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1.
Stem Cell Res ; 79: 103459, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38896971

RESUMEN

Here we present the generation of HIMRi006-A and HIMRi007-A Pompe disease (PD) patient derived human induced pluripotent stem cell (hiPSC) lines. HIMRi006-A represents an infantile onset disease (IOPD) phenotype caused by a homozygous c.307 T > G mutation in the GAA gene. HIMRi007-A is characterized by heterozygous mutations c.-32-13 T > G/c.1716C > G and is associated with an adult onset of disease symptoms (LOPD). Both lines are generated via lentiviral expression of OCT4, SOX2, KLF4, and c-MYC. The lines display a typical embryonic stem cell morphology, express pluripotency markers, retain a normal karyotype (46, XX/XY) and have the differentiation capacity in all three germ layers. Altogether, both lines provide a resource tool to the community for future in depth molecular studies of PD pathomechanism.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II , Células Madre Pluripotentes Inducidas , Factor 4 Similar a Kruppel , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo II/patología , Enfermedad del Almacenamiento de Glucógeno Tipo II/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Diferenciación Celular , Línea Celular , Masculino , Lactante , Mutación , Femenino
2.
J Neuromuscul Dis ; 8(6): 949-962, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34180419

RESUMEN

BACKGROUND: Myotonic Dystrophies type 1 and type 2 are hereditary myopathies with dystrophic muscle degeneration in varying degrees. Differences in muscle diffusion between both diseases have not been evaluated yet. OBJECTIVE: To evaluate the ability of muscle diffusion tensor imaging (mDTI) and Dixon fat-quantification to distinguish between Myotonic Dystrophy (DM) type 1 and type 2 and if both diseases show distinct muscle involvement patterns. METHODS: We evaluated 6 thigh and 7 calf muscles (both legs) of 10 DM 1, 13 DM 2 and 28 healthy controls (HC) with diffusion tensor imaging, T1w and mDixonquant sequences in a 3T MRI scanner. The quantitative mDTI-values axial diffusivity (λ1), mean diffusivity (MD), radial diffusivity (RD) and fractional anisotropy (FA) as well as fat-fraction were analysed. CTG-triplet repeat-length of DM 1 patients was correlated with diffusion metrics and fat-fraction. RESULTS: mDTI showed significant differences between DM 1 and DM 2 vs. healthy controls in diffusion parameters of the thigh (all p < 0.001) except for FA (p = 0.0521 / 0.8337). In calf muscles mDTI showed significant differences between DM 1 and DM 2 patients (all p < 0.0001) as well as between DM 1 patients and controls (all p = 0.0001). Thigh muscles had a significant higher fat-fraction in both groups vs. controls (p < 0.05). There was no correlation of CTG triplet length with mDTI values and fat-fraction. DISCUSSION: mDTI reveals specific changes of the diffusion parameters and fat-fraction in muscles of DM 1 and DM 2 patients. Thus, the quantitative MRI methods presented in this study provide a powerful tool in differential diagnosis and follow-up of DM 1 and DM 2, however, the data must be validated in larger studies.


Asunto(s)
Imagen de Difusión Tensora/métodos , Distrofia Miotónica/diagnóstico por imagen , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Pierna/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Músculo Esquelético , Estudios Prospectivos , Adulto Joven
3.
Eur Radiol ; 29(6): 3224-3232, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30560358

RESUMEN

PURPOSE: To evaluate differences in diffusion parameters in thigh muscles in patients with glycogen storage disease type V (McArdle disease) using muscle diffusion tensor imaging (mDTI) compared to healthy controls METHODS: In this prospective study, we evaluated thigh muscles from hip to knee of 10 McArdle patients (5 female, mean age 33.7 ± 14.4 years) and 10 healthy age- and gender-matched volunteers. MRI scans were performed at 3 T and comprised mDTI, T1-weighted and T2-weighted imaging between May 2015 and May 2017. Needle biopsy of the vastus lateralis muscle was performed in three McArdle patients. The muscle tissue was analyzed by using histochemical and enzyme-histochemical techniques for glycogen content and histopathological changes. Mean values of the eigenvalues (λ1-λ3), fractional anisotropy (FA), and mean diffusivity (MD) were obtained for the vastus lateralis, vastus medialis, rectus femoris, biceps femoris, semitendinosus, and semimembranosus and compared between groups using Student's t tests, as well as ANCOVA; significance level was set at p < 0.05. RESULTS: Needle biopsy showed intracellular glycogen accumulation in skeletal muscle fibers of three McArdle patients. Extracellular histopathological changes were not found. Muscle DTI analysis did not show statistically significant differences between patients and controls for any of the muscles. CONCLUSION: Despite intracellular glycogen accumulation in the three biopsy samples, mDTI parameters were not altered in McArdle patients compared to controls. We conclude that the currently used mDTI acquisition and processing lack the sensitivity to detect intracellular changes due to accumulated glycogen in this cohort of McArdle patients. KEY POINTS: • Despite intracellular glycogen accumulation in three examined biopsy samples, mDTI parameters were not altered in McArdle patients compared to controls. • In its current form, diffusion MR does not provide additional information in quantifying intracellular glycogen accumulations within skeletal muscle fibers in McArdle patients.


Asunto(s)
Imagen de Difusión Tensora , Enfermedad del Almacenamiento de Glucógeno Tipo V/diagnóstico por imagen , Músculo Esquelético/diagnóstico por imagen , Muslo/diagnóstico por imagen , Adulto , Anisotropía , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo V/patología , Músculos Isquiosurales/diagnóstico por imagen , Músculos Isquiosurales/patología , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Estudios Prospectivos , Músculo Cuádriceps/diagnóstico por imagen , Músculo Cuádriceps/patología , Muslo/patología , Adulto Joven
4.
Diabetes Obes Metab ; 18 Suppl 1: 102-9, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27615138

RESUMEN

Type 2 diabetes is characterized by insulin resistance and a progressive loss of ß-cell function induced by a combination of both ß-cell loss and impaired insulin secretion from remaining ß-cells. Here, we review the fate of the ß-cell under chronic hyperglycaemic conditions with regard to ß-cell mass, gene expression, hormone content, secretory capacity and the ability to de- or transdifferentiate into other cell types. We compare data from various in vivo and in vitro models of diabetes with a novel mouse model of inducible, reversible hyperglycaemia (ßV59M mice). We suggest that insulin staining using standard histological methods may not always provide an accurate estimation of ß-cell mass or number. We consider how ß-cell identity is best defined, and whether expression of transcription factors normally found in islet progenitor cells, or in α-cells, implies that mature ß-cells have undergone dedifferentiation or transdifferentiation. We propose that even in long-standing diabetes, ß-cells predominantly remain ß-cells-but not as we know them.


Asunto(s)
Desdiferenciación Celular , Transdiferenciación Celular , Diabetes Mellitus Tipo 2/metabolismo , Hiperglucemia/metabolismo , Células Secretoras de Insulina/citología , Animales , Células Secretoras de Glucagón/citología , Humanos , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Ratones , Células Madre/citología
7.
Mol Microbiol ; 87(1): 132-51, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23136884

RESUMEN

Analysing culture supernatants of yeast and hyphal cells of Candida albicans, we found two close homologues of pathogenesis-related (PR-) 1 proteins, Rbe1p and Rbt4p, in the secretome. Due to sequence homology, three additional, yet not characterized open reading frames, ORF19.6200, ORF19.2787 and ORF19.2336, together with RBE1 and RBT4 were assigned to a novel family of CaPRY proteins. In a Δrbe1/Δrbt4 deletion strain, genome-wide transcriptional analysis revealed differential transcription of only a limited set of genes implicated in virulence and oxidative stress response. Single deletion of RBE1 or RBT4 in a clinical C. albicans isolate resulted in a moderate but significant attenuation in virulence in a mouse model for disseminated candidiasis. However, a synergistic effect was observed in a Δrbe1/Δrbt4 double deletion strain, where virulence was strongly affected. Remarkably, transcription of RBT4 and RBE1 was each upregulated in blastospores of Δrbe1 or hyphae of Δrbt4 deletion strains respectively, indicating functional complementation thereby compensating a potential virulence defect in the single deletion strains. Furthermore, the double deletion strain showed increased sensitivity to attack by polymorphonuclear leucocytes. Therefore, the crucial contribution of both C. albicans pathogenesis-related proteins to virulence might be vested in protection against phagocyte attack.


Asunto(s)
Candida albicans/genética , Candida albicans/patogenicidad , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Secuencia de Aminoácidos , Animales , Candida albicans/metabolismo , ADN de Hongos/genética , Perfilación de la Expresión Génica , Regulación Fúngica de la Expresión Génica , Genoma Fúngico , Ratones , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Estrés Oxidativo/genética , Fenotipo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Alineación de Secuencia , Eliminación de Secuencia , Virulencia/genética
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