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RSC Medicinal Chemistry Nov 2023A loss of prosecretory Cl channel CFTR activity in the intestine is considered as the key cause of gastrointestinal problems in cystic fibrosis (CF): meconium ileus,...
A loss of prosecretory Cl channel CFTR activity in the intestine is considered as the key cause of gastrointestinal problems in cystic fibrosis (CF): meconium ileus, distal intestinal obstruction syndrome (DIOS) and constipation. Since CFTR modulators have minimal effects on gastrointestinal symptoms, there is an unmet need for novel treatments for CF-associated gastrointestinal disorders. Meconium ileus and DIOS mainly affect the ileum (distal small intestine). SLC26A6 (putative anion transporter 1, PAT1) is a Cl/HCO exchanger at the luminal membrane of small intestinal epithelial cells which facilitates Cl and fluid absorption. We recently identified first-in-class PAT1 inhibitors by high-throughput screening. Isoxazolopyrimidine PAT1-A01 was a hit compound, which had low potency (IC 5.2 μM) for SLC26A6 inhibition precluding further preclinical development. Here we performed structure-activity relationship studies to optimize isoxazolopyrimidine SLC26A6 inhibitors and tested a potent inhibitor in mouse models of intestinal fluid absorption. Structure-activity studies of 377 isoxazolopyrimidine analogs identified PAT1-A0030 (ethyl 4-(benzyl(methyl)amino)-3-methylisoxazolo[5,4-]pyrimidine-6-carboxylate) as the most potent SLC26A6 inhibitor with a 1.0 μM IC. Selectivity studies showed that PAT1-A030 has no activity on relevant ion transporters/channels (SLC26A3, SLC26A4, SLC26A9, CFTR, TMEM16A). In a closed-loop model of intestinal fluid absorption, intraluminal PAT1-A0030 treatment inhibited fluid absorption in the ileum of wild-type and CF mice () with >90% prevention of a decrease in loop fluid volume and loop weight/length ratio at 30 minutes. These results suggest that SLC26A6 is the key transporter mediating Cl and fluid absorption in the ileum and SLC26A6 inhibitors are novel drug candidates for treatment of CF-associated small intestinal disorders.
PubMed: 37974969
DOI: 10.1039/d3md00302g -
Journal of Human Genetics Oct 2023Cystic fibrosis (CF) is an autosomal recessive disease caused by pathogenic variants in CF transmembrane conductance regulator (CFTR). While CF is the most common...
Cystic fibrosis (CF) is an autosomal recessive disease caused by pathogenic variants in CF transmembrane conductance regulator (CFTR). While CF is the most common hereditary disease in Caucasians, it is rare in East Asia. In the present study, we have examined clinical features and the spectrum of CFTR variants of CF patients in Japan. Clinical data of 132 CF patients were obtained from the national epidemiological survey since 1994 and CF registry. From 2007 to 2022, 46 patients with definite CF were analyzed for CFTR variants. All exons, their boundaries, and part of promoter region of CFTR were sequenced and the presence of large deletion and duplications were examined by multiplex ligation-dependent probe amplification. CF patients in Japan were found to have chronic sinopulmonary disease (85.6%), exocrine pancreatic insufficiency (66.7%), meconium ileus (35.6%), electrolyte imbalance (21.2%), CF-associated liver disease (14.4%), and CF-related diabetes (6.1%). The median survival age was 25.0 years. The mean BMI percentile was 30.3%ile in definite CF patients aged < 18 years whose CFTR genotypes were known. In 70 CF alleles of East Asia/Japan origin, CFTR-dele16-17a-17b was detected in 24 alleles, the other variants were novel or very rare, and no pathogenic variants were detected in 8 alleles. In 22 CF alleles of Europe origin, F508del was detected in 11 alleles. In summary, clinical phenotype of Japanese CF patients is similar to European patients, but the prognosis is worse. The spectrum of CFTR variants in Japanese CF alleles is entirely different from that in European CF alleles.
Topics: Humans; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Mutation; Japan; Genotype
PubMed: 37217688
DOI: 10.1038/s10038-023-01160-2 -
Pediatric Surgery International Jun 2024To characterise the investigations, management and ultimate diagnosis of neonates with distal intestinal obstruction.
PURPOSE
To characterise the investigations, management and ultimate diagnosis of neonates with distal intestinal obstruction.
METHODS
Retrospective review of term (> 37 weeks) neonates with admission diagnosis of distal intestinal obstruction over 10 years (2012-2022). Patient pathways were identified and associations between presentations, response to treatments and outcome investigated.
RESULTS
A total of 124 neonates were identified and all included. Initial management was colonic irrigation in 108, contrast enema in 4, and laparotomy in 12. Of those responding to irrigations none underwent contrast enema. Ultimately, 22 neonates proceeded to laparotomy. Overall, 106 had a suction rectal biopsy and 41 had genetic testing for cystic fibrosis. Final diagnosis was Hirschsprung disease (HD) in 67, meconium ileus with cystic fibrosis (CF) in 9, meconium plug syndrome in 19 (including 3 with CF), intestinal atresia in 10 and no formal diagnosis in 17. Median length of neonatal unit stay was 11 days (7-19).
CONCLUSIONS
Initial management of neonates with distal bowel obstruction should be colonic irrigation since this is therapeutic in the majority and significantly reduces the need for contrast enema. These infants should all have suction rectal biopsy to investigate for HD unless another diagnosis is evident. If a meconium plug is passed, testing for CF is recommended. Evaluation and therapy are multimodal and time consuming, placing burden on resources and families.
Topics: Humans; Infant, Newborn; Retrospective Studies; Intestinal Obstruction; Enema; Male; Female; Contrast Media; Therapeutic Irrigation; Laparotomy; Treatment Outcome
PubMed: 38852109
DOI: 10.1007/s00383-024-05725-w -
Pediatric Surgery International Jun 2024Preserving the ileocecal valve (ICV) has shown significant benefits. We present our experience with 18 infants who underwent ileocecal valve-preservation ileocecostomy...
PURPOSE
Preserving the ileocecal valve (ICV) has shown significant benefits. We present our experience with 18 infants who underwent ileocecal valve-preservation ileocecostomy (IVPI) with an extremely short distal ileum after primary ileostomy.
METHODS
A retrospective analysis was conducted on IVPI cases between 2014 and 2020. Medical records were reviewed, including birth weight, age, primary diseases, length of ileus stump, surgical time and procedure, time to enteral feeding, postoperative hospital stay, and complications.
RESULTS
Eighteen patients (male: female = 12:6, median birth weight 1305 (750-4000) g, median gestational age 29 + 5 (27 + 6-39 + 6) weeks) were included in the analysis. Causes of surgery included necrotizing enterocolitis (13), ileocecal intestinal atresia (1), ileum volvulus (2), meconium peritonitis (1), and secondary intestinal fistula (1). The median corrected age of ileostomy closure was 3.2 months (2.0-8.0 months). The distance from the distal ileal stoma to the ICV ranged from 0.5 to 2 cm. The median length of the residual bowel was 90 cm (50-130 cm). ICV-plasty was performed in 3 cases due to secondary ICV occlusion or stenosis. All patients resumed feeding within 6 to 11 days after surgery. The postoperative hospital stay ranged from 12 to 108 days (median: 16.5 days). Complications included incisional infections in 2 cases, anastomotic stricture and adhesive ileus in 1 case, nosocomial sepsis and septic shock in 1 case. All children showed normal growth and development during a 6-65 month follow-up.
CONCLUSIONS
IVPI is safe and feasible for infants with an extremely short distal ileal stump. ICV-plasty could be applicable for cases with ileocecal occlusion/stenosis.
Topics: Humans; Male; Retrospective Studies; Ileocecal Valve; Female; Ileostomy; Infant, Newborn; Infant; Ileum; Postoperative Complications
PubMed: 38822835
DOI: 10.1007/s00383-024-05699-9 -
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 -
The Journal of Biological Chemistry Jan 2024Mutations in receptor guanylyl cyclase C (GC-C) cause severe gastrointestinal disease, including meconium ileus, early onset acute diarrhea, and pediatric inflammatory...
Mutations in receptor guanylyl cyclase C (GC-C) cause severe gastrointestinal disease, including meconium ileus, early onset acute diarrhea, and pediatric inflammatory bowel disease that continues into adulthood. Agonists of GC-C are US Food and Drug Administration-approved drugs for the treatment of constipation and irritable bowel syndrome. Therapeutic strategies targeting GC-C are tested in preclinical mouse models, assuming that murine GC-C mimics human GC-C in its biochemical properties and downstream signaling events. Here, we reveal important differences in ligand-binding affinity and GC activity between mouse GC-C and human GC-C. We generated a series of chimeric constructs of various domains of human and mouse GC-C to show that the extracellular domain of mouse GC-C contributed to log-orders lower affinity of mouse GC-C for ligands than human GC-C. Further, the Vmax of the murine GC domain was lower than that of human GC-C, and allosteric regulation of the receptor by ATP binding to the intracellular kinase-homology domain also differed. These altered properties are reflected in the high concentrations of ligands required to elicit signaling responses in the mouse gut in preclinical models and the specificity of a GC inhibitor towards human GC-C. Therefore, our studies identify considerations in using the murine model to test molecules for therapeutic purposes that work as either agonists or antagonists of GC-C, and vaccines for the bacterial heat-stable enterotoxin that causes watery diarrhea in humans.
Topics: Animals; Child; Humans; Mice; Diarrhea; Enterotoxins; Guanylate Cyclase; Ligands; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Gastrointestinal Diseases
PubMed: 38029963
DOI: 10.1016/j.jbc.2023.105505 -
Archives of Disease in Childhood Mar 2024The West Midlands Newborn Bloodspot Screening Laboratory is one of 16 in the UK and serves two tertiary paediatric cystic fibrosis (CF) centres (Staffordshire Children's...
BACKGROUND
The West Midlands Newborn Bloodspot Screening Laboratory is one of 16 in the UK and serves two tertiary paediatric cystic fibrosis (CF) centres (Staffordshire Children's Hospital at Royal Stoke and Birmingham Children's Hospital). CF newborn bloodspot screening (NBS) in this region started in November 2006 prior to the UK national roll-out in 2007. It uses an immunoreactive trypsinogen (IRT)/DNA/IRT protocol. We report the outcomes from 15 years of CF screening.
METHODS
The West Midlands CF NBS outcomes from 1 November 2006 to 31 October 2021 were reviewed. Clinical data were also obtained for babies referred to the CF centres as 'CF suspected'.
RESULTS
1 075 161 babies were screened, with 402 referred as 'CF suspected' and 205 identified as CF carriers. Of the 'CF suspected' babies, 268 were diagnosed with CF, 33 with CF screen positive, inconclusive diagnosis (CFSPID) and 17 as a CF carrier. Any CF-related diagnosis was excluded in 67. Outcome data were not available for 17, of whom 14 had died. Eighteen children with a negative CF NBS have subsequently been diagnosed with CF, 10 had meconium ileus and 8 were true 'affected not detected', presenting with respiratory symptoms or failure to thrive. This gives the West Midlands a CF birth prevalence of 1 in 4012 live births and the NBS protocol a sensitivity of 97.1% and a positive predictive value of 66.7%.
CONCLUSIONS
This large regional data set has excellent case ascertainment and demonstrates successful performance of the CF NBS protocol, with low numbers identified as CFSPID or CF carriers.
Topics: Infant; Infant, Newborn; Humans; Child; Cystic Fibrosis; Neonatal Screening; Genetic Testing; Cystic Fibrosis Transmembrane Conductance Regulator; Trypsinogen; United Kingdom
PubMed: 37973197
DOI: 10.1136/archdischild-2023-325955 -
BMJ Case Reports Dec 2023Cardiac tamponade is a rare but life-threatening complication of umbilical venous catheter (UVC) placement in neonates. Mortality rates are high; therefore, early...
Cardiac tamponade is a rare but life-threatening complication of umbilical venous catheter (UVC) placement in neonates. Mortality rates are high; therefore, early diagnosis is important. We present a case of a preterm infant with a UVC in situ who underwent a laparotomy on the first day of life for pneumoperitoneum secondary to meconium ileus. The operation was uneventful; however, 2 hours after surgery, the patient developed cardiac tamponade, requiring resuscitation and pericardiocentesis. In retrospect, near-infrared spectroscopy (NIRS) showed a gradual decline in cerebral oxygenation (crSO2) in the 30 min prior to the cardiac arrest, while other vital signs were within normal ranges. Our case demonstrates that cerebral NIRS monitoring can serve as an additional clinical marker for early recognition of impending cardiac tamponade.
Topics: Humans; Infant, Newborn; Cardiac Tamponade; Infant, Premature; Oxygen; Pericardiocentesis; Resuscitation; Spectroscopy, Near-Infrared
PubMed: 38087490
DOI: 10.1136/bcr-2023-256014 -
European Journal of Pediatric Surgery :... Oct 2023The gold standard for diagnosing Hirschsprung disease (HD) in patients younger than 6 months is pathological examination of rectal suction biopsy (RSB). The aim of...
BACKGROUND
The gold standard for diagnosing Hirschsprung disease (HD) in patients younger than 6 months is pathological examination of rectal suction biopsy (RSB). The aim of this study was to gain insight into the following: (1) complications following RSB, (2) final diagnosis of patients referred for RSB, and (3) factors associated with HD.
METHODS
Patients suspected of HD referred for RSB at our center were analyzed retrospectively. Severity of complications of RSB was assessed using Clavien-Dindo (CD) grading. Factors associated with HD were tested using multivariate logistic regression analysis.
RESULTS
From 2000 to 2021, 371 patients underwent RSB because of infrequent defecation, at a median age of 44 days. Three patients developed ongoing rectal bleeding (0.8%) graded CD1. Most frequent final diagnoses were: HD (n = 151, 40.7%), functional constipation (n = 113, 31%), idiopathic meconium ileus (n = 11, 3%), and food intolerance (n = 11, 3%). Associated factors for HD were male sex (odds ratio [OR], 3.19; confidence interval [CI], 1.56-6.53), presence of syndrome (OR, 7.18; CI, 1.63-31.69), younger age at time of RSB (OR, 0.98; CI, 0.85-0.98), meconium passage for more than 48 hours (OR, 3.15; CI, 1.51-6.56), distended abdomen (OR, 2.09; CI, 1.07-4.07), bilious vomiting (OR, 6.39; CI, 3.28-12.47), and failure to thrive (OR, 8.46; CI, 2.11-34.02) (model = 0.566).
CONCLUSION
RSB is a safe procedure with few and only minor complications. In the majority of patients referred for RSB under the age of 6 months, HD was found followed by a functional cause for the defecation problems. RSB should be obtained on a low threshold in all patients under the age of 6 months with the suspicion of HD.
Topics: Humans; Male; Child; Infant; Female; Hirschsprung Disease; Retrospective Studies; Suction; Incidence; Biopsy; Rectum; Abdomen
PubMed: 36724825
DOI: 10.1055/s-0043-1760839 -
Pediatric Pulmonology May 2024Cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs target the underlying defect and improve CFTR function. They are a part of standard care in...
INTRODUCTION
Cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs target the underlying defect and improve CFTR function. They are a part of standard care in many countries, but not all patients are eligible for these drugs due to age and genotype. Here, we aimed to determine the characteristics of non-eligible patients for CFTR modulators in the CF registry of Turkey (CFRT) to highlight their clinical needs.
METHODS
This retrospective cohort study included CF patient data from the CFRT in 2021. The decision of eligibility for the CFTR modulator was determined according to the 'Vertex treatment-Finder' on the Vertex® website. Demographic and clinical characteristics of patients were compared between eligible (group 1) and ineligible (group 2) groups for CFTR modulators.
RESULTS
Among the study population (N = 1527), 873 (57.2%) were in group 1 and 654 (42.8%) were in group 2. There was no statistical difference between groups regarding sex, meconium ileus history, diagnoses via newborn screening, FEV1 z-score, CF-associated complications, organ transplant history, and death. Patients in group 2 had a higher incidence of pancreatic insufficiency (87.7% vs. 83.2%, p = .010), lower median height z-scores (-0.87 vs. -0.55, p < .001), lower median body mass index z-scores (-0.65 vs. -0.50, p < .001), longer days receiving antibiotics due to pulmonary exacerbation (0 [interquartile range, IQR: 0-2] vs. 0 [IQR: 0-7], p = 0.001), and more non-invasive ventilation support (2.6% vs. 0.9%, p = 0.008) than patients in group 1.
CONCLUSION
The ineligible group had worse clinical outcomes than the eligible group. This highlights their need for life-changing drugs to improve clinical outcomes.
PubMed: 38771207
DOI: 10.1002/ppul.27051