Digestive smooth muscle mitochondrial myopathy in patients with mitochondrial-neuro-gastro-intestinal encephalomyopathy (MNGIE)

We report 3 new cases of Mitochondrial-Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE) (or Pseudo-Obstruction-Leukoencephalopathy-Intestinal-Pseudoobstruction Syndrome [POLIP]), a rare disease that associates chronic intestinal pseudo-obstruction (CIPO) and neurological symptoms. A review of the 72 reported cases together with these 3 cases revealed that this condition was associated with (a) a specific cluster of neurological symptoms including leukoencephalopathy (96%), polyneuropathy (96%), ophthalmoplegia (91%) and hearing loss (55%); (b) a CIPO syndrome with the presence of small bowel diverticulae (53%); and (c) mitochondrial cytopathy in 36 of the 37 tested patients (2 of our 3 cases), and thymidine phosphorylase gene mutations in all the 37 tested patients (2 of our cases). The etiology of POLIP/MNGIE syndrome appears therefore to be due to a mitochondrial cytopathy secondary to thymidine phosphorylase gene mutation(s). In 3 cases, including 2 of our 3 patients, mitochondrial abnormalities were evidenced at the ultrastructural level in digestive smooth muscle demonstrating that the pathogenesis of gastrointestinal involvement was directly related to mitochondrial alterations in digestive smooth muscle cells.     

Macroautophagy in lymphatic endothelial cells inhibits T cell–mediated autoimmunity

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.     

Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

A clinical impact of cognitive reserve (CR) has been demonstrated in Alzheimer's disease, whereas its role in vascular cognitive impairment (VCI) is largely unknown. In this study, we investigated the impact of CR in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of pure VCI. A total of 247 NOTCH3 mutation carriers from a two-center study were investigated using detailed neuropsychological and neuroimaging protocols. CR was operationalized as years of formal education. Brain pathology was assessed by MRI using normalized brain volume and lacunar lesion volume as proxies. Multivariate analyses were done for each structural measure with scores of processing speed, executive function, and memory as dependent variables. Additional linear regression models were conducted with interaction terms for education × brain volume and education × lacunar lesion volume. Education had an independent impact on cognitive performance in subjects with mild and moderate degrees of brain pathology, whereas there was no significant influence of education on cognition in patients with severe MRI changes. This interaction was found for processing speed, the cognitive domain most impaired in our patients. Our findings demonstrate an interaction of education and brain pathology in regard to cognitive impairment: the effect of education seems most pronounced in early disease stages but may ultimately be overwhelmed by the pathological changes. The results extend the concept of CR to VCI.     

Intra-left ventricular electromechanical asynchrony. A new independent predictor of severe cardiac events in heart failure patients

OBJECTIVES: We sought to assess the electromechanical parameters, using tissue Doppler echocardiography, as potential independent predictors of heart failure (HF) worsening. BACKGROUND: Ventricular conduction disorders worsen the prognosis for HF patients. However, the relationships between the QRS width and morphology, hemodynamic parameters, and presence and magnitude of intra-left ventricular (LV) and inter-ventricular (V) asynchrony have not been well clarified. METHOD: A total of 104 patients with an LV ejection fraction (EF) 相似文献