Gastroesophageal reflux is not associated with dental erosion in children.

BACKGROUND & AIMS: Dental erosion is a complication of gastroesophageal reflux (GER) in adults; in children, it is not clear if GER has a role in dental pathologic conditions. Dietary intake, oral hygiene, high bacterial load, and decreased salivary flow might contribute independently to GER development or dental erosion, but their potential involvement in dental erosion from GER is not understood. We investigated the prevalence of dental erosion among children with and without GER symptoms, and whether salivary flow rate or bacterial load contribute to location-specific dental erosion. METHODS: We performed a cross-sectional study of 59 children (ages, 9-17 y) with symptoms of GER and 20 asymptomatic children (controls); all completed a questionnaire on dietary exposure. Permanent teeth were examined for erosion into dentin, erosion locations, and affected surfaces. The dentist was not aware of GER status, and the gastroenterologist was not aware of dental status. Stimulated salivary flow was measured and salivary bacterial load was calculated for total bacteria, Streptococcus mutans, and Lactobacilli. RESULTS: Controlling for age, dietary intake, and oral hygiene, there was no association between GER symptoms and dental erosion by tooth location or affected surface. Salivary flow did not correlate with GER symptoms or erosion. Erosion location and surface were independent of total bacteria and levels of Streptococcus mutans and Lactobacilli. CONCLUSIONS: Location-specific dental erosion is not associated with GER, salivary flow, or bacterial load. Prospective studies are required to determine the pathogenesis of GER-associated dental erosion and the relationship between dental caries to GER and dental erosion.

Pseudo gallbladder sign in biliary atresia--an imaging pitfall.

BACKGROUND: Ultrasound (US) is used to identify causes of neonatal cholestasis. We describe a potential sonographic pitfall, the "pseudo gallbladder," in biliary atresia (BA). OBJECTIVE: To describe the Pseudo Gallbladder sign (PsGB sign). MATERIALS AND METHODS: Sonograms/clinical records of 20 confirmed BA infants and 20 non-BA cases were reviewed retrospectively. For the BA group, preoperative sonography and surgical and pathological findings were examined. For the non-BA group, sonographic features and pathological findings were examined. The PsGB sign is defined as a fluid-filled structure, located in the expected region of the gallbladder, measuring ≤ 15 mm in length but without a well-defined or normal-appearing gallbladder wall. RESULTS: A recognizable gallbladder and normal gallbladder wall were present in all non-BA infants. However, none of the BA infants had a sonographically normal gallbladder. Seventy-three percent of BA patients had a PsGB, and in 27% no gallbladder or gallbladder-like structure was detected. CONCLUSION: A gallbladder-like structure in BA is common and can be misinterpreted as a normal gallbladder, delaying diagnosis and therapy. Recognition of this imaging pitfall, described here as the pseudo gallbladder sign, will help avoid this error.

Abnormal parathyroid cell proliferation precedes biochemical abnormalities in a mouse model of primary hyperparathyroidism.

The properties of neoplastic proliferation and hormonal dysregulation are tightly linked in primary hyperparathyroidism (HPT). However, whether abnormal parathyroid proliferation is the cause or result of a shift in calcium-sensitive parathyroid hormonal regulation has been controversial. We addressed this issue by analyzing the temporal sequence of these fundamental abnormalities in a mouse model of primary HPT. These transgenic mice (PTH-D1) harbor a transgene that targets overexpression of the cyclin D1 oncogene to parathyroid cells, resulting in parathyroid hypercellularity with a phenotype of chronic biochemical HPT and, notably, an abnormal in vivo PTH-calcium set point. We examined parathyroid cell proliferation and biochemical alterations in PTH-D1 and control wild-type mice from ages 1-14 months. Strikingly, abnormal parathyroid proliferation regularly preceded dysregulation of the calcium-PTH axis, supporting the concept that disturbed parathyroid proliferation is the crucial primary initiator leading to the development of the biochemical phenotype of HPT. Furthermore, we observed that decreased expression of the calcium-sensing receptor in the parathyroid glands occurs several months before development of biochemical HPT, suggesting that decreased calcium-sensing receptor may not be sufficient to cause PTH dysregulation in this animal model of primary HPT.

Molecular pathogenesis of primary hyperparathyroidism.

This article will primarily focus on the molecular pathogenesis of common, sporadic (nonfamilial) parathyroid adenomas; two genes currently have established roles in the development of these tumors. The cyclin D1/PRAD1 gene was identified as a clonally activated oncogene in parathyroid adenomas and has subsequently been established as a major contributor to human neoplasia. Overexpression of cyclin D1, a key regulator of the cell cycle, has been implicated in the pathogenesis of 20-40% of sporadic parathyroid adenomas. That such cyclin D1 overexpression indeed constitutes a stimulus to excessive parathyroid cell proliferation has been confirmed experimentally by the development of a transgenic mouse model with parathyroid-targeted overexpression of cyclin D1. Parathyroid hormone (PTH)-cyclin D1 transgenic mice develop parathyroid hypercellularity, biochemical hyperparathyroidism, and a shifted in vivo parathyroid-calcium setpoint; these mice constitute an animal model of human hyperparathyroidism in which aspects of tumorigenesis, parathyroid secretory setpoint control, and the pathophysiology of the chronic hyperparathyroid state can be further investigated. The MEN1 tumor suppressor is the only other gene to date with an established role in the pathogenesis of sporadic parathyroid adenomatosis. Specific clonal alterations involving somatic mutation and/or deletion of both MEN1 alleles have been demonstrated in about 15-20% of sporadic parathyroid adenomas. Allelic losses on 11q occur in roughly twice this number of adenomas, raising the still-unresolved possibility that an additional tumor suppressor gene on 11q may be the functional target of many of these acquired deletions. A mouse model of MEN1 deficiency causes a phenotype that includes parathyroid hypercellularity albeit unaccompanied by biochemical hyperparathyroidism, and additional mouse models in which menin deficiency is targeted to the parathyroids will likely provide additional important insights. The MEN1 gene product menin may have a role in transcriptional regulation involving JunD; several other menin-interacting proteins have also been identified. The in vivo mechanism of menin's actions, with special attention to its role as a parathyroid oncosuppressor, will be important to establish, as will the potential interrelationships between these pathways and those involving cyclin D1. A number of genes, put forth as candidate tumor suppressors based on their genomic locations, roles in familial disease, and/or other relevant biological functions, have been examined for pathogenetic mutations in sporadic parathyroid tumors with negative results; these include the calcium-sensing receptor protein (CaR), vitamin-D receptor (VDR), and RET. However, the CaR, which when partially or markedly deficient because of germline mutation can cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism, must still be considered as having a potentially important secondary role in the manifestations of sporadic parathyroid tumors. Future goals include identifying additional parathyroid oncogenes and tumor suppressor genes; exploiting tools of complex trait genetics to ascertain whether development of "sporadic" hyperparathyroidism might be influenced by predisposing polymorphic alleles in the population; obtaining molecular insights into the relationship between proliferative and hormone regulatory abnormalities of hyperparathyroidism; and obtaining molecular insights into the observed association of parathyroid neoplasia with exposure to ionizing irradiation and with the postmenopausal state.

Cystic fibrosis transmembrane conductance regulator knockout mice exhibit aberrant gastrointestinal microbiota.

The composition of the gastrointestinal microbiome is increasingly recognized as a crucial contributor to immune and metabolic homeostasis-deficiencies in which are characteristic of cystic fibrosis (CF) patients. The murine model (CFTR (-/-) , CF), has, in previous studies, demonstrated characteristic CF gastrointestinal (GI) manifestations including slowed transit and significant upregulation of genes associated with inflammation. To determine if characteristics of the microbiome are associated with these phenotypes we used a phylogenetic microarray to compare small intestine bacterial communities of wild type and congenic CF mice. Loss of functional CFTR is associated with significant decreases in GI bacterial community richness, evenness and diversity and reduced relative abundance of putative protective species such as Acinetobacter lwoffii and a multitude of Lactobacilliales members. CF mice exhibited significant enrichment of Mycobacteria species and Bacteroides fragilis, previously associated with GI infection and immunomodulation. Antibiotic administration to WT and CF animals resulted in convergence of their microbiome composition and significant increases in community diversity in CF mice. These communities were characterized by enrichment of members of the Lactobacillaceae and Bifidobacteriaceae and reduced abundance of Enterobacteriaceae and Clostridiaceae. These data suggest that Enterobacteria and Clostridia species, long associated with small intestinal overgrowth and inflammatory bowel disease, may suppress both ileal bacterial diversity and the particular species which maintain motility and immune homeostasis in this niche. Thus, these data provide the first indications that GI bacterial colonization is strongly impacted by the loss of functional CFTR and opens up avenues for alternative therapeutic approaches to improve CF disease management.