Objective Since P188 poloxamer is effective in promoting cell survival in models of acute trauma the objectives were to understand the mechanism of its action focusing on GSK3 activation, IL-6 and p38 signaling. Design Sixteen normal human tali were impacted using 4mm diameter indenter with an impulse of 1Ns. 8mm cartilage plugs containing the 4mm impacted core and 4mm adjacent non-impacted ring were removed and cultured with or without P188. Cell lysates were analyzed using Western blots with antibodies against total and phosphorylated ERK, JNK, p38, ATF-2, GSK3, Stat1 and Stat3. Additional tests were performed with the p38 inhibitor (p38i) SB203580. Results Studied pathways were activated after impaction with the peak of activity at 1hour. P188 completely attenuated phosphorylation of Stat1 and ATF-2 and inhibited p38, Stat3, JNK, ERK, and GSK3. The p38i partially offset phosphorylation of Stat3, GSK3, and ERK suggesting a role of p38 in these three pathways. Additionally, the p38i improved cell survival (p=0.053) and reduced apoptosis (by about 20%, p=0.046, vs almost 40% by P188) thus confirming that P188 acts (at least in part) via p38 pathway. Conclusion Our results report a novel mechanism through which P188 exerts its protective effects on cartilage in the model of acute injury. In addition to its effect on cellular membrane, P188 affects stress-related p38 signaling, apoptosis-related GSK3, and inflammation-related IL-6 signaling. Taken together these findings suggest that P188 alone or in combination with pro-anabolic agents may have a therapeutic potential in preventing progressive cartilage degeneration and the development of post-traumatic osteoarthritis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and a major contributor to disability of young adults in western countries. MS prevalence is highest in areas with low vitamin D. Vitamin D is a fat-soluble compound with numerous physiologic responses, including immune regulation. An increasing volume of work suggests that lower levels of serum vitamin D are associated with an increased risk of MS and a more severe disease course. With the suggestion of a role in MS disease activity, increasing attention is being paid to the potential of using vitamin D as an add-on therapy to established MS disease-modifying therapies. Several preliminary studies have reported results which have shown some promise, but none has yet provided significant evidence of a clinically meaningful improvement. We review our recommendations for off-label supplementation in the context of these findings.

Myelitis is a rare complication of radiation exposure to the spinal cord and is often a diagnosis of exclusion. A retrospective review of clinical records and serial imaging was performed to identify subjects with documented myelitis and a history of prior radiation. Eleven patients fulfilled the inclusion criteria. All patients had longitudinally extensive cord involvement with homogeneous precontrast T1 hyperintense signal in the adjacent vertebrae, corresponding to the radiation field. T2 signal abnormalities involving the central two-thirds of the cord were seen in 6/11 patients (55%). The degree of cord expansion and contrast enhancement was variable but was seen in 6 (54%) and 5 (45%) patients, respectively. On follow-up, 2 patients developed cord atrophy, while complete resolution was noted in 1. Clinical improvement was noted in 5 patients, with symptom progression in 2 patients. Our results suggest that radiation myelitis is neither universally progressive nor permanent, and some radiographic and clinical improvement may occur.

Paroxysmal dysarthria and ataxia (PDA) is a rare syndrome characterized by brief, stereotyped episodes of slurred speech, clumsiness with extremities, or vertigo. It is usually observed in young patients suffering from multiple sclerosis with numerous lesions. PDA is challenging to identify in those presenting with atypical patterns. Here, a non-ataxic variant of PDA in an otherwise neurologically healthy elderly man is presented who had a single midbrain lesion. A broad diagnostic workup illustrates the challenges of identifying PDA. Teaching points emphasize the significance of the midbrain lesion and response to anti-epileptic medication.