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Cureus Apr 2022Background and objective Intestinal perforations and necrotizing enterocolitis (NEC) requiring the formation of temporary intestinal stoma are prevalent conditions...
Background and objective Intestinal perforations and necrotizing enterocolitis (NEC) requiring the formation of temporary intestinal stoma are prevalent conditions worldwide. This prospective study aimed to address the following research question: does sutureless enterostomy lead to fewer complications compared to conventional enterostomy in critically sick surgical neonates who need a stoma? Methods We conducted a randomized control trial (TCTR20211011004) from October 2020 to October 2021. A total of 120 patients were randomized to the following two study groups: Group A: conventional sutured enterostomy; Group B: sutureless enterostomy, with 60 patients in each group. The operative time, complications, and mortality were compared between the two groups using the chi-squared test. Results The groups were comparable with respect to the mean age at presentation, gestational age, weight, and sex ratio. In Group A, the main operative diagnoses were NEC in 22 patients, pneumoperitoneum in 25, complicated meconium ileus in nine, bowel atresia in three, and midgut volvulus in one; while in Group B, 25 patients had NEC, 20 had pneumoperitoneum, eight had meconium ileus, two had bowel atresia, and five had midgut volvulus. The mean operative time (93.5 ± 28.71 minutes) was significantly longer in the conventional group compared to the sutureless group (52.08 ± 18.53 minutes). Oral feed was started significantly earlier in the sutureless stoma group. Mortality was 43.3% in Group A and 46.6% in Group B. Complication rate was significantly higher in sutured stoma group. Conclusion The management of critically sick neonates, especially those with NEC and intestinal perforation, still presents a surgical dilemma. Based on our findings, the sutureless enterostomy may reduce operative time and complications in critically sick neonates.
PubMed: 35573560
DOI: 10.7759/cureus.24057 -
International Journal of Pediatrics &... Mar 2022Meconium ileus (MI) is one of the most common causes of intestinal obstruction in newborns. It is the earliest clinical manifestation of cystic fibrosis (CF). MI is...
INTRODUCTION
Meconium ileus (MI) is one of the most common causes of intestinal obstruction in newborns. It is the earliest clinical manifestation of cystic fibrosis (CF). MI is suspected if a baby fails to pass meconium shortly after birth and develops symptoms of bowel obstruction, such as distention of the abdomen or vomiting. MI can lead to bowel perforation, a twisting of the bowel, or inflammation and infection of the abdominal cavity.
OBJECTIVES
To find the incidence and prevalence of meconium ileus in cystic fibrosis patients and to report on the most common gene mutation of MI in CF patients.
METHODOLOGY
Retrospective review of the medical documentations of all MI patients during the period of 1989-2018.
RESULTS
A total of 40 CF confirmed patients were presented with MI. Twenty-nine patients (71%) are alive and 11 patients (29%) died or lost to follow-up. The following CFTR mutations were found: Eight patients (20%) with c.2988+1G>A; Intron 18. Seven patients (17.5%) with c.1418delG; Exon 11. Five patients (12.5%) with c.579+1G>T; Intron 5. Four patients (10%) with c.1911delG; Exon 14. Four patients (10%) with c.1521_1523delCTT; Exon 11. Four patients (10%) with c.416A>T; Exon 13. Three patients (7.5%) with c.2421A>G; Exon 14. Two patients (5%) with c.3908A>C; Exon 21. One patient (2.5%) with c.3889dupT; Exon 24. One patient (2.5%) with c.1657C>T; Exon 12. One patient (2.5%) with c.2547C>A; Exon 14a. Eighteen patients (45%) were presented with vomiting, 38 patients (95%) had postnatal radiological findings, 7 patients (17.5%) had electrolytes imbalance. Five patients (12.5%) had cholestasis and 4 patients (10%) developed chronic liver disease. Thirty-five patients (79.5%) underwent surgical repair and 9 patients (20.5%) were treated medically. Mean age of operation was 2.25 (2) days. Of 9 patients, 6 (66.6%) were treated with gastrograffin enema, 2 patients (22.2%) with oral N-acetylcysteine and 1 patient (11.1%) with saline rectal wash. Thirteen patients (31.5%) required TPN. Five patients had recurrent operation.
CONCLUSION
CF and meconium ileus are commonly present in CF patients in Saudi Arabia. Prognosis is similar to other CFs without MI, if treated early. Thirty percent of our CF/MI patients have intronic mutations.
PubMed: 35573065
DOI: 10.1016/j.ijpam.2021.03.008 -
Cellular and Molecular Life Sciences :... Sep 2020The solute carrier family 6 member 14 (SLC6A14) protein imports and concentrates all neutral amino acids as well as the two cationic acids lysine and arginine into the... (Review)
Review
The solute carrier family 6 member 14 (SLC6A14) protein imports and concentrates all neutral amino acids as well as the two cationic acids lysine and arginine into the cytoplasm of different cell types. Primarily described as involved in several cancer and colonic diseases physiopathological mechanisms, the SLC6A14 gene has been more recently identified as a genetic modifier of cystic fibrosis (CF) disease severity. It was indeed shown to have a pleiotropic effect, modulating meconium ileus occurrence, lung disease severity, and precocity of P. aeruginosa airway infection. The biological mechanisms explaining the impact of SLC6A14 on intestinal and lung phenotypes of CF patients are starting to be elucidated. This review focuses on SLC6A14 in lung and gastrointestinal physiology and physiopathology, especially its involvement in the pathophysiology of CF disease.
Topics: Amino Acid Transport Systems; Colonic Diseases; Cystic Fibrosis; Gastrointestinal Tract; Genetic Variation; Humans; Linkage Disequilibrium; Lung; Neoplasms; Severity of Illness Index
PubMed: 32166393
DOI: 10.1007/s00018-020-03487-x -
AJP Reports Jan 2022Today, more infants weighing less than or equal to 300 g are born, and they survive because of the improvements in neonatal care and treatment. However, their detailed...
Today, more infants weighing less than or equal to 300 g are born, and they survive because of the improvements in neonatal care and treatment. However, their detailed clinical course and neonatal intensive care unit management remain unknown due to their low survival rate and dearth of reports. A male infant was born at 24 weeks and 5 days of gestation and weighed 258 g. The infant received 72 days of invasive and 92 days of noninvasive respiratory support, including high-frequency oscillatory ventilation with volume guarantee and noninvasive neurally adjusted ventilatory assist. Meconium-related ileus was safely treated using diatrizoate. Although the infant was diagnosed with severe bronchopulmonary dysplasia and retinopathy of prematurity requiring laser photocoagulation, he had no other severe complications. He was discharged 201 days postdelivery (3 months of corrected age) with a weight of 3.396 kg. Although managing infants weighing less than or equal to 300 g is difficult, our experience shows that it is possible by combining traditional and modern management methods. The management of such infants requires an understanding of the expected difficulties and adaptation of existing methods to their management. The management techniques described here should help improve their survival and long-term prognosis.
PubMed: 35154903
DOI: 10.1055/a-1678-3755 -
JCI Insight Apr 2024Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, with F508del being the most prevalent mutation. The combination of...
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, with F508del being the most prevalent mutation. The combination of CFTR modulators (potentiator and correctors) has provided benefit to CF patients carrying the F508del mutation; however, the safety and effectiveness of in utero combination modulator therapy remains unclear. We created a F508del ferret model to test whether ivacaftor/lumacaftor (VX-770/VX-809) therapy can rescue in utero and postnatal pathologies associated with CF. Using primary intestinal organoids and air-liquid interface cultures of airway epithelia, we demonstrate that the F508del mutation in ferret CFTR results in a severe folding and trafficking defect, which can be partially restored by treatment with CFTR modulators. In utero treatment of pregnant jills with ivacaftor/lumacaftor prevented meconium ileus at birth in F508del kits and sustained postnatal treatment of CF offspring improved survival and partially protected from pancreatic insufficiency. Withdrawal of ivacaftor/lumacaftor treatment from juvenile CF ferrets reestablished pancreatic and lung diseases, with altered pulmonary mechanics. These findings suggest that in utero intervention with a combination of CFTR modulators may provide therapeutic benefits to individuals with F508del. This CFTR-F508del ferret model may be useful for testing therapies using clinically translatable endpoints.
Topics: Animals; Female; Pregnancy; Aminophenols; Aminopyridines; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Drug Combinations; Ferrets; Mutation; Quinolones
PubMed: 38646935
DOI: 10.1172/jci.insight.157229 -
JCI Insight Oct 2017Cystic fibrosis (CF) is a genetic disorder in which epithelium-generated fluid flow from the lung, intestine, and pancreas is impaired due to mutations disrupting CF...
Cystic fibrosis (CF) is a genetic disorder in which epithelium-generated fluid flow from the lung, intestine, and pancreas is impaired due to mutations disrupting CF transmembrane conductance regulator (CFTR) channel function. CF manifestations of the pancreas and lung are present in the vast majority of CF patients, and 15% of CF infants are born with obstructed gut or meconium ileus. However, constipation is a significantly underreported outcome of CF disease, affecting 47% of the CF patients, and management becomes critical in the wake of increasing life span of CF patients. In this study, we unraveled a potentially novel molecular role of a membrane-bound cyclic guanosine monophosphate-synthesizing (cGMP-synthesizing) intestinal enzyme, guanylate cyclase 2C (GCC) that could be targeted to ameliorate CF-associated intestinal fluid deficit. We demonstrated that GCC agonism results in functional rescue of murine F508del/F508del and R117H/R117H Cftr and CFTR mutants in CF patient-derived intestinal spheres. GCC coexpression and activation facilitated processing and ER exit of F508del CFTR and presented a potentially novel rescue modality in the intestine, similar to the CF corrector VX-809. Our findings identify GCC as a biological CFTR corrector and potentiator in the intestine.
Topics: Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Intestinal Mucosa; Mice, Mutant Strains; Mutation; Organoids; Receptors, Enterotoxin; Stem Cells
PubMed: 28978796
DOI: 10.1172/jci.insight.93686 -
The Journal of Clinical Investigation Jun 2013Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary...
Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid-binding protein (iFABP) promoter would alleviate the meconium ileus. We produced 5 CFTR-/-;TgFABP>pCFTR lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time. These data indicate that expressing CFTR in intestine without pancreatic or hepatic correction is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type CFTR mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies.
Topics: Animals; Animals, Genetically Modified; Animals, Newborn; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Fatty Acid-Binding Proteins; Female; Gene Expression; Humans; Ileum; Ileus; Infant, Newborn; Lung; Male; Meconium; Pancreas; Phenotype; Promoter Regions, Genetic; Radiography; Rats; Sus scrofa; Trachea
PubMed: 23676501
DOI: 10.1172/JCI68867 -
Arquivos Brasileiros de Cirurgia... 2023Bishop-Koop ileostomy has been widely used in pediatric patients with the intention of including as much bowel as possible in the intestinal transit early in the... (Review)
Review
BACKGROUND
Bishop-Koop ileostomy has been widely used in pediatric patients with the intention of including as much bowel as possible in the intestinal transit early in the management of children with meconium ileus and intestinal atresia. In recent years, we have been using it as an alternative to test the distal bowel function before closure of a previously constructed ostomy in selected children with questionable distal bowel motility.
AIMS
The aim of this study was to present our experience with this alternative use of the Bishop-Koop ostomy.
METHODS
This is a cross-sectional retrospective review of hospital records, combined with a comprehensive literature review.
RESULTS
Seven children were included: five had suspected aganglionosis, one had gastroschisis complicated with ileal atresia, and one had a colonic stricture secondary to necrotizing enterocolitis. In this short series of patients, motility of the distal bowel was correctly assessed in six patients and partially correctly assessed in one patient. One patient did not pass stools per anus after the Bishop-Koop, and he was later confirmed to have Hirschsprung disease. Four patients resumed normal evacuation pattern after closure of the Bishop-Koop. One patient had a Bishop-Koop colostomy because of recurrent enterocolitis after a transanal pull-through. Although he evacuated normally while having the colostomy, the diarrhea recurred after the ostomy was closed. An additional patient, with a severe behavioral problem, did not evacuate per anus after her colostomy was transformed in a Bishop-Koop-type ostomy, despite the apparent presence of normal ganglia in the bowel wall.
CONCLUSIONS
Data from the present series allow us to affirm that Bishop-Koop-type ostomy is a safe and efficient procedure that can be used to assess distal bowel function before a definitive transit reconstruction, in children with uncertain motility issues.
Topics: Humans; Male; Child; Female; Cross-Sectional Studies; Neoplasm Recurrence, Local; Ostomy; Intestinal Atresia; Intestinal Obstruction; Retrospective Studies
PubMed: 36946847
DOI: 10.1590/0102-672020230002e1722 -
American Journal of Human Genetics Oct 2022Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related...
Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related diabetes (CFRD) is a distinct form of diabetes with a variable age of onset that occurs frequently in individuals with CF, while meconium ileus (MI) is a severe neonatal intestinal obstruction affecting ∼20% of newborns with CF. CFRD and MI are slightly correlated traits with previous evidence of overlap in their genetic architectures. To better understand the genetic commonality between CFRD and MI, we used whole-genome-sequencing data from the CF Genome Project to perform genome-wide association. These analyses revealed variants at 11 loci (6 not previously identified) that associated with MI and at 12 loci (5 not previously identified) that associated with CFRD. Of these, variants at SLC26A9, CEBPB, and PRSS1 associated with both traits; variants at SLC26A9 and CEBPB increased risk for both traits, while variants at PRSS1, the higher-risk alleles for CFRD, conferred lower risk for MI. Furthermore, common and rare variants within the SLC26A9 locus associated with MI only or CFRD only. As expected, different loci modify risk of CFRD and MI; however, a subset exhibit pleiotropic effects indicating etiologic and mechanistic overlap between these two otherwise distinct complications of CF.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Diabetes Mellitus; Genome-Wide Association Study; Humans; Infant, Newborn; Infant, Newborn, Diseases; Intestinal Obstruction
PubMed: 36206743
DOI: 10.1016/j.ajhg.2022.09.004 -
PLoS Genetics Feb 2019Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in...
Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in ~15%. Individuals with the same causal CFTR mutations show variable disease presentation which is partly attributed to modifier genes. With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10(-16), 2.81x10(-11), respectively); and replicated a suggestive locus on chromosome 7 near PRSS1 (min p = 2.55x10(-7)). PRSS1 is exclusively expressed in the exocrine pancreas and was previously associated with non-CF pancreatitis with functional characterization demonstrating impact on PRSS1 gene expression. We thus asked whether the other meconium ileus modifier loci impact gene expression and in which organ. We developed and applied a colocalization framework called the Simple Sum (SS) that integrates regulatory and genetic association information, and also contrasts colocalization evidence across tissues or genes. The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10(-8)), SLC6A14 (p = 1.12x10(-10)) and SLC26A9 (p = 4.48x10(-5)) in the pancreas, even though meconium ileus manifests in the intestine. The meconium ileus susceptibility locus on chromosome X appeared shifted in location from a previously identified locus for CF lung disease severity. Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10(-4)). Cystic Fibrosis is realizing the promise of personalized medicine, and identification of the contributing organ and understanding of tissue specificity for a gene modifier is essential for the next phase of personalizing therapeutic strategies.
Topics: Amino Acid Transport Systems; Amino Acid Transport Systems, Neutral; Antiporters; Cystic Fibrosis; Female; Gene Expression Profiling; Gene Expression Regulation; Genome-Wide Association Study; H(+)-K(+)-Exchanging ATPase; Humans; Lung; Male; Organ Specificity; Pancreas, Exocrine; Sulfate Transporters; Trypsin
PubMed: 30807572
DOI: 10.1371/journal.pgen.1008007