Binge drinking and alcohol abuse are common during adolescence and cause both cognitive deficits and lasting cholinergic pathology in the adult basal forebrain. Acetylcholine is anti-inflammatory and studies using the preclinical adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2 day on/2 day off from postnatal day [P]25 to P54) model of human adolescent binge drinking report decreased basal forebrain cholinergic neurons (BFCNs) and induction of proinflammatory genes that persist long into adulthood. Recent studies link AIE-induced neuroimmune activation to cholinergic pathology, but the underlying mechanisms contributing to the persistent loss of BFCNs are unknown. We report that treatment with the cholinesterase inhibitor galantamine (4.0 mg/kg, i.p.) administered during AIE (i.e., P25–P54) or following the conclusion of AIE (i.e., P57–P72) recovered the persistent loss of cholinergic neuron phenotype markers (i.e., ChAT, TrkA, and p75NTR) and somal shrinkage of residual ChAT + neurons known to persist in AIE-exposed adults. Galantamine treatment also recovered the AIE-increased expression of the proinflammatory receptors TLR4 and RAGE, the endogenous TLR4/RAGE agonist HMGB1, and the transcription activation marker pNF-κB p65. Interestingly, we find BFCNs express TLR4 and RAGE, and that AIE treatment increased pNF-κB p65 expression in adult ChAT + IR neurons, consistent with intracellular HMGB1-TLR4/RAGE signaling within BFCNs. AIE increased epigenetic transcription silencing markers (i.e., H3K9me2 and H3K9me3) in the adult basal forebrain and H3K9me2 occupancy at cholinergic phenotype gene promoters (i.e., ChAT and TrkA). The finding of no AIE-induced changes in total basal forebrain NeuN + neurons with galantamine reversal of AIE-induced ChAT + neuron loss, TLR4/RAGE-pNF-κB p65 signals, and epigenetic transcription silencing markers suggests that AIE does not cause cell death, but rather the loss of the cholinergic phenotype. Together, these data suggest that AIE induces HMGB1-TLR4/RAGE-pNF-κB p65 signals, causing the loss of cholinergic phenotype (i.e., ChAT, TrkA, and p75NTR) through epigenetic histone transcription silencing that result in the loss of the BFCN phenotype that can be prevented and restored by galantamine.
A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was: in patients with non-small-cell lung cancer that is found to be unresectable at thoracotomy, is incomplete resection superior for achieving survival advantage? Altogether more than 400 papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. In total, data from an estimated 1083 patients were analysed. Three-year survival rates varied from 0 to 22% in incomplete resection and from 0 to 10% in exploratory thoracotomy. Median survival ranged from 6.5 to 19.1 months in incomplete resection and from 5.3 to 17 months in exploratory thoracotomy. The majority of studies (8/9) found survival in incomplete resection to be superior. However, only 3/9 studies presented statistical analysis of results. The largest of these found superior postoperative survival in incomplete resection (including residual nodal disease), one study showed a significant survival difference for R1 but not R2 resection and another with small patient numbers (n = 29) found no significant difference. We conclude that the best evidence suggests that there may be a survival advantage from incomplete resection of non-small-cell lung cancer when there is microscopic (R1) or nodal residual disease, but not when macroscopic residual (R2) disease remains.
Background: Adolescent intermittent ethanol (AIE) exposure causes long-term changes in the brain and behavior of adult male rodents, including persistent induction of innate immune pathways, reductions in hippocampal neurogenic and forebrain cholinergic neuronal markers, and reversal learning deficits. The current study tests the hypothesis that proinflammatory induction mediates AIE-induced (1) loss of adult neurogenesis (i.e., doublecortin (DCX) expressing immature neurons), (2) reductions in forebrain and hippocampal cholinergic markers, and (3) reversal learning deficits.Methods: Male and female rats underwent AIE (5.0 g/kg/day ethanol or water, i.g., 2 day-on/2 day-off from postnatal day (PND) 25-54), followed by a 2-week regimen of the anti-inflammatory compound indomethacin (4.0 g/kg/day, PND 56-69) or vehicle, after which one cohort was euthanized for immunohistochemical markers (PND 70) and the second underwent the Morris water maze to assess reversal learning.Results: AIE reduced adult (PND 70) DCX+ immunoreactivity (IR) and increased hippocampal expression of the innate immune signal's high-mobility group box protein 1 (HMGB1 + IR) and cyclooxygenase-2 (COX-2 + IR) in adult male and female rats. AIE also reduced choline acetyltransferase (ChAT+IR) in the basal forebrain and colabeling of hippocampal vesicular acetylcholine transporter (VAChT+) cholinergic terminals on DCX + IR neurons. Indomethacin treatment after AIE restored molecular endpoints to control levels and rescued AIE-induced reversal learning deficits in the Morris water maze in both sexes. Of note, indomethacin produced several adverse effects selectively in control conditions, highlighting the uniquely beneficial effect of indomethacin in AIE rats.Conclusions: These data suggest that in males and females, (1) AIE persistent neuroimmune induction mediates both the loss of adult hippocampal DCX and loss of basal forebrain cholinergic neurons and their innervation to hippocampal targets, and (2)| 471
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.