Probiotics and microbial metabolites maintain barrier and neuromuscular functions and clean protein aggregation to delay disease progression in TDP43 mutation mice.

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. The ALS mice expressing human mutant of transactive response DNA binding protein of 43 kDa (hmTDP43) showed intestinal dysfunction before neuromuscular symptoms. We hypothesize that restoring the intestinal and microbial homeostasis with a bacterial metabolite or probiotics delays the ALS disease onset. We investigate the pathophysiological changes in the intestine and neurons, intestinal and blood-brain barriers, and inflammation during the ALS progression. We then cultured enteric glial cells (EGCs) isolated from TDP43 mice for mechanistic studies. TDP43 mice had significantly decreased intestinal mobility, increased permeability, and weakened muscle, compared with the age-matched wild-type mice. We observed increased hmTDP43 and Glial fibrillary acidic protein (GFAP), and decreased expression of α-smooth muscle actin (α-SMA), tight junction proteins (ZO-1 and Claudin-5) in the colon, spinal cord, and brain in TDP43 mice. TDP43 mice had reduced Butyryl-coenzyme A CoA transferase, decreased butyrate-producing bacteria Butyrivibrio fibrisolvens, and increased Bacteroides fragilis, compared to the WT mice. Serum inflammation cytokines (IL-6, IL-17, and IFN-γ) and LPS were elevated in TDP43 mice. EGCs from TDP43 mice showed aggregation of hmTDP43 associated with increased GFAP and ionized calcium-binding adaptor molecule (IBA1, a microglia marker). TDP43 mice treated with butyrate or probiotic VSL#3 had significantly increased rotarod time, increased intestinal mobility and decreased permeability, compared to the untreated group. Butyrate or probiotics treatment decreased the expression of GFAP, TDP43, and increased α-SMA, ZO-1, and Claudin-5 in the colon, spinal cord, and brain. Also, butyrate or probiotics treatment enhanced the Butyryl-coenzyme A CoA transferase, Butyrivibrio fibrisolvens, and reduced inflammatory cytokines in TDP43 mice. The TDP43 EGCs treated with butyrate or probiotics showed reduced GFAP, IBA1, and TDP43 aggregation. Restoring the intestinal and microbial homeostasis by beneficial bacteria and metabolites provide a potential therapeutic strategy to treat ALS.

Role of scalp nerve block in improving the quality of rehabilitation in patients after meningioma resection: A randomized controlled clinical trial.

BACKGROUND: In this study, we analyzed whether scalp nerve block with ropivacaine can improve the quality of rehabilitation in patients after meningioma resection. METHODS: We included 150 patients who were undergoing craniotomy in our hospital and categorized them into 2 groups - observation group (patients received an additional regional scalp nerve block anesthesia) and control group (patients underwent intravenous general anesthesia for surgery), using the random number table method approach (75 patients in each group). The main indicator of the study was the Karnofsky Performance Scale scores of patients at 3 days postoperatively, and the secondary indicator was the anesthesia satisfaction scores of patients after awakening from anesthesia. The application value of different anesthesia modes was studied and compared in the 2 groups. RESULTS: Patients in the observation group showed better anesthesia effects than those in the control group, with significantly higher Karnofsky Performance Scale scores at 3 days postoperatively (75.02 vs 66.43, P < .05) and anesthesia satisfaction scores. Compared with patients in the control group, patients in the observation group had lower pain degrees at different times after the surgery, markedly lower dose of propofol and remifentanil for anesthesia, and lower incidence of adverse reactions and postoperative complications. In addition, the satisfaction score of the patients and their families for the treatment was higher and the results of all the indicators were better in the observation group than in the control group, with statistically significant differences (P < .05). CONCLUSION: Scalp nerve block with ropivacaine significantly improves the quality of short-term postoperative rehabilitation in patients undergoing elective craniotomy for meningioma resection. This is presumably related to the improvements in intraoperative hemodynamics, relief from postoperative pain, and reduction in postoperative nausea and vomiting.

Intestinal Epithelial Axin1 Deficiency Protects Against Colitis via Altered Gut Microbiota.

Intestinal homeostasis is maintained by specialized host cells and the gut microbiota. Wnt/ß-catenin signaling is essential for gastrointestinal development and homeostasis, and its dysregulation has been implicated in inflammation and colorectal cancer. Axin1 negatively regulates activated Wnt/ß-catenin signaling, but little is known regarding its role in regulating host-microbial interactions in health and disease. Here, we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation. Axin1 expression was analyzed in human inflammatory bowel disease datasets. To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis, we generated new mouse models with Axin1 conditional knockout in intestinal epithelial cell (IEC; Axin1 ΔIEC) and Paneth cell (PC; Axin1 ΔPC) to compare with control (Axin1 LoxP; LoxP: locus of X-over, P1) mice. We found increased Axin1 expression in the colonic epithelium of human inflammatory bowel disease (IBD). Axin1 ΔIEC mice exhibited altered goblet cell spatial distribution, PC morphology, reduced lysozyme expression, and enriched Akkermansia muciniphila (A. muciniphila). The absence of intestinal epithelial and PC Axin1 decreased susceptibility to dextran sulfate sodium (DSS)-induced colitis in vivo. Axin1 ΔIEC and Axin1 ΔPC mice became more susceptible to DSS-colitis after cohousing with control mice. Treatment with A. muciniphila reduced DSS-colitis severity. Antibiotic treatment did not change the IEC proliferation in the Axin1 Loxp mice. However, the intestinal proliferative cells in Axin1 ΔIEC mice with antibiotic treatment were reduced compared with those in Axin1 ΔIEC mice without treatment. These data suggest non-colitogenic effects driven by the gut microbiome. In conclusion, we found that the loss of intestinal Axin1 protects against colitis, likely driven by epithelial Axin1 and Axin1-associated A. muciniphila. Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the microbiota. Further mechanistic studies using specific Axin1 mutations elucidating how Axin1 modulates the microbiome and host inflammatory response will provide new therapeutic strategies for human IBD.

Case report: Rapid development of acute symptomatic portal vein system thrombosis after endoscopic variceal therapy in a patient with liver cirrhosis.

Acute portal vein thrombosis (PVST), a serious complication of liver cirrhosis, is characterized as abdominal pain secondary to intestinal ischemia, and even intestinal necrosis. Anticoagulation is recommended for the treatment of acute PVST, but is often postponed in cirrhotic patients with acute variceal bleeding or those at a high risk of variceal bleeding. Herein, we reported a 63-year-old male with a 14-year history of alcoholic liver cirrhosis who developed progressive abdominal pain related to acute portal vein and superior mesenteric vein thrombosis immediately after endoscopic variceal ligation combined with endoscopic cyanoacrylate glue injection for acute variceal bleeding. Fortunately, acute PVST was successfully recanalized by the use of low molecular weight heparin. Collectively, this case suggests that acute symptomatic PVST can be secondary to endoscopic variceal therapy in liver cirrhosis, and can be safely and successfully treated by anticoagulation.

Case Report: First attempt by off-label use of tenecteplase to treat acute extensive portal venous system thrombosis.

Acute extensive portal venous system thrombosis (PVST) can cause lethal complications. Herein, we have for the first time reported the use of anticoagulation combined with systemic thrombolysis by tenecteplase in a male patient with a diagnosis of acute extensive PVST but without liver cirrhosis. After thrombolytic therapy, abdominal pain obviously alleviated. However, urinary bleeding developed, which was reversible by stopping thrombolytic drugs. Finally, this case developed cavernous transformation of the portal vein without portal venous recanalization. In future, the efficacy and safety of tenecteplase should be explored in acute extensive PVST cases.

Multiple cystic echinococcosis in abdominal and pelvic cavity treated by surgery with a 4-year follow-up: a case report.

We report a case of a male patient who presented with multiple abdominal and pelvic echinococcosis. The patient had been diagnosed with hepatic echinococcosis for 7 years and developed intermittent distension and discomfort in the upper abdomen after an accidental fall. In recent years, the patient's abdominal distention increased gradually. Computed tomography revealed multiple hydatid cysts in the liver, spleen, abdominal cavity, and pelvic cavity. Abdominal organs were severely compressed, such that he could not eat normally except for a liquid diet. The patient underwent radical surgical resection based on the multi-disciplinary treatment (MDT) and the operation lasted 10 h, nearly 100 hydatid cysts were excised, about 18 liters of cyst fluid and cyst contents were removed, and the patient lost 20 kg of weight after surgery. The operation was successful, but there were still some postoperative complications such as hypovolemic shock, postoperative ascites, postoperative bile leakage. Treatment measures for the patient were anti-infection, antishock, clamping the abdominal drainage tube, and negative pressure abdominal puncture drainage. At follow up the patient's quality of life had been significantly improved with 15 kg weight gain compared to before.

Conditional Vitamin D Receptor Deletion Induces Fungal and Archaeal Dysbiosis and Altered Metabolites.

A vitamin D receptor (VDR) deficiency leads to the dysbiosis of intestinal bacteria and is associated with various diseases, including cancer, infections, and inflammatory bowel disease. However, the impact of a VDR deficiency on fungi and archaea is unknown. We conditionally deleted the VDR in Paneth cells (VDRΔPC), intestinal epithelial cells (VDRΔIEC), or myeloid cells (VDRΔLyz) in mice and collected feces for shotgun metagenomic sequencing and untargeted metabolomics. We found that fungi were significantly altered in each knockout (KO) group compared to the VDRLoxp control. The VDRΔLyz mice had the most altered fungi species (three depleted and seven enriched), followed by the VDRΔPC mice (six depleted and two enriched), and the VDRΔIEC mice (one depleted and one enriched). The methanogen Methanofollis liminatans was enriched in the VDRΔPC and VDRΔLyz mice and two further archaeal species (Thermococcus piezophilus and Sulfolobus acidocaldarius) were enriched in the VDRΔLyz mice compared to the Loxp group. Significant correlations existed among altered fungi, archaea, bacteria, and viruses in the KO mice. Functional metagenomics showed changes in several biologic functions, including decreased sulfate reduction and increased biosynthesis of cobalamin (vitamin B12) in VDRΔLyz mice relative to VDRLoxp mice. Fecal metabolites were analyzed to examine the involvement of sulfate reduction and other pathways. In conclusion, a VDR deficiency caused the formation of altered fungi and archaea in a tissue- and sex-dependent manner. These results provide a foundation about the impact of a host factor (e.g., VDR deficiency) on fungi and archaea. It opens the door for further studies to determine how mycobiome and cross-kingdom interactions in the microbiome community and metabolites contribute to the risk of certain diseases.

Thrifty effect of subanesthetic-dose S-ketamine on postoperative opioids and its safety and analgesic effectiveness: A prospective, triple-blind, randomized controlled, polycentric clinical trial.

Aim: To investigate the thrifty effects of subanesthetic-dose S-ketamine on postoperative opioids and its safety and analgesic efficacy. Methods: Four-hundred and twenty patients were divided into the control group (CON group), the S-ketamine 0.2 mg/kg group (ES0.2 group), and the S-ketamine 0.3 mg/kg group (ES0.3 group) randomly. Major indicators include the Visual Analogue Scale (VAS), the times of compression with analgesic pumps after surgery, and analgesic drug consumption from anesthesia induction to 48 h after surgery. Minor records include vital signs, the use of vasoactive drugs, the Ramsay scores, the occurrence of adverse events including nervous system reaction, and the patient's satisfaction with anesthesia. Results: Compared with the CON group, VAS scores decreased in the ES0.2 and ES0.3 groups (p < 0.05). At 10 min after extubation, the VAS scores of the ES0.3 group were lower than that of the ES0.2 group (p < 0.05). The total number of compression with analgesic pumps of the ES0.3 group was lower than that of the CON group (p < 0.05). The opioid consumption after surgery of the ES0.3 group was lower than those of the CON group and the ES0.2 group (p < 0.05). The ES0.3 group's heart rate (HR) was faster but the use of vasoactive, drug consumption was less than the other two groups (p < 0.05). There were no significant differences in the incidence of postoperative adverse events and anesthetic satisfaction among the three groups. Conclusion: Subanesthetic-dose S-ketamine at 0.2-0.3 mg/kg especially the 0.3 mg/kg in general anesthesia induction can safely and effectively reduce postoperative pain and save postoperative opioid consumption.

Microbiome and intestinal pathophysiology in post-acute sequelae of COVID-19.

Long COVID, also known for post-acute sequelae of COVID-19, describes the people who have the signs and symptoms that continue or develop after the acute COVID-19 phase. Long COVID patients suffer from an inflammation or host responses towards the virus approximately 4 weeks after initial infection with the SARS CoV-2 virus and continue for an uncharacterized duration. Anyone infected with COVID-19 before could experience long-COVID conditions, including the patients who were infected with SARS CoV-2 virus confirmed by tests and those who never knew they had an infection early. People with long COVID may experience health problems from different types and combinations of symptoms over time, such as fatigue, dyspnea, cognitive impairments, and gastrointestinal (GI) symptoms (e.g., nausea, vomiting, diarrhea, decreased or loss of appetite, abdominal pain, and dysgeusia). The critical role of the microbiome in these GI symptoms and long COVID were reported in clinical patients and experimental models. Here, we provide an overall view of the critical role of the GI tract and microbiome in the development of long COVID, including the clinical GI symptoms in patients, dysbiosis, viral-microbiome interactions, barrier function, and inflammatory bowel disease patients with long COVID. We highlight the potential mechanisms and possible treatment based on GI health and microbiome. Finally, we discuss challenges and future direction in the long COVID clinic and research.

The Impact of Maternal Probiotics on Intestinal Vitamin D Receptor Expression in Early Life.

Vitamin D signaling via the Vitamin D Receptor (VDR) has been shown to protect against intestinal inflammation. Previous studies have also reported the mutual interactions of intestinal VDR and the microbiome, indicating a potential role of probiotics in modulating VDR expression. In preterm infants, although probiotics have been shown to reduce the incidence of necrotizing enterocolitis (NEC), they are not currently recommended by the FDA due to potential risks in this population. No previous studies have delved into the effect of maternally administered probiotics on intestinal VDR expression in early life. Using an infancy mouse model, we found that young mice exposed to maternally administered probiotics (SPF/LB) maintained higher colonic VDR expression than our unexposed mice (SPF) in the face of a systemic inflammatory stimulus. These findings indicate a potential role for microbiome-modulating therapies in preventing diseases such as NEC through the enhancement of VDR signaling.

Myeloid vitamin D receptor regulates Paneth cells and microbial homeostasis.

Cross talk between immune cells and the intestinal crypt is critical in maintaining intestinal homeostasis. Recent studies highlight the direct impact of vitamin D receptor (VDR) signaling on intestinal and microbial homeostasis. However, the tissue-specific role of immune VDR signaling is not fully understood. Here, we generated a myeloid-specific VDR knockout (VDRΔLyz ) mouse model and used a macrophage/enteroids coculture system to examine tissue-specific VDR signaling in intestinal homeostasis. VDRΔLyz mice exhibited small intestine elongation and impaired Paneth cell in maturation and localization. Coculture of enteroids with VDR-/- macrophages increased the delocalization of Paneth cells. VDRΔLyz mice exhibited significant changes in the microbiota taxonomic and functional files, and susceptibility to Salmonella infection. Interestingly, loss of myeloid VDR impaired Wnt secretion in macrophages, thus inhibiting crypt ß-catenin signaling and disrupting Paneth cell differentiation in the epithelium. Taken together, our data have demonstrated that myeloid cells regulate crypt differentiation and the microbiota in a VDR-dependent mechanism. Dysregulation of myeloid VDR led to high risks of colitis-associated diseases. Our study provided insight into the mechanism of immune/Paneth cell cross talk in regulating intestinal homeostasis.

Intestinal vitamin D receptor protects against extraintestinal breast cancer tumorigenesis.

The microbiota plays critical roles in regulating the function and health of the intestine and extraintestinal organs. A fundamental question is whether an intestinal-microbiome-breast axis exists during the development of breast cancer. If so, what are the roles of host factors? Vitamin D receptor (VDR) involves host factors and the human microbiome. Vdr gene variation shapes the human microbiome, and VDR deficiency leads to dysbiosis. We hypothesized that intestinal VDR protects hosts against tumorigenesis in the breast. We examined a 7,12-dimethylbenzanthracene (DMBA)-induced breast cancer model in intestinal epithelial VDR knockout (VDRΔIEC) mice with dysbiosis. We reported that VDRΔIEC mice with dysbiosis are more susceptible to breast cancer induced by DMBA. Intestinal and breast microbiota analysis showed that VDR deficiency leads to a bacterial profile shift from normal to susceptible to carcinogenesis. We found enhanced bacterial staining within breast tumors. At the molecular and cellular levels, we identified the mechanisms by which intestinal epithelial VDR deficiency led to increased gut permeability, disrupted tight junctions, microbial translocation, and enhanced inflammation, thus increasing tumor size and number in the breast. Furthermore, treatment with the beneficial bacterial metabolite butyrate or the probiotic Lactobacillus plantarum reduced breast tumors, enhanced tight junctions, inhibited inflammation, increased butyryl-CoA transferase, and decreased levels of breast Streptococcus bacteria in VDRΔIEC mice. The gut microbiome contributes to the pathogenesis of diseases not only in the intestine but also in the breast. Our study provides insights into the mechanism by which intestinal VDR dysfunction and gut dysbiosis lead to a high risk of extraintestinal tumorigenesis. Gut-tumor-microbiome interactions represent a new target in the prevention and treatment of breast cancer.

Effects of postoperative use of proton pump inhibitors on gastrointestinal bleeding after endoscopic variceal treatment during hospitalization.

BACKGROUND: Endoscopic variceal treatment (EVT) is recommended as the mainstay choice for the management of high-risk gastroesophageal varices and acute variceal bleeding in liver cirrhosis. Proton pump inhibitors (PPIs) are widely used for various gastric acid-related diseases. However, the effects of PPIs on the development of post-EVT complications, especially gastrointestinal bleeding (GIB), remain controversial. AIM: To evaluate the effects of postoperative use of PPIs on post-EVT complications in patients with liver cirrhosis during hospitalization. METHODS: Patients with a diagnosis of liver cirrhosis who were admitted to the Department of Gastroenterology of the General Hospital of Northern Theater Command, treated by an attending physician between January 2016 and June 2020 and underwent EVT during their hospitalization were included. Logistic regression analyses were performed to explore the effects of postoperative use of PPIs on the development of post-EVT complications during hospitalization. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 143 patients were included. The incidence of post-EVT GIB and other post-EVT complications was 4.90% and 46.85%, respectively. In the overall analyses, postoperative use of PPIs did not significantly reduce the risk of post-EVT GIB (OR = 0.525, 95%CI = 0.113-2.438, P = 0.411) or other post-EVT complications (OR = 0.804, 95%CI = 0.413-1.565, P = 0.522). In the subgroup analyses according to the enrollment period, type and route of PPIs after the index EVT, use of PPIs before the index EVT, use of vasoactive drugs after the index EVT, indication of EVT (prophylactic and therapeutic), and presence of portal venous system thrombosis, ascites, and hepatocellular carcinoma, the effects of postoperative use of PPIs on the risk of post-EVT GIB or other post-EVT complications remain not statistically significant. CONCLUSION: Routine use of PPIs after EVT should not be recommended in patients with liver cirrhosis for the prevention of post-EVT complications during hospitalization.

Disruption to tRNA Modification by Queuine Contributes to Inflammatory Bowel Disease.

BACKGROUNDS AND AIMS: Transfer RNA (tRNA) is the most extensively modified RNA in cells. Queuosine modification is a fundamental process for ensuring the fidelity and efficiency of translation from RNA to protein. In eukaryotes, Queuosine tRNA (Q-tRNA) modification relies on the intestinal microbial product queuine. However, the roles and potential mechanisms of Q-containing tRNA (Q-tRNA) modifications in inflammatory bowel disease (IBD) are unknown. METHODS: We explored the Q-tRNA modifications and expression of QTRT1 (queuine tRNA-ribosyltransferase 1) in patients with IBD by investigating human biopsies and reanalyzing datasets. We used colitis models, QTRT1 knockout mice, organoids, and cultured cells to investigate the molecular mechanisms of Q-tRNA modifications in intestinal inflammation. RESULTS: QTRT1 expression was significantly downregulated in ulcerative colitis and Crohn's disease patients. The 4 Q-tRNA-related tRNA synthetases (asparaginyl-, aspartyl-, histidyl-, and tyrosyl-tRNA synthetase) were decreased in IBD patients. This reduction was further confirmed in a dextran sulfate sodium-induced colitis model and interleukin-10-deficient mice. Reduced QTRT1 was significantly correlated with cell proliferation and intestinal junctions, including downregulation of ß-catenin and claudin-5 and the upregulation of claudin-2. These alterations were confirmed in vitro by deleting the QTRT1 gene from cells and in vivo using QTRT1 knockout mice. Queuine treatment significantly enhanced cell proliferation and junction activity in cell lines and organoids. Queuine treatment also reduced inflammation in epithelial cells. Moreover, altered QTRT1-related metabolites were found in human IBD. CONCLUSIONS: tRNA modifications play an unexplored novel role in the pathogenesis of intestinal inflammation by altering epithelial proliferation and junction formation. Further investigation of the role of tRNA modifications will uncover novel molecular mechanisms for the prevention and treatment of IBD.

The role of hydrophilic/hydrophobic group ratio of polyvinyl alcohol on the miscibility of amlodipine in orodispersible films: From molecular mechanism study to product attributes.

The miscibility of the therapeutic drug in the polymer matrix is the key to the successful design and development of orodispersible films (ODFs). In the present study, four hydrolyzed polyvinyl alcohols (PVAs) with identical polymerization degree were investigated as carriers for Amlodipine (AML) ODFs systematically. The drug-polymer miscibility and the intermolecular interaction were investigated by Flory-Huggins theory, Gordon-Taylor theory, molecular simulation, FTIR, Raman and 1H NMR. The product attributes of ODFs were also studied. A pharmacokinetic study in rats was then conducted using the film product of PVA5-72, the best performer tested. The results revealed that the drug-polymer miscibility decreased linearly with the increase of hydrolyzed degree of PVA. Hydrogen bonds formed between the drug and the hydrophilic and hydrophobic groups of PVAs were the main intermolecular interaction that caused the differences in drug-polymer miscibility. Furthermore, drug-polymer interaction influenced the product attributes of ODFs, including dissolution profile, mechanical properties and physical stability. The pharmacokinetic study showed the ODFs disintegrated rapidly, and the amorphous AML dissolved and absorbed in the gastrointestinal tract, which was comparable to the commercial product. The research offered a foundation for development scientists in designing and formulating PVA films.

Bacterial translocation and barrier dysfunction enhance colonic tumorigenesis.

In the development of colon cancer, the intestinal dysbiosis and disruption of barrier function are common manifestations. In the current study, we hypothesized that host factors, e.g., vitamin D receptor deficiency or adenomatous polyposis coli (APC) mutation, contribute to the enhanced dysbiosis and disrupted barrier in the pathogenesis of colorectal cancer (CRC). Using the human CRC database, we found enhanced tumor-invading bacteria and reduced colonic VDR expression, which was correlated with a reduction of Claudin-10 mRNA and protein. In the colon of VDRΔIEC mice, deletion of intestinal epithelial VDR led to lower protein of tight junction protein Claudin-10. Lacking VDR and a reduction of Claudin-10 are associated with an increased number of tumors in the mice without myeloid VDR. Intestinal permeability was significantly increased in the mice with myeloid VDR conditional deletion. Further, mice with conditional colonic APC mutation showed reduced mucus layer, enhanced bacteria in tumors, and loss of Claudin-10. Our data from human samples and colon cancer models provided solid evidence- on the host factor regulation of bacterial translocation and dysfunction on barriers in colonic tumorigenesis. Studies on the host factor regulation of microbiome and barriers could be potentially applied to risk assessment, early detection, and prevention of colon cancer.

The Incidence of Acute Pancreatitis After Device Assisted Enteroscopy: a Systematic Review and Meta-analysis.

Background: The diagnosis of small bowel diseases is challenging and device assisted enteroscopy (DAE) is a technique for visualizing the entire small bowel. DAE is considered as a safe procedure and the reported rate of adverse events associated with DAE in the literature is low. Objective: The present study tried to investigate the actual incidence of AP after DAE with a systematic review and meta-analysis of available relevant studies. Methods: Studies were searched through the PubMed, EMBASE, and Cochrane library databases. The following data were extracted from all eligible studies: author, country, publication year, publication type, study design, type of DAE used, route of DAE, number of patients with AP after DAE, and number of patients with hyperamylasemia after DAE.A random-effects model with RStudio version 4.2.0 was performed in all analyses. Heterogeneity was assessed using the I2 test. The risk of bias was assessed by the Newcastle-Ottawa Scale criteria and the publication bias was assessed by the Egger test. Results: Twenty three studies involving a total of 11145 patients were included in the analysis. The overall, pooled AP rate after DAE was 1% (95% CI:0-1%). There was significant heterogeneity among the studies (I2 = 65%; P < 0.01).The pooled AP rate was 1% (95% CI:0-2 %)in peroral route group. The pooled proportion of patients having hyperamylasemia after DAE was 29% (95% CI: 16-46%).Among the patients who had hyperamylasemia AP were identified in 2% (95% CI: 0-6%) of patients. Conclusion: The incidence of AP after DAE is about 1%. Hyperamylasemia is a common change in the patients undergoing DAE and only 2% of the patients with hyperamylasemia present with AP.

Target Metabolites to Slow Down Progression of Amyotrophic Lateral Sclerosis in Mice.

Microbial metabolites affect the neuron system and muscle cell functions. Amyotrophic lateral sclerosis (ALS) is a multifactorial neuromuscular disease. Our previous study has demonstrated elevated intestinal inflammation and dysfunction of the microbiome in patients with ALS and an ALS mouse model (human-SOD1G93A transgenic mice). However, the metabolites in ALS progression are unknown. Using an unbiased global metabolomic measurement and targeted measurement, we investigated the longitudinal changes of fecal metabolites in SOD1G93A mice over the course of 13 weeks. We further compared the changes of metabolites and inflammatory response in age-matched wild-type (WT) and SOD1G93A mice treated with the bacterial product butyrate. We found changes in carbohydrate levels, amino acid metabolism, and the formation of gamma-glutamyl amino acids. Shifts in several microbially contributed catabolites of aromatic amino acids agree with butyrate-induced changes in the composition of the gut microbiome. Declines in gamma-glutamyl amino acids in feces may stem from differential expression of gamma-glutamyltransferase (GGT) in response to butyrate administration. Due to the signaling nature of amino acid-derived metabolites, these changes indicate changes in inflammation, e.g., histamine, and contribute to differences in systemic levels of neurotransmitters, e.g., γ-Aminobutyric acid (GABA) and glutamate. Butyrate treatment was able to restore some of the healthy metabolites in ALS mice. Moreover, microglia in the spinal cord were measured by IBA1 staining. Butyrate treatment significantly suppressed the IBA1 level in the SOD1G93A mice. Serum IL-17 and LPS were significantly reduced in the butyrate-treated SOD1G93A mice. We have demonstrated an inter-organ communications link among microbial metabolites, neuroactive metabolites from the gut, and inflammation in ALS progression. The study supports the potential to use metabolites as ALS hallmarks and for treatment.

Repetitive non-typhoidal Salmonella exposure is an environmental risk factor for colon cancer and tumor growth.

During infection, Salmonella hijacks essential host signaling pathways. These molecular manipulations disrupt cellular integrity and may induce oncogenic transformation. Systemic S. Typhi infections are linked to gallbladder cancer, whereas severe non-typhoidal Salmonella (NTS) infections are associated with colon cancer (CC). These diagnosed infections, however, represent only a small fraction of all NTS infections as many infections are mild and go unnoticed. To assess the overall impact of NTS infections, we performed a retrospective serological study on NTS exposure in patients with CC. The magnitude of exposure to NTS, as measured by serum antibody titer, is significantly positively associated with CC. Repetitively infecting mice with low NTS exposure showed similar accelerated tumor growth to that observed after high NTS exposure. At the cellular level, NTS preferably infects (pre-)transformed cells, and each infection round exponentially increases the rate of transformed cells. Thus, repetitive exposure to NTS associates with CC risk and accelerates tumor growth.

Effect of Remimazolam Tosilate on Respiratory Depression in Elderly Patients Undergoing Gastroscopy: A Multicentered, Prospective, and Randomized Study.

Background: Remimazolam tosilate (RT) is a new type of γ-aminobutyric acid subtype A (GABAA) receptor agonist, having the possibility to be an ideal sedative drug for procedural sedation. At present, there are few studies on the effect of RT on respiratory depression in elderly patients. We aimed to evaluate the effect of RT on respiratory depression in elderly patients undergoing gastroscopy. Methods: This prospective, randomized, single-blinded trial recruited patients from eight centers in China between May 2022 and July 2022. A total of 346 elderly patients undergoing gastroscopy were randomly divided into RT group (0.2 mg/kg) or propofol group (1.5 mg/kg), respectively. The primary outcome was the incidence of respiratory depression. Secondary outcomes include the incidence of sedative-related adverse events, the success rate of sedation, time to fully alert, time to loss of consciousness (LOC), time to ready for discharge, as well as the the patients, endoscopists and anethetists' satisfaction. Results: The incidence of respiratory depression was significantly reduced in the RT group compared with the propofol group (9.8% vs 17.9%, P=0.042). The time of LOC and fully alert in the RT group were longer than that in the propofol group (P < 0.05). The incidences of hypotention (50.9% vs 32.4%, P=0.001) and hypotension requiring treatment (5.8% vs 1.7%, P=0.031) were significantly higher in the propofol group than that in the RT group. The incidence and severity of injection pain were more frequently recorded in the propofol group than that in the RT group (40.5% vs 12.1%, P<0.05). There were no statistically significant differences between the two groups in terms of sedation success rates, time to ready for discharge, endoscopists and anethetists' satisfaction and other sedative-related adverse events. Conclusion: RT may be a suitable alternative sedative agent for elderly patients undergoing gastroscopy due to its safety profile.