Somatic nerve stimulation evokes qualitatively different somatosympathetic responses in the cervical and splanchnic sympathetic nerves in the rat

Input from unmyelinated and myelinated nociceptors drives somatosympathetic responses to painful stimuli. Here we report that somatosympathetic responses recorded simultaneously in the cervical and splanchnic sympathetic nerves of the urethane-anaesthetized rat are qualitatively different. High intensity electrical stimulation of the sciatic nerve (SN) evoked characteristic biphasic responses in splanchnic nerve activity (N = 6), but only monophasic responses in the cervical nerve (N = 4). By colliding sympathoexcitatory responses to SN stimulation with precisely triggered baroinhibition evoked by electrical stimulation of the aortic depressor nerve, we found that cervical responses are analogous to the first phase of the splanchnic response, and that the biphasic splanchnic response is due to the arrival of two distinct afferent volleys at the site of sympathetic integration. Extracellular recordings of responses to SN stimulation in barosensitive neurons in the rostral ventrolateral medulla (RVLM; N = 16) support these findings; responses were typically biphasic, although the relative magnitudes of the two phases were highly variable, and in some cases the longer-latency volley was completely absent. Our results suggest that sympathetic responses to somatic stimuli, mediated by the RVLM, are non-uniform and are dependent on the target of the particular sympathetic output. The identification of RVLM sympathetic premotor neurons with both biphasic and monophasic responses indicates that the difference in the splanchnic and cervical nerve responses is due to specific channeling of activity evoked by myelinated and unmyelinated nociceptors to the medulla. The results are discussed with regard to the differential control of sympathetic nerve activity.9 page(s

Antibodies to myelin oligodendrocyte glycoprotein have a demyelination phenotype in children and affect oligodendrocyte cytoskeleton

Objective: To examine the clinical features of paediatric CNS demyelination associated with positive myelin oligodendrocyte glycoprotein (MOG) antibodies, and examine the functional effects of MOG antibody on oligodendrocyte cytoskeleton. Methods: We measured MOG antibody using a flow cytometry live cell-based assay in acute sera of 73 children with CNS demyelination (DEM) (median age 8 years, range 1.3–15.3), followed for a median of 4 years. We used MO3.13 cells to examine IgG effects on oligodendrocyte cytoskeleton using 3-D deconvolution imaging. Results: MOG antibodies were found in 31/73 DEM (42%, n =73), but in 0/24 controls. At first presentation, MOG antibody-positive patients were more likely to have bilateral rather than unilateral optic neuritis (ON) (9/10 vs 1/5, respectively, p= 0.03), less likely to have brainstem findings (2/31 vs 16/42, p= 0.005), more likely to have a raised erythrocyte sedimentation rate N20 mm/h (9/19 vs 3/21, p= 0.05), less likely to have intrathecal oligoclonal band (0/16 v 5/27, p =0.18), and were less likely to be homozygous or heterozygous for HLA-DRB1*1501 (3/18 vs 7/22, p=0.46). MOG antibody positivity varied according to clinical phenotype, with ON and relapsing ON being most likely to be seropositive. Two relapsing MOG antibody-positive patients treated with mycophenolate mofetil remain in remission and have become MOG antibody seronegative. Oligodendrocytes incubated with purified IgG from MOG antibodypositive patients showed a striking loss of organization of the thin filaments and the microtubule cytoskeleton, as evidenced by F-actin and β-tubulin immunolabelings. Conclusions: MOG antibody may define a separate demyelination syndrome which has therapeutic implications. MOG antibody has functional effects on oligodendrocyte cytoskeleton.1 page(s

Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton

Objective: To examine the clinical features of pediatric CNS demyelination associated with positive myelin oligodendrocyte glycoprotein (MOG) antibodies and to examine the functional effects of MOG antibody on oligodendrocyte cytoskeleton. Methods: We measured MOG antibody using a fluorescence-activated cell sorting live cell-based assay in acute sera of 73 children with CNS demyelination (DEM) (median age 8 years, range 1.3-15.3) followed for a median of 4 years. We used MO3.13 cells to examine immunoglobulin (Ig) G effects on oligodendrocyte cytoskeleton using 3D deconvolution imaging. Results: MOG antibodies were found in 31/73 patients with DEM (42%) but in 0/24 controls. At first presentation, MOG antibody-positive patients were more likely to have bilateral than unilateral optic neuritis (ON) (9/10 vs 1/5, respectively, p = 0.03), less likely to have brainstem findings (2/31 vs 16/42, p = 0.005), more likely to have a raised erythrocyte sedimentation rate >20 mm/h (9/19 vs 3/21, p = 0.05), less likely to have intrathecal oligoclonal bands (0/16 vs 5/27, p = 0.18), and less likely to be homozygous or heterozygous for human leukocyte antigen DRB1*1501 (3/18 vs 7/22, p = 0.46). MOG antibody positivity varied according to clinical phenotype, with ON and relapsing ON most likely to be seropositive. Two relapsing MOG antibody-positive patients treated with mycophenolate mofetil remain in remission and have become MOG antibody seronegative. Oligodendrocytes incubated with purified IgG from MOG antibody-positive patients showed a striking loss of organization of the thin filaments and the microtubule cytoskeleton, as evidenced by F-actin and β-tubulin immunolabelings. Conclusions: MOG antibody may define a separate demyelination syndrome, which has therapeutic implications. MOG antibody has functional effects on oligodendrocyte cytoskeleton.10 page(s

Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption

Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases