mean TFI reduction from baseline favored OTO-313 at Week 2, 4, and 8. A clinically meaningful, 13-point improvement on the TFI was observed in 43% (6/14) of OTO-313 patients at both Weeks 4 and 8 versus 13% (2/16) of placebo patients (ad hoc responder analysis, p-value < 0.05). Reductions in daily ratings of tinnitus loudness and annoyance favored OTO-313 compared with placebo. In OTO-313 responders, a strong correlation existed between change from baseline in TFI score and changes in tinnitus loudness, tinnitus annoyance, and PGIC. CONCLUSIONS: OTO-313 was well-tolerated and demonstrated a higher proportion of responders than placebo across consecutive visits (Weeks 4 and 8) supporting further clinical development of OTO-313 for the treatment of tinnitus.

Asunto(s)

Acúfeno , Método Doble Ciego , Humanos , Inyección Intratimpánica , Acúfeno/tratamiento farmacológico , Resultado del Tratamiento

RESUMEN

Cardiomyopathy is the leading cause of increased mortality in diabetes. In the present study, we investigated the effects of decorin (DCN) gene therapy on left ventricular function, cardiac inflammation and fibrosis in type 2 diabetes. Type 2 diabetes was induced in male Wistar rats by high fat diet (HFD, 60% of calories as fat) and STZ (20 mg/kg, intraperitoneal). Diabetic rats were divided into (n=6 for each group) the control group, the GFP-treated group and the DCN-treated group, received intravenous injection of saline solution, recombinant adeno-associated viral (rAAV)-GFP, and rAAV-DCN, respectively. We evaluated cardiac inflammation, fibrosis, left ventricular function at 6 months after gene delivery. Results turned out that rAAV-DCN treatment attenuated diabetic cardiomyopathy with improved LV function compared with control animals, which might be related to the reduced cardiac inflammation and fibrosis. These protective effects were associated with TGFß1 pathway (ERK1/2 and smad-2) and NF-κB pathway, which may due to the decreased activation level of IGF-IR, increased expression of PKC-α and Hsp70. In conclusion, our results show that rAAV-mediated DCN therapy may be beneficial in the treatment of Diabetic Cardiomyopathy.

Asunto(s)

Decorina/genética , Decorina/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/metabolismo , Animales , Glucemia/metabolismo , Dependovirus/fisiología , Cardiomiopatías Diabéticas/prevención & control , Fibrosis/metabolismo , Terapia Genética/métodos , Células HEK293 , Humanos , Inflamación/etiología , Inflamación/genética , Inflamación/prevención & control , Metabolismo de los Lípidos , Masculino , Miocardio/metabolismo , Ratas Wistar

RESUMEN

Student housing significantly influences the quality and competitiveness of the university education environment. Whereas the traditional post-occupancy evaluations (POEs) of buildings have typically focussed on investigating users' satisfaction, an earlier study developed the gap theory based post-occupancy evaluation (GTbPOE) method, by which both the users' expectation and satisfaction (viz. performance gap) of a university dormitory were investigated. To validate the applicability of the GTbPOE method, further research was undertaken to evaluate the building performance of another dormitory. Using face-to-face interviews, responses of 104 dormitory users were collected, of which the relative importance ratings of six essential aspects (namely: visual comfort, thermal comfort, aural comfort, fire safety, hygiene, and communication via information technology) were analyzed via the Analytic Hierarchy Process (AHP). A series of gap analyses on the users' expectation and satisfaction levels corroborated the existence of the adaptation effect on the users' perception: that is, the longer the stay, the smaller the performance gap. A comparative analysis on the findings between the two dormitories - one from the earlier study and the other from the present study - further demonstrated the usefulness of the GTbPOE method in benchmarking building performance. Adoption of this method in future POE studies will enable reliable identification of any shortcoming in building performance and hence, can form the basis for improvement measures to augment the performance of buildings within the built environment.

RESUMEN

Power-frequency electromagnetic fields (PF-EMFs) at 50 Hz are potential health risk factors. This study aimed to explore the effects of long-term exposure to 50-Hz PF-EMFs on general physiological conditions in Sprague-Dawley (SD) rats. During a 24-week exposure period, the body mass and water and food intake of the animals were recorded regularly. The hematologic parameters were detected every 12 weeks, and blood chemistry analyses were performed every 4 weeks. After sacrifice, morphology was identified by hematoxylin-eosin, Masson, and immunohistochemical staining. Fibrosis-related gene expression and oxidative stress status were also detected. Compared with the control group, exposure to 30, 100, or 500 µT PF-EMF did not exert any effect on body mass, food intake, or water intake. Similarly, no significant differences were found in hematologic parameters or blood chemistry analyses among these groups. Furthermore, morphological assays showed that exposure to PF-EMFs had no influence on the structure of the liver or kidney. Finally, fibrosis-related gene expression and oxidative stress status were unaltered by PF-EMF exposure. The present study indicates that 24 weeks of exposure to PF-EMFs at intensities of 30, 100, or 500 µT might not affect hemograms, blood chemistry, fibrosis, or oxidative stress in the liver or kidney in SD rats. © 2020 Bioelectromagnetics Society.

Asunto(s)

Análisis Químico de la Sangre , Campos Electromagnéticos/efectos adversos , Riñón/patología , Riñón/efectos de la radiación , Cirrosis Hepática/etiología , Estrés Oxidativo/efectos de la radiación , Animales , Regulación de la Expresión Génica/efectos de la radiación , Pruebas Hematológicas , Riñón/metabolismo , Cirrosis Hepática/sangre , Cirrosis Hepática/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo

RESUMEN

Background: Whether electromagnetic field (EMF) exposure affects the function of the cardiovascular system is under debate. The present study aimed to investigate the effects of 500 µT EMF exposure on the cardiovascular system in rats. Methods: Forty-eight-week-old male Sprague-Dawley rats were randomly divided into two groups: the sham group and the exposure group. During 24-week EMF exposure (20 h per day), the blood pressure and pulse rate were recorded every 4 weeks. Before sacrifice, electrocardiography, echocardiography, and cardiac catheterization analysis were conducted to evaluate the cardiac function. Meanwhile, hematoxylin-eosin (HE) staining, Western blot, and real-time polymerase chain reaction (PCR) were performed to identify morphological and molecular changes indicative of cardiac remodeling. Results: The heart rate, blood pressure, and pulse rate were not influenced by EMF exposure compared with the control group. In addition, HE staining showed no change in the morphology and arrangement of cardiomyocytes. Further, we found that the mRNA and protein levels of cardiac hypertrophy-related genes were not affected by EMF exposure. Finally, no significant difference was observed in cardiac function between the two groups by echocardiography and cardiac catheterization detection. Conclusion: The 24-week exposure to EMF at 500 µT did not have apparent effects on the cardiovascular system in rats, at least for the variables studied.

Asunto(s)

Sistema Cardiovascular , Campos Electromagnéticos , Animales , Presión Sanguínea , Campos Electromagnéticos/efectos adversos , Corazón/diagnóstico por imagen , Masculino , Ratas , Ratas Sprague-Dawley

RESUMEN

Multiple studies indicate that microRNAs (miRNAs) are involved in diabetes. However, the roles of miRNA in the target organ damages in diabetes remain unclear. This study investigated the functions of miR-320a in diabetic nephropathy (DN). In this study, db/db mice were used to observe the changes in podocytes and their function in vivo, as well as in cultured mouse podocyte cells (MPC5) exposed to high glucose in vitro. To further explore the role of miR-320a in DN, recombinant adeno-associated viral particle was administered intravenously to manipulate the expression of miR-320a in db/db mice. Overexpression of miR-320a markedly promoted podocyte loss and dysfunction in DN, including mesangial expansion and increased levels of proteinuria, serum creatinine and urea nitrogen. Furthermore, MafB was identified as a direct target of miR-320a through AGO2 co-immunoprecipitation, luciferase reporter assay, and Western blotting. Moreover, re-expression of MafB rescued miR-320a-induced podocyte loss and dysfunction by upregulating the expressions of Nephrin and glutathione peroxidase 3 (Gpx3). Our data indicated that miR-320a aggravated renal disfunction in DN by targeting MafB and downregulating Nephrin and Gpx3 in podocytes, which suggested that miR-320a could be a potential therapeutic target of diabetic nephropathy.

Asunto(s)

Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/etiología , Factor de Transcripción MafB/metabolismo , MicroARNs/metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Glutatión Peroxidasa/metabolismo , Riñón/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Podocitos/metabolismo , Podocitos/patología

RESUMEN

BACKGROUND: Long non-coding RNAs (lncRNAs) participate in the pathogenesis of cardiovascular diseases. However, whether circulating lncRNAs serve as dilated cardiomyopathy (DCM) biomarkers remains unclear. METHODS: Totally, 266 controls and 818 patients were enrolled. First, microarray-based circulating lncRNA profiling was performed in 10 normal controls and 10 patients with DCM. Second, the top 20 differentially expressed lncRNAs were validated by real-time qPCR in 64 controls and 64 DCM patients. Moreover, lncRNA sequencing was performed in three human heart-derived cell types, and the correlation between circulating lncRNA levels and the severity of heart failure was evaluated in the validated population. The validated two lncRNAs were assessed in 198 DCM patients and 198 matched controls. Finally, the sensitivity and specificity of circulating lncRNA expression in DCM diagnosis were evaluated using receiver-operating characteristic curve analysis, while Cox regression and Kaplan-Meier curve analysis were further performed in 552 DCM patients. RESULTS: Eight candidate lncRNA biomarkers were obtained after microarray screening and real-time PCR validation. Among them, five were validated in the second cohort. However, only the levels of circulating lncRNA ENST00000507296 and ENST00000532365 were significantly correlated with the cardiac function, as well as detectable in at least one of the human heart-derived cell types by lncRNA-seq. Importantly, low circulating ENST00000507296 level was associated with high event-free survival in patients with DCM. CONCLUSIONS: Circulating lncRNA ENST00000507296 was a prognostic biomarker in patients with DCM.

RESUMEN

OBJECTIVES: To compare survival of Hispanic white (HW) and non-Hispanic white (NHW) women with type II endometrial adenocarcinoma (EC). METHODS: Patients with serous, clear cell or grade 3 endometrioid EC were identified from the Surveillance, Epidemiology, and End Results (SEER) program 1988-2009 and were divided into HW and NHW. HW were subdivided into natives and immigrants. RESULTS: Of the 14,434 women, 13,012 (90.2%) were NHW and 1422 (9.8%) were HW. HW were younger than NHW (mean 63 vs. 68years, p<0.001). A higher proportion of HW presented with late stage disease than NHW (43.8% vs. 36.6%, p=0.04). Performing lymphadenectomy was not different but HW were more likely to have positive lymph nodes than NHW (27.6% vs. 23.1%, p=0.02). Further, HW were less likely to receive radiation than NHW (39.5% vs. 42.3%, p=0.04). No difference in clinicopathologic characteristics was found between immigrant and native HW. In multivariate models adjusting for age, stage, histology, surgical treatment, extent of lymphadenectomy, and radiation therapy, no difference in overall survival (OS) (HR 1.06, 95% CI 0.97-1.16, p=0.19) and cancer-specific survival (CSS) (HR 1.02, 95% CI 0.91-1.14, p=0.75) was found between HW and NHW. Interestingly, immigrant HW had better OS (HR 0.74, 95% CI 0.62-0.89, p<0.001) and CSS (HR 0.72, 95% CI 0.58-0.90, P=0.003) than native HW. CONCLUSIONS: Although they were more likely to present with advanced stage and positive nodal disease, no difference in outcome was noted between Hispanic and non-Hispanic whites with EC. Interestingly, immigrant HW had more favorable outcome compared to native HW.

Asunto(s)

Adenocarcinoma/patología , Emigrantes e Inmigrantes , Neoplasias Endometriales/patología , Disparidades en el Estado de Salud , Disparidades en Atención de Salud/etnología , Hispánicos o Latinos , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Población Blanca , Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/terapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Endometrioide/mortalidad , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/terapia , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/terapia , Femenino , Humanos , Histerectomía/estadística & datos numéricos , Metástasis Linfática , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Estadificación de Neoplasias , Radioterapia Adyuvante , Programa de VERF , Resultado del Tratamiento , Estados Unidos , Adulto Joven

RESUMEN

HYPOTHESIS: OTO-201 can provide sustained release to the middle ear and effectively treat otitis media, when compared with FDA-approved ciprofloxacin otic drop formulations. BACKGROUND: There is an unmet medical need for antibiotic therapy that can provide a full course of treatment from a single administration by an otolaryngologist at the time of tympanostomy tube placement, obviating the need for twice daily multiday treatment with short-acting otic drops. METHODS: Studies in guinea pigs and chinchillas were conducted. OTO-201 was administered as a single intratympanic injection and compared with the twice daily multi-day treatment with Ciprodex or Cetraxal otic drops. RESULTS: OTO-201 demonstrated sustained release of ciprofloxacin in the middle ear compartment for days to approximately 2 weeks depending on the dose. The substantial C(max) values and steady drug exposure yielded by OTO-201 were in contrast to the pulsatile short lasting exposure seen with Ciprodex and Cetraxal. OTO-201 was also effective in a preclinical chinchilla model of Streptococcus pneumoniae-induced otitis media. The degree of cure was comparable to that afforded by Ciprodex and Cetraxal. There was no evidence of middle or inner ear pathology in guinea pigs treated with OTO-201, unlike Ciprodex and Cetraxal, which both demonstrated mild cochlear ototoxicity. No adverse effects of the poloxamer 407 vehicle were noted. CONCLUSION: Intratympanic injection of OTO-201 constitutes an attractive treatment option to twice daily multiday dosing with ciprofloxacin ear drops for the treatment of otitis media, as evidenced by superior middle ear drug exposure, efficacy in an acute otitis media model, safety of administration, and convenience of a single dose regimen.

Asunto(s)

Antibacterianos/uso terapéutico , Ciprofloxacina/uso terapéutico , Preparaciones de Acción Retardada/uso terapéutico , Hidrogeles/uso terapéutico , Otitis Media/tratamiento farmacológico , Administración Tópica , Animales , Antibacterianos/administración & dosificación , Chinchilla , Ciprofloxacina/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Modelos Animales de Enfermedad , Cobayas , Hidrogeles/administración & dosificación

RESUMEN

A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.

Asunto(s)

Disponibilidad Biológica , Diseño de Fármacos , Relación Estructura-Actividad , Antivirales/farmacocinética , Química Farmacéutica , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Genotipo , Hepacivirus/efectos de los fármacos , Hepatitis C , Estructura Molecular , ARN Polimerasa Dependiente del ARN , Proteínas no Estructurales Virales/antagonistas & inhibidores

RESUMEN

5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).

Asunto(s)

ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piridonas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Haplorrinos , Piridonas/administración & dosificación , Piridonas/química , Piridonas/farmacocinética , Relación Estructura-Actividad

RESUMEN

A flow-injection system was devised to mimic continuous flow-through pasteurization systems for laboratory thermal inactivation studies. Air bubbles were introduced into the sample stream to create separate moving segments (plugs) of liquid stream during pasteurization while residence time was adjusted by a combination of pump speed and column length. The method was used to obtain thermal inactivation data for Listeria monocytogenes Scott A and Salmonella enteritidis ATCC 13076 in liquid whole eggs at different temperatures and heating times. Thermal inactivation of L. monocytogenes using the capillary tube method (Zcap = 7.3°C) gave results comparable to those obtained with the flow-injection system (Zflow = 7.2°C). The flow-injection system also was used to examine thermal inactivation of S. enteritidis (SE) grown in either tryptic soy broth (TSB) or egg yolk medium (EYM) before inoculation into liquid whole egg (LWE). D-values were obtained by regression analysis and the data showed that SE grown in EYM gave D-values 15 to 120% higher than those obtained for SE grown in TSB. Thermal inactivation studies performed with S. enteritidis grown in commercial broth media may therefore inaccurately represent thermal resistance of S. enteritidis grown in liquid or shell raw egg as may occur in egg-associated outbreaks. The continuous flow-injection system described herein may be adapted to study continuous flow pasteurization processes not easily examined by the traditional capillary tube method.