Introduction

Agonists and antagonists of G protein-coupled receptors (GPCRs) are widely used medications that serve in the therapy of constipation, diarrhea, and pain. However, little is known about how the effect of those drugs is modulated by Regulator of G Protein Signaling (RGS) proteins which promote timely silencing of the GPCR responses. RGS proteins have been documented to regulate the magnitude and duration of signals initiated by several types of GPCRs occurring in the GI tract, including opioid and cannabinoid receptors. Serving as a central control point in GPCR signaling cascades, RGS proteins hold great promises as targets for the drug development however their expression profile and function in the gut constitute a major gap in the knowledge.

Aims & Methods

The major emphasis of this study is on elucidating the expression and function of RGS proteins in physiology and pathophysiology of the GI tract. We hypothesize that identification of RGS proteins and GPCR signaling pathways that they control will reveal novel molecular targets combating GI disorders. METHODS: We used total RNA sequencing to evaluate the expression profile of RGS proteins in the mouse ileum and colon. Then we confirmed the expression of the most abundant transcripts with the qPCR and measured the expression of proteins with Western blot. Then in the in vivo conditions we used an RGS6 knockout (RGS-/-) mouse model to evaluate the effect of this protein on intestinal motility, pain and inflammation in naïve mice as well in the presence of the cannabinoid agonist WIN 55,212-2.

Results

RNA sequencing showed similar profile of expression of RGS proteins in the ileum and colon. qPCR analyses showed that Rgs2, 5 and 6 are the most abundant transcripts in the colon. At the level of protein we observed that RGS6 exhibits the highest expression in the ileum colon as well as intestinal intraepithelial lymphocytes. Moreover we observed a significant increase in RGS6 expression in the mouse colon samples during intestinal inflammation. In vivo experiments showed that RGS6-/- animals exhibit increased intestinal motility in physiological conditions and resistance to stress-induced diarrhea. Moreover RGS6-/- animals exhibit anti-nociceptive phenotype and are more susceptible to the analgesic effect of WIN 55,212-2. We did not observe the impact of RGS6 on the severity of colitis in the DSS-induced model.

Conclusion

Here we present RGS6 protein as a novel candidate for drug targeting in the GI tract. Our study suggests that loss and perhaps also pharmacological blockade of RGS6 might be used as standalone or an adjunct treatment to increase the potency of cannabinoids in the gut. The project is ongoing and further experiments are pending.

Introduction

Several risk stratification scores have been developed for predicting endoscopic treatment or patient survival in non-variceal upper gastrointestinal bleeding (NVUGIB).

Aims & Methods

Our aim was to compare the performance of some previously described scores such as Canada-United Kingdom-Adelaide score (CANUKA), Glasgow-Blatchford score (GBS), Harbinger score, neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW) and Rockall (pre-endoscopy and complete) scores in predicting with the following outcomes in patients with variceal upper gastrointestinal bleeding (VUGIB): 30-day mortality, in-hospital mortality, need for interventional radiological procedure, need for RBC transfusion and rebleeding. Patients undergoing emergency endoscopy for upper GI bleeding at the Department of Emergency Medicine at Semmelweis University between January 1, 2022 and December 31, 2023 were included in a retrospective cohort analysis. Cases with VUGIB were managed according to the ESGE guideline. Statistical methods included ROC analysis, through which we obtained the AUROC values.

Results

There were 126 patients with VUGIB (79 males, 47 females, mean age 58). In-hospital rebleeding rate was 7.9% (n=10/126) for VUGIB. Second look endoscopy was performed in 30 cases (23.8%). The indication for second look endoscopy was inadequate index endoscopy in 10 cases, suspicion of re-bleeding in 6 cases, control of endoscopic intervention in 12 cases. The 30-day mortality rate was 23.8% (n=30/126). Due to missing data in 5 patients scoring systems were analyzed in 121 patients. Area under receiver operator characteristic curves (AUROC) for predicting various outcomes were as follow: 30-day mortality (HARBINGER: 0.63, CANUKA: 0.75, Rockall (pre-endoscopy): 0.73, Rockall (complete): 0.73, GBS: 0.71, NLR: 0.65, RDW: 0,54); in-hospital mortality (HARBINGER: 0.59, CANUKA: 0.7, Rockall (pre-endoscopy): 0.67, Rockall (complete): 0.67, GBS: 0.65, NLR: 0.63, RDW: 0.56); need for interventional radiological procedure (HARBINGER: 0.62, CANUKA: 0.49, Rockall (pre-endoscopy): 0.56, Rockall (complete): 0.56, GBS: 0.54, NLR: 0.54, RDW: 0.67); need for RBC transfusion (HARBINGER: 0.66, CANUKA: 0.83, Rockall (pre-endoscopy): 0.7, Rockall (complete): 0.7, GBS: 0.78, NLR: 0.65, RDW: 0.63); rebleeding (HARBINGER: 0.45, CANUKA: 0.44, Rockall (pre-endoscopy): 0.42, Rockall (complete): 0.42, GBS: 0.5, NLR: 0.53, RDW: 0.56).

Conclusion

Currently available risk stratification scores developed mainly for NVUGIB, when used for VUGIB have a suboptimal performance (AUROC ≤0.8) in predicting important clinical outcomes as mortality, rebleeding, need for endoscopic or interventional radiological procedure. CANUKA was clinically effective and superior to other scoring systems in estimating the need for RBC transfusion. Further prospective studies on larger patient cohorts are needed to further analyze and improve risk stratification scores for VUGIB.

Disclosure

No Conflict of Interest

Introduction

ERCP is a commonly used endoscopic procedure for diagnosing and treating disorders of pancreaticobiliary system. NSAIDs have been proven to minimize the risk of post-ERCP pancreatitis, which occurs in approximately 8% of average-risk procedures (1,2). This study aimed to analyze the occurrence of post-ERCP pancreatitis in patients in whom ERCP was performed for the first time, before and after the use of NSAIDs in routine clinical practice.

Aims & Methods

Between January 2012 and December 2014 and between January 2019 and December 2021, 621 and 664 patients, respectively, were consecutively evaluated. In all those patients therapeutic ERCP procedure with biliary sphyncteroctomy has been done for the first time and the post-procedure complications were consecutively evaluated. NSAIDs were administered in a form of rectal suppositories at least an hour before the procedure. Post-ERCP pancreatitis was defined as an appearance of pain with elevated amylase concentrations at least 3x above the upper limit of normal for more than 24 hours after the procedure. Chi-Square test and Mann-Whitney U tests were used to compare discrete and continuous variables where p<0.05 was considered statistically significant.

Results

A total of 1285 ERCP-naïve patients were analyzed. Patients were split into two groups, one receiving and the other not receiving NSAID prophylaxis (667 vs 618 patients, respectively). Patients who received NSAID prophylaxis showed a significantly lower incidence of post-ERCP pancreatitis (2.9% vs. 7.8%, p<0.05) and transient hyperamylasemia (9.3% vs. 28.2%, p<0.05), as well (Table 1).

Table 1. NSAID non-NSAID

Conclusion

Real-life experience from a single tertiary center demonstrated that including NSAID prophylaxis into standard clinical practice resulted in a considerable reduction in post-ERCP pancreatitis and hyperamylasemia.

References

1. Buxbaum JL, Freeman M, Amateau SK, Chalhoub JM, Coelho-Prabhu N, Desai M, Elhanafi SE, Forbes N, Fujii-Lau LL, Kohli DR, Kwon RS, Machicado JD, Marya NB, Pawa S, Ruan WH, Sheth SG, Thiruvengadam NR, Thosani NC, Qumseya BJ; (ASGE Standards of Practice Committee Chair). American Society for Gastrointestinal Endoscopy guideline on post-ERCP pancreatitis prevention strategies: summary and recommendations. Gastrointest Endosc. 2023 Feb;97(2):153-162. doi: 10.1016/j.gie.2022.10.005. Epub 2022 Dec 12. PMID: 36517310.
2. Pekgöz M. Post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review for prevention and treatment. World J Gastroenterol 2019;25:4019-4042.

Disclosure

no conflict of interest

Introduction

Acute non-variceal upper gastrointestinal bleeding (NVUGIB) is a common emergency with high morbidity and mortality. Lactate levels and comorbidity indices, such as the Charlson Comorbidity Index (CCI), have shown promise in predicting patient outcomes. While these parameters individually provide valuable prognostic insights, their collective utility in predicting mortality among NVUGIB patients has not been explored.

Aims & Methods

The data for this study were collected from hospital records of patients admitted to Hitit University Hospital with NVUGIB between June 2021 and June 2024.
Demographic information, including age, gender, chronic illnesses, current medications, and history of previous gastrointestinal bleeding, was retrieved from computer database. Clinical data, such as outcomes (discharge or death), reasons for mortality, length of hospital stay were documented. Laboratory parameters, including lactate levels were recorded. Additionally, CCI and Glasgow Blatchford Score (GBS) were calculated for each patient.
Patients were stratified based on mortality status, which was considered the primary outcome. The associations between mortality and potential predictive factors were statistically analyzed. To improve mortality prediction, parameters that were significant in the logistic regression analysis were combined and assessed independently.

Results

A total of 390 patients with acute upper gastrointestinal bleeding were initially assessed. Of these, 180 patients were excluded due to missing data, leaving 210 patients included in the final study cohort. Key variables such as age, CCI, GBS, length of hospital stay, and mortality status were presented. Laboratory findings upon admission and the etiological distribution of gastrointestinal bleeding sources were also detailed.
Variables significantly associated with mortality in the univariate analysis include age, CCI, GBS, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate levels. In the logistic regression analysis, significant predictors of mortality were CCI (OR: 1.318, p=0.001) and lactate levels (OR: 1.575, p=0.003). GBS was not a predictor for mortality (p=0.468). CCI plus lactate levels were significantly higher in deceased patients compared to survivors (12.96 vs.7.31, p<0.001).
The correlation coefficients (r) showed significant positive correlations between the combination of lactate levels and CCI with GBS (r=0.498, p<0.001), length of stay (r=0.213, p=0.014), age (r=0.634, p<0.001) and urea levels (r=0.417, p<0.001). No significant correlation was found with AST or ALT.
ROC curves for lactate levels, CCI and CCI plus lactate levels predicting mortality showed that the area under the curve (AUC) for lactate was 0.704 (95% CI: 0.577–0.830, p=0.002) with a cut-off value of 1.83, yielding a sensitivity of 76% and a specificity of 52%. For CCI, the AUC was 0.769 (95% CI: 0.670–0.869, p<0.001) with a cut-off value of 6.5, showing a sensitivity of 76% and a specificity of 70%. And for the ‘CCI plus lactate’ level, the AUC was higher as 0.799 (95% CI: 0.703–0.895, p<0.001) with a cut-off value of 8.3, showing a sensitivity of 88% and a specificity of 62%.

Conclusion

Both lactate levels and the CCI are valuable tools for predicting mortality in NVUGIB patients. Our findings support the use of these parameters collectively to improve risk stratification. Combining lactate levels and CCI offers the advantage of better predicting mortality and improving sensitivity compared to using lactate levels or CCI alone.