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Acta Physiologica (Oxford, England) Jan 2022Slc26a9 is a member of the Slc26 multifunctional anion transporter family. Polymorphisms in Slc26a9 are associated with an increased incidence of meconium ileus and...
AIM
Slc26a9 is a member of the Slc26 multifunctional anion transporter family. Polymorphisms in Slc26a9 are associated with an increased incidence of meconium ileus and diabetes in cystic fibrosis patients. We investigated the expression of Slc26a9 in the murine pancreatic ducts, islets and parenchyma, and elucidated its role in pancreatic ductal electrolyte and fluid secretion and endocrine function.
METHODS
Pancreatic Slc26a9 and CFTR mRNA expression, fluid and bicarbonate secretion were assessed in slc26a9 mice and their age- and sex-matched wild-type (wt) littermates. Glucose and insulin tolerance tests were performed.
RESULTS
Compared with stomach, the mRNA expression of Slc26a9 was low in pancreatic parenchyma, 20-fold higher in microdissected pancreatic ducts than parenchyma, and very low in islets. CFTR mRNA was ~10 fold higher than Slc26a9 mRNA expression in each pancreatic cell type. Significantly reduced pancreatic fluid secretory rates and impaired glucose tolerance were observed in female slc26a9 mice, whereas alterations in male mice did not reach statistical significance. No significant difference was observed in peripheral insulin resistance in slc26a9 compared to sex- and aged-matched wt controls. In contrast, isolated slc26a9 islets in short term culture displayed no difference in insulin content, but a significantly reduced glucose-stimulated insulin secretion compared to age- and sex-matched wt islets, suggesting that the impaired glucose tolerance in the absence of Slc26a9 expression these is a pancreatic defect.
CONCLUSIONS
Deletion of Slc26a9 is associated with a reduction in pancreatic fluid secretion and impaired glucose tolerance in female mice. The results underline the importance of Slc26a9 in pancreatic physiology.
Topics: Aged; Animals; Antiporters; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Insulin; Insulin Secretion; Male; Mice; Pancreas; Sulfate Transporters
PubMed: 34525257
DOI: 10.1111/apha.13729 -
Journal of Cystic Fibrosis : Official... Mar 2022To assess cancer incidence in the UK cystic fibrosis (CF) population and determine the associated risk factors, we undertook a nested case-control study of patients...
To assess cancer incidence in the UK cystic fibrosis (CF) population and determine the associated risk factors, we undertook a nested case-control study of patients with CF, registered with the UK CF Registry. Each case with a first reported cancer between 1999 and 2017 was matched with up to 4 controls: by age (±2-years) and year of cancer diagnosis. Conditional logistic regressions were adjusted for sex, lung function (FEV%), CF related diabetes (CFRD), F508del status, transplant status, DIOS, gastro-oesophageal reflux disease, meconium ileus, Pseudomonas aeruginosa infection, pancreatic insufficiency, proton pump inhibitor (PPI) use, IV antibiotic days and BMI. Results: From 12,886 registered patients, 146 (1.1%) cases of malignancy were identified with 14.3% of cases occurring post solid organ transplant. Site of primary cancer was available for 98 patients: 22% were gastro-intestinal in origin (77% lower, 23% upper GI), 13% skin, 13% breast and 11% lymphomas/leukaemia. In univariable analysis, transplantation increased the odds of reporting any cancer by 2.46 times (95%CI: 1.3-4.6). CFRD also increased the odds of reporting any cancer (OR 2.35; CI: 1.37-4.0) and PPI use (OR 2.0; CI 1.28-3.19). In the multivariable models significant associations with CFRD and transplant remained, while PA infection, PPI use and being overweight showed increased, but statistically insignificant risks. The incidence of GI cancer was strongly associated with CFRD (OR=4.04; 1.47-11.1). Conclusions: We observed a high incidence of lower GI cancers in our cohort which was significantly affected by the presence of CFRD. Screening for gastrointestinal cancers could benefit patients at higher risk.
Topics: Case-Control Studies; Cystic Fibrosis; Humans; Incidence; Neoplasms; Risk Factors; United Kingdom
PubMed: 34348871
DOI: 10.1016/j.jcf.2021.07.004 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Aug 2021To analyze the cystic fibrosis transmembrane conductance regulator (CFTR) gene variations and phenotypes in 7 Chinese children. In this retrospective study, the data...
To analyze the cystic fibrosis transmembrane conductance regulator (CFTR) gene variations and phenotypes in 7 Chinese children. In this retrospective study, the data of 7 children with CFTR gene variations admitted to Children's Hospital of Chongqing Medical University from December 2013 to October 2020 were extracted. The general information, clinical manifestations, gene variations, diagnosis and treatment were summarized. Among the 7 children, 2 were males and 5 were females, aged 5.2(0.5-11.3) years. Main clinical manifestations included malnutrition (5 cases), recurrent respiratory infection (4 cases), bronchiectasis (3 cases), steatorrhea (3 cases), vomiting in infancy (2 cases), liver cirrhosis (2 cases), meconium ileus (1 case), metabolic alkalosis and hypochloremia (1 case). A total of 15 variations were found by whole exon sequencing and Sanger sequencing, among which 3 were newly discovered, and 7 were missense mutations. Four children were diagnosed as CF, and the other 3 were diagnosed as CFTR related disease (CFTR-RD). Compared with CF patients, the pancreatic insufficiency and typical CF lung disease were relatively mild in CFTR-RD patients. After treatment, 6 children were clinically improved, while the rest one withdrew treatment due to critical pulmonary infection and disturbance of water-electrolyte metabolism. The loci and phenotypes of CFTR gene variants vary hugely and the pathogenicity of some variations are not clear. Whole exon sequencing can facilitate the identification of CF-and CFTR-RD-causing variaions. For the cases not compatible with CF, CFTR-RD should be considered and evaluated by timely gene detection, so as to carry out appropriate long term management.
Topics: Child; Child, Preschool; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Infant; Male; Mutation; Phenotype; Retrospective Studies
PubMed: 34333923
DOI: 10.3760/cma.j.cn112140-20210112-00033 -
Wiener Klinische Wochenschrift Jul 2021To evaluate gastrointestinal tract (GIT) perforations in very low birth weight infants and the effects on neurodevelopmental outcome.
PURPOSE
To evaluate gastrointestinal tract (GIT) perforations in very low birth weight infants and the effects on neurodevelopmental outcome.
METHODS
Between 2000 and 2017 all cases with GIT perforation were analyzed regarding causes, associated morbidities and neurodevelopmental outcome and compared with matched (gestational age, birth weight, gender, year of birth) by 1:2 controls.
RESULTS
The incidence of GIT perforation was 2.0% (n = 38/1878). Diagnoses associated with GIT were meconium obstruction of prematurity (MOP,n = 19/50%), spontaneous intestinal perforation (SIP, n = 7/18%), necrotizing enterocolitis (NEC, n = 6/16%), iatrogenic perforation (n = 3/8%), volvulus (n = 2/5%) and meconium ileus (n = 1/3%). The NEC-associated perforations occurred later compared to those associated with MOP and SIP (median 8 days and 6 days vs. 17 days, p = 0.001 and 0.023, respectively) and main localization was the terminal ileum (84%). Cases had higher rates of late onset sepsis (55% vs. 24%, p = 0.003), longer duration of mechanical ventilation (median 30 days vs 18 days, p = 0.013) and longer stays at the hospital (median 122 days vs 83 days, p < 0.001); mortality rates did not differ. The 2‑year neurodevelopment follow-up revealed no differences between groups (normal development 49% vs. 40%).
CONCLUSION
Despite increased morbidities preterm infants with GIT perforation did not have a higher mortality rate and groups did not differ regarding neurodevelopmental outcome at the corrected for prematurity age of 2 years.
Topics: Child, Preschool; Gastrointestinal Tract; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intestinal Perforation; Retrospective Studies
PubMed: 34110498
DOI: 10.1007/s00508-021-01886-z -
JCI Insight Jun 2021SLC26A6 (also known as putative anion transporter 1 [PAT1]) is a Cl-/HCO3- exchanger expressed at the luminal membrane of enterocytes where it facilitates intestinal Cl-...
SLC26A6 (also known as putative anion transporter 1 [PAT1]) is a Cl-/HCO3- exchanger expressed at the luminal membrane of enterocytes where it facilitates intestinal Cl- and fluid absorption. Here, high-throughput screening of 50,000 synthetic small molecules in cells expressing PAT1 and a halide-sensing fluorescent protein identified several classes of inhibitors. The most potent compound, the pyrazolo-pyrido-pyrimidinone PAT1inh-B01, fully inhibited PAT1-mediated anion exchange (IC50 ~350 nM), without inhibition of the related intestinal transporter SLC26A3 (also known as DRA). In closed midjejunal loops in mice, PAT1inh-B01 inhibited fluid absorption by 50%, which increased to >90% when coadministered with DRA inhibitor DRAinh-A270. In ileal loops, PAT1inh-B01 blocked fluid absorption by >80%, whereas DRAinh-A270 was without effect. In colonic loops, PAT1inh-B01 was without effect, whereas DRAinh-A270 completely blocked fluid absorption. In a loperamide constipation model, coadministration of PAT1inh-B01 with DRAinh-A270 increased stool output compared with DRAinh-A270 alone. These results provide functional evidence for complementary and region-specific roles of PAT1 and DRA in intestinal fluid absorption, with PAT1 as the predominant anion exchanger in mouse ileum. We believe that PAT1inh-B01 is a novel tool to study intestinal ion and fluid transport and perhaps a drug candidate for small intestinal hyposecretory disorders such as cystic fibrosis-related meconium ileus and distal intestinal obstruction syndrome.
Topics: Animals; Antidiarrheals; Antiporters; Colon; Constipation; Dopamine Plasma Membrane Transport Proteins; Drug Evaluation, Preclinical; HEK293 Cells; Humans; Ileum; Intestinal Absorption; Intestine, Small; Jejunum; Loperamide; Mice; Small Molecule Libraries; Sulfate Transporters
PubMed: 34100381
DOI: 10.1172/jci.insight.147699 -
Journal of Surgical Case Reports May 2021Fetal intestinal volvulus is rare, but it is a serious condition due to its life-threatening complications. The bowel loop becomes twisted; thus, impaired venous return...
Fetal intestinal volvulus is rare, but it is a serious condition due to its life-threatening complications. The bowel loop becomes twisted; thus, impaired venous return leads to bowel necrosis. Prenatal volvulus is most secondary to intestinal atresia, arterial supply defect or without any underlying cause, with consideration that cystic fibrosis is the cause of the intestinal obstruction, because of meconium ileus. We report a case of prenatal volvulus complicated with intestinal perforation and meconium peritonitis in the context of meconium ileus.
PubMed: 34055287
DOI: 10.1093/jscr/rjab192 -
Journal of Pediatric Surgery Jul 2021therapeutic strategy for meconium-related ileus (MRI) in very-low-birth-weight infants (VLBWs) has not been established. This study aims to clarify the optimum...
BACKGROUND/PURPOSE
therapeutic strategy for meconium-related ileus (MRI) in very-low-birth-weight infants (VLBWs) has not been established. This study aims to clarify the optimum therapeutic strategy for MRI in VLBWs.
METHODS
MRI was defined as delayed meconium excretion and microcolon on contrast enema with Gastrografin (diatrizoate acid). Forty-two infants with MRI were treated at our institution between 2009 and 2019, and are reviewed here. They were classified into two groups: in group A (n=21), Gastrografin regurgitated into the dilated intestine during the first or second round of Gastrografin enema (GaE), while in group B (N = 21), Gastrografin did not regurgitate. Laparotomy was indicated if the intestine was perforated, or if abdominal distention was not relieved by two rounds of GaE.
RESULTS
in group A, meconium was excreted in all cases within 24 h after GaE, and no cases required laparotomy. In group B, twelve cases (57%) underwent laparotomy (P < 0.01), six cases in this group (29%), showed free air on X-ray images (P < 0.01). The median hospital stay in groups A and B were 89.0 and 136.5 days, respectively (P < 0.05). Overall mortality was 2.4%.
CONCLUSIONS
early therapeutic diagnosis by GaE followed by early surgery is suggested as the optimum strategy for MRI in VLBWs.
Topics: Diatrizoate Meglumine; Enema; Humans; Ileus; Infant, Newborn; Infant, Very Low Birth Weight; Intestinal Obstruction; Meconium; Meconium Ileus
PubMed: 33896618
DOI: 10.1016/j.jpedsurg.2021.03.029 -
Journal of Cystic Fibrosis : Official... Sep 2021
Topics: Cystic Fibrosis; Humans; India; Infant, Newborn; Male; Meconium Ileus; Mutation, Missense; Receptors, Enterotoxin
PubMed: 33883099
DOI: 10.1016/j.jcf.2021.03.023 -
Oman Medical Journal Mar 2021Cystic fibrosis (CF) is a genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator () gene that affects multisystems in the body,...
Cystic fibrosis (CF) is a genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator () gene that affects multisystems in the body, particularly the lungs and digestive system. We report a case of an Omani newborn who presented with meconium ileus and high suspicion of CF. Thus, full gene sequencing was performed, which revealed a homozygous unreported C.4242+1G>C novel gene mutation. Both parents were found to be heterozygous for this mutation. This case sheds light on the importance of the extensive genetic testing of typical CF cases in the absence of family history or during neonatal presentations, especially when the sweat test cannot be performed and the diagnosis can be challenging.
PubMed: 33854794
DOI: 10.5001/omj.2021.28 -
Cureus Mar 2021Interstitial obstruction in newborn infants can be caused by several factors such as malrotation, meconium plug syndrome, meconium ileus, Hirschsprung's disease, atresia...
Interstitial obstruction in newborn infants can be caused by several factors such as malrotation, meconium plug syndrome, meconium ileus, Hirschsprung's disease, atresia and stenosis. Neonates who have been diagnosed with an interstitial obstruction are in need of immediate treatment; otherwise, they can deteriorate rapidly. Surgery remains the mainstay of treatment in most cases. Pediatric gastrointestinal tumours are very rare, especially in newborn infants. Their management is usually different as compared to adults. We present the case of a newborn infant who was born with interstitial obstruction. At the 31 weeks scan, a significant dilation of the small bowel was observed and the diagnosis of interstitial obstruction was made. When born, the newborn was transferred to a specialised unit and underwent a laparotomy. The findings were consistent with a tumour causing the obstruction; the histology reported this tumour as benign lymphoid hyperplasia. Pseudolymphoma is a very rare cause of fetal interstitial obstruction, and it should be considered in the differential diagnosis.
PubMed: 33842123
DOI: 10.7759/cureus.13746