The myelin sheath on vertebrate axons is critical for neural impulse transmission, but whether electrically active axons are preferentially myelinated by glial cells, and if so, whether axo-glial synapses are involved, are long-standing questions of significance to nervous system development, plasticity and disease. Here we show using an in vitro system that oligodendrocytes preferentially myelinate electrically active axons, but synapses from axons onto myelin-forming oligodendroglial cells are not required. Instead, vesicular release at nonsynaptic axo-glial junctions induces myelination. Axons releasing neurotransmitter from vesicles that accumulate in axon varicosities induces a local rise in cytoplasmic calcium in glial cell processes at these nonsynaptic functional junctions, and this signalling stimulates local translation of myelin basic protein to initiate myelination.

In the adult brain, both neurons and oligodendrocytes can be generated from neural stem cells located within the Sub-Ventricular Zone (SVZ). Physiological signals regulating neuronal versus glial fate are largely unknown. Here we report that a thyroid hormone (T3)-free window, with or without a demyelinating insult, provides a favorable environment for SVZ-derived oligodendrocyte progenitor generation. After demyelination, oligodendrocytes derived from these newly-formed progenitors provide functional remyelination, restoring normal conduction. The cellular basis for neuronal versus glial determination in progenitors involves asymmetric partitioning of EGFR and TRα1, expression of which favor glio- and neuro-genesis, respectively. Moreover, EGFR+ oligodendrocyte progenitors, but not neuroblasts, express high levels of a T3-inactivating deiodinase, Dio3. Thus, TRα absence with high levels of Dio3 provides double-pronged blockage of T3 action during glial lineage commitment. These findings not only transform our understanding of how T3 orchestrates adult brain lineage decisions, but also provide potential insight into demyelinating disorders.

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Oligodendrocyte precursor cells (OPCs) are a major source of remyelinating oligodendrocytes in demyelinating diseases such as Multiple Sclerosis (MS). While OPCs are innervated by unmyelinated axons in the normal brain, the fate of such synaptic contacts after demyelination is still unclear. By combining electrophysiology and immunostainings in different transgenic mice expressing fluorescent reporters, we studied the synaptic innervation of OPCs in the model of lysolecithin (LPC)-induced demyelination of corpus callosum. Synaptic innervation of reactivated OPCs in the lesion was revealed by the presence of AMPA receptor-mediated synaptic currents, VGluT1+ axon-OPC contacts in 3D confocal reconstructions and synaptic junctions observed by electron microscopy. Moreover, 3D confocal reconstructions of VGluT1 and NG2 immunolabeling showed the existence of glutamatergic axon-OPC contacts in post-mortem MS lesions. Interestingly, patch-clamp recordings in LPC-induced lesions demonstrated a drastic decrease in spontaneous synaptic activity of OPCs early after demyelination that was not caused by an impaired conduction of compound action potentials. A reduction in synaptic connectivity was confirmed by the lack of VGluT1+ axon-OPC contacts in virtually all rapidly proliferating OPCs stained with EdU (50-ethynyl-20-deoxyuridine). At the end of the massive proliferation phase in lesions, the proportion of innervated OPCs rapidly recovers, although the frequency of spontaneous synaptic currents did not reach control levels. In conclusion, our results demonstrate that newly-generated OPCs do not receive synaptic inputs during their active proliferation after demyelination, but gain synapses during the remyelination process. Hence, glutamatergic synaptic inputs may contribute to inhibit OPC proliferation and might have a physiopathological relevance in demyelinating disorders.

Objectives: To assess the prevalence and prognostic value of right ventricular dysfunction as measured by echocardiography in patients treated with venovenous extracorporeal membrane oxygenation. Design: Retrospective cohort study. The primary endpoint was survival to discharge. Survival to extracorporeal membrane oxygenation decannulation was the secondary endpoint. Setting: ICU at an academic quaternary medical center. Subjects: Sixty-four consecutive patients treated with venovenous extracorporeal membrane oxygenation between January 2013 and December 2018 with an echocardiogram performed after cannulation. Interventions: Transthoracic or transesophageal echocardiography was used to assess several standard right and left ventricular characteristics after cannulation with venovenous extracorporeal membrane oxygenation. Measurements and Main Results: No single echo variable was predictive of outcomes. Composite markers such as right ventricular dysfunction (right ventricular dilation and abnormal septal motion) or a small dynamic left ventricle (left ventricle internal diastolic diameter < 4.0 cm and left ventricular ejection fraction > 60%) were associated with significantly decreased survival to decannulation (45% vs 83%; p < 0.01) and survival to hospital discharge (32% vs 64%; p = 0.02). Regression models confirmed the absence of both right ventricular dysfunction, and small left ventricle was highly predictive of increased survival to decannulation (odds ratio, 6; 95% CI, 1.87–19.28; p < 0.01) and discharge (odds ratio, 3.86; 95% CI, 1.29–11.55; p = 0.02). Conclusions: Echocardiographic variables consistent with right ventricular dysfunction or a small dynamic left ventricle were associated with decreased survival to decannulation and hospital discharge. These results enhance prognostic capabilities while implicating right ventricular dysfunction in the high mortality observed in this patient population.

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The level of the renin-angiotensin-aldosterone system (RAAS) activity in kidney transplant recipients has not been extensively studied or serially profiled. To describe this axis and to determine its association with GFR change, interstitial expansion and end-stage renal disease (ESRD) we measured plasma renin activity (PRA) and plasma aldosterone levels annually for 5 years in 153 kidney transplant recipients randomly assigned to losartan or placebo. PRA and plasma aldosterone levels were in the normal range at all times and did not vary by immunosuppression regimen. Those on losartan exhibited higher PRA but similar plasma aldosterone levels. Neither baseline nor serial PRA or plasma aldosterone levels were associated with GFR decline, proteinuria or interstitial expansion. Losartan use, [HR 0.48 (95% CI 0.21–1.0), insignificant], and Caucasian donor, [HR 0.18 (95% CI 0.07–0.4), significant] were associated with less doubling of serum creatinine, death or ESRD. Hypertension, less than 3 HLA-matches, the combination of tacrolimus-rapamycin and acute rejection were associated with more events. Neither PRA nor plasma aldosterone levels were independently associated with this outcome. Higher serial plasma aldosterone levels were associated, however, with a significantly higher risk of ESRD, [HR 1.01 (95% CI 1.00–1.02)]. Thus, systemic RAAS is not overly activated in kidney transplant recipients but this may not reflect the intrarenal system. Importantly, plasma aldosterone levels may be associated with more ESRD.