RESUMEN
BACKGROUND: Marinesco-Sjögren syndrome (MSS) is an autosomal recessive neuromuscular disorder that arises in early childhood and is characterized by congenital cataracts, myopathy associated with muscle weakness, and degeneration of Purkinje neurons leading to ataxia. About 60% of MSS patients have loss-of-function mutations in the SIL1 gene. Sil1 is an endoplasmic reticulum (ER) protein required for the release of ADP from the master chaperone Bip, which in turn will release the folded proteins. The expression of non-functional Sil1 leads to the accumulation of unfolded proteins in the ER and this triggers the unfolded protein response (UPR). A dysfunctional UPR could be a key element in the pathogenesis of MSS, although our knowledge of the molecular pathology of MSS is still incomplete. METHODS: RNA-Seq transcriptomics was analysed using the String database and the Ingenuity Pathway Analysis platform. Fluorescence confocal microscopy was used to study the remodelling of the extracellular matrix (ECM). Transmission electron microscopy (TEM) was used to reveal the morphology of the ECM in vitro and in mouse tendon. RESULTS: Our transcriptomic analysis, performed on patient-derived fibroblasts, revealed 664 differentially expressed (DE) transcripts. Enrichment analysis of DE genes confirmed that the patient fibroblasts have a membrane trafficking issue. Furthermore, this analysis indicated that the extracellular space/ECM and the cell adhesion machinery, which together account for around 300 transcripts, could be affected in MSS. Functional assays showed that patient fibroblasts have a reduced capacity of ECM remodelling, reduced motility, and slower spreading during adhesion to Petri dishes. TEM micrographs of negative-stained ECM samples from these fibroblasts show differences of filaments in terms of morphology and size. Finally, structural analysis of the myotendinous junction of the soleus muscle and surrounding regions of the Achilles tendon revealed a disorganization of collagen fibres in the mouse model of MSS (woozy). CONCLUSIONS: ECM alterations can affect the proper functioning of several organs, including those damaged in MSS such as the central nervous system, skeletal muscle, bone and lens. On this basis, we propose that aberrant ECM is a key pathological feature of MSS and may help explain most of its clinical manifestations.
Asunto(s)
Matriz Extracelular , Fibroblastos , Degeneraciones Espinocerebelosas , Tendones , Fibroblastos/metabolismo , Fibroblastos/patología , Matriz Extracelular/metabolismo , Humanos , Animales , Tendones/patología , Tendones/metabolismo , Degeneraciones Espinocerebelosas/patología , Degeneraciones Espinocerebelosas/genética , Degeneraciones Espinocerebelosas/metabolismo , Respuesta de Proteína Desplegada , Ratones , Factores de Intercambio de Guanina Nucleótido/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Perfilación de la Expresión GénicaRESUMEN
We sought to prospectively assess the diagnostic performance of a high-resolution positron emission tomography (PET) scanner using mild breast compression (positron emission mammography [PEM]). Data were collected on concomitant medical conditions to assess potential confounding factors. At four centers, 94 consecutive women with known breast cancer or suspicious breast lesions received 18F-fluorodeoxyglucose (FDG) intravenously, followed by PEM scans. Readers were provided clinical histories and x-ray mammograms (when available). After excluding inevaluable cases and two cases of lymphoma, PEM readings were correlated with histopathology for 92 lesions in 77 women: 77 index lesions (42 malignant), 3 ipsilateral lesions (3 malignant), and 12 contralateral lesions (3 malignant). Of 48 cancers, 16 (33%) were clinically evident; 11 (23%) were ductal carcinoma in situ (DCIS), and 37 (77%) were invasive (30 ductal, 4 lobular, and 3 mixed; median size 21 mm). PEM depicted 10 of 11 (91%) DCIS and 33 of 37 (89%) invasive cancers. PEM was positive in 1 of 2 T1a tumors, 4 of 6 T1b tumors, 7 of 7 T1c tumors, and 4 of 4 cases where tumor size was not available (e.g., no surgical follow-up). PEM sensitivity for detecting cancer was 90%, specificity 86%, positive predictive value (PPV) 88%, negative predictive value (NPV) 88%, accuracy 88%, and area under the receiver-operating characteristic curve (Az) 0.918. In three patients, cancer foci were identified only on PEM, significantly changing patient management. Excluding eight diabetic subjects and eight subjects whose lesions were characterized as clearly benign with conventional imaging, PEM sensitivity was 91%, specificity 93%, PPV 95%, NPV 88%, accuracy 92%, and Az 0.949 when interpreted with mammographic and clinical findings. FDG PEM has high diagnostic accuracy for breast lesions, including DCIS.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/diagnóstico por imagen , Femenino , Humanos , Persona de Mediana Edad , Variaciones Dependientes del Observador , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
Diffusion-tensor fiber tracking was used to identify the cores of several long-association fibers, including the anterior (ATR) and posterior (PTR) thalamic radiations, and the uncinate (UNC), superior longitudinal (SLF), inferior longitudinal (ILF), and inferior fronto-occipital (IFO) fasciculi. Tracking results were compared to existing anatomical knowledge, and showed good qualitative agreement. Guidelines were developed to reproducibly track these fibers in vivo. The interindividual variability of these reconstructions was assessed in a common spatial reference frame (Talairach space) using probabilistic mapping. As a first illustration of this technical capability, a reduction in brain connectivity in a patient with a childhood neurodegenerative disease (X-linked adrenoleukodystrophy) was demonstrated.