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Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gaiting, exacerbation of neuropathy, sensory defects and deafness. We generated a novel line of CMT2E mice expressing an hNF-LE397K transgene, which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons and decreased nerve conduction velocity. In this study, we showed that hNF-LE397K mice developed abnormal gait of the hind limbs. The identification of severe gaiting defects in combination with previously observed muscle atrophy, reduced axon caliber and decreased nerve conduction velocity suggests that hNF-LE397K mice recapitulate many of clinical signs associated with CMT2E. Therefore, hNF-LE397K mice provide a context for potential therapeutic intervention. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by the loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology. We had previously found that glial derived neurotrophic factor (GDNF) is reduced in SMA astrocytes. However, reduced GDNF expression does not play a major role in SMA pathology as viral-mediated GDNF re-expression did not improve astrocyte function or motor neuron loss. In contrast, we found that SMA astrocytes increased microRNA (miR) production and secretion compared to control astrocytes, suggesting potential toxic gain-of-function properties. Specifically, we found that miR-146a was significantly upregulated in SMA induced pluripotent stem cell (iPSC)-derived astrocytes and SMNΔ7 mouse spinal cord. Moreover, increased miR-146a was sufficient to induce motor neuron loss in vitro, whereas miR-146a inhibition prevented SMA astrocyte-induced motor neuron loss. Together, these data indicate that altered astrocyte production of miR-146a may be a contributing factor in astrocyte-mediated SMA pathology., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Lung donation and transplantation is increasing in volume annually, yet there continues to be a shortage of available organs for transplant. Despite this shortage, suitable lungs are occasionally not transplanted due to logistical issues. Issues such as time and distance can be a major barrier in deceased donor organ recovery and transplantation. This single case study serves as an example of the teamwork and cooperation that resulted in the successful transplantation of lungs in spite of long-distance logistical issues between the donor and the recipient. All of the members who contributed to this collaboration recognized the need and urgency to overcome these challenges. The organ procurement organization's collaboration with multiple transplant centers across multiple regions resulted in a successful outcome for the lung recipient., (© 2016, NATCO.)

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disease occurring during childhood. The gene responsible for disease development is a ubiquitously expressed protein, IGHMBP2. Mutations in IGHMBP2 result in the loss of α-motor neurons leading to muscle atrophy in the distal limbs accompanied by respiratory complications. Although genetically and clinically distinct, proximal SMA is also caused by the loss of a ubiquitously expressed gene (SMN). Significant preclinical success has been achieved in proximal SMA using viral-based gene replacement strategies. We leveraged the technologies employed in SMA to demonstrate gene replacement efficacy in an SMARD1 animal model. Intracerebroventricular (ICV) injection of single-stranded AAV9 expressing the full-length cDNA of IGHMBP2 in a low dose led to a significant level of rescue in treated SMARD1 animals. Consistent with drastically increased survival, weight gain, and strength, the rescued animals demonstrated a significant improvement in muscle, NMJ, motor neurons, and axonal pathology. In addition, increased levels of IGHMBP2 in lumbar motor neurons verified the efficacy of the virus to transduce the target tissues. Our results indicate that AAV9-based gene replacement is a viable strategy for SMARD1, although dosing effects and potential negative impacts of high dose and ICV injection should be thoroughly investigated.

Objective: To evaluate the safety and assess the different symptom improvements found after a combined low-frequency primary motor cortex and high-frequency prefrontal cortex (PFC) stimulation using the deep TMS (dTMS) H-coil, as an add-on treatment for Parkinson's disease (PD)., Methods: Forty-five PD patients underwent 14 dTMS sessions; each consisting of 1 Hz stimulation of the primary motor cortex for 15 min, followed by 10 Hz stimulation of the PFC for 15 min. Clinical assessments were performed, BEFORE, at the MIDDLE, and END of therapy as well as at FOLLOW-UP after 30 days, using Movement Disorder Society-Unified Parkinson's Disease Rating Scale, TINETTI, UP&GO, SCOPA, HDRS21, Beck Depression Inventory, and self-applied daily motor assessment scales., Results: Treatment was well-tolerated, without serious adverse effects. dTMS-induced significant PD symptom improvements at END and at FOLLOW-UP, in all subscales of the UPDRS, gait speed, depressive symptoms, balance, autonomic symptoms, and a 73% increase in daily ON time., Conclusion: In the cohort of PD patients treated, dTMS was well-tolerated with only minor adverse effects. The dTMS-induced significant improvements in motor, postural, and motivational symptoms of PD patients and may potentiate concurrent levodopa treatment., Significance: The present study demonstrates that dTMS may have a much wider spectrum of beneficial effects than previously reported for TMS, including enhancement of levodopa effects, suggesting that future clinical trials with dTMS should include a broader range of symptom measurements.

The Gbx family of transcription factors consists of two closely related proteins GBX1 and GBX2. A defining feature of the GBX family is a highly conserved 60 amino acid DNA-binding domain, which differs by just two amino acids. Gbx1 and Gbx2 are co-expressed in several areas of the developing central nervous system including the forebrain, anterior hindbrain, and spinal cord, suggesting the potential for genetic redundancy. However, there is a spatiotemporal difference in expression of Gbx1 and Gbx2 in the forebrain and spinal cord. Gbx2 has been shown to play a critical role in positioning the midbrain/hindbrain boundary and developing anterior hindbrain, whereas gene-targeting experiments in mice have revealed an essential function for Gbx1 in the spinal cord for normal locomotion. To determine if Gbx2 could potentially compensate for a loss of Gbx1 in the developing spinal cord, we performed real-time PCR to examine levels of Gbx2 expression in Gbx1(-/-) spinal cord at embryonic day (E) 13.5, a developmental stage when Gbx2 is rapidly downregulated. We demonstrate that Gbx2 expression is elevated in the spinal cord of Gbx1(-/-) embryos.

The degree of parasitism by the parasitic copepod Sphyrion laevigatum on kingclip Genypterus blacodes in the Falkland Islands was investigated. In a sample of 719 kingclip, ranging in size from 35 to 145 cm total length, the prevalence of infection was 49%. The number of parasites per fish ranged from 0 to 24, with only 2% of the sample having more than 5 parasites. There was a significant increase in mean abundance of parasites with increasing fish age and length (P < 0.01 and P < 0.05, respectively). In addition, there was a significant difference in the prevalence in 1 of 3 geographical areas for the largest size class.