International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Cortical edema in moderate fluid percussion brain injury is attenuated by vagus nerve stimulation

Development of cerebral edema (intracellular and/or extracellular water accumulation) following traumatic brain injury contributes to mortality and morbidity that accompanies brain injury. Chronic intermittent vagus nerve stimulation (VNS) initiated at either 2 h or 24 h (VNS: 30 s train of 0.5 mA, 20 Hz, biphasic pulses every 30 min) following traumatic brain injury enhances recovery of motor and cognitive function in rats in the weeks following brain injury; however, the mechanisms of facilitated recovery are unknown. The present study examines the effects of VNS on development of acute cerebral edema following unilateral fluid percussion brain injury (FPI) in rats, concomitant with assessment of their behavioral recovery. Two hours following FPI, VNS was initiated. Behavioral testing, using both beam walk and locomotor placing tasks, was conducted at 1 and 2 days following FPI. Edema was measured 48 h post-FPI by the customary method of region-specific brain weights before and after complete dehydration. Results of this study replicated that VNS initiated at 2 h after FPI: 1) effectively facilitated the recovery of vestibulomotor function at 2 days after FPI assessed by beam walk performance (P\u3c0.01); and 2) tended to improve locomotor placing performance at the same time point (P=0.18). Most interestingly, results of this study showed that development of edema within the cerebral cortex ipsilateral to FPI was significantly attenuated at 48 h in FPI rats receiving VNS compared with non-VNS FPI rats (P\u3c0.04). Finally, a correlation analysis between beam walk performance and cerebral edema following FPI revealed a significant inverse correlation between behavior performance and cerebral edema. Together, these results suggest that VNS facilitation of motor recovery following experimental brain injury in rats is associated with VNS-mediated attenuation of cerebral edema. © 2007 IBRO

Vagus nerve stimulation may protect GABAergic neurons following traumatic brain injury in rats: An immunocytochemical study

Seizures and subclinical seizures occur following experimental brain injury in rats and may result from inhibitory neuron loss. This study numerically compares cortical and hippocampal glutamic acid decarboxylase (GAD) positive neurons between sham fluid percussion injury (FPI), FPI with sham Vagus Nerve Simulation (VNS), and FPI with chronic intermittent VNS initiated at 24 h post FPI in rats. Rats (n = 8/group) were prepared for immunocytochemistry of GAD at 15 days post FPI. Serial sections were collected and GAD immunoreactive neurons were counted in the hippocampal hilus and two levels of the cerebral cortex. Numbers of quantifiable GAD cells in the rostral cerebral cortices were different between groups, both ipsilateral and contralateral to the FPI. Post hoc analysis of cell counts rostral to the ipsilateral epicenter, revealed a significant 26% reduction in the number of GAD cells/unit area of cerebral cortex following FPI. In the FPI-VNS group, this percentage loss was attenuated to only an 8.5% reduction, a value not significantly different from the sham group. In the contralateral side of the rostral cerebral cortex, FPI induced a significant 24% reduction in GAD cells/unit area; whereas, the VNS-treated rats showed no appreciable diminution of GAD cells rostral to the contralateral epicenter. Hippocampal analysis revealed a similar reduction of GAD cells in the FPI group; however, unlike the cortex this was not statistically significant. In the FPI-VNS group, a trend towards increased numbers of hilar GAD cells was observed, even over and above that of the sham FPI group; however, this was also not statistically significant. Together, these data suggest that VNS protects cortical GAD cells from death subsequent to FPI and may increase GAD cell counts in the hippocampal hilus of the injured brain. © 2006 Elsevier B.V. All rights reserved