Morphological correlates of pyramidal cell axonal myelination in mouse and human neocortex.

The axons of neocortical pyramidal neurons are frequently myelinated. Heterogeneity in the topography of axonal myelination in the cerebral cortex has been attributed to a combination of electrophysiological activity, axonal morphology, and neuronal-glial interactions. Previously, we showed that axonal segment length and caliber are critical local determinants of fast-spiking interneuron myelination. However, the factors that determine the myelination of individual axonal segments along neocortical pyramidal neurons remain largely unexplored. Here, we used structured illumination microscopy to examine the extent to which axonal morphology is predictive of the topography of myelination along neocortical pyramidal neurons. We identified critical thresholds for axonal caliber and interbranch distance that are necessary, but not sufficient, for myelination of pyramidal cell axons in mouse primary somatosensory cortex (S1). Specifically, we found that pyramidal neuron axonal segments with a caliber < 0.24 µm or interbranch distance < 18.10 µm are rarely myelinated. Moreover, we further confirmed that these findings in mice are similar for human neocortical pyramidal cell myelination (caliber < 0.25 µm, interbranch distance < 19.00 µm), suggesting that this mechanism is evolutionarily conserved. Taken together, our findings suggest that axonal morphology is a critical correlate of the topography and cell-type specificity of neocortical myelination.

Transcriptome analysis reveals tumor microenvironment changes in glioblastoma.

A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.

Clinical Outcome for Surgical Treatment of Traumatic Neuroma With a Processed Nerve Allograft: Results of a Small Prospective Case Series.

Processed nerve allografts are used increasingly in the treatment of traumatic neuroma in small sensory nerves. The goal of the present study was to investigate the use of an allograft after different intervals between injury and repair and to analyze results, not only for the success of pain relief, but also for potential recovery of sensation in time. Four patients with painful neuroma in small sensory nerves in the lower extremity were surgically treated with a decellularized allograft. Patients were followed prospectively for at least 1 y. Clinical outcome was assessed using the Likert scale. Recovery of sensation was tested using Semmes-Weinstein monofilaments. In all 4 cases an allograft of 3-cm was used to reconstruct a defect in the superficial peroneal (3) or sural nerve (1) after excision of the neuroma. Complete relief of pain symptoms was achieved in 2 patients: 1 case concerned the reconstruction of a neuroma with an interval of less than 1 y between injury and repair and 1 case a neuroma-in-continuity. Sensation recovered completely in these 2 cases. In the other 2 cases, that had an interval between injury and reconstruction of more than 1 y, there was neither successful pain relief nor recovery of sensation. This prospective study shows that processed nerve allografts can be successful for the reconstruction of small sensory nerves after excision of the traumatic neuroma both for recovery of pain and sensation, but in this small case series only if the interval between injury and reconstruction was <1 y.

Novel experimental surgical strategy to prevent traumatic neuroma formation by combining a 3D-printed Y-tube with an autograft.

OBJECTIVE Traumatic neuromas may develop after nerve injury at the proximal nerve stump, which can lead to neuropathic pain. These neuromas are often resistant to therapy, and excision of the neuroma frequently leads to recurrence. In this study, the authors present a novel surgical strategy to prevent neuroma formation based on the principle of centro-central anastomosis (CCA), but rather than directly connecting the nerve ends to an autograft, they created a loop using a 3D-printed polyethylene Y-shaped conduit with an autograft in the distal outlets. METHODS The 3D-printed Y-tube with autograft was investigated in a model of rat sciatic nerve transection in which the Y-tube was placed on the proximal sciatic nerve stump and a peroneal graft was placed between the distal outlets of the Y-tube to form a closed loop. This model was compared with a CCA model, in which a loop was created between the proximal tibial and peroneal nerves with a peroneal autograft. Additional control groups consisted of the closed Y-tube and the extended-arm Y-tube. Results were analyzed at 12 weeks of survival using nerve morphometry for the occurrence of neuroma formation and axonal regeneration in plastic semi-thin sections. RESULTS Among the different surgical groups, the Y-tube with interposed autograft was the only model that did not result in neuroma formation at 12 weeks of survival. In addition, a 13% reduction in the number of myelinated axons regenerating through the interposed autograft was observed in the Y-tube with autograft model. In the CCA model, the authors also observed a decrease of 17% in the number of myelinated axons, but neuroma formation was present in this model. The closed Y-tube resulted in minimal nerve regeneration inside the tube together with extensive neuroma formation before the entrance of the tube. The extended-arm Y-tube model clearly showed that the majority of the regenerating axons merged into the Y-tube arm, which was connected to the autograft, leaving the extended plastic arm almost empty. CONCLUSIONS This pilot study shows that our novel 3D-printed Y-tube model with interposed autograft prevents neuroma formation, making this a promising surgical tool for the management of traumatic neuromas.