Association between frailty and C-terminal agrin fragment with 3-month mortality following ST-elevation myocardial infarction.

The objective of this study was to evaluate the association between frailty, evaluated by the Clinical Frailty Scale (CFS) and FRAIL scale, and C-terminal agrin fragment (CAF) levels with 3-month mortality following ST-segment elevation myocardial infarction (STEMI). This was a prospective observational study that included patients over the age of 18 years with STEMI admitted to the coronary intensive care unit. Within 48 h of admission, the CFS and FRAIL scale were applied and blood samples collected for serum CAF evaluation. Patients were followed for 3 months after hospital discharge, and mortality was recorded. One hundred and eleven patients were included; mean age was 62.3 ±â€¯12.4 years, 61.3% were male and 11.7% died during the 3 months of follow-up. According to the CFS, 79.3% of the patients were classified as not frail, 12.6% as pre-frail and 8.1% as frail. According to the FRAIL scale, 31.5% of the patients were classified as not frail, 53.2% as pre-frail and 15.3% as frail. In univariate analysis, the CFS but not FRAIL scale was associated with mortality. In multiple logistic regression analysis, pre-frail/frail according to CFS (odds ratio [OR]: 6.118; CI 95%: 1.344-27.848; p = 0.019) and CAF levels (OR: 0.943; CI 95%: 0.896-0.992; p = 0.024) were associated with increased 3-month mortality. In a sub-analysis of 53 patients ≥65 years, CFS and CAF levels were associated with 3-month mortality. In conclusion, CAF levels and frailty determined by the CFS were associated with 3-month mortality after STEMI in the general and older population.

The extracellular matrix protein Agrin is expressed by osteoblasts and contributes to their differentiation.

The extracellular matrix protein Agrin has been detected in chondrocytes and endosteal osteoblasts but its function in osteoblast differentiation has not been investigated yet. Thus, it is possible that Agrin contributes to osteoblast differentiation and, due to Agrin and wingless-related integration site (Wnt) sharing the same receptor, transmembrane low-density lipoprotein receptor-related protein 4 (Lrp4), and the crosstalk between Wnt and bone morphogenetic protein (BMP) signalling, both pathways could be involved in this Agrin-mediated osteoblast differentiation. Confirming this, Agrin and its receptors Lrp4 and α-dystroglycan (Dag1) were expressed during differentiation of osteoblasts from three different sources. Moreover, the disruption of Agrin impaired the expression of its receptors and osteoblast differentiation, and the treatment with recombinant Agrin slightly increase this process. In addition, whilst Agrin knockdown downregulated the expression of genes related to Wnt and BMP signalling pathways, the addition of Agrin had no effect on these genes. Altogether, these data uncover the contribution of Agrin to osteoblast differentiation and suggest that, at least in part, an Agrin-Wnt-BMP circuit is involved in this process. This makes Agrin a candidate as target for developing new therapeutic strategies to treat bone-related diseases and injuries.

Possible implications of dysregulated nicotinic acetylcholine receptor diffusion and nanocluster formation in myasthenia gravis.

Myasthenia gravis is a rare and invalidating disease affecting the neuromuscular junction of voluntary muscles. The classical form of this autoimmune disease is characterized by the presence of antibodies against the most abundant protein in the neuromuscular junction, the nicotinic acetylcholine receptor. Other variants of the disease involve autoimmune attack of non-receptor scaffolding proteins or enzymes essential for building or maintaining the integrity of this peripheral synapse. This review summarizes the participation of the above proteins in building the neuromuscular junction and the destruction of this cholinergic synapse by autoimmune aggression in myasthenia gravis. The review also covers the application of a powerful biophysical technique, superresolution optical microscopy, to image the nicotinic receptor in live cells and follow its motional dynamics. The hypothesis is entertained that anomalous nanocluster formation by antibody crosslinking may lead to accelerated endocytic internalization and elevated turnover of the receptor, as observed in myasthenia gravis.