Bradley J. Snyder

Mechanisms of Reversible GABAA Receptor Plasticity after Ethanol Intoxication

The time-dependent effects of ethanol (EtOH) intoxication on GABAA receptor (GABAAR) composition and function were studied in rats. A cross-linking assay and Western blot analysis of microdissected CA1 area of hippocampal slices obtained 1 h after EtOH intoxication (5 g/kg, gavage), revealed decreases in the cell-surface fraction of α4 and δ, but not α1, α5, or γ2 GABAAR subunits, without changes in their total content. This was accompanied (in CA1 neuron recordings) by decreased magnitude of the picrotoxin-sensitive tonic current (Itonic), but not miniature IPSCs (mIPSCs), and by reduced enhancement of Itonic by EtOH, but not by diazepam. By 48 h after EtOH dosing, cell-surface α4 (80%) and γ2 (82%) subunit content increased, and cell-surface α1 (−50%) and δ (−79%) and overall content were decreased. This was paralleled by faster decay of mIPSCs, decreased diazepam enhancement of both mIPSCs and Itonic, and paradoxically increased mIPSC responsiveness to EtOH (10–100 mm). Sensitivity to isoflurane- or diazepam-induced loss of righting reflex was decreased at 12 and 24 h after EtOH intoxication, respectively, suggesting functional GABAAR tolerance. The plastic GABAAR changes were gradually and fully reversible by 2 weeks after single EtOH dosing, but unexplainably persisted long after withdrawal from chronic intermittent ethanol treatment, which leads to signs of alcohol dependence. Our data suggest that early tolerance to EtOH may result from excessive activation and subsequent internalization of α4βδ extrasynaptic GABAARs. This leads to transcriptionally regulated increases in α4 and γ2 and decreases in α1 subunits, with preferential insertion of the newly formed α4βγ2 GABAARs at synapses.

Development and validation of a novel patient educational booklet to enhance colonoscopy preparation.

OBJECTIVES:The success of colonoscopy depends on high-quality bowel preparation by patients; yet inadequate preparation is common. We developed and tested an educational booklet to improve bowel preparation quality.METHODS:We conducted patient cognitive interviews to identify knowledge and belief barriers to colonoscopy preparation. We used these interviews to create an educational booklet to enhance preparatory behaviors. We then prospectively randomized patients scheduled for outpatient colonoscopy at a VA Medical Center to receive usual instructions vs. the booklet before colonoscopy. Patients in both groups received standard pharmacy instructions for single-dose bowel preparation; the protocol did not specify which purgatives to prescribe. The primary outcome was preparation quality based on blinded ratings using the validated Ottawa score. We performed bivariate analyses to compare mean scores between groups using a t-test, and logistic regression to measure the booklet effect on preparation quality, adjusting for potential confounders.RESULTS:A total of 436 patients were randomized between arms. In an intention-to-treat analysis of the primary outcome, mean Ottawa scores were superior in patients allocated to booklet vs. controls (P=0.03). An intention-to-treat analysis of the secondary outcome revealed a “good” preparation in 68 vs. 46% of booklet and control patients, respectively (P=0.054). In a per-protocol analysis limited to patients who actually received the booklet, preparation was good in 76 vs. 46% patients, respectively (P<0.00001). Regression analysis revealed that booklet receipt increased the odds of good preparation by 3.7 times (95% confidence interval=2.3–5.8).CONCLUSIONS:Provision of a novel educational booklet considerably improves preparation quality in patients receiving single-dose purgatives. The effect of the booklet on split-dose purgatives remains untested and will be evaluated in future research.

Development of an Online Library of Patient-Reported Outcome Measures in Gastroenterology: The GI-PRO Database

OBJECTIVES:Because gastrointestinal (GI) illnesses can cause physical, emotional, and social distress, patient-reported outcomes (PROs) are used to guide clinical decision making, conduct research, and seek drug approval. It is important to develop a mechanism for identifying, categorizing, and evaluating the over 100 GI PROs that exist. Here we describe a new, National Institutes of Health (NIH)-supported, online PRO clearinghouse—the GI-PRO database.METHODS:Using a protocol developed by the NIH Patient-Reported Outcome Measurement Information System (PROMIS®), we performed a systematic review to identify English-language GI PROs. We abstracted PRO items and developed an online searchable item database. We categorized symptoms into content “bins” to evaluate a framework for GI symptom reporting. Finally, we assigned a score for the methodological quality of each PRO represented in the published literature (0–20 range; higher indicates better).RESULTS:We reviewed 15,697 titles (κ>0.6 for title and abstract selection), from which we identified 126 PROs. Review of the PROs revealed eight GI symptom “bins”: (i) abdominal pain, (ii) bloat/gas, (iii) diarrhea, (iv) constipation, (v) bowel incontinence/soilage, (vi) heartburn/reflux, (vii) swallowing, and (viii) nausea/vomiting. In addition to these symptoms, the PROs covered four psychosocial domains: (i) behaviors, (ii) cognitions, (iii) emotions, and (iv) psychosocial impact. The quality scores were generally low (mean 8.88±4.19; 0 (min)–20 (max). In addition, 51% did not include patient input in developing the PRO, and 41% provided no information on score interpretation.CONCLUSIONS:GI PROs cover a wide range of biopsychosocial symptoms. Although plentiful, GI PROs are limited by low methodological quality. Our online PRO library (www.researchcore.org/gipro/) can help in selecting PROs for clinical and research purposes.

Mo1030 Less Experienced Endoscopists are More Likely to Report “Sub-Optimal” Bowel Preparation Quality vs. More Experienced Endoscopists

Less Experienced Endoscopists are More Likely to Report “Sub-Optimal” Bowel Preparation Quality vs. More Experienced Endoscopists Hank S. Wang, Scott Kubomoto, Aaron Lee, Luis H. Ocampo, Michael D. Baek, Gobind N. Sharma, Jessica Liu, Rusha Modi, Nattapaun N. Thepyasuwan, Alexander Levy, Michelle Vu, Victoria Sheen, Mary A. Atia, Kamyar Shahedi, Bradley J. Snyder, Poyrung Poysophon, Brennan M. Spiegel

Diagnostic Yield of Endoscopy for Weight Loss: Results of a Comparative Cohort Study vs. Non-Weight Loss Controls

Background: Gastroenterologists are commonly asked to perform pan-endoscopy in patients with weight loss. This request is based on historical series revealing a high prevalence of GI causes of involuntary weight loss (Lankisch J Int Med 2001). However, in the absence of specific GI symptoms or signs, such as bleeding, dysphagia, diarrhea, constipation, or anemia, the yield of endoscopy may be low and its appropriateness unclear. We studied patients referred for endoscopy because of weight loss, and evaluated the yield of endoscopy vs. non-weight loss controls. Methods: We performed a retrospective analysis of patients referred to the endoscopy unit of a University-based VA medical center from 2000-2010 with a primary indication of weight loss. We excluded patients who would otherwise qualify for endoscopy regardless of weight loss, such as those with positive fecal occult blood, iron deficiency, previous imaging study with a colonic abnormality, familial GI cancer syndrome, GI bleeding, or prior colon cancer. Although we allowed for diarrhea and constipation, we performed a sensitivity analysis in which this sub-group was also excluded. We gathered data on patient characteristics, duration and amount of weight loss, body mass index (BMI), and endoscopy findings. We calculated the proportion of cases in which an explanatory luminal diagnosis was identified by endoscopy, and compared this to the yield in 2 age and sex-matched control groups: 1) group undergoing screening colonoscopy; and 2) group undergoing diagnostic colonoscopy for a non-weight loss indication. We conducted separate analyses for colonoscopy and upper endoscopy (EGD). We employed chi-squared for pairwise comparisons. Results: There were 95 colons and 61 EGDs identified (mean age=65; 93% male; BMI=23). Patients lost a mean of 22 lbs over a 9 month average period. The Figure reveals the diagnostic yield of the study groups. Two of the 95 colonoscopy patients (2.1%) had primary colon cancer and 3 had colitis as the explanation for weight loss. The screening colonoscopy control group resulted in no colon cancers, and the diagnostic colonoscopy control group revealed 4 cancers (4.2%) and 1 case of colitis (1.1%). After excluding diarrhea and constipation, there was 1 case of colitis (1.8%) and no cancer. There were no significant differences among any pair-wise comparisons. Of the EGD cases, there was 1 gastric cancer (1.6%); the non-weight loss control EGDs revealed 2 gastric cancers (3.3%) (p=NS). Conclusion: In the absence of other GI “red flag” features, patients with weight loss rarely harbor an underlying luminal disease; there is no difference in diagnostic yield of endoscopy vs. age and sex-matched controls. These data suggest that pan-endoscopy for weight loss is unlikely to be cost-effective in the absence of other concurrent indications for a GI procedure.