Circulating MicroRNA-15a Associates With Retinal Damage in Patients With Early Stage Type 2 Diabetes

: Circulating microRNAs are potential biomarkers of type 2 diabetes mellitus (T2DM) and related complications. Here, we investigated the association of microRNA-15a with early retinal damage in T2DM. A cohort of untreated subjects screened for intermediate/high risk of T2DM, according to a score assessment questionnaire, and then recognized to have a normal (NGT) or impaired (IGT) glucose tolerance or T2DM was studied. The thickness of the ganglion cell complex (GCC), an early marker of retinal degeneration anteceding overt retinopathy was assessed by Optical Coherence Tomography. Total and extracellular vesicles (EV)-associated microRNA-15a quantity was measured in plasma by real time PCR. MicroRNA-15a level was significantly higher in subjects with IGT and T2DM compared with NGT. MicroRNA-15a abundance was correlated to body mass index and classical diabetes biomarkers, including fasting glucose, HbA1c, insulinemia, and HOMA-IR. Moreover, GCC thickness was significantly reduced in IGT and T2DM subjects compared with NGT controls. Importantly, total microRNA-15a correlated with GCC in IGT subjects, while in T2DM subjects, EV-microRNA-15a negatively correlated with GCC, suggesting that microRNA-15a may monitor initial retinal damage. The assessment of plasma microRNA-15a may help refining risk assessment and secondary prevention in patients with preclinical T2DM

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1−/− induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis

Effects of assisted ventilation on the work of breathing: volume-controlled versus pressure-controlled ventilation

During assisted ventilation, the same tidal volume can be delivered in different ways, with the possibility for the physician to vary the ventilatory target (pressure or volume) and the peak flow setting. We compared the effects on the respiratory work rate of assisted ventilation, delivered either with a square wave flow pattern (assist control ventilation [ACV]) or with a decelerating flow pattern and a constant pressure (assisted pressure-control ventilation [APCV]). In the first part of the study where seven patients were studied, inspiratory time and tidal volume were similar in the two modes of ventilation. High and moderate levels of tidal volume (VT) were studied (12 ml/kg and 8 ml/kg, respectively). To obtain moderate VT, inspiratory time was kept constant and, therefore, mean inspiratory flow was reduced. At high VT, no difference between ACV and APCV was noted for breathing pattern, respiratory drive indexes, respiratory muscle work, or arterial blood gases. All patients exhibited respiratory alkalosis. At moderate VT, normal pH was achieved. In this situation significantly lower levels were observed during APCV than during ACV for the power of breathing (10 +/- 2 versus 19 +/- 5 J/min, p<0.05), transdiaphragmatic pressure swing (7 +/- 1 versus 11 +/- 2 cm H2O, p<0.05), and pressure-time index (252 +/- 43 versus 484 +/- 114 cm H2O.s, p<0.05), even though breathing pattern and gas exchange were similar. In the second part of the study where six additional patients were studied, tidal volume was kept constant at a moderate level (8 ml/kg), and we studied the effect of shortening inspiratory time and increasing mean inspiratory flow. At moderate VT and high inspiratory flow, no significant differences could be found between ACV and APCV, and although pressure-time index tended to be lower during APCV, absolute levels of effort were of small magnitude (56 +/- 55 versus 76 +/- 55 cm H2O.s). We conclude that at moderate VT and low flow rates only, inspiratory assistance delivered at a constant pressure reduces the respiratory work rate more effectively than assist control ventilation