Hepatocyte death results in a sterile inflammatory response that amplifies the initial insult and increases overall tissue injury. One important example of this type of injury is acetaminophen-induced liver injury, in which the initial toxic injury is followed by innate immune activation. Using mice deficient in Tlr9 and the inflammasome components Nalp3 (NACHT, LRR, and pyrin domain-containing protein 3), ASC (apoptosis-associated specklike protein containing a CARD), and caspase-1, we have identified a nonredundant role for Tlr9 and the Nalp3 inflammasome in acetaminophen-induced liver injury. We have shown that acetaminophen treatment results in hepatocyte death and that free DNA released from apoptotic hepatocytes activates Tlr9. This triggers a signaling cascade that increases transcription of the genes encoding pro-IL-1β and pro-IL-18 in sinusoidal endothelial cells. By activating caspase-1, the enzyme responsible for generating mature IL-1β and IL-18 from pro-IL-1β and pro-IL-18, respectively, the Nalp3 inflammasome plays a crucial role in the second step of proinflammatory cytokine activation following acetaminophen-induced liver injury. Tlr9 antagonists and aspirin reduced mortality from acetaminophen hepatotoxicity. The protective effect of aspirin on acetaminophen-induced liver injury was due to downregulation of proinflammatory cytokines, rather than inhibition of platelet degranulation or COX-1 inhibition. In summary, we have identified a 2-signal requirement (Tlr9 and the Nalp3 inflammasome) for acetaminophen-induced hepatotoxicity and some potential therapeutic approaches.

Background & Aims Bowel preparation is defined as adequate if it is sufficient for identification of polyps >5mm. However, adequate preparation has not been quantified. We performed a prospective observational study to provide an objective definition of adequate preparation, based on the Boston Bowel Prep Scale (BBPS, 0–3 points for each of 3 colon segments). Methods We collected data from 438 men who underwent screening or surveillance colonoscopies and then repeat colonoscopy examinations within 60 days by a different blinded endoscopist (1161 colon segments total) at the West Haven Veterans Affairs Medical Center from January, 2014 to February, 2015. Missed polyps were defined as those detected on the second examination of patients with the best possible bowel preparation (colon segment BBPS score of 3) on the second examination. The primary outcome was proportion of colon segments with adenomas >5mm that were missed in the first examination. We postulated that the miss rate was non-inferior for segments with BBPS scores of 2 vs those with BBPS scores of 3 (non-inferiority margin, <5%). Our secondary hypotheses were that miss rates were higher in segments with BBPS scores of 1 vs those with scores of 3 or of 2. Results The adjusted proportion with missed adenomas >5mm was non-inferior for segments with BBPS scores of 2 (5.2%) vs those with BBPS scores of 3 (5.6%) (a difference of −0.4%; 95% confidence interval [CI], −2.9% to 2.2%). Of study subjects, 347 (79.2%) had BBPS scores ≥2 in all segments on initial examination. A higher proportion of segments with BBPS scores of 1 had missed adenomas >5mm (15.9%) than segments with BBPS scores of 3 (5.6%) (a difference of 10.3%; 95% CI, 2.7%–17.9%) or 2 (5.2%) (a difference of 10.7%; 95% CI, 3.2–18.1%). Screening and surveillance intervals based solely on the findings at the first examination would have been incorrect for 16.3% of patients with BBPS scores of 3 in all segments, for 15.3% with BBPS scores of 2 or 3 in all segments, and 43.5% of patients with a BBPS score of 1 in 1 or more segments. Conclusions Patients with BBPS scores of 2 or 3 for all colon segments have adequate bowel preparation for detection of adenomas >5 mm and should return for screening or surveillance colonoscopy at standard guideline-recommended intervals. Colon segments with a BBPS score of 1 have a significantly higher rate of missed adenomas >5mm than segments with scores of 2 or 3. This finding supports a recommendation for early repeat colonoscopic evaluation in patients with a BBPS score of 0 or 1 in any colon segment.

Endoscopic variceal ligation (EVL) and nonselective beta-blockers (hereafter just called beta-blockers) are both effective for primary prophylaxis for variceal hemorrhage; however, the route of administration and side effects of these treatments are distinct. The objective of this study was to examine predicted preferences of patients and physicians for the primary prevention of variceal hemorrhage. Untreated patients with newly diagnosed esophageal varices and practicing gastroenterologists were enrolled in this study. Patients with contraindications to either EVL or beta-blockers were excluded. Predicted preferences for treatment were evaluated with an interactive computer task designed to elicit subjects' trade-offs related to the route of administration, risk of fatigue, sexual dysfunction, dysphagia, shortness of breath and/or hypotension, procedure-related bleeding, and perforation. Fifty-three patients and 61 physicians were enrolled. Thirty-four (64%) patients and 35 (57%) physicians preferred EVL over beta-blockers. Patients' predicted preferences were most strongly influenced by the risks of shortness of breath or hypotension, fatigue, and procedure-related bleeding, whereas physicians placed greater importance on procedure-related bleeding, sexual dysfunction, and perforation. Forty-eight patients were prescribed beta-blockers, two were not given prophylaxis, and three were lost to follow-up. Conclusion: Predicted treatment preferences among both patients and physicians for primary prophylaxis of variceal hemorrhage vary significantly. Physicians in this study preferring EVL stated that they prescribe beta-blockers as first-line therapy in order to remain compliant with guidelines. Physicians should discuss both EVL and beta-blockers with patients requiring primary prophylaxis for variceal hemorrhage. Future guidelines should incorporate individual patient preferences. (HEPATOLOGY 2008;47:169-176.)