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Cannabidiol (CBD), a non-psychoactive compound derived from the cannabis plant, has been confirmed to induce anxiolytic-like and antipsychotic-like effects. However, the exact mechanisms remain unclear. This study substantiated CBD's interaction with the 5-HT1A receptor (5-HT1AR) in vitro (CHO cells expressing human 5-HT1AR) and in vivo (rat lower lip retraction test, LLR test). We then assessed the impact of CBD in mice using the stress-induced hyperthermia (SIH) model and the phencyclidine (PCP)-induced negative symptoms of schizophrenia model, respectively. Concurrently, we investigated whether WAY-100635, a typical 5-HT1AR antagonist, could attenuate these effects. Furthermore, the neurotransmitter changes through high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were studied. Results revealed that CBD exhibits selective 5-HT1AR agonists-mediated effects in the rat lower lip retraction test, aligning with the robust agonistic (EC50 = 1.75 µM) profile observed in CHO cells. CBD at 3 mg/kg significantly reduced SIH (ΔT), a response that WAY-100635 abolished. Chronic administration of CBD at 100 mg/kg mitigated the increase in PCP-induced immobility time in the forced swim test (FST) and tail suspension test (TST). Moreover, it induced significant alterations in gamma-aminobutyric acid (GABA) and norepinephrine (NE) levels within the hippocampus (HPC). Thus, we concluded that the 5-HT1AR mediates CBD's anxiolytic-like effects. Additionally, CBD's effects on the negative symptoms of schizophrenia may be linked to changes in GABA and NE levels in the hippocampus. These findings offer novel insights for advancing the exploration of CBD's anxiolytic-like and antipsychotic-like effects.
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Ansiolíticos , Antipsicóticos , Cannabidiol , Cricetinae , Ratones , Ratas , Humanos , Animales , Antipsicóticos/farmacología , Ansiolíticos/farmacología , Cannabidiol/farmacología , Serotonina , Cricetulus , Cromatografía Liquida , Espectrometría de Masas en Tándem , Ácido gamma-AminobutíricoRESUMEN
Cannabinoid CB2R agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to CB1R agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CB2R agonists rather than CB2R antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3' site and the cycloalkyl group at the C-4' site for CB2R activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB2 receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CB2R and 5-HT1AR dual agonist, albeit with some undesired antagonist activity for CB1R. It demonstrated significant CB2R partial agonism while maintaining a level of 5-HT1AR agonistic and CB1R antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.
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Cannabidiol , Receptor de Serotonina 5-HT1A , Humanos , Simulación del Acoplamiento Molecular , Serotonina , Depresión/tratamiento farmacológico , Agonismo Inverso de Drogas , Agonistas de Receptores de Cannabinoides , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Agonistas de Receptores de Serotonina , Ansiedad , Receptor Cannabinoide CB2 , Receptor Cannabinoide CB1RESUMEN
The regulation of fatty acid metabolism is crucial for milk flavor and quality. Therefore, it is important to explore the genes that play a role in fatty acid metabolism and their mechanisms of action. The RNA-binding protein Musashi2 (MSI2) is involved in the regulation of numerous biological processes and plays a regulatory role in post-transcriptional translation. However, its role in the mammary glands of dairy cows has not been reported. The present study examined MSI2 expression in mammary glands from lactating and dry milk cows. Experimental results in bovine mammary epithelial cells (BMECs) showed that MSI2 was negatively correlated with the ability to synthesize milk fat and that MSI2 decreased the content of unsaturated fatty acids (UFAs) in BMECs. Silencing of Msi2 increased triglyceride accumulation in BMECs and increased the proportion of UFAs. MSI2 affects TAG synthesis and milk fat synthesis by regulating fatty acid synthase (FASN). In addition, RNA immunoprecipitation experiments in BMECs demonstrated for the first time that MSI2 can bind to the 3'-UTR of FASN mRNA to exert a regulatory effect. In conclusion, MSI2 affects milk fat synthesis and fatty acid metabolism by regulating the triglyceride synthesis and UFA content through binding FASN.
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Ácidos Grasos , Lactancia , Femenino , Bovinos , Animales , Ácidos Grasos/metabolismo , Glándulas Mamarias Animales/metabolismo , Ácidos Grasos Insaturados/metabolismo , Leche/química , Triglicéridos/metabolismo , Ácido Graso Sintasas/genética , Células Epiteliales/metabolismoRESUMEN
In this paper, we consider a diffusive SIS epidemic reaction-diffusion model with linear source in a heterogeneous environment in which the frequency-dependent incidence function is SI/(c + S + I) with c a positive constant. We first derive the uniform bounds of solutions, and the uniform persistence property if the basic reproduction number $\mathcal{R}_{0}>1$. Then, in some cases we prove that the global attractivity of the disease-free equilibrium and the endemic equilibrium. Lastly, we investigate the asymptotic profile of the endemic equilibrium (when it exists) as the diffusion rate of the susceptible or infected population is small. Compared to the previous results [1, 2] in the case of c=0, some new dynamical behaviors appear in the model studied here; in particular, $\mathcal{R}_{0}$ is a decreasing function in c∈[0, ∞) and the disease dies out once c is properly large. In addition, our results indicate that the linear source term can enhance the disease persistence.
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Número Básico de Reproducción , Enfermedades Transmisibles/transmisión , Epidemias , Enfermedades Transmisibles/epidemiología , Simulación por Computador , Susceptibilidad a Enfermedades/epidemiología , Transmisión de Enfermedad Infecciosa , Humanos , Incidencia , Modelos Biológicos , Dinámica PoblacionalRESUMEN
Inorganic persulfate salts were identified as efficient reagents for the oxidative aromatization of 3,4-dihydroquinolin-2(1 H)-ones through the activation of readily available transition metals, such as iron and copper. The feasible protocol conforming to the requirement of green chemistry was utilized in the preparation of the key intermediate (7-(4-chlorobutoxy)quinolin-2(1 H)-one 2) of brexpiprazole in 80% isolated yield on a 100 g scale, and different quinolin-2(1 H)-one derivatives with various functional groups were demonstrated in 52-89% yields.
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Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.
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Hipertensión Pulmonar/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/farmacología , Inhibidores de Fosfodiesterasa 5/farmacocinética , Pirimidinas/farmacología , Pirimidinas/farmacocinética , Animales , Perros , Diseño de Fármacos , Femenino , Semivida , Masculino , Inhibidores de Fosfodiesterasa 5/síntesis química , Pirimidinas/síntesis química , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Citrato de Sildenafil/farmacología , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Objective To evaluate the association between small,dense low-density lipoprotein cholesterol (sdLDL-C)and severity of coronary atherosclerosis disease (CAD).Methods A total of 436 outpatients with suspected coronary atherosclerotic heart disease (CAD) and underwent coronary computed tomography (CT) were consecutively enrolled from July 2015 to March 2016 in Fuwai Hospital.Correlations between serum sdLDL-C and the severity of CAD including characteristics of plaque,the number of stenosed coronary vessels,the degree of stenosis were analyzed.Results sdLDL-C was positively correlated with apolipoprotein B (apoB),triglyceride (TG),total cholesterol (TC),low-density lipoprotein cholesterol (LDL-C),blood glucose (Glu)with the coefficient correlation 0.644,0.631,0.558,0.434 and 0.145 successively(P < 0.01),and negatively correlated with high-density lipoprotein cholesterol (HDL-C) (r =-0.241,P < 0.01).sdLDL-C and apoB were the risk factors for severe CAD (triple-vessel disease and severe stenosis),independent of traditional risk factors (age,gender,hypertension,diabetes,smoking,alcohol consumption)and the use of lipidlowering agents.For the patients with triple-vessel disease,odds ratio of LDL-C,sdLDL-C and apoB were 1.936,2.673 and 31.707 respectively.For the patients with severe stenosis,LDL-C was not an independent factor,while sdLDL-C and apoB still had predictive value (odds ratio were 2.000 and 9.457 respectively).Conclusion sdLDL-C should be a predictor of severe CAD independent of traditional risk factors that may be useful for further risk stratification in the patients with CAD.
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To delineate the influence of hemodynamic force on cell adhesion processes, model in vitro fluidic assays that mimic physiological conditions are commonly employed. Herein, we offer a framework for solution of the three-dimensional Navier-Stokes equations using computational fluid dynamics (CFD) to estimate the forces resulting from fluid flow near a plane acting on a sphere that is either stationary or in free flow, and we compare these results to a widely used theoretical model that assumes Stokes flow with a constant shear rate. We find that while the full three-dimensional solutions using a parabolic velocity profile in CFD simulations yield similar translational velocities to those predicted by the theoretical method, the CFD approach results in approximately 50% larger rotational velocities over the wall shear stress range of 0.1-5.0â dynesâ cm(-2). This leads to an approximately 25% difference in force and torque calculations between the two methods. When compared with experimental measurements of translational and rotational velocities of microspheres or cells perfused in microfluidic channels, the CFD simulations yield significantly less error. We propose that CFD modelling can provide better estimations of hemodynamic force levels acting on perfused microspheres and cells in flow fields through microfluidic devices used for cell adhesion dynamics analysis.
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Wall shear stress (WSS) has been investigated as a prognostic marker for the prospective identification of rapidly progressing coronary artery disease (CAD) and atherosclerotic lesions likely to gain high-risk (vulnerable) characteristics. The goal of this study was to compare biplane angiographic vs. intravascular ultrasound (IVUS) derived reconstructed coronary geometries to evaluate agreement in geometry, computed WSS, and association of WSS and CAD progression. Baseline and 6-month follow-up angiographic and IVUS imaging data were collected in patients with non-obstructive CAD (n = 5). Three-dimensional (3D) reconstructions of the coronary arteries were generated with each technique, and patient-specific computational fluid dynamics models were constructed to compute baseline WSS values. Geometric comparisons were evaluated in arterial segments (n = 9), and hemodynamic data were evaluated in circumferential sections (n = 468). CAD progression was quantified from serial IVUS imaging data (n = 277), and included virtual-histology IVUS (VH-IVUS) derived changes in plaque composition. There was no significant difference in reconstructed coronary segment lengths and cross-sectional areas (CSA), however, IVUS derived geometries exhibited a significantly larger left main CSA than the angiographic reconstructions. Computed absolute time-averaged WSS (TAWSSABS) values were significantly greater in the IVUS derived geometries, however, evaluations of relative TAWSS (TAWSSREL) values revealed improved agreement and differences within defined zones of equivalence. Associations between VH-IVUS defined CAD progression and angiographic or IVUS derived WSS exhibited poor agreement when examining TAWSSABS data, but improved when evaluating the association with TAWSSREL data. We present data from a small cohort of patients highlighting strong agreement between angiographic and IVUS derived coronary geometries, however, limited agreement is observed between computed WSS values and associations of WSS with CAD progression.
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Angiografía por Tomografía Computarizada/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Circulación Coronaria , Vasos Coronarios/diagnóstico por imagen , Hemodinámica , Imagenología Tridimensional/métodos , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Ultrasonografía Intervencional/métodos , Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/fisiopatología , Progresión de la Enfermedad , Humanos , Modelos Cardiovasculares , Modelación Específica para el Paciente , Placa Aterosclerótica , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estrés Mecánico , Factores de TiempoRESUMEN
AIMS: Large plaque burden, certain phenotypes, and low wall shear stress (WSS) are associated with adverse outcomes and high WSS with development of plaque vulnerability. We aimed to investigate the incremental value of the combination of plaque burden, WSS and plaque phenotype for prediction of coronary atherosclerotic plaque progression and vulnerability. METHODS: Twenty patients with CAD underwent baseline and 6-month follow-up coronary virtual histology-intravascular ultrasound (VH-IVUS) and computational fluid dynamics modeling for calculation of WSS. Low WSS was defined as <10 dynes/cm(2) and high WSS as ≥25 dynes/cm(2). Baseline plaque characteristics and WSS were related to plaque progression and vulnerability. RESULTS: In 2249 VH-IVUS frames analyzed, coronary segments with both plaque burden >40% and low WSS had significantly greater change in plaque area at follow-up (+0.68 ± 1.05 mm(2)), compared to segments with plaque burden >40% without low WSS (-0.28 ± 1.32 mm(2)) or segments with low WSS and plaque burden ≤40% (+0.05 ± 0.71 mm(2)) (p = 0.047). Among plaque phenotypes, pathologic intimal thickening (PIT) had the greatest increase in necrotic core (NC) area (p = 0.06) and greatest decrease in fibro-fatty (FF) area (p < 0.0001). At follow-up, compared to segments with either plaque burden >60%, PIT, or high WSS, those with a combination of plaque burden >60%, PIT, and high WSS developed greater increase in NC area (p = 0.002), greater decrease in FF (p = 0.004) and fibrous areas (p < 0.0001), and higher frequency of expansive remodeling (p = 0.019). CONCLUSION: Combination of plaque burden, WSS, and plaque phenotype has incremental value for prediction of coronary plaque progression and increased plaque vulnerability in patients with non-obstructive CAD.
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Enfermedad de la Arteria Coronaria/patología , Endotelio Vascular/patología , Placa Aterosclerótica/patología , Anciano , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Progresión de la Enfermedad , Endotelio Vascular/diagnóstico por imagen , Femenino , Humanos , Hidrodinámica , Masculino , Persona de Mediana Edad , Fenotipo , Placa Aterosclerótica/diagnóstico por imagen , Pronóstico , Resistencia al Corte , Estrés Mecánico , Ultrasonografía IntervencionalRESUMEN
Cell therapies offer exciting new opportunities for effectively treating many human diseases. However, delivery of therapeutic cells by intravenous injection, while convenient, relies on the relatively inefficient process of homing of cells to sites of injury. To address this limitation, a novel strategy has been developed to load cells with superparamagnetic iron oxide nanoparticles (SPIOs), and to attract them to specific sites within the body by applying an external magnetic field. The feasibility of this approach is demonstrated using human mesenchymal stem cells (hMSCs), which may have a significant potential for regenerative cell therapies due to their ease of isolation from autologous tissues, and their ability to differentiate into various lineages and modulate their paracrine activity in response to the microenvironment. The efficient loading of hMSCs with polyethylene glycol-coated SPIOs is achieved, and it is found that SPIOs are localized primarily in secondary lysosomes of hMSCs and are not toxic to the cells. Further, the key stem cell characteristics, including the immunophenotype of hMSCs and their ability to differentiate, are not altered by SPIO loading. Through both experimentation and mathematical modeling, it is shown that, under applied magnetic field gradients, SPIO-containing cells can be localized both in vitro and in vivo. The results suggest that, by loading SPIOs into hMSCs and applying appropriate magnetic field gradients, it is possible to target hMSCs to particular vascular networks.
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Compuestos Férricos/química , Nanopartículas de Magnetita/química , Células Madre Mesenquimatosas/citología , Nanopartículas/química , Humanos , Nanopartículas de Magnetita/efectos adversos , Nanopartículas/efectos adversosRESUMEN
BACKGROUND: Extremes of wall shear stress (WSS) have been associated with plaque progression and transformation, which has raised interest in the clinical assessment of WSS. We hypothesized that calculated coronary WSS is predicted only partially by luminal geometry and that WSS is related to plaque composition. METHODS AND RESULTS: Twenty-seven patients with coronary artery disease underwent virtual histology intravascular ultrasound and Doppler velocity measurement for computational fluid dynamics modeling for WSS calculation in each virtual histology intravascular ultrasound segment (N=3581 segments). We assessed the association of WSS with plaque burden and distribution and with plaque composition. WSS remained relatively constant across the lower 3 quartiles of plaque burden (P=0.08) but increased in the highest quartile of plaque burden (P<0.001). Segments distal to lesions or within bifurcations were more likely to have low WSS (P<0.001). However, the majority of segments distal to lesions (80%) and within bifurcations (89%) did not exhibit low WSS. After adjustment for plaque burden, there was a negative association between WSS and percent necrotic core and calcium. For every 10 dynes/cm(2) increase in WSS, percent necrotic core decreased by 17% (P=0.01), and percent dense calcium decreased by 17% (P<0.001). There was no significant association between WSS and percent of fibrous or fibrofatty plaque components (P=NS). CONCLUSIONS: IN PATIENTS WITH CORONARY ARTERY DISEASE: (1) Luminal geometry predicts calculated WSS only partially, which suggests that detailed computational techniques must be used to calculate WSS. (2) Low WSS is associated with plaque necrotic core and calcium, independent of plaque burden, which suggests a link between WSS and coronary plaque phenotype. (J Am Heart Assoc. 2012;1:e002543 doi: 10.1161/JAHA.112.002543.).
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Cyclic nucleotide phosphodiesterase type 5 (PDE5) is a prime drug target for treating the diseases associated with a lower level of the cyclic guanosine monophosphate (cGMP), which is a specific substrate for PDE5 hydrolysis. Here we report a series of novel PDE5 inhibitors with the new scaffold of the monocyclic pyrimidin-4(3H)-one ring developed using the structure-based discovery strategy. In total, 37 derivatives of the pyrimidin-4(3H)-ones, were designed, synthesized, and evaluated for their inhibitory activities to PDE5, resulting in 25 compounds with IC50 ranging from 1 to 100 nM and 11 compounds with IC50 ranging from 1 to 10 nM. Compound 5, 5,6-diethyl-2-[2-n-propoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]pyrimid-4(3H)-one, the most potent compound, has an excellent IC50 (1.6 nM) in vitro and a good efficacy in a rat model of erection. It thus provides a potential candidate for the further development into a new drug targeting PDE5.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/efectos de los fármacos , Diseño de Fármacos , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Pirimidinonas/química , Pirimidinonas/farmacología , Dominio Catalítico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Inhibidores de Fosfodiesterasa/síntesis química , Pirimidinonas/síntesis química , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
Ore sample, pretreated at 650 degrees C, was decomposed with aqua regia. Gold in the sample solution was then pre-concentrated by adsorbing with polyurethane foam plastic, released with thiourea solution, and determined by inductively coupled plasma-atomic emission spectrometry and flame atomic absorption spectrometry. Based on the characteristic of the copper matte and sinter containing copper, the effects of sample dissolving condition, matrix effect and interference of coexisting elements were investigated. The accuracy, precision and detection limit were discussed. The results of test show that both of the two methods were suitable for determining the contents of gold in copper matte and sintered copper material.
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BACKGROUND: Experimental studies suggest that low wall shear stress (WSS) promotes plaque development and high WSS is associated with plaque destabilization. We hypothesized that low-WSS segments in patients with coronary artery disease develop plaque progression and high-WSS segments develop necrotic core progression with fibrous tissue regression. METHODS AND RESULTS: Twenty patients with coronary artery disease underwent baseline and 6-month radiofrequency intravascular ultrasound (virtual histology intravascular ultrasound) and computational fluid dynamics modeling for WSS calculation. For each virtual histology intravascular ultrasound segment (n=2249), changes in plaque area, virtual histology intravascular ultrasound-derived plaque composition, and remodeling were compared in low-, intermediate-, and high-WSS categories. Compared with intermediate-WSS segments, low-WSS segments developed progression of plaque area (P=0.027) and necrotic core (P<0.001), whereas high-WSS segments had progression of necrotic core (P<0.001) and dense calcium (P<0.001) and regression of fibrous (P<0.001) and fibrofatty (P<0.001) tissue. Compared with intermediate-WSS segments, low-WSS segments demonstrated greater reduction in vessel (P<0.001) and lumen area (P<0.001), and high-WSS segments demonstrated an increase in vessel (P<0.001) and lumen (P<0.001) area. These changes resulted in a trend toward more constrictive remodeling in low- compared with high-WSS segments (73% versus 30%; P=0.06) and more excessive expansive remodeling in high- compared with low-WSS segments (42% versus 15%; P=0.16). CONCLUSIONS: Compared with intermediate-WSS coronary segments, low-WSS segments develop greater plaque and necrotic core progression and constrictive remodeling, and high-WSS segments develop greater necrotic core and calcium progression, regression of fibrous and fibrofatty tissue, and excessive expansive remodeling, suggestive of transformation to a more vulnerable phenotype. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00576576.
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Enfermedad de la Arteria Coronaria , Vasos Coronarios , Placa Aterosclerótica , Ultrasonografía Intervencional/métodos , Anciano , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Calcinosis/fisiopatología , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/patología , Vasos Coronarios/fisiopatología , Progresión de la Enfermedad , Femenino , Fibrosis , Humanos , Hidrodinámica , Masculino , Persona de Mediana Edad , Necrosis , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/patología , Placa Aterosclerótica/fisiopatología , Estudios Prospectivos , Estrés MecánicoRESUMEN
BACKGROUND: Although culprit lesions in ST-segment elevation myocardial infarction (STEMI) cluster in the proximal coronary arteries, their relationship to bifurcations and curvatures, where blood flow is disturbed, is unknown. We hypothesized that (a) culprit lesions localize to disturbed flow distal to bifurcations and curvatures and (b) the distribution of culprit lesions in the left (LCA) and right coronary arteries (RCA) and resulting infarct size are related to the location of bifurcations and curvatures. METHODS: Emory University's contribution to the National Cardiovascular Data Registry was queried for STEMIs. Using quantitative coronary angiography, the distances from the vessel ostium, major bifurcations, and major curvatures to the culprit lesion were measured in 385 patients. RESULTS: Culprit lesions were located within 20 mm of a bifurcation in 79% of patients and closer to the bifurcation in the LCA compared with the RCA (7.4 ± 7.3 vs 17.7 ± 14.8 mm, P < .0001). Of RCA culprit lesions, 45% were located within 20 mm of a major curvature. Compared with those in the RCA, culprit lesions in the LCA were located more proximally (24.4 ± 16.5 vs 44.7 ± 28.8 mm, P = .0003) and were associated with larger myocardial infarctions as assessed by peak creatine kinase-MB (208 ± 222 vs 140 ± 153 ng/dL, P = .001) and troponin I (59 ± 62 vs 40 ± 35 ng/dL, P = .0006) and with higher in-hospital mortality (5.2% vs 1.1%, P = .04). CONCLUSIONS: In patients with STEMI, culprit lesions are frequently located immediately distal to bifurcations and in proximity to major curvatures where disturbed flow is known to occur. This supports the role of wall shear stress in the pathogenesis of STEMI.
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Vasos Coronarios/patología , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/patología , Placa Aterosclerótica/patología , Síndrome Coronario Agudo/patología , Anciano , Angiografía Coronaria , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/fisiopatología , Placa Aterosclerótica/fisiopatología , Flujo Sanguíneo RegionalRESUMEN
OBJECTIVE: To investigate the biocompatibility of a novel copper-containing composite to provide preclinical data for clinical application of intrauterine device (IUD) or intra-vas device (IVD). DESIGN: Prospective experimental study. SETTING: Good laboratory practices laboratories. ANIMALS: Twenty healthy adult mice (SPF grade Kunming white mice, animal code SCXK 2003-0005). INTERVENTION(S): Cytotoxicity tests in vitro were conducted to evaluate the influence of the materials on the morphology, growth, and proliferation of cultured L929 mouse fibroblasts. Acute systemic toxicity tests were conducted to investigate the acute systemic toxic reaction with mice, and then the materials were implanted into the spinal muscle of rabbits (n = 15). The rabbits were sacrificed for pathologic examination at 1, 4, and 12 weeks after surgery. MAIN OUTCOME MEASURE(S): Evaluation of cytotoxicity by MTT assay, cytotoxicity test by direct contact assay, acute systemic toxicity test, and material implantation test. RESULT(S): The cytotoxicity grade of the copper-containing composite was 0-1, suggesting that the material was free of cytotoxicity; no acute systemic toxicity was found in any mice; mild inflammatory reaction was observed in the surrounding tissues of the implanted material in the early implantation stage, which was similar to that of the sham-operated sides. Twelve weeks after implantation, the inflammatory reaction was completely disappeared in the implanted tissue, similarly to the sham-operated sides. The fibrosis membrane surrounding the material became stable gradually over time. CONCLUSION: The copper-containing composite has excellent biocompatibility, which is feasible and safe for the clinical application as a novel contraceptive material.
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Anticoncepción/instrumentación , Anticoncepción/normas , Dispositivos Intrauterinos de Cobre/normas , Animales , Células Cultivadas , Femenino , Ratones , Estudios Prospectivos , ConejosRESUMEN
Disturbed, nonlaminar flow distal to arterial bifurcations contributes to atherosclerosis development and progression. We hypothesized that the presence of a ramus intermedius (RI) amplifies the flow disturbances in the proximal left anterior descending (LAD) artery causing more proximal LAD lesions and larger ST-segment elevation myocardial infarction (STEMI). Emory University's contribution to the National Cardiovascular Data Registry was queried for STEMIs from January 2006 to July 2008. The distance from the LAD ostium to the lesion was measured in patients with angiographically visible culprit lesions. The peak troponin-I, creatinine kinase-MB, and left ventricular ejection fraction were used as markers for infarct size. Of the 386 patients with STEMI, 150 had LAD culprit lesions. The mean lesion distance from the LAD ostium was 15.2 +/- 11.0 mm in the patients with RI (n = 44) and 29 +/- 19 mm in those without RI (n = 106; p <0.01). LAD lesions were more proximal in the patients with RI, with 43% and 63% of lesions occurring in the first 10 and 20 mm of the LAD, respectively, versus 10% and 32% in those without RI (p <0.01). Patients with RI had greater peak troponin-I (69 +/- 40 ng/ml vs 50 +/- 39 ng/ml, p = 0.01) and peak creatinine kinase-MB (277 +/- 271 ng/ml vs 174 +/- 190 ng/ml, p = 0.01). A trend was seen toward a lower left ventricular ejection fraction in patients with RI (36 +/- 10% versus 40 +/- 11%, p = 0.06). In conclusion, the presence of RI was associated with more proximal LAD lesions and larger anterior infarctions, suggesting anatomy-induced flow disturbances have important clinical implications.
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Anomalías de los Vasos Coronarios/patología , Vasos Coronarios , Infarto del Miocardio/patología , Anciano , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
Despite the well-known close association, direct evidence linking disturbed flow to atherogenesis has been lacking. We have recently used a modified version of carotid partial ligation methods to show that it acutely induces low and oscillatory flow conditions, two key characteristics of disturbed flow, in the mouse common carotid artery. Using this model, we have provided direct evidence that disturbed flow indeed leads to rapid and robust atherosclerosis development in Apolipoprotein E knockout mouse. We also developed a method of endothelial RNA preparation with high purity from the mouse carotid intima. Using this mouse model and method, we found that partial ligation causes endothelial dysfunction in a week, followed by robust and rapid atheroma formation in two weeks in a hyperlipidemic mouse model along with features of complex lesion formation such as intraplaque neovascularization by four weeks. This rapid in vivo model and the endothelial RNA preparation method could be used to determine molecular mechanisms underlying flow-dependent regulation of vascular biology and diseases. Also, it could be used to test various therapeutic interventions targeting endothelial dysfunction and atherosclerosis in considerably reduced study duration.
Asunto(s)
Aterosclerosis/fisiopatología , Enfermedades de las Arterias Carótidas/fisiopatología , Modelos Animales de Enfermedad , Endotelio Vascular/química , ARN/aislamiento & purificación , Animales , Aterosclerosis/genética , Arterias Carótidas/química , Arterias Carótidas/fisiopatología , Arterias Carótidas/cirugía , Enfermedades de las Arterias Carótidas/genética , Ligadura , Ratones , Túnica Íntima/químicaRESUMEN
Although traditional cardiovascular risk factors 'prime the soil' for atherogenesis systemically, atherosclerosis primarily occurs in a site-specific manner with a predilection towards the inner wall of curvatures and outer wall of bifurcations with sparing of flow-dividers. Wall shear stress is a frictional force exerted parallel to the vessel wall that leads to alteration of the endothelial phenotype, endothelial cell signaling, gene and protein expression leading to a proinflammatory phenotype, reduced nitric oxide availability and disruption of the extracellular matrix, which in turn leads to plaque development. Clinical and experimental data are emerging that suggest the pathobiology associated with abnormal wall shear stress results in atherosclerotic plaque development and progression.