A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritis

Complement is an important component of the innate and adaptive immune response, yet complement split products generated through activation of each of the three complement pathways (classical, alternative, and lectin) can cause inflammation and tissue destruction. Previous studies have shown that complement activation through the alternative, but not classical, pathway is required to initiate antibody-induced arthritis in mice, but it is unclear if the alternative pathway (AP) plays a role in established disease. Previously, we have shown that human complement receptor of the immunoglobulin superfamily (CRIg) is a selective inhibitor of the AP of complement. Here, we present the crystal structure of murine CRIg and, using mutants, provide evidence that the structural requirements for inhibition of the AP are conserved in human and mouse. A soluble form of CRIg reversed inflammation and bone loss in two experimental models of arthritis by inhibiting the AP of complement in the joint. Our data indicate that the AP of complement is not only required for disease induction, but also disease progression. The extracellular domain of CRIg thus provides a novel tool to study the effects of inhibiting the AP of complement in established disease and constitutes a promising therapeutic with selectivity for a single complement pathway.     

The same dorsal root ganglion neurons innervate uterus and colon in the rat

The purpose of this study was to determine whether primary sensory neurons that innervate the uterus receive convergent input from the colon. To test this, in the rat, cell bodies of colonic and uterine dorsal root ganglia were retrogradely labeled with fluorescent tracer dyes microinjected into the colon/rectum and bilaterally into the uterine horns. Ganglia were harvested, cryoprotected and cut into 20 microm slices to identify positively stained cells for fluorescent microscopy. Up to 5% of neurons were colon-specific or uterus-specific, and 10-15% of labeled ganglion neurons innervate both viscera in the L1, L2, L6 and S1-S3 levels. These results suggest a novel form of visceral sensory integration in the dorsal root ganglion that may underlie comorbidity of many functional pain syndromes.     

Distinct neurophysiological mechanisms mediate mixing costs and switch costs

Using event-related potentials (ERPs), we investigated the neural response associated with preparing to switch from one task to another. We used a cued task-switching paradigm in which the interval between the cue and the imperative stimulus was varied. The difference between response time (RT) to trials on which the task switched and trials on which the task repeated (switch cost) decreased as the interval between cue and target (CTI) was increased, demonstrating that subjects used the CTI to prepare for the forthcoming task. However, the RT on repeated-task trials in blocks during which the task could switch (mixed-task blocks) were never as short as RTs during single-task blocks (mixing cost). This replicates previous research. The ERPs in response to the cue were compared across three conditions: single-task trials, switch trials, and repeat trials. ERP topographic differences were found between single-task trials and mixed-task (switch and repeat) trials at approximately 160 and approximately 310 msec after the cue, indicative of changes in the underlying neural generator configuration as a basis for the mixing cost. In contrast, there were no topographic differences evident between switch and repeat trials during the CTI. Rather, the response of statistically indistinguishable generator configurations was stronger at approximately 310 msec on switch than on repeat trials. By separating differences in ERP topography from differences in response strength, these results suggest that a reappraisal of previous research is appropriate.     

Neonatal and juvenile stress induces changes in adult social behavior without affecting cognitive function

The aim of the present study was to test the hypothesis that exposure to neonatal and/or juvenile stress results in distinct persisting modification of adult male rats' emotional and social competence. Compared to non-stressed control rats, neonatally stressed rats and rats exposed to combined neonatal and juvenile stress, had reduced frequency and duration of social encounters, and lower anxiety levels. Juvenile stress alone, induced more frequent, but shorter social encounters in adulthood. No significant differences in aggressive behavior were found between any of the groups. The findings confirm the existence of developmental time windows during which exposure to unpredictable stress can affect adult emotional and social behavior without affecting cognitive function.     

Testosterone replacement therapy and motor function in men with spinal cord injury: a retrospective analysis

OBJECTIVE: To evaluate motor function in men with spinal cord injury (SCI) given testosterone replacement therapy (TRT). DESIGN: American Spinal Injury Association (ASIA) rehabilitation discharge motor index scores were compared between men with SCI given TRT (testosterone cypionate, 200 mg, monthly; n = 50) and a comparison group (n = 480) in a retrospective study. Covariates included admission motor and FIM scores, level of injury (paraplegia/tetraplegia), days since injury, and age. RESULTS: ASIA discharge motor scores for ASIA impairment scale grades C and D were significantly different (P < 0.05) in men with incomplete SCI given TRT, relative to the comparison group. The covariate-adjusted mean discharge score for the TRT group was higher than for the comparison group. There were no significant differences in discharge FIM scores (P = 0.34) for men with incomplete injuries and no differences in the adjusted discharge ASIA motor scores (P = 0.92) or adjusted discharge FIM scores (P = 0.16) for men with complete injuries. CONCLUSION: The data support a relationship between TRT and strength gains in men with residual motor function after SCI. Prospective studies are necessary to validate these findings.