Effect of Bacillus coagulans SNZ 1969 on the Improvement of Bowel Movement in Loperamide-Treated SD Rats.

Bacillus coagulans SNZ 1969 (B. coagulans SNZ 1969) is a spore-forming bacterium reported to be effective in attenuating constipation. However, there is no study on whether B. coagulans SNZ 1969 could improve constipation through mucin secretion and changes in intestinal hormones. To address this knowledge gap, rats were orally administrated with various treatments for four weeks. The normal control (NOR) group received saline only. There were four constipation-induced groups. The LOP group received only loperamide (LOP), a constipation-inducing agent. The BIS group received both LOP and Bisacodyl (BIS, a constipation treatment agent). The SNZ-L group received both LOP and B. coagulans SNZ 1969 at 1 × 108 CFU/day. The SNZ-H group received LOP and B.coagulans SNZ 1969 at 1 × 1010 CFU/day. As indicators of constipation improvement, fecal pellet weight, fecal water content, gastrointestinal transit time, and intestinal motility were measured. Mucus secretion in the colon was determined by histological colon analysis and mucin-related gene expressions. Gastrointestinal (GI) hormones were also measured. SNZ-L and SNZ-H groups showed significantly increased fecal weights, fecal water contents, and intestinal motility than the LOP group. SNZ-L and SNZ-H groups also showed higher secretion of mucin in the colon and mRNA expression levels of Mucin 2 and Aquaporin 8 than the LOP group. The SNZ-H group showed significantly increased substance P but significantly decreased somatostatin and vasoactive intestinal peptide than the LOP group. The results of this study suggest that B. coagulans SNZ 1969 intake could attenuate constipation through mucin secretion and alteration of GI hormones.

Adenosine receptors: Emerging non-opioids targets for pain medications.

Physical and emotional pain deteriorates the quality of well-being. Also, numerous non-invasive and invasive treatments for diagnosed diseases such as cancer medications and surgical procedures cause various types of pain. Despite the multidisciplinary approaches available to manage pain, the unmet needs for medication with minimal side effects are substantial. Especially with the surge of opioid crisis during the last decades, non-opioid analgesics may reduce life-threatening overdosing and addictive liability. Although many clinical trials supported the potential potency of cannabis and cannabidiol (CBD) in pain management or treatment, the long-term benefits of cannabis or CBD are still not evident. At the same time, growing evidence shows the risk of overusing cannabis and CBD. Therefore, it is urgent to develop novel analgesic medications that minimize side effects. All four well-identified adenosine receptors, A1, A2A, A2B, and A3, are implicated in pain. Recently, a report demonstrated that an adenosine A1R-specific positive allosteric modulator (PAM) is a potent analgesic without noticeable side effects. Also, several A3R agonists are being considered as promising analgesic agent. However, the importance of adenosine in pain is relatively underestimated. To help readers understand, first, we will summarize the historical perspective of the adenosine system in preclinical and clinical studies. Then, we will discuss possible interactions of adenosine and opioids or the cannabis system focusing on pain. Overall, this review will provide the potential role of adenosine and adenosine receptors in pain treatment.

Comparison of Clinical and Radiologic Findings Between Perforated and Non-Perforated Choledochal Cysts in Children.

OBJECTIVE: To compare the clinical and radiologic findings between perforated and non-perforated choledochal cysts in children. MATERIALS AND METHODS: Fourteen patients (mean age ± standard deviation, 1.7 ± 1.2 years) with perforated choledochal cysts (perforated group) and 204 patients (3.6 ± 3.8 years) with non-perforated choledochal cysts (non-perforated group) were included between 2000 and 2019. All patients underwent choledochal cyst excision after ultrasound, CT, or MR cholangiopancreatography. Relevant data including demographics, clinical symptoms, laboratory findings, imaging findings, and outcomes were analyzed. Statistical differences were compared using the Mann-Whitney U test and Fisher's exact test. RESULTS: Choledochal cyst perforation occurred only in children under the age of 4 years. Acute symptoms, including fever (p < 0.001), were more common in the perforated group than in the non-perforated group. High levels of white blood cells (p = 0.004), C-reactive protein (p < 0.001), and serum amylase (p = 0.002), and low levels of albumin (p < 0.001) were significantly associated with the perforated group. All 14 patients with perforated choledochal cysts had ascites, whereas only 16% (33/204) of patients in the non-perforated group had ascites (p < 0.001). In the subgroup of patients who had ascites, a large amount of ascites (p = 0.001), increase in the amount of ascites in a short time (p < 0.001), complex ascites (p < 0.001), and perihepatic pseudocysts (p < 0.001) were more common in the perforated group than in the non-perforated group. CONCLUSION: Children with perforated choledochal cysts have characteristic clinical and radiologic findings compared to those with non-perforated choledochal cysts. In young children with choledochal cysts, perforation should be differentiated in cases with acute symptoms, laboratory abnormalities, and characteristic ascites findings.

Abnormal Orientation of the Superior Mesenteric Vessels Detected in Asymptomatic Infants: What Is Its Destiny?

Background: Ultrasonography (USG) has been described as an alternative diagnostic tool for malrotation that evaluates the orientation of the superior mesenteric vessels. However, literature concerning the management of patients who do not have abdominal symptoms is limited. We aimed to review the clinical course of infants showing abnormal orientation of the superior mesenteric vessels on USG who were asymptomatic at the time of diagnosis. Methods: Seventy asymptomatic infants with abnormal orientation of the superior mesenteric vessels in a single center between 2014 and 2018 were retrospectively analyzed. Results: The 70 patients, 21 underwent upper gastrointestinal series (UGIS) and 11 underwent abdominal surgery for other surgical conditions. Among the 32 (45.7%) patients who underwent UGIS or abdominal surgery, 11 were proven to have malrotation. Of the 38 (54.3%) patients who did not undergo UGIS or abdominal surgery, six patients were too unstable to undergo UGIS, five died due to cardiac complications, and the remaining patient developed midgut volvulus and died 3 days after emergency surgery. The remaining 32 patients who did not undergo UGIS or abdominal surgery were discharged without additional tests, and all were asymptomatic until their last follow-up. In the multivariate analysis, history of heart surgery and the presence of more than three anomalies were significantly associated with malrotation. Conclusion: A significant number of malrotation were diagnosed in asymptomatic infants with abnormal orientation of the superior mesenteric vessels on USG. Infants with major cardiac or multiple anomalies need special attention and should undergo UGIS in a promptly manner to confirm malrotation.

Factors Associated with Failure of Pneumatic Reduction in Children with Ileocolic Intussusception.

Intussusception is one of the most common causes of intestinal obstruction in children. Pneumatic reduction is the treatment of choice and has a high success rate. The most common cause of pneumatic reduction failure is the presence of a pathological leading point. We aimed to identify other factors that can lead to pneumatic reduction failure in children with ileocolic intussusception. This was a retrospective study conducted in two centers. Data were collected from January 2013 to December 2014. A total of 156 patients were diagnosed with intussusception and underwent pneumatic reduction, with the exception of one patient with peritonitis. We included patients with ileocolic-type intussusception without apparent pathological leading points. Logistic regression analysis of clinical parameters was performed to identify factors associated with pneumatic reduction failure. Of 156 patients diagnosed with intussusception in both hospitals, 145 were enrolled in the study. The overall efficacy of pneumatic reduction was 85.7%, and surgical reduction was performed in 21 patients. Univariate analysis showed that a high segmented neutrophil count, low hemoglobin level, high body temperature, and higher weight percentile were associated with pneumatic reduction failure. Multivariate analysis showed that a high segmented neutrophil count, low hemoglobin level, and higher weight percentile were significantly associated with pneumatic reduction failure. Pneumatic reduction is safe and effective as a first-line treatment for pediatric intussusception. However, a high segmented neutrophil count, low hemoglobin level, and higher weight percentile are associated with the failure of this treatment.

Multidisciplinary intestinal rehabilitation in acute type II intestinal failure: Results from an intestinal rehabilitation team.

BACKGROUND: Type II (acute) intestinal failure (IF) is usually caused by complications of abdominal surgery resulting in enteric fistulas or proximal stomas and requires parenteral nutrition (PN) for several months. This study aimed to evaluate clinical management and outcome of type II IF patients in a single center. METHODS: Medical records of patients referred to the Intestinal Rehabilitation Team (IRT) at Samsung Medical Center (Seoul, Korea) were retrospectively analyzed. RESULTS: From 2014 to 2019, 34 patients with IF were referred. 28 patients were type II IF and were included in the analysis. There were 17 males and 11 females. Mean age of patients was 56.7 years. Pathophysiology of IF were high-output stoma in 16 cases, extensive bowel resection (with bowel in continuity) in 7 cases, and enterocutaneous fistula in 5 cases. The catastrophic events necessitating abdominal surgery in the patients were adhesive ileus in 9 cases, superior mesenteric artery thrombosis in 8 cases, internal herniation of bowel in 5 cases, traumatic bowel injury in 3 cases, and ischemic enteritis in 3 cases. Following medical and surgical rehabilitation, 10 patients (35.7%) were weaned off PN and overall mortality was 28.5%. Deaths were related to progression of underlying malignancies in 4 cases, liver failure in 3 cases, and sepsis in 1 case. Thirteen patients underwent surgery to restore bowel continuity. Six postoperative complications occurred in 4 patients (30.7%) and there were no postoperative mortalities. CONCLUSION: Standardized care including restorative surgery resulted in successful outcomes in type II IF patients in this cohort.

Minimal dissection of posterior wall of rectum reduces rectal prolapse in laparoscopic assisted anorectal pull-through.

PURPOSE: To determine if minimal dissection of the posterior wall of rectum can reduce rectal prolapse after laparoscopic assisted anorectal pull-through (LAARP) in male anorectal malformation (ARM) with rectourethral fistula. METHODS: Eighty-six male patients with ARM who underwent LAARP in our center between 2007 and 2018 were retrospectively analyzed. There were 45 cases of prostatic urethral fistula, 24 bulbar urethral fistulas, and 15 bladder neck fistulas. Two patients had no fistula. To prevent rectal prolapses, we markedly shortened the length of posterior rectal dissection from mid-2016. Dissection of posterior wall of rectum was performed minimally around the level of the fistula and the dissected portion of the posterior rectum was significantly shorter than the previous cases. For comparative analysis, patients were divided into two groups (before and after application of minimal dissection of posterior wall of rectum): Group A, from 2007 to mid-2016 and Group B, from mid-2016 to 2018. RESULTS: There were 60 patients in Group A and 26 patients in Group B. Demographic characteristics were not significantly different between the two groups. The median follow-up duration was 52.4 months for Group A and 26.9 months for Group B. Group B had lower incidence of rectal prolapse (11.5%) than Group A (68.3%) (p < 0.001). Upon our subgroup analysis based on types of fistula, patients with recto-prostatic urethral fistula and recto-bulbar urethral fistula showed significant reduction in the incidence of rectal prolapse (both p < 0.001). However, patients with recto-bladder neck fistula showed no statistical significance (p = 0.264). CONCLUSION: Minimal dissection of the posterior wall of rectum can reduce rectal prolapse in LAARP. LEVEL OF EVIDENCE: III. Retrospective Comparative Treatment Study.

Potential association between TSGA13 variants and risk of total colonic aganglionosis in Hirschsprung disease.

Hirschsprung disease (HSCR) is a congenital rare disorder and a kind of developmental neuropathies, characterized by the lack of enteric neurons in variable segments of distal bowel. Our recent genome-wide association study identified a variant (rs13223150) of testis-specific A13 (TSGA13) as a potential risk locus for total colonic aganglionosis (TCA) in HSCR. The aim of this study was to identify the impact of the variant (rs13223150) and potential association of genetic variations of TSGA13 with TCA in HSCR. This study performed a fine mapping and extended analyses in Korean population. A total of 9 single nucleotide polymorphisms (SNPs) of TSGA13 were genotyped in a larger HSCR cohort (187 HSCR patients and 283 unaffected controls), and extended genetic analyses using various genetic modelling, haplotype, and combined analyses were performed. The rs13223150_A allele showed a significant association with TCA (P = 0.003), even after correcting for multiple testing (Pcorr = 0.02). One haplotype (BL1_ht1, G-A-C-C) including rs13223150 also showed a significant association with TCA (P = 0.002, Pcorr = 0.01). Further combined imputation analysis indicated that several single nucleotide polymorphisms of TSGA13 were significantly associated with TCA in HSCR. Although replications in other population cohorts and functional evaluations are needed, our results suggest that TSGA13 genetic variants may affect TCA in HSCR and/or the extent of aganglionosis during enteric nervous system development.

Potential association between ITPKC genetic variations and Hirschsprung disease.

Hirschsprung disease (HSCR) is a congenital and complex disorder characterized by intestinal obstruction due to the absence of enteric neurons along variable lengths of the hindgut. Our recent genome-wide association study (GWAS) has revealed regional associations with HSCR at several loci of inositol-trisphosphate 3-kinase C (ITPKC). For fine mapping, we additionally selected and genotyped a total of 12 single nucleotide polymorphisms (SNPs) of ITPKC in 187 HSCR patients and 283 unaffected controls, and performed a further combined imputation analysis based on genotype data from this second stage of fine mapping and our previous GWAS stage, totaling 902 subjects (187 HSCR cases and 715 controls). As a result, several SNPs (minimum P = 0.004) and a haplotype (P = 0.02) were found to be significantly associated with HSCR. In further in silico analyses to ascertain the potential functions of the significant variants, the change from the common allele to the rare allele of the highly conserved nonsynonymous rs76785336 showed a difference in mRNA folding structure. In the case of intronic SNPs, rs2607420 with a high consensus value was predicted to be a new splice site. Although this study has limitations (such as lack of functional evaluations, small number of cases, and further need of replication in other cohorts), our findings suggest that genetic variants of ITPKC may have a potential association with HSCR susceptibility and/or developmental diseases related to enteric nervous system development.

RNA-Seq for Gene Expression Profiling of Human Necrotizing Enterocolitis: a Pilot Study.

Necrotizing enterocolitis (NEC) characterized by inflammatory intestinal necrosis is a major cause of mortality and morbidity in newborns. Deep RNA sequencing (RNA-Seq) has recently emerged as a powerful technology enabling better quantification of gene expression than microarrays with a lower background signal. A total of 10 transcriptomes from 5 pairs of NEC lesions and adjacent normal tissues obtained from preterm infants with NEC were analyzed. As a result, a total of 65 genes (57 down-regulated and 8 up-regulated) revealed significantly different expression levels in the NEC lesion compared to the adjacent normal region, based on a significance at fold change ≥ 1.5 and P ≤ 0.05. The most significant gene, DPF3 (P < 0.001), has recently been reported to have differential expressions in colon segments. Our gene ontology analysis between NEC lesion and adjacent normal tissues showed that down-regulated genes were included in nervous system development with the most significance (P = 9.3 × 10⁻7; P(corr) = 0.0003). In further pathway analysis using Pathway Express based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, genes involved in thyroid cancer and axon guidance were predicted to be associated with different expression (P(corr) = 0.008 and 0.020, respectively). Although further replications using a larger sample size and functional evaluations are needed, our results suggest that altered gene expression and the genes' involved functional pathways and categories may provide insight into NEC development and aid in future research.

A genome-wide association study identifies potential susceptibility loci for Hirschsprung disease.

Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder characterized by the absence of intramural nervous plexuses along variable lengths of the hindgut. Although RET is a well-established risk factor, a recent genome-wide association study (GWAS) of HSCR has identified NRG1 as an additional susceptibility locus. To discover additional risk loci, we performed a GWAS of 123 sporadic HSCR patients and 432 unaffected controls using a large-scale platform with coverage of over 1 million polymorphic markers. The result was that our study replicated the findings of RET-CSGALNACT2-RASGEF1A genomic region (rawP = 5.69×10(-19) before a Bonferroni correction; corrP = 4.31×10(-13) after a Bonferroni correction) and NRG1 as susceptibility loci. In addition, this study identified SLC6A20 (adjP = 2.71×10(-6)), RORA (adjP = 1.26×10(-5)), and ABCC9 (adjP = 1.86×10(-5)) as new potential susceptibility loci under adjusting the already known loci on the RET-CSGALNACT2-RASGEF1A and NRG1 regions, although none of the SNPs in these genes passed the Bonferroni correction. In further subgroup analysis, the RET-CSGALNACT2-RASGEF1A genomic region was observed to have different significance levels among subgroups: short-segment (S-HSCR, corrP = 1.71×10(-5)), long-segment (L-HSCR, corrP = 6.66×10(-4)), and total colonic aganglionosis (TCA, corrP>0.05). This differential pattern in the significance level suggests that other genomic loci or mechanisms may affect the length of aganglionosis in HSCR subgroups during enteric nervous system (ENS) development. Although functional evaluations are needed, our findings might facilitate improved understanding of the mechanisms of HSCR pathogenesis.

Long-term results of biliary atresia in the era of liver transplantation.

PURPOSE: The purpose of this study was to analyze the survival of patients with biliary atresia (BA) after Kasai operation and liver transplantation (LT) and to analyze the factors affecting survival. METHODS: Seventy-two patients diagnosed with BA were operated on between April 1995 and December 2009 and retrospectively analyzed. RESULTS: Out of the 72 patients, 59 received Kasai operation and 13 received LT without prior Kasai operation. Twenty-seven patients received LT after Kasai operation. Survival with native liver was 39 % at 10 years. With the application of LT, overall 10-year survival for patients with BA was 94.9 %. Among patients alive with native livers after Kasai operation, 14 patients (58.3 %) have at least one complication associated with biliary cirrhosis and portal hypertension. Age at which Kasai operation was performed (60 days) and postoperative normalization of bilirubin were independent risk factors for survival with the native liver, according to multivariate analysis (HR 2.90, p = 0.033 and HR 9.89, p = 0.002). CONCLUSIONS: Survival of BA patients has greatly increased in the era of LT. However, many patients surviving with native livers after Kasai operation continue to have signs of biliary cirrhosis and abnormal liver function.

Experience with laparoscopic-assisted anorectal pull-through in 25 males with anorectal malformation and rectourethral or rectovesical fistulae: postoperative complications and functional results.

INTRODUCTION: LAARP (laparoscopic-assisted anorectal pull-through) has become an established operation for anorectal malformation (ARM) with rectourethral or rectovesical fistula. The aim of this study was to review post-LAARP operation complications and midterm functional results. METHODS: Between 2003 and 2010, we performed 28 LAARPs in ARM patients with rectourethral or rectovesical fistula. We retrospectively analyzed the clinical outcomes in 25 male patients with rectourethral or vesical fistulae. RESULT: The mean age of the patients at the time of LAARP was 2.7 ± 1.4 months. The most common ARM type was rectoprostatic urethral fistula (n=16). Few immediate postoperative complications (urinary tract infection (1), ileus (1), and one case of pneumonia) occurred. Rectal mucosal prolapse developed and was excised 6 months later in 13 (52%) patients. Urethral diverticulum occurred in one patient with a rectobulbar urethral fistula. Immediate postoperative high rectal tone developed in six patients during the early study period (2003-2004). Six of the 12 patients older than 3 years had voluntary bowel movement and no soiling. CONCLUSION: LAARP was a safe procedure. Shorter dissection of rectum in the intra-abdominal space may be helpful in preventing rectal mucosal prolapse. Intermittent rectal tube insertion may be useful for the patient with high rectal tone in the immediate postoperative period. LAARP is not recommended for the bulbar fistula with a long common wall.

The relationship between biliary amylase and the clinical features of choledochal cysts in pediatric patients.

BACKGROUND: Although the clinical features of choledochal cysts (CC) in different age groups have been widely studied, the causes of differences in clinical features are unknown. To determine the relationship between biliary amylase and the clinical features of CC in pediatric patients, clinical outcomes were compared in two groups with different amylase levels. METHODS: From May 1995 to August 2010, 80 patients under 18 years old who underwent choledochal cyst excision and hepaticojejunostomy and measurements of biliary amylase levels were allocated to a low-amylase-level group (amylase level < 200 U/L, n = 26) and a high-amylase-level group (amylase level > 200 U/L, n = 54). Their medical records were retrospectively reviewed. RESULTS: The median age was 4 months (range = 17 days-169 months) in the low group and 48 months (range = 22 days-147 months) in the high group (p = 0.008). In the low group, jaundice was the most common symptom, while abdominal pain was the main symptom in the high group. In histological findings, bile duct proliferation and cholestasis predominated in the low group and portal inflammation predominated in the high group. Radiological findings and preoperative laboratory data were also significantly different between the groups. Postoperative complications occurred in the high group only. There was no mortality in either group. CONCLUSION: This study shows a relationship between biliary amylase level and clinical manifestations in pediatric patients with CC, implying that there are different underlying pathophysiologies with anomalous pancreaticobiliary ductal union (APBDU).

PELD score and age as a prognostic index of biliary atresia patients undergoing Kasai portoenterostomy.

PURPOSE: This study was designed to evaluate the validity of the pediatric end-stage liver disease (PELD) score as a prognostic index of native liver survival in biliary atresia before Kasai portoenterostomy. METHODS: Medical records of 63 patients who underwent Kasai portoenterostomy at our hospital were reviewed retrospectively. Rate of jaundice clearance and cumulative survival with native liver were calculated. Patients who were alive and did not require transplantation until the last follow up were included in the native-liver survival group. And patients who underwent any event, defined as death without transplantation, transplantation or listing for transplantation, were included in the native-liver failure group. Cox analysis was done. RESULTS: 10-year survival rate with native liver was 41.9%. PELD scores of ≥ 15 and an age at operation of ≥ 60 days were found to be significant risk factors of failure(P = 0.007, OR = 2.851 and P = 0.010, OR = 3.222, respectively). Furthermore, patients with both risk factors showed significantly higher risk of failure (P = 0.001, OR = 8.809). CONCLUSION: Since failure rate is higher for patients with high PELD score and older age, these factors should be helpful in estimating the prognosis. And with high-risk patients, cautious monitoring and consultation should be made whether the liver fails and requires transplantation.

Posteromedial diaphragmatic hernia following pediatric liver transplantation.

Diaphragmatic hernia is a rare complication following pediatric LT. Here, four children who developed right-sided posteromedial diaphragmatic hernias after LT are reported. The primary disease was biliary atresia in two patients, hemangioendothelioma in one, and angiosarcoma in one patient. All of the patients underwent living-donor LT using a left lateral graft. The patients presented with abdominal and/or pulmonary signs and symptoms. The diaphragmatic hernias were diagnosed at 28 days to seven months post-transplant by standard radiographs or chest CT. The defects were located at the posteromedial aspect of the diaphragm and were closed by primary closure. After diaphragm repair, the post-operative course was unremarkable and there were no recurrences. Thermal or mechanical injuries to the bare area, especially in cases of excessive adhesion between the liver and diaphragm after Kasai operation, were the possible causes of the posteromedial diaphragmatic hernia after pediatric LT.