Chronic delivery of anti-nociceptive molecules by means of cell grafts near the pain processing centers of the spinal cord is a newly developing technique for the treatment of neuropathic pain. The rat neuronal cell line, RN33B, derived from E13 rat brainstem raphe and immortalized with the SV40 temperature-sensitive allele of large T antigen (tsTag), was transfected with rat brain-derived neurotrophic factor cDNA (BDNF), and the BDNF-synthesizing cell line, 33BDNF.4, was isolated. The 33BDNF.4 cells synthesized mature BDNF protein at permissive temperature (33 degrees C), when the cells were proliferating, and during differentiation at non-permissive temperature (39 degrees C) in vitro. The bio-active BDNF protein was also secreted by the cells during both growth conditions, as measured by ELISA analysis of BDNF content and secretion. The bio-activity of the BDNF in 33BDNF.4 cell conditioned media was assessed by neurite outgrowth from E15 dorsal root ganglion (DRG) cultures. A control cell line, 33V1, transfected with the vector alone, did not synthesize or secrete any significant BDNF at either growth condition. Both cell lines were used as grafts in a model of chronic neuropathic pain induced by unilateral chronic constriction injury (CCI) of the sciatic nerve. Pain-related behaviors, including cold and tactile allodynia and thermal and tactile hyperalgesia, were evaluated after CCI in the affected hindpaw. When 33BDNF.4 and 33V1 cells were transplanted in the lumbar subarachnoid space of the spinal cord 1 week after CCI, they survived greater than 7 weeks on the pia mater around the spinal cord and the 33BDNF.4 cells continued to synthesize BDNF in vivo. Furthermore, the tactile and cold allodynia and tactile and thermal hyperalgesia induced by CCI was significantly reduced during the 2-7 week period after grafts of 33BDNF.4 cells. The maximal effect on chronic pain behaviors with the BDNF grafts occurred 2-3 weeks after transplant and the anti-nociceptive effects of the BDNF cell grafts was permanent. Transplants of the control 33V1 cells had no effect on the allodynia and hyperalgesia induced by CCI and these cells did not synthesize BDNF in vivo. These data suggest that a chronically applied, low local dose of BDNF supplied by transplanted cells near the spinal dorsal horn was able to reverse the development of chronic neuropathic pain following CCI. The use of neural cell lines that are able to deliver anti-nociceptive molecules, such as BDNF, in a model of chronic pain offers a novel approach to pain management and such 'biologic minipumps' can be developed for safe use in humans.

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Introduction: Inappropriate sinus tachycardia (IST) is characterized by increased heart rate out of proportion to normal physiologic demand. IST ablation is challenging for the electrophysiology community due to the epicardial location of the sinus node and the risk of phrenic nerve (PN) injury during catheter ablation. In this study, we investigated the safety and efficacy of a minimally invasive thoracoscopic surgery for elimination of IST. Methods: Patients with IST who failed medical therapy or endocardial ablation underwent minimally invasive thoracoscopic epicardial ablation. Epicardial activation mapping was performed to identify the earliest activation site and any possible migration of earliest activation along the lateral right atrium. The PN in each patient was protected by a pericardial retraction suture. Results: From 1 January 2000 to 15 June 2018, 10 patients (eight females and two males) underwent minimally invasive thoracoscopic IST ablation. Mean age of the patients was 36.7 ± 12.5 years. Mean baseline sinus rate was 113.8 ± 21.8 beats per minute. After surgery, the mean heart rate significantly decreased to 79.8 ± 8.2 at postoperative day 1 and to 75.8 ± 8.1 at day 30 (both P < .001). No in-hospital death, stroke, or PN injury occurred. One patient required reintubation, one patient developed postoperative pericarditis, and another patient had a pulmonary embolus. Median followup was 6 months (range, 1-50). Freedom from reintervention was 88% at 6 months. Conclusion: Minimally invasive thoracoscopic ablation for IST is a safe and effective approach that preserves the phrenic nerve. Due to the possibility of IST activation site migration, continued follow-up after surgery is required. K E Y W O R D S inappropriate sinus tachycardia, minimally invasive thoracoscopic ablation, phrenic nerve

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