Eliciting inflammation enables successful rehabilitative training in chronic spinal cord injury.

Rehabilitative training is one of the most successful therapies to promote motor recovery after spinal cord injury, especially when applied early after injury. Polytrauma and management of other medical complications in the acute post-injury setting often preclude or complicate early rehabilitation. Therefore, interventions that reopen a window of opportunity for effective motor training after chronic injury would have significant therapeutic value. Here, we tested whether this could be achieved in rats with chronic (8 weeks) dorsolateral quadrant sections of the cervical spinal cord (C4) by inducing mild neuroinflammation. We found that systemic injection of a low dose of lipopolysaccharide improved the efficacy of rehabilitative training on forelimb function, as assessed using a single pellet reaching and grasping task. This enhanced recovery was found to be dependent on the training intensity, where a high-intensity paradigm induced the biggest improvements. Importantly, in contrast to training alone, the combination of systemic lipopolysaccharide and high-intensity training restored original function (reparative plasticity) rather than enhancing new motor strategies (compensatory plasticity). Accordingly, electrophysiological and tract-tracing studies demonstrated a recovery in the cortical drive to the affected forelimb muscles and a restructuration of the corticospinal innervation of the cervical spinal cord. Thus, we propose that techniques that can elicit mild neuroinflammation may be used to enhance the efficacy of rehabilitative training after chronic spinal cord injury.

Spontaneous recovery of bilateral congenital idiopathic laryngeal paralysis: systematic non-meta-analytical review.

OBJECTIVES: To systematically review the frequency and time to spontaneous recovery in pediatric patients with bilateral congenital idiopathic laryngeal paralysis (BCILP). METHODS: The databases of Medline, EMBASE, Scopus, CINAHL, Cochrane Library and Proquest Dissertations were searched for English language articles reporting on laryngeal paralysis in pediatric patients. A bibliography search of the selected studies was done to identify additional articles. We included prospective or retrospective case-series studies of children and neonates diagnosed with BCILP at age <60 days and confirmed by direct laryngoscopy, with sufficient follow up and objective assessment for recovery. Two authors independently extracted the data and assessed the quality of each study. Discrepancies were resolved by consensus and adjudication by a third author. RESULTS: Of the 4229 articles identified by the search, only one study met our inclusion criteria. The study was a retrospective case series, and was of low quality. The mean age at diagnosis was fourteen days. Sixty-five percent of the patients recovered spontaneously, and the mean time to recovery was twenty-five months. Tracheostomy was performed in 71% of the patients. CONCLUSIONS: The available literature is of low quality and provides weak evidence on the natural history of BCILP in pediatric population.

Characterization of A11 neurons projecting to the spinal cord of mice.

The hypothalamic A11 region has been identified in several species including rats, mice, cats, monkeys, zebrafish, and humans as the primary source of descending dopamine (DA) to the spinal cord. It has been implicated in the control of pain, modulation of the spinal locomotor network, restless leg syndrome, and cataplexy, yet the A11 cell group remains an understudied dopaminergic (DAergic) nucleus within the brain. It is unclear whether A11 neurons in the mouse contain the full complement of enzymes consistent with traditional DA neuronal phenotypes. Given the abundance of mouse genetic models and tools available to interrogate specific neural circuits and behavior, it is critical first to fully understand the phenotype of A11 cells. We provide evidence that, in addition to tyrosine hydroxylase (TH) that synthesizes L-DOPA, neurons within the A11 region of the mouse contain aromatic L-amino acid decarboxylase (AADC), the enzyme that converts L-DOPA to dopamine. Furthermore, we show that the A11 neurons contain vesicular monoamine transporter 2 (VMAT2), which is necessary for packaging DA into vesicles. On the contrary, A11 neurons in the mouse lack the dopamine transporter (DAT). In conclusion, our data suggest that A11 neurons are DAergic. The lack of DAT, and therefore the lack of a DA reuptake mechanism, points to a longer time of action compared to typical DA neurons.

Acquired bilateral adductor laryngeal paralysis in neonates and children: a case series and a systematic review.

OBJECTIVES: To present a series of acquired bilateral adductor laryngeal paralysis (BAdLP) and review the literature on clinical manifestations and management. METHODS: A retrospective review of a single tertiary care practice of pediatric otolaryngology was conducted. Patients were identified from a surgical database spanning twelve years of practice (2002-2013). The variables documented included gender, age at presentation, co-morbid conditions, documented laryngeal findings on endoscopy, management and outcome. A systematic review of the literature was conducted to identify reports on BAdLP in children and associated conditions. RESULTS: Five cases (four girls and one boy) ranging from 3 months to 16 years of age were identified. All cases were documented using rigid and/or flexible laryngoscopy. In four cases, the onset was after major cardiac surgery complicated by cerebral vascular accidents, while one followed a thalamic stroke. Four were managed with tube feeding. Only three papers reported BAdLP in children. CONCLUSIONS: The cases identified were all acquired after a central neurological insult. The profile is distinct from the congenital adductor form of laryngeal paralysis previously described. However, the symptom complex is identical. We believe this is the largest case series from one center to be reported.

Lipopolysaccharide can induce errors in anatomical measures of neuronal plasticity by increasing tracing efficacy.

Evidence suggests that activating certain components of the immune system may increase regeneration and plasticity in the injured central nervous system. Investigating the effect of lipopolysaccharide (LPS), a potent endotoxin and immune activator, on neuronal plasticity in rat models of spinal cord injury, we discovered that systemic administration of LPS can increase the number of descending motor axons that transport neuronal tracers anterogradely to the spinal cord. This effect of LPS was not observed across all motor tracts traced in two different experiments, but was significant for two different tracers administered to corticospinal tract neurons. Densitometry measurement of traced corticospinal axons within the cervical gray matter revealed that normalization to the number of traced axons is crucial to avoid false-positive reports of increased plasticity following LPS injection. These findings indicate that assessments of neuronal growth based on neuronal tracing techniques should be normalized when inflammation or immune activation is an experimental variable.

Spinal cord injury and plasticity: opportunities and challenges.

There is still no effective treatment to promote functional recovery following spinal cord injury. However, promoting injury-induced adaptive changes (plasticity) within the central nervous system, associated with repair, promise new treatment strategies. Recent contributions from our group and current challenges of this relatively young field are discussed in this review.

Training-induced plasticity in rats with cervical spinal cord injury: effects and side effects.

We investigated the contribution of corticospinal tract (CST) plasticity to training-induced recovery and side effects following spinal cord injury (SCI). Rats were divided into three lesion groups: a unilateral lesion of the dorsal funiculus, the lateral funiculus or a lesion of the entire dorsolateral quadrant (DLQ). Following surgery, rats were distributed into a training group and an untrained group. Trained rats received rehabilitative training in skilled reaching 6 days a week, starting 4 days post-lesion. Following 6 weeks, all rats were tested in reaching (trained task) and crossing a horizontal ladder (untrained task). We found that trained rats with a lesion involving the dorsal column were significantly better in reaching compared to untrained animals. However, when crossing the horizontal ladder, trained rats made significantly more mistakes than untrained animals. Interestingly, rats with a lateral funiculus lesion did not show either effect. A subsequent ablation of the pyramidal tract (pyramidotomy) in rats with a DLQ-lesion significantly reduced but did not eliminate the reaching success. This spared function suggests that other descending systems contributed to the training-induced recovery. In addition, motor-evoked potentials (MEP) from cortical stimulation could still be evoked after pyramidotomy. Further, blocking synaptic transmission passing through the red nucleus using muscimol did not influence the occurrence of MEP's, suggesting that other descending pathways, like the reticulospinal tract, were involved in functional recovery. In summary, this study demonstrates that training-induced CST plasticity may contribute to recovery of motor function, but may also negatively affect untrained tasks as previously reported.

Histomorphological and functional impacts of postoperative motor training in rats after allograft sciatic nerve transplantation under low-dose FK 506.

This study aimed to determine the effect of motor training on recovery after nerve transplantation under low-dose FK 506. Rats (n=30) of two strains were randomly assigned to three groups. Group I served as untreated controls; groups II and III received allograft transplants for reconstruction of the sciatic nerve and FK 506 (0.1 mg/kg/d). Nonoperated limbs served as intra-animal controls. Group III received postoperative motor training. Functional and histomorphological outcomes were assessed by walking track analysis and by blob analysis for myelinization of nerve sections. Regeneration occurred in both groups II and III. The control sections of the nonoperated limbs in group III showed significantly higher myelinization compared with group I and II; regeneration of the operated side was superior in group II. With regard to postoperative motor training, no benefit could be seen; however, the impact of postoperative motor training on the nonoperated limb were identified.

Advantages of delaying the onset of rehabilitative reaching training in rats with incomplete spinal cord injury.

We have previously reported that rehabilitative reaching training initiated 4 days following an incomplete cervical spinal cord injury (SCI) in adult rats promotes plasticity and task-specific recovery. This training, however, also resulted in impairments in an untrained task. Here we examined whether delaying the rehabilitative training following cervical SCI is still effective in promoting task-specific recovery, but circumvents impairments in an untrained task, comparable to what has been reported in stroke models. Therefore, reaching training for a period of 6 weeks was initiated at Day 12 following a cervical dorso-lateral quadrant lesion. Thereupon the rats' ability to reach and to walk on a horizontal ladder (i.e. the untrained task) was assessed, and 8 weeks post-injury cortical map changes were investigated through microstimulation. Further, we examined changes in phospho protein kinase A (pPKA) levels following an immediate and a delayed onset of reaching training in rats with cervical SCI. We found that delayed rehabilitative training was comparably effective as immediate training in promoting task-specific recovery and sprouting of injured axons. Importantly, delayed training did not impair the performance on horizontal ladder walking. Strikingly, only delayed reaching training restored cortical PKA levels that had dropped significantly over 2 weeks post-injury. Additionally, delayed training did not influence cortical map changes following injury, but decreased white matter damage. In conclusion, our results show that a short delay in the onset of training in a forelimb task significantly alters our outcome measures, which should be considered in future rehabilitative approaches.

Matrix formation in sustained release tablets: possible mechanism of dose dumping.

Conditions under which poly(ethyl acrylate, methyl methacrylate) 2:1 (poly(EA-MMA), Eudragit NE) forms a stable matrix were investigated in tablets with diclofenac sodium (DS) as an active substance. DS was granulated with the aqueous polymer dispersion. Granules and/or tablets were cured under various temperature and humidity conditions. A six position rotating disk (200 rpm) apparatus was used for the release studies conducted in 37 degrees C acid then phosphate buffer (0.4 M) pH 6.8 or buffer only as the dissolution media. Morphological characteristics of the tablet surface were observed under SEM. Changes in tablet structure upon curing were evaluated through changes in tablet mechanical characteristics. Modulus of rupture, Young's modulus, AUC, AUC(max), where AUC=AUC(max), were determined by the three-point bending test. Some poorly cured tablets dose-dumped when placed directly into buffer but not if first placed in acid and then buffer. A higher content of polymer in the matrix, led to formation of a stronger polymer network upon higher curing temperature and/or longer curing duration, whereas relative humidity had a minor effect.