The Effects of Neck-Specific Training Versus Prescribed Physical Activity on Pain and Disability in Patients With Cervical Radiculopathy: A Randomized Controlled Trial.

OBJECTIVE: To compare the effects of a neck-specific training program to prescribed physical activity with both groups receiving a cognitive behavioral approach, on pain and disability in patients with cervical radiculopathy (CR). DESIGN: Parallel-group randomized clinical trial with follow-up at 3, 6, 12, and 24 months. SETTING: Recruitment and assessments of participants were performed at a university hospital. Interventions were performed in primary care setting at outpatient physiotherapy clinics. PARTICIPANTS: Patients (N=144) with CR were recruited to participate in this clinical trial. INTERVENTIONS: Patients were randomly assigned to 3 months of either of a neck-specific training program or prescribed physical activity. MAIN OUTCOME MEASURES: Primary outcomes included self-rated neck and arm pain as collected by the visual analog scale (VAS). Secondary outcomes were self-rated headache measured with the VAS, the Neck Disability Index, the EuroQol 5D, the Fear Avoidance Beliefs Questionnaire, and the Hospital Anxiety and Depression Scale. Assessments were performed at baseline and at 3-, 6-, 12-, and 24-month follow-up periods. RESULTS: Intention-to-treat and per-protocol analyses showed no significant interaction (group × time) or group effects. There were, however, significant time effects indicating improvement over time for both groups for all outcomes except for levels of depression. CONCLUSIONS: The study revealed that neck-specific training as well as prescribed physical activity both including additional cognitive behavioral approach decreased the pain in patients with CR, that is, participants improved regardless of the intervention received. There is a lack of consensus of how to best manage individuals with CR. However, our findings suggest that CR has a natural favorable long-term outcome when patients are prescribed neck-specific training and exercise in combination with a behavioral approach.

Cell Fusion along the Anterior-Posterior Neuroaxis in Mice with Experimental Autoimmune Encephalomyelitis.

BACKGROUND: It is well documented that bone marrow-derived cells can fuse with a diverse range of cells, including brain cells, under normal or pathological conditions. Inflammation leads to robust fusion of bone marrow-derived cells with Purkinje cells and the formation of binucleate heterokaryons in the cerebellum. Heterokaryons form through the fusion of two developmentally differential cells and as a result contain two distinct nuclei without subsequent nuclear or chromosome loss. AIM: In the brain, fusion of bone marrow-derived cells appears to be restricted to the complex and large Purkinje cells, raising the question whether the size of the recipient cell is important for cell fusion in the central nervous system. Purkinje cells are among the largest neurons in the central nervous system and accordingly can harbor two nuclei. RESULTS: Using a well-characterized model for heterokaryon formation in the cerebellum (experimental autoimmune encephalomyelitis - a mouse model of multiple sclerosis), we report for the first time that green fluorescent protein-labeled bone marrow-derived cells can fuse and form heterokaryons with spinal cord motor neurons. These spinal cord heterokaryons are predominantly located in or adjacent to an active or previously active inflammation site, demonstrating that inflammation and infiltration of immune cells are key for cell fusion in the central nervous system. While some motor neurons were found to contain two nuclei, co-expressing green fluorescent protein and the neuronal marker, neuron-specific nuclear protein, a number of small interneurons also co-expressed green fluorescent protein and the neuronal marker, neuron-specific nuclear protein. These small heterokaryons were scattered in the gray matter of the spinal cord. CONCLUSION: This novel finding expands the repertoire of neurons that can form heterokaryons with bone marrow-derived cells in the central nervous system, albeit in low numbers, possibly leading to a novel therapy for spinal cord motor neurons or other neurons that are compromised in the central nervous system.

Secondary insults following traumatic brain injury enhance complement activation in the human brain and release of the tissue damage marker S100B.

OBJECT: Complement activation has been suggested to play a role in the development of secondary injuries following traumatic brain injury (TBI). The present study was initiated in order to analyze complement activation in relation to the primary brain injury and to secondary insults, frequently occurring following TBI. METHODS: Twenty patients suffering from severe TBI (Glasgow coma score ≤ 8) were included in the study. The "membrane attack complex," C5b9, which is the cytolytic end product of the complement system was analyzed in cerebrospinal fluid (CSF). The degree of brain tissue damage was assessed using the release of S100B and neuron-specific enolase (NSE) to the CSF and blood. The blood-brain barrier was assessed using the CSF/serum quotient of albumin (Q (A)). RESULTS: Following impact, initial peaks (0-48 h) of C5b9, S100B, and NSE with a concomitant loss of integrity of the blood-brain barrier were observed. Secondary insults at the intensive care unit were monitored. Severe secondary insults were paralleled by a more pronounced complement activation (C5b9 in CSF) as well as increased levels of S100B (measured in CSF), but not with NSE. CONCLUSION: This human study indicates that complement activation in the brain is triggered not only by the impact of trauma per se but also by the amount of secondary insults that frequently occur at the scene of accident as well as during treatment in the neurointensive care unit. Complement activation and in particular the end product C5b9 may in turn contribute to additional secondary brain injuries by its membrane destructive properties.

TLR activation induces TNF-alpha production from adult neural stem/progenitor cells.

Adult neural stem cells (NSCs) are believed to facilitate CNS repair and tissue regeneration. However, it is not yet clear how these cells are influenced when the cellular environment is modified during neurotrauma or neuroinflammatory conditions. In this study, we determine how different proinflammatory cytokines modulate the expression of TLR2 and TLR4 in NSCs and how these cells respond to TLR2 and TLR4 agonists. Primary cultures of neural stem/progenitor cells isolated from the subventricular zone of brains from adult Dark Agouti rats were exposed to 1) supernatants from activated macrophages; 2) proinflammatory cytokines IFN-gamma, TNF-alpha, or both; and 3) agonists for TLR2 and TLR4. Both TLR2 and TLR4 were expressed during basal conditions and their mRNA levels were further increased following cytokine exposure. TLR4 was up-regulated by IFN-gamma and this effect was reversed by TNF-alpha. TLR2 expression was increased by supernatants from activated macrophages and by TNF-alpha, which synergized with IFN-gamma. TLR agonists induced the expression of TNF-alpha mRNA. Importantly, TNF-alpha could be translated into protein and released into the supernatants where it was quantified by cytokine ELISA. In conclusion, we demonstrate that NSCs constitutively express TLR2 and TLR4 and that their expression is increased as a consequence of exposure to proinflammatory mediators. Additionally, activation of these receptors can induce production of proinflammatory cytokines. These findings suggest that NSCs may be primed to participate in cytokine production during neuroinflammatory or traumatic conditions.

Nitric oxide exposure diverts neural stem cell fate from neurogenesis towards astrogliogenesis.

Regeneration of cells in the central nervous system is a process that might be affected during neurological disease and trauma. Because nitric oxide (NO) and its derivatives are powerful mediators in the inflammatory cascade, we have investigated the effects of pathophysiological concentrations of NO on neurogenesis, gliogenesis, and the expression of proneural genes in primary adult neural stem cell cultures. After exposure to NO, neurogenesis was downregulated, and this corresponded to decreased expression of the proneural gene neurogenin-2 and beta-III-tubulin. The decreased ability to generate neurons was also found to be transmitted to the progeny of the cells. NO exposure was instead beneficial for astroglial differentiation, which was confirmed by increased activation of the Janus tyrosine kinase/signal transducer and activator of transcription transduction pathway. Our findings reveal a new role for NO during neuroinflammatory conditions, whereby its proastroglial fate-determining effect on neural stem cells might directly influence the neuroregenerative process.