Search

Objectives: The prevalence of celiac disease (CeD) is increasing, yet it is still underdiagnosed, in part because of its heterogeneous presentation. Diagnostic criteria are evolving and management with strict adherence to a gluten-free diet is challenging for many. We aimed to characterize the clinical presentation of CeD among a large multicenter cohort of pediatric patients and to identify factors associated with gluten-free diet adherence., Methods: Patients with CeD aged 0-18 years were recruited from 11 United States health centers. Parents completed surveys about gluten-free diet adherence and patient electronic health records were reviewed. Logistic regression analyses were performed to identify risk factors associated with gluten exposure., Results: Charts were reviewed for 460 children with a median age of 6.4 years. Abdominal pain was reported in 57% of the cohort, but diverse symptoms were identified. Parent surveys were completed for 455 participants. Sixty-five (14%) participants were at high risk for gluten exposure based on parental reports of weekly or daily gluten exposure or eating gluten by choice in the past year. Participants under the age of 5 years had a lower risk of gluten exposure, while participants without repeat serology testing 18 months after initial diagnosis were at higher risk of gluten exposure., Conclusions: In a large, multicenter cohort of pediatric CeD patients, clinical presentation is highly variable, necessitating a high index of suspicion to make a diagnosis. Parent surveys indicate that 14% of patients are at high risk of gluten exposure, with patient age and lack of close follow-up associated with gluten-free diet adherence., (© 2024 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background & Aims: Celiac disease (CD) mass screening remains controversial in part because of a paucity of data to support its benefit. The Autoimmunity Screening for Kids study is a mass screening study for pediatric CD and type 1 diabetes in Colorado., Methods: This study prospectively follows up children ages 1 to 17 years who screened positive for tissue transglutaminase IgA autoantibodies in the Autoimmunity Screening for Kids study subsequently referred for diagnostic evaluation. Children diagnosed with CD by biopsy or serologic criteria were included in this study. Evaluation at baseline and 12 month follow-up evaluation included demographics, laboratory studies, symptoms, health-related quality of life, anxiety/depression, and gluten-free diet adherence. Paired Student t test, chi-square, and Wilcoxon sign rank tests compared baseline and follow-up data. For symptom scores, odds of improvement were assessed., Results: Of the 52 children with CD enrolled, 42 children completed 12-month follow-up evaluation. On the symptom questionnaire completed at diagnostic evaluation, 38 of 42 children reported 1 or more symptoms. CD mean symptom severity and frequency scores improved from baseline to follow-up evaluation (P < .001). Reported health-related quality of life scores improved among caregivers (P = .002). There was no significant change in reported anxiety or depression. Iron deficiency without anemia was common at baseline (21 of 24 children; 87.5%) and normalized at follow-up evaluation (11 of 21 children; 52.3%). Twenty-six of 28 families reported good or excellent gluten-free diet adherence., Conclusions: This novel study of children with CD identified through a mass screening program demonstrated improvement in symptoms, quality of life, and iron deficiency after 1 year follow-up evaluation. This demonstrates that there may be benefit to CD mass screening., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Food insecurity is a rising concern for US households and leads to adverse child health outcomes. Pediatric gastroenterology providers are uniquely equipped to help guide families experiencing this challenge given their specialized training in nutritional support and dietary therapy for disease management. Hence, this study aimed to evaluate food insecurity screening practices from the perspectives of patient caregivers and healthcare providers in a tertiary pediatric gastroenterology practice. A survey was administered to 1279 caregivers and 121 providers. Of the 248 completed caregiver responses, 10%-15% reported being asked about food insecurity. Among the 36 healthcare provider responses, 53% expressed comfort in conducting food insecurity screening but only 14% routinely screened. The most cited barrier to screening was the lack of readily available patient resources. Further research is imperative to address these screening barriers and assess the impact of food insecurity screening and interventions on pediatric gastrointestinal health outcomes., Competing Interests: M. G. S.: Consultant for Takeda (celiac disease advisory board) and Pfizer (DSMB for celiac disease clinical trial). E. L.: Consultant for Takeda Pharmaceuticals. The remaining authors declare no conflict of interest., (© 2024 The Authors. JPGN Reports published by Wiley Periodicals LLC on behalf of The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Patients with Trisomy 21 (T21) commonly have gastrointestinal symptoms and diseases that prompt evaluation with esophagogastroduodenoscopy (EGD). Our objective is to characterize duodenal histological abnormalities in these patients when undergoing EGD. A secondary aim is to explore associations of histologic findings with different therapies., Methods: Patients 30 years old or younger with T21 who underwent EGD from 2000 to 2020 at 6 hospitals were included in this retrospective cohort study. Duodenal biopsies were categorized based on reported histopathology findings as normal or abnormal. Abnormal pathology reports were reviewed and categorized into villous atrophy (VA) and duodenitis without VA. The VA group was further categorized based on the presence or absence of celiac disease (CD)., Results: We identified 836 patients with T21 who underwent EGD, 419 (50.1%) of whom had duodenal histologic abnormalities. At the time of the first (index) abnormal duodenal biopsy, 290 of 419 had VA and of those, 172 of 290 met CD diagnostic criteria, while 118 of 290 did not meet CD criteria (nonspecific VA). Among the patients with an abnormal biopsy, acid suppression at the time of the index biopsy was less common in patients with VA-CD compared to patients without VA or patients with nonspecific VA (12.2% vs 45.7% vs 44.9%)., Conclusions: Half of the T21 patients in this cohort had abnormal duodenal biopsies including a subgroup with nonspecific VA. In this cohort, acid suppression use was more prevalent in patients with abnormalities other than CD., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Mental health is a growing concern in pediatric celiac disease (CD). This study utilized the Revised Children's Anxiety and Depression Scale (RCADS) to investigate anxiety and depression symptom rates. Participants were children ages 8 to 17 years (M = 11.7, SD = 2.7; N = 175) with biopsy-proven CD (Median = 1.1 years post-diagnosis, IQR = 0-4) categorized into groups based on the child's age, caregiver or child respondent, presence or absence of comorbidities, and gluten-free diet duration. Self-reported RCADS scores showed 39% of children having clinically significant concerns for anxiety or depression ( P < 0.0001) but only 7% of caregiver-proxy RCADS scores indicated significant concerns for the child's anxiety and 14% for the child's depression. Rates of child-reported anxiety and depression symptoms were significantly higher for those without medical comorbidities than those with ( P = 0.04). Therefore, screening for mental health concerns, particularly anxiety and depression, should be routinely performed in pediatric patients with CD., Competing Interests: Edwin Liu is on the advisory board for Takeda Pharmaceuticals and I.M. Therapeutics. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Purpose: To evaluate the impact of celiac disease (CD) and the gluten-free diet (GFD) on the health-related quality of life (HRQoL) in children with CD in the United States using validated measures. We hypothesize that CD negatively impacts the child and caregivers' HRQoL., Methods: Participants included children with a confirmed diagnosis of CD and their caregivers (n = 246) seen in a CD multidisciplinary clinic. Caregivers completed the Pediatric Quality of Life (PedsQL) parent-proxy scale to report on their child's HRQoL and the Family Impact Module (FIM), which assesses the impact of caring for a child with a chronic illness. Their children completed the age-appropriate PedsQL. PedsQL and FIM results were compared to published data for children with gastroenterological conditions and a healthy cohort using non-parametric tests., Results: Children with CD reported significantly lower HRQoL than reports from healthy controls across all PedsQL domains (P < 0.001, Cohen d = 0.8), and lower compared to children with other organic gastrointestinal conditions in Social Functioning (P < 0.001, Cohen d = 0.5) and overall Psychosocial Functioning (P < 0.001, Cohen d = 0.3) domains. Results from the caregiver's report on their own HRQoL were significantly worse than that reported by historical controls in the domains of Communication (P < 0.001, Cohen d = 0.3) and Worry (P < 0.001, Cohen d = 0.8), yet similar on all other domains., Conclusions: In our population, CD is associated with low HRQoL scores for both children and their caregivers. Screening children and families for HRQoL can identify patients and families in need of additional support in this higher-risk population., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: To describe quality improvement efforts to reduce variability in the care of children diagnosed with celiac disease through use of an institutional patient registry and a chronic care index., Study Design: An institutional patient registry tracked rates of follow-up visits and repeat serologic testing. A Celiac Care Index that included anthropometrics, biopsy expectations, dietician consultation, and baseline laboratory evaluation was developed to standardize evaluation at diagnosis. Provider education sessions communicated expectations for this standard of care and order sets within the electronic medical record simplified test collection. Data was recorded and reviewed weekly and structured communications with providers were provided biweekly., Results: Adherence with follow-up expectations (77%-89% P = .03) and repeat serologic testing (50%-90% P < .0001) significantly increased during the study period. Adherence with completion of the Celiac Care Index resulted in significant improvement in obtaining complete blood count (80%-98% P < .0001), iron (25%-78% P < .0001), ferritin (34%-80% P < .0001), alanine aminotransferase/aspartate aminotransferase (74%-96% P < .0001), thyroid-stimulating hormone (64%-90% P < .0001), vitamin D (36%-83% P < .0001), and hepatitis B immune status (30%-80% P < .0001). Iron deficiency demonstrated by low ferritin levels was common (41%) and a high rate of nonimmunity to hepatitis B (70%) was detected., Conclusions: The Celiac Care Index improved adherence with published care recommendations and reduced variability in baseline evaluation at diagnosis. Laboratory test results indicate further studies are needed to evaluate these recommendations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: We determined complications in infants undergoing voiding cystourethrography as part of the evaluation for prenatally detected hydronephrosis., Materials and Methods: We retrospectively reviewed the records of infants referred to our institution for the evaluation of prenatal hydronephrosis from 1992 to 1997. Infants with a prenatal history of bilateral hydronephrosis, bladder distention and oligohydramnios, oligohydramnios only or a prenatal abnormality involving any other organ system were excluded from study. Of 206 patients 129 male and 49 female infants underwent postnatal voiding cystourethrography at our institution. Chart review and a telephone interview with the parents were done to assess lower urinary tract infection, pyelonephritis, hospital admission for urosepsis, gross hematuria, urinary retention or skin rash., Results: Postnatal voiding cystourethrography was normal in 138 patients but it diagnosed bilateral vesicoureteral reflux in 15, unilateral vesicoureteral reflux in 20, ureterocele in 4 and refluxing megaureter in 1. Of the 129 male infants evaluated 101 had undergone circumcision as a newborn, 14 were uncircumcised and the circumcision status of 14 was unknown. At voiding cystourethrography suppressive antibiotics were administered to 166 infants, 7 were not on suppressive antibiotics and antibiotic status was unknown in 5. No patient had a lower urinary tract infection, pyelonephritis or urosepsis. In addition, there were no episodes of urinary retention, gross hematuria or skin rash., Conclusions: While the reported rate of new or recurrent infection associated with voiding cystourethrography is as high as 6%, we did not identify any infectious or other complications in infants undergoing voiding cystourethrography for prenatal hydronephrosis. When properly performed, we believe that voiding cystourethrography is safe and presents little risk in these patients.

Expression patterns of TGF-beta s during embryogenesis and in adult reproductive organs, as well as the activities of these molecules in in vitro assays of biological processes relating to reproduction and development, have suggested that TGF-beta s may play a role in both reproductive function and embryonic development. To investigate the function of TGF-beta 1 in vivo, the murine TGF-beta 1 gene was disrupted by gene targeting, and animals that lacked TGF-beta 1 activity were generated. Homozygous mutant animals were obtained which exhibited a multifocal inflammatory disease. However, the observed numbers of homozygous mutant offspring were less than expected, suggesting the occurrence of some type of prenatal lethality. This paper reviews the proposed role of the TGF-beta s in reproductive and developmental processes and discusses observations obtained from the TGF-beta 1 gene-targeting experiments as they relate to these processes.

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional growth factor that has profound regulatory effects on many developmental and physiological processes. Disruption of the TGF-beta 1 gene by homologous recombination in murine embryonic stem cells enables mice to be generated that carry the disrupted allele. Animals homozygous for the mutated TGF-beta 1 allele show no gross developmental abnormalities, but about 20 days after birth they succumb to a wasting syndrome accompanied by a multifocal, mixed inflammatory cell response and tissue necrosis, leading to organ failure and death. TGF-beta 1-deficient mice may be valuable models for human immune and inflammatory disorders, including autoimmune diseases, transplant rejection and graft versus host reactions.

Objectives: To determine whether the alpha 2 and or beta 1 isoforms of the Na+,K(+)-adenosine triphosphatase (Na+,K(+)-ATPase) are involved in the pathogenesis of essential hypertension., Design: Segregation analysis of polymorphic DNA markers was used to test the involvement of Na+,K(+)-ATPase in essential hypertension., Participants: Children with persistent hypertension having one parent with essential hypertension were included in the study. Criteria for persistent hypertension were blood pressure readings with systolic and/or diastolic levels exceeding the 95th percentile based upon age and sex. The diagnosis of hypertension for adults, including parents and older siblings, was confirmed using criteria recommended in the 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure., Results: In three essential hypertensive families consisting of 18 members including 11 hypertensives, several obligate recombinants between the Na+,K(+)-ATPase alpha 2 isoform marker and the hypertension phenotype were observed. Similarly, in one hypertension family consisting of four members, obligate recombinants between the beta 1 isoform marker and the disease were observed., Conclusions: The discordant segregation of the alpha 2 and beta 1 isoform markers and essential hypertension suggests that neither the Na+,K(+)-ATPase alpha 2 nor beta 1 isoform genes play a primary role in the pathogenesis of hypertension in the families studied.

We have determined the sequence of the 5'-flanking region and first three exons of the human Na,K-ATPase alpha 1 gene, ATP1A1. Primer extension and S1 nuclease protection analyses of RNA from human kidney, brain, and skeletal muscle indicate that transcription initiates 273 nucleotides upstream of the translation start site. The promoter region contains a potential TATA box at position -27 relative to the transcription initiation site; however, no CCAAT sequence is observed. The 5'-untranslated and 5'-flanking regions are G + C rich. Five sequence elements exhibiting similarity to binding sites for the transcription factor Sp1 are located within the 5'-flanking region. This region also contains potential binding sites for the transcription factors AP-1, AP-2, AP-3, and NF-1, as well as a site which exhibits perfect identity to an 8-bp sequence element important for calcium induction. A comparison of the 5'-flanking region of the alpha 1 and alpha 2 genes reveals differences in potential transcription factor and hormone receptor binding sites which may be important in mediating the tissue- and developmental stage-specific expression of these genes. We have also identified an intragenic DNA probe which detects a restriction fragment length polymorphism at the alpha 1 locus. This marker should facilitate genetic linkage studies designed to evaluate the role of the sodium pump in human disease.

Researchers in the past few years have successfully used molecular-genetic approaches to determine the primary structures of several P-type ATPases. The amino-acid sequences of distinct members of this class of ion-transport ATPases (Na,K-, H,K-, and Ca-ATPases) have been deduced by cDNA cloning and sequencing. The Na,K-ATPase belongs to a multiple gene family, the principal diversity apparently resulting from distinct catalytic alpha isoforms. Computer analyses of the hydrophobicity and potential secondary structure of the alpha subunits and primary sequence comparisons with homologs from various species as well as other P-type ATPases have identified common structural features. This has provided the molecular foundation for the design of models and hypotheses aimed at understanding the relationship between structure and function. Development of a hypothetical transmembrane organization for the alpha subunit and application of site-specific mutagenesis techniques have allowed significant progress to be made toward identifying amino acids involved in cardiac glycoside resistance and possibly binding. However, the complex structural and functional features of this protein indicate that extensive research is necessary before a clear understanding of the molecular basis of active cation transport is achieved. This is complicated further by the paucity of information regarding the structural and functional contributions of the beta subunit. Until such information is obtained, the proposed model and functional hypotheses should be considered judiciously. Considerable progress also has been made in characterizing the regulatory complexity involved in expression of multiple alpha-isoform and beta-subunit genes in various tissues and cells during development and in response to hormones and cations. The regulatory mechanisms appear to function at several molecular levels, involving transcriptional, posttranscriptional, translational, and posttranslational processes in a tissue- or cell-specific manner. However, much research is needed to precisely define the contributions of each of these mechanisms. Recent isolation of the genes for these subunits provides the framework for future advances in this area. Continued application of biochemical, biophysical, and molecular genetic techniques is required to provide a detailed understanding of the mechanisms involved in cation transport of this biologically and pharmacologically important enzyme.

The growth velocities (weight and length) of vegetarian preschool children were compared to norms established from the Harvard growth study. At first measurement vegetarian subjects weighed less and were shorter than expected from Harvard standards. Growth velocities of children under 2 years of age were depressed, while among those over the age of 2 growth velocities were generally comparable to Harvard norms. Vegetarian boys over age 2 exhibited a higher mean weight velocity. Macrobiotics' mean weight and length velocities were not significantly different from those of nonmacrobiotics before age 2. However, the mean weight velocity of macrobiotics over age 2 was significantly greater than the mean weight velocity of nonmacrobiotics over 2 years. Low growth velocities of vegetarian children are more apparent in infants under the age of 2. When breast-feeding, possibly inadequate supplemental feeding may be present past 6 months of age. Since it is then that the velocities are more likely to be depressed, this may be the most appropriate time for surveillance and possible intervention.

We have determined the structure of the gene that encodes the alpha 2 isoform of the human Na,K-ATPase. The gene contains 23 exons and spans approximately 25 kilobases. The amino acid sequence of the human alpha 2 isoform deduced from the genomic sequence exhibits 99% identity to the rat alpha 2 isoform. One of the nine amino acid differences between the human and rat sequences occurs at an amino acid position which is known to be involved in species differences in sensitivity of the alpha 1 isoform to cardiac glycosides. Approximately 1500 base pairs of sequence flanking the 5' end of the alpha 2 gene have been determined. This region contains numerous potential AP-1, AP-2, and NF-1-binding sites, a potential Sp1 recognition site, and several sequences that are similar to the glucocorticoid receptor-binding site. The transcription start site was mapped by primer extension and S1 nuclease protection analyses of RNA from human brain, skeletal muscle, and heart. Multiple transcription initiation sites are clustered between residues -104 to -99 relative to the translation initiation codon. A potential TATA box is located 29 base pairs upstream of the first transcription initiation site. Immediately 5' to the apparent TATA box is a 35-base pair polypurine.polypyrimidine tract containing an imperfect mirror repeat which resembles sequences that form triple-stranded structures. Two intragenic DNA probes which detect restriction fragment length polymorphisms associated with the alpha 2 gene have been identified. These probes will be useful in genetic linkage analyses designed to define the possible role of the Na,K-ATPase in certain hereditary disorders.

Retinoblastoma is a childhood cancer, predisposition to which is inherited as an autosomal dominant trait. We used restriction-fragment-length and isozymic alleles of loci on chromosome 13 in five families predisposed to retinoblastoma, to provide identification before illness of persons likely to have tumors. The likelihood of disease was predicted in two cases, and freedom from disease in three. The calculated predictive accuracy was greater than 94 percent in cases with informative loci flanking the retinoblastoma (RB1) locus, and our prediction has been fulfilled in each such instance. A case that was informative at several loci indicated the occurrence of meiotic recombination, and accurate prediction was based on data obtained with DNA markers and isozymic forms of esterase D. The calculated predictive accuracy in another case, which was informative only for loci distal to the retinoblastoma locus, was about 70 percent. This patient was expected to acquire the disease but had not done so at the age of one year, illustrating the need for more markers that are also more informative and genetically closer to the retinoblastoma locus. These studies provide the basis for prenatal and postnatal prediction of susceptibility to inherited cancer using arbitrary recombinant DNA markers. Such predictions should make genetic counseling for familial retinoblastoma more accurate and lead to earlier tumor detection and more effective therapy.

A total of 29 human genomic DNA clones that hybridize with cDNAs for the sheep and rat Na,K-ATPase beta subunits have been isolated, classified by restriction endonuclease mapping and Southern blot hybridization analysis, and sequenced. One class of clones, designated ATP1BL1, represents a processed pseudogene for the beta subunit. The second class, designated ATP1B, includes 15 overlapping genomic clones and represents a functional gene for the human Na,K-ATPase beta subunit. ATP1B spans about 26.7 kb of genomic DNA and includes 24 kb of intron sequence. The complete mRNA transcript for the human beta subunit is encoded by six exons, ranging in size from 81 to 1427 bp. Primer extension and S1 nuclease protection experiments with human kidney RNA indicate the presence of two major transcription initiation sites at -510 and -201 to -191, with minor initiation sites at -268, -182 to -174, and -142. The distal initiation site at -510 is preceded by consensus sequences for CAAT and TATA boxes. The DNA sequence preceding the proximal heterogeneous initiation sites contains a CAAT box, but no TATA box. Two of the 12 GC boxes (GGCGGG and CCCGCC) located in the 5' region of ATP1B are located between this CAAT box and the proximal clusters of transcription initiation sites.

Na+, K+-ATPase is a heterodimeric enzyme responsible for the active maintenance of sodium and potassium gradients across the plasma membrane. Recently, cDNAs for several tissue-specific isoforms of the larger catalytic alpha-subunit and the smaller beta-subunit have been cloned. We have hybridized rat brain and human kidney cDNA probes, as well as human genomic isoform-specific DNA fragments, to Southern filters containing panels of rodent X human somatic cell hybrid lines. The results obtained have allowed us to assign the loci for the ubiquitously expressed alpha-chain (ATP1A1) to human chromosome 1, region 1p21----cen, and for the alpha 2 isoform that predominates in neural and muscle tissues (ATP1A2) to chromosome 1, region cen----q32. A common PstI RFLP was detected with the ATP1A2 probe. The alpha 3 gene, which is expressed primarily in neural tissues (ATP1A3), was assigned to human chromosome 19. A fourth alpha gene of unknown function (alpha D) that was isolated by molecular cloning (ATP1AL1) was mapped to chromosome 13. Although evidence to date had suggested a single gene for the beta-subunit, we found hybridizing restriction fragments derived from two different human chromosomes. On the basis of knowledge of conserved linkage groups on human and murine chromosomes, we propose that the coding gene ATP 1B is located on the long arm of human chromosome 1 and that the sequence on human chromosome 4 (ATP 1BL1) is either a related gene or a pseudogene.

The use of genetic tools has been invaluable for examining the potential number of alpha and beta subunits of the Na,K-ATPase. To date at least five genes corresponding to the alpha subunit have been described. Two of these encode the alpha and alpha+ isoforms while the third encodes the novel alpha III subunit. The products of the other two genes have not yet been described; these genes may be pseudogenes or may encode new alpha isoforms or related transport ATPases. The determination of the tissue distribution of the various isoforms of the alpha subunit using Northern blot and slot blot analyses has yielded several interesting findings. Each tissue differs in the abundance and combination of isoforms. While alpha is the major isoform mRNA in kidney, alpha+ mRNA predominates in skeletal muscle. All three alpha subunit mRNAs are present in brain in roughly equal amounts. The newly discovered alpha III isoform mRNA is found not only in brain but in low amounts in stomach and lung. It is possible that individual cell types may contain a defined combination of isoforms which allow the Na,K-ATPase to fulfill its specific physiological role in those cells. It will be interesting to compare the functional properties, i.e., affinity for Na+ and K+, turnover number, response to external changes in environment and response to effector molecules for the enzymes containing each of the alpha subunit isoforms.