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1.
Nature ; 584(7822): 589-594, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32814899

RESUMEN

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease.


Asunto(s)
Enfermedades Cardiovasculares/genética , Fractales , Predisposición Genética a la Enfermedad , Corazón/anatomía & histología , Corazón/fisiología , Miocardio/metabolismo , Adulto , Anciano , Animales , Enfermedades Cardiovasculares/fisiopatología , Citoesqueleto/genética , Citoesqueleto/fisiología , Técnicas de Inactivación de Genes , Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo , Corazón/embriología , Hemodinámica , Humanos , Persona de Mediana Edad , Miocardio/citología , Oryzias/embriología , Oryzias/genética , Fenotipo
2.
Eur Radiol ; 29(1): 232-240, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29992384

RESUMEN

OBJECTIVES: We investigated the feasibility and reproducibility of free-breathing motion-corrected multiple inversion time (multi-TI) pulsed renal arterial spin labelling (PASL), with general kinetic model parametric mapping, to simultaneously quantify renal perfusion (RBF), bolus arrival time (BAT) and tissue T1. METHODS: In a study approved by the Health Research Authority, 12 healthy volunteers (mean age, 27.6 ± 18.5 years; 5 male) gave informed consent for renal imaging at 3 T using multi-TI ASL and conventional single-TI ASL. Glyceryl trinitrate (GTN) was used as a vasodilator challenge in six subjects. Flow-sensitive alternating inversion recovery (FAIR) preparation was used with background suppression and 3D-GRASE (gradient and spin echo) read-out, and images were motion-corrected. Parametric maps of RBF, BAT and T1 were derived for both kidneys. Agreement was assessed using Pearson correlation and Bland-Altman plots. RESULTS: Inter-study correlation of whole-kidney RBF was good for both single-TI (r2 = 0.90), and multi-TI ASL (r2 = 0.92). Single-TI ASL gave a higher estimate of whole-kidney RBF compared to multi-TI ASL (mean bias, 29.3 ml/min/100 g; p <0.001). Using multi-TI ASL, the median T1 of renal cortex was shorter than that of medulla (799.6 ms vs 807.1 ms, p = 0.01), and mean whole-kidney BAT was 269.7 ± 56.5 ms. GTN had an effect on systolic blood pressure (p < 0.05) but the change in RBF was not significant. CONCLUSIONS: Free-breathing multi-TI renal ASL is feasible and reproducible at 3 T, providing simultaneous measurement of renal perfusion, haemodynamic parameters and tissue characteristics at baseline and during pharmacological challenge. KEY POINTS: • Multiple inversion time arterial spin labelling (ASL) of the kidneys is feasible and reproducible at 3 T. • This approach allows simultaneous mapping of renal perfusion, bolus arrival time and tissue T 1 during free breathing. • This technique enables repeated measures of renal haemodynamic characteristics during pharmacological challenge.


Asunto(s)
Riñón/irrigación sanguínea , Imagen por Resonancia Magnética/métodos , Arteria Renal/diagnóstico por imagen , Vasodilatación/fisiología , Vasodilatadores/farmacología , Adulto , Femenino , Voluntarios Sanos , Humanos , Masculino , Estudios Prospectivos , Arteria Renal/efectos de los fármacos , Arteria Renal/fisiología , Reproducibilidad de los Resultados , Marcadores de Spin
3.
Am J Physiol Heart Circ Physiol ; 315(4): H950-H957, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-29775415

RESUMEN

Coupling of right ventricular (RV) contractility to afterload is maintained at rest in the early stages of pulmonary arterial hypertension (PAH), but exercise may unmask depleted contractile reserves. We assessed whether elevated afterload reduces RV contractile reserve despite compensated resting function using noninvasive exercise imaging. Fourteen patients with PAH (mean age: 39.1 yr, 10 women and 4 men) and 34 healthy control subjects (mean ageL 35.6 yr, 17 women and 17 men) completed real-time cardiac magnetic resonance imaging during submaximal exercise breathing room air. Control subjects were then also exercised during acute normobaric hypoxia (fraction of inspired O2: 12%). RV contractile reserve was assessed by the effect of exercise on ejection fraction. In control subjects, the increase in RV ejection fraction on exercise was less during hypoxia ( P = 0.017), but the response of left ventricular ejection fraction to exercise did not change. Patients with PAH had an impaired RV reserve, with half demonstrating a fall in RV ejection fraction on exercise despite comparable resting function to controls (PAH: rest 53.6 ± 4.3% vs. exercise 51.4 ± 10.7%; controls: rest 57.1 ± 5.2% vs. exercise 69.6 ± 6.1%, P < 0.0001). In control subjects, the increase in stroke volume index on exercise was driven by reduced RV end-systolic volume, whereas patients with PAH did not augment the stroke volume index, with increases in both end-diastolic and end-systolic volumes. From baseline hemodynamic and exercise capacity variables, only the minute ventilation-to-CO2 output ratio was an independent predictor of RV functional reserve ( P = 0.021). In conclusion, noninvasive cardiac imaging during exercise unmasks depleted RV contractile reserves in healthy adults under hypoxic conditions and patients with PAH under normoxic conditions despite preserved ejection fraction at rest. NEW & NOTEWORTHY Right ventricular (RV) reserve was assessed using real-time cardiac magnetic resonance imaging in patients with pulmonary arterial hypertension and in healthy control subjects under normobaric hypoxia, which has been previously associated with acute pulmonary hypertension. Hypoxia caused a mild reduction in RV reserve, whereas chronic pulmonary arterial hypertension was associated with a marked reduction in RV reserve.


Asunto(s)
Prueba de Esfuerzo , Hipertensión Pulmonar/complicaciones , Hipoxia/complicaciones , Imagen por Resonancia Magnética , Volumen Sistólico , Disfunción Ventricular Derecha/diagnóstico por imagen , Función Ventricular Derecha , Adulto , Estudios de Casos y Controles , Enfermedad Crónica , Femenino , Humanos , Hipertensión Pulmonar/fisiopatología , Hipoxia/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/fisiopatología
4.
Radiology ; 288(2): 386-395, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29869959

RESUMEN

Purpose To measure right ventricular (RV) trabecular complexity by its fractal dimension (FD) in healthy subjects and patients with pulmonary hypertension (PH) and to assess its relationship with hemodynamic and functional parameters and future cardiovascular events. Materials and Methods This retrospective study used data acquired from May 2004 to October 2013 in 256 patients with newly diagnosed PH who underwent cardiac MRI, right-sided heart catheterization, and 6-minute walk distance testing, with median follow-up of 4.0 years. A total of 256 healthy control subjects underwent cardiac MRI only. Biventricular FD, volumes, and function were assessed on short-axis cine images. Reproducibility was assessed with the intraclass correlation coefficient, correlation between variables was assessed with the Pearson correlation test, and mortality prediction was compared by using uni- and multivariable Cox regression analyses. Results RV FD reproducibility had an intraclass correlation coefficient of 0.97 (95% confidence interval [CI]: 0.96, 0.98). RV FD was higher in patients with PH (median, 1.310; interquartile range [IQR], 1.281-1.341) than in healthy subjects (median, 1.264; IQR, 1.242-1.295; P < .001), with the greatest difference near the apex. RV FD was associated with pulmonary vascular resistance (r = 0.30, P < .001). At univariable Cox regression analysis, RV FD was a significant predictor of death (hazard ratio [HR], 1.256; 95% CI: 1.011, 1.560; P = .04); however, at multivariable analysis, RV FD did not enable prediction of survival independently of conventional parameters of RV remodeling (HR, 1.179; 95% CI: 0.871, 1.596; P = .29). Conclusion Fractal analysis of RV trabecular complexity is a highly reproducible measure of remodeling in patients with PH that is associated with afterload, although the gain in survival prediction over traditional markers is not significant. Published under a CC BY 4.0 license. Online supplemental material is available for this article.


Asunto(s)
Fractales , Hipertensión Pulmonar/fisiopatología , Imagen por Resonancia Magnética/métodos , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatología , Anciano , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Hemodinámica/fisiología , Humanos , Hipertensión Pulmonar/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Resistencia Vascular/fisiología
5.
Radiology ; 280(2): 398-404, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26909648

RESUMEN

Purpose To determine the relationship between pulmonary artery (PA) stiffness and both right ventricular (RV) mass and function with cardiac magnetic resonance (MR) imaging. Materials and Methods The study was approved by the local research ethics committee, and all participants gave written informed consent. Cardiac MR imaging was performed at 1.5 T in 156 healthy volunteers (63% women; age range, 19-61 years; mean age, 36.1 years). High-temporal-resolution phase-contrast imaging was performed in the main and right PAs. Pulmonary pulse wave velocity (PWV) was determined by the interval between arterial systolic upslopes. RV function was assessed with feature tracking to derive peak systolic strain and strain rate, as well as peak early-diastolic strain rate. RV volumes, ejection fraction (RVEF), and mass were measured from the cine images. The association of pulmonary PWV with RV function and mass was quantified with univariate linear regression. Interstudy repeatability was assessed with intraclass correlation. Results The repeatability coefficient for pulmonary PWV was 0.96. Increases in pulmonary PWV and RVEF were associated with increases in age (r = 0.32, P < .001 and r = 0.18, P = .025, respectively). After adjusting for age (P = .090), body surface area (P = .073), and sex (P = .005), pulmonary PWV demonstrated an independent positive association with RVEF (r = 0.34, P = .026). Significant associations were also seen with RV mass (r = 0.41, P = .004), RV radial strain (r = 0.38, P = .022), and strain rate (r = 0.35, P = .002), and independent negative associations were seen with radial (r = 0.27, P = .003), longitudinal (r = 0.40, P = .007), and circumferential (r = 0.31, P = .005) peak early-diastolic strain rate with the same covariates. Conclusion Pulmonary PWV is reliably assessed with cardiac MR imaging. In subjects with no known cardiovascular disease, increasing PA stiffness is associated with increasing age and is also moderately associated with both RV mass and function after controlling for age, body surface area, and sex. (©) RSNA, 2016 Online supplemental material is available for this article.


Asunto(s)
Imagen por Resonancia Magnética/métodos , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatología , Adulto , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto Joven
6.
J Am Coll Cardiol ; 78(11): 1097-1110, 2021 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-34503678

RESUMEN

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population. OBJECTIVES: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults. METHODS: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status. RESULTS: The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001). CONCLUSIONS: In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.


Asunto(s)
Cardiomiopatía Hipertrófica/genética , Sarcómeros/genética , Anciano , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Estudios de Cohortes , Aprendizaje Profundo , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Penetrancia , Fenotipo
7.
Mol Vis ; 16: 144-53, 2010 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-20142845

RESUMEN

PURPOSE: A reduction in the power of the crystalline lens during childhood is thought to be important in the emmetropization of the maturing eye. However, in humans and model organisms, little is known about the factors that determine the dimensions of the crystalline lens and in particular whether these different parameters (axial thickness, surface curvatures, equatorial diameter, and volume) are under a common source of control or regulated independently of other aspects of eye size and shape. METHODS: Using chickens from a broiler-layer experimental cross as a model system, three-dimensional magnetic resonance imaging (MRI) scans were obtained at 115-microm isotropic resolution for one eye of 501 individuals aged 3-weeks old. After fixation with paraformaldehyde, the excised eyes were scanned overnight (16 h) in groups of 16 arranged in a 2x2x4 array. Lens dimensions were calculated from each image by fitting a three-dimensional mesh model to the lens, using the semi-automated analysis program mri3dX. The lens dimensions were compared to measures of eye and body size obtained in vivo using techniques that included keratometry and A-scan ultrasonography. RESULTS: A striking finding was that axial lens thickness measured using ex vivo MRI was only weakly correlated with lens thickness measured in vivo by ultrasonography (r=0.19, p<0.001). In addition, the MRI lens thickness estimates had a lower mean value and much higher variance. Indeed, about one-third of crystalline lenses showed a kidney-shaped appearance instead of the typical biconvex shape. Since repeat MRI scans of the same eye showed a high degree of reproducibility for the scanning and mri3dX analysis steps (the correlation in repeat lens thickness measurements was r=0.95, p<0.001) and a recent report has shown that paraformaldehyde fixation induces a loss of water from the human crystalline lens, it is likely that the tissue fixation step caused a variable degree of shrinkage and a change in shape to the lenses examined here. Despite this serious source of imprecision, we found significant correlations between lens volume and eye/body size (p<0.001) and between lens equatorial diameter and eye/body size (p<0.001) in these chickens. CONCLUSIONS: Our results suggest that certain aspects of lens size (specifically, lens volume and equatorial diameter) are controlled by factors that also regulate the size of the eye and body (presumably, predominantly genetic factors). However, since it has been shown previously that axial lens thickness is regulated almost independently of eye and body size, these results suggest that different systems might operate to control lens volume/diameter and lens thickness in normal chickens.


Asunto(s)
Cristalino/anatomía & histología , Imagen por Resonancia Magnética , Animales , Tamaño Corporal , Pollos , Cristalino/diagnóstico por imagen , Tamaño de los Órganos , Carácter Cuantitativo Heredable , Reproducibilidad de los Resultados , Propiedades de Superficie , Ultrasonografía
8.
J Psychopharmacol ; 34(9): 981-989, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32762272

RESUMEN

BACKGROUND: Cannabidiol (CBD) is being investigated as a potential treatment for several medical indications, many of which are characterised by altered memory processing. However, the mechanisms underlying these effects are unclear. AIMS: Our primary aim was to investigate how CBD influences cerebral blood flow (CBF) in regions involved in memory processing. Our secondary aim was to determine if the effects of CBD on CBF were associated with differences in working and episodic memory task performance. METHODS: We used a randomised, crossover, double-blind design in which 15 healthy participants were administered 600 mg oral CBD or placebo on separate days. We measured regional CBF at rest using arterial spin labelling 3 h after drug ingestion. We assessed working memory with the digit span (forward, backward) and n-back (0-back, 1-back, 2-back) tasks, and we used a prose recall task (immediate and delayed) to assess episodic memory. RESULTS: CBD increased CBF in the hippocampus (mean (95% confidence intervals) = 15.00 (5.78-24.21) mL/100 g/min, t14 = 3.489, Cohen's d = 0.75, p = 0.004). There were no differences in memory task performance, but there was a significant correlation whereby greater CBD-induced increases in orbitofrontal CBF were associated with reduced reaction time on the 2-back working memory task ( r= -0.73, p = 0.005). CONCLUSIONS: These findings suggest that CBD increases CBF to key regions involved in memory processing, particularly the hippocampus. These results identify potential mechanisms of CBD for a range of conditions associated with altered memory processing, including Alzheimer's disease, schizophrenia, post-traumatic stress disorder and cannabis-use disorders.


Asunto(s)
Cannabidiol/farmacología , Moduladores de Receptores de Cannabinoides/farmacología , Circulación Cerebrovascular/efectos de los fármacos , Hipocampo/efectos de los fármacos , Memoria Episódica , Memoria a Corto Plazo/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Adulto , Cannabidiol/administración & dosificación , Moduladores de Receptores de Cannabinoides/administración & dosificación , Femenino , Hipocampo/diagnóstico por imagen , Hipocampo/fisiología , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria a Corto Plazo/fisiología , Recuerdo Mental/fisiología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiología , Desempeño Psicomotor/fisiología , Marcadores de Spin , Adulto Joven
9.
Exp Eye Res ; 89(4): 511-21, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19540232

RESUMEN

Magnetic resonance imaging (MRI) is a powerful tool for generating 3-dimensional structural and functional image data. MRI has already proven valuable in creating atlases of mouse and quail development. Here, we have exploited high resolution MRI to determine the parameters necessary to acquire images of the chick embryo eye. Using a 9.4 Tesla (400 MHz) high field ultra-shielded and refrigerated magnet (Bruker), MRI was carried out on paraformaldehyde-fixed chick embryos or heads at E4, E6, E8, and E10. Image data were processed using established and custom packages (MRICro, ImageJ, ParaVision, Bruker and mri3dX). Voxel dimensions ranged from 62.5 microm to 117.2 microm. We subsequently used the images obtained from the MRI data in order to make precise measurements of chick embryo eye surface area, volume and axial length from E4 to E10. MRI was validated for accurate sizing of ocular tissue features by direct comparison with previously published literature. Furthermore, we demonstrate the utility of high resolution MRI for making accurate measurements of morphological changes due to experimental manipulation of chick eye development, thereby facilitating a better understanding of the effects on chick embryo eye development and growth of such manipulations. Chondroitin sulphate or heparin were microinjected into the vitreous cavity of the right eyes of each of 3 embryos at E5. At E10, embryos were fixed and various eye parameters (volume, surface area, axial length and equatorial diameter) were determined using MRI and normalised with respect to the un-injected left eyes. Statistically significant alterations in eye volume (p < 0.05; increases with chondroitin sulphate and decreases with heparin) and changes in vitreous homogeneity were observed in embryos following microinjection of glycosaminoglycans. Furthermore, in the heparin-injected eyes, significant disturbances at the vitreo-retinal boundary were observed as well as retinal folding and detachment confirming histological observations. These data reveal the utility and superiority of MRI for producing images enabling quantification of experimentally induced changes in eye volume and structure. The results indicate that MRI is an important tool that could become a routine approach for rapid and sensitive phenotypic analysis of normal chick ocular development and morphology as well as potentially the effects of surgical or genetic manipulations of chick embryo eyes in live embryos in ovo.


Asunto(s)
Embrión no Mamífero , Ojo/embriología , Imagenología Tridimensional , Imagen por Resonancia Magnética , Morfogénesis , Animales , Embrión de Pollo , Sulfatos de Condroitina/administración & dosificación , Heparina/administración & dosificación , Procesamiento de Imagen Asistido por Computador , Inyecciones , Cristalino/embriología , Cuerpo Vítreo
10.
J Cereb Blood Flow Metab ; 37(4): 1349-1361, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27317655

RESUMEN

In order to test therapeutics, functional assessments are required. In pre-clinical stroke research, there is little consensus regarding the most appropriate behavioural tasks to assess deficits, especially when testing over extended times in milder models with short occlusion times and small lesion volumes. In this study, we comprehensively assessed 16 different behavioural tests, with the aim of identifying those that show robust, reliable and stable deficits for up to two months. These tasks are regularly used in stroke research, as well as being useful for examining striatal dysfunction in models of Huntington's and Parkinson's disease. Two cohorts of male Wistar rats underwent the intraluminal filament model of middle cerebral artery occlusion (30 min) and were imaged 24 h later. This resulted in primarily subcortical infarcts, with a small amount of cortical damage. Animals were tested, along with sham and naïve groups at 24 h, seven days, and one and two months. Following behavioural testing, brains were processed and striatal neuronal counts were performed alongside measurements of total brain and white matter atrophy. The staircase, adjusting steps, rotarod and apomorphine-induced rotations were the most reliable for assessing long-term deficits in the 30 min transient middle cerebral artery occlusion model of stroke.


Asunto(s)
Técnicas de Observación Conductual/métodos , Conducta Animal , Encéfalo , Infarto de la Arteria Cerebral Media/psicología , Accidente Cerebrovascular/psicología , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Inmunohistoquímica , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Infarto de la Arteria Cerebral Media/patología , Imagen por Resonancia Magnética , Masculino , Ratas Wistar , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/patología
11.
Eur J Radiol ; 81(9): 2069-74, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21802234

RESUMEN

OBJECTIVE: Transgenic mouse models of tuberous sclerosis (TSC) develop renal cysts, cystadenomas, solid adenomas and carcinomas. Identification and characterisation of these lesions in vivo may help in TSC pre-clinical trials. This study was to evaluate T2 weighted MRI for assessment of renal lesions in two Tsc mouse models. MATERIALS AND METHODS: Tsc1(+/-), Tsc2(+/-) and wild type mice were subjected to a first MRI scan at 12 months of age and a second scan 2 months later. One Tsc2(+/-) mouse was treated with rapamycin for two months after the initial scan. Immediately following the second scan, mice were sacrificed and MRI images were compared to renal histological findings. RESULTS: MRI identified all types of Tsc-associated renal lesions in both Tsc1(+/-) and Tsc2(+/-) mice. The smallest detectable lesions were <0.1 mm(3). Eighty three percent of all renal lesions detected in the first scan were re-identified in the second scan. By MRI, these lesions demonstrated significant growth in the 9 untreated Tsc1(+/-) and Tsc2(+/-) mice but shrinkage in the rapamycin treated Tsc2(+/-) mouse. Between the two scans, MRI also revealed significant increase in both the total number and volume of lesions in untreated mice and decrease in the rapamycin treated mouse, respectively. In comparison to histological analysis MRI detected most cysts and cystadenomas (66%) but only a minority of solid tumours (29%). CONCLUSION: These results suggest that T2 weighted MRI may be a useful tool for assessing some renal lesions in pre-clinical studies using Tsc mouse models. However, improved sensitivity for T2 weighted MRI is required, particularly for solid renal lesions.


Asunto(s)
Modelos Animales de Enfermedad , Neoplasias Renales/patología , Imagen por Resonancia Magnética/métodos , Esclerosis Tuberosa/patología , Animales , Humanos , Ratones , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
12.
Mol Endocrinol ; 23(6): 914-24, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19299444

RESUMEN

Circulating ghrelin elevates abdominal adiposity by a mechanism independent of its central orexigenic activity. In this study we tested the hypothesis that peripheral ghrelin induces a depot-specific increase in white adipose tissue (WAT) mass in vivo by GH secretagogue receptor (GHS-R(1a))-mediated lipolysis. Chronic iv infusion of acylated ghrelin increased retroperitoneal and inguinal WAT volume in rats without elevating superficial sc fat, food intake, or circulating lipids and glucose. Increased retroperitoneal WAT mass resulted from adipocyte enlargement probably due to reduced lipid export (ATP-binding cassette transporter G1 mRNA expression and circulating free fatty acids were halved by ghrelin infusion). In contrast, ghrelin treatment did not up-regulate biomarkers of adipogenesis (peroxisome proliferator-activated receptor-gamma2 or CCAAT/enhancer binding protein-alpha) or substrate uptake (glucose transporter 4, lipoprotein lipase, or CD36) and although ghrelin elevated sterol-regulatory element-binding protein 1c expression, WAT-specific mediators of lipogenesis (liver X receptor-alpha and fatty acid synthase) were unchanged. Adiposity was unaffected by infusion of unacylated ghrelin, and the effects of acylated ghrelin were abolished by transcriptional blockade of GHS-R(1a), but GHS-R(1a) mRNA expression was similar in responsive and unresponsive WAT. Microarray analysis suggested that depot-specific sensitivity to ghrelin may arise from differential fine tuning of signal transduction and/or lipid-handling mechanisms. Acylated ghrelin also induced hepatic steatosis, increasing lipid droplet number and triacylglycerol content by a GHS-R(1a)-dependent mechanism. Our data imply that, during periods of energy insufficiency, exposure to acylated ghrelin may limit energy utilization in specific WAT depots by GHS-R(1a)-dependent lipid retention.


Asunto(s)
Abdomen/patología , Ghrelina/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Obesidad/metabolismo , Obesidad/patología , Receptores de Ghrelina/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Adiposidad/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Hígado Graso/metabolismo , Hígado Graso/patología , Regulación de la Expresión Génica/efectos de los fármacos , Bombas de Infusión , Masculino , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/genética , Transducción de Señal/efectos de los fármacos
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