Cdc42 coordinates proliferation, polarity, migration, and differentiation of small intestinal epithelial cells in mice.

BACKGROUND & AIMS: Cdc42 is a Rho GTPase that regulates diverse cellular functions, including proliferation, differentiation, migration, and polarity. In the intestinal epithelium, a balance among these events maintains homeostasis. We used genetic techniques to investigate the role of Cdc42 in intestinal homeostasis and its mechanisms. METHODS: We disrupted Cdc42 specifically in intestinal epithelial cells by creating Cdc42flox/flox-villin-Cre+ and Cdc42flox/flox-Rosa26-CreER+ mice. We collected intestinal and other tissues, and analyzed their cellular, molecular, morphologic, and physiologic features, compared with the respective heterozygous mice. RESULTS: In all mutant mice studied, the intestinal epithelium had gross hyperplasia, crypt enlargement, microvilli inclusion, and abnormal epithelial permeability. Cdc42 deficiency resulted in defective Paneth cell differentiation and localization without affecting the differentiation of other cell lineages. In mutant intestinal crypts, proliferating stem and progenitor cells increased, compared with control mice, resulting in increased crypt depth. Cdc42 deficiency increased migration of stem and progenitor cells along the villi, caused a mild defect in the apical junction orientation, and impaired intestinal epithelium polarity, which can contribute to the observed defective intestinal permeability. The intestinal epithelium of the Cdc42flox/flox-villin-Cre+ and Cdc42flox/flox-Rosa26-CreER+ mice appeared similar to that of patients with microvillus inclusion disease. In the digestive track, loss of Cdc42 also resulted in crypt hyperplasia in the colon, but not the stomach. CONCLUSIONS: Cdc42 regulates proliferation, polarity, migration, and differentiation of intestinal epithelial cells in mice and maintains intestine epithelial barrier and homeostasis. Defects in Cdc42 signaling could be associated with microvillus inclusion disease.

High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders.

BACKGROUND: Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease mediated by immune hypersensitization to multiple foods and strongly associated with atopy and esophageal remodeling. OBJECTIVE: We provide clinical and molecular evidence indicating a high prevalence of EoE in patients with inherited connective tissue disorders (CTDs). METHODS: We examined the rate of EoE among patients with CTDs and subsequently analyzed esophageal mRNA transcript profiles in patients with EoE with or without CTD features. RESULTS: We report a cohort of 42 patients with EoE with a CTD-like syndrome, representing 0.8% of patients with CTDs and 1.3% of patients with EoE within our hospital-wide electronic medical record database and our EoE research registry, respectively. An 8-fold risk of EoE in patients with CTDs (relative risk, 8.1; 95% confidence limit, 5.1-12.9; χ(2)1 = 112.0; P < 10(-3)) was present compared with the general population. Esophageal transcript profiling identified a distinct subset of genes, including COL8A2, in patients with EoE and CTDs. CONCLUSION: There is a remarkable association of EoE with CTDs and evidence for a differential expression of genes involved in connective tissue repair in this cohort. Thus, we propose stratification of patients with EoE and CTDs into a subset referred to as EoE-CTD.

Inequalities in neighborhood child asthma admission rates and underlying community characteristics in one US county.

OBJECTIVES: To characterize variation and inequalities in neighborhood child asthma admission rates and to identify associated community factors within one US county. STUDY DESIGN: This population-based prospective, observational cohort study consisted of 862 sequential child asthma admissions among 167 653 eligible children ages 1-16 years in Hamilton County, Ohio. Admissions occurred at a tertiary-care pediatric hospital and accounted for nearly 95% of in-county asthma admissions. Neighborhood admission rates were assessed by geocoding addresses to city- and county-defined neighborhoods. The 2010 US Census provided denominator data. Neighborhood admission distribution inequality was assessed by the use of Gini and Robin Hood indices. Associations between neighborhood rates and socioeconomic and environmental factors were assessed using ANOVA and linear regression. RESULTS: The county admission rate was 5.1 per 1000 children. Neighborhood rates varied significantly by quintile: 17.6, 7.7, 4.9, 2.2, and 0.2 admissions per 1000 children (P < .0001). Fifteen neighborhoods containing 8% of the population had zero admissions. The Gini index of 0.52 and Robin Hood index of 0.38 indicated significant inequality. Neighborhood-level educational attainment, car access, and population density best explained variation in neighborhood admission rates (R(2) = 0.55). CONCLUSION: In a single year, asthma admission rates varied 88-fold across neighborhood quintiles in one county; a reduction of the county-wide admission rate to that of the bottom quintile would decrease annual admissions from 862 to 34. A rate of zero was present in 15 neighborhoods, which is evidence of what may be attainable.

Low incidence of pathology detection and high cost of screening in the evaluation of asymptomatic short children.

OBJECTIVE: To determine the incidence of pathology during routine screening of healthy short children, testing adherence to a consensus statement on the diagnosis and treatment of children with idiopathic short stature, and the cost per identified diagnosis resulting from comprehensive screening. STUDY DESIGN: Retrospective chart review of 1373 consecutive short stature referrals evaluated at the Cincinnati Children's Hospital Medical Center Pediatric Endocrinology Clinic between 2008 and 2011. We identified 235 patients with a height of <3rd percentile, negative history and review of systems, and normal physical examination. Outcome measures were incidence of pathology detection, diagnostic group characteristics, clinicians' adherence to testing guidelines, and screening costs. ANOVA and χ(2) were used to analyze the data. RESULTS: Nearly 99% of patients were diagnosed as possible variants of normal growth: 23% with familial short stature, 41% with constitutional delay of growth and maturation, and 36% with idiopathic short stature. The incidence of newly diagnosed pathology was 1.3%: 1 patient with biopsy-proved celiac disease, 1 with unconfirmed celiac disease, and 1 with potential insulin-like growth factor I receptor defect. On average, each patient had 64.3% of the recommended tests for age and sex; 2.1% of patients had all of the recommended testing. The total screening tests costs were $315321, yielding $105107 per new diagnosis entertained. CONCLUSIONS: Healthy short children do not warrant nondirected, comprehensive screening. Future guidelines for evaluating short stature should include patient-specific testing.

Diffusion tensor imaging study of pediatric patients with congenital hydrocephalus: 1-year postsurgical outcomes.

OBJECTIVE The purpose of this study was to investigate white matter (WM) structural abnormalities using diffusion tensor imaging (DTI) in children with hydrocephalus before CSF diversionary surgery (including ventriculoperitoneal shunt insertion and endoscopic third ventriculostomy) and during the course of recovery after surgery in association with neuropsychological and behavioral outcome. METHODS This prospective study included 54 pediatric patients with congenital hydrocephalus (21 female, 33 male; age range 0.03-194.5 months) who underwent surgery and 64 normal controls (30 female, 34 male; age range 0.30-197.75 months). DTI and neurodevelopmental outcome data were collected once in the control group and 3 times (preoperatively and at 3 and 12 months postoperatively) in the patients with hydrocephalus. DTI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values were extracted from the genu of the corpus callosum (gCC) and the posterior limb of internal capsule (PLIC). Group analysis was performed first cross-sectionally to quantify DTI abnormalities at 3 time points by comparing the data obtained in the hydrocephalus group for each of the 3 time points to data obtained in the controls. Longitudinal comparisons were conducted pairwise between different time points in patients whose data were acquired at multiple time points. Neurodevelopmental data were collected and analyzed using the Adaptive Behavior Assessment System, Second Edition, and the Bayley Scales of Infant Development, Third Edition. Correlation analyses were performed between DTI and behavioral measures. RESULTS Significant DTI abnormalities were found in the hydrocephalus patients in both the gCC (lower FA and higher MD, AD, and RD) and the PLIC (higher FA, lower AD and RD) before surgery. The DTI measures in the gCC remained mostly abnormal at 3 and 12 months after surgery. The DTI abnormalities in the PLIC were significant in FA and AD at 3 months after surgery but did not persist when tested at 12 months after surgery. Significant longitudinal DTI changes in the patients with hydrocephalus were found in the gCC when findings at 3 and 12 months after surgery were compared. In the PLIC, trend-level longitudinal changes were observed between preoperative findings and 3-month postoperative findings, as well as between 3- and 12-month postoperative findings. Significant correlation between DTI and developmental outcome was found at all 3 time points. Notably, a significant correlation was found between DTI in the PLIC at 3 months after surgery and developmental outcome at 12 months after surgery. CONCLUSIONS The data showed significant WM abnormality based on DTI in both the gCC and the PLIC in patients with congenital hydrocephalus before surgery, and the abnormalities persisted in both the gCC and the PLIC at 3 months after surgery. The DTI values remained significantly abnormal in the gCC at 12 months after surgery. Longitudinal analysis showed signs of recovery in both WM structures between different time points. Combined with the significant correlation found between DTI and neuropsychological measures, the findings of this study suggest that DTI can serve as a sensitive imaging biomarker for underlying neuroanatomical changes and postsurgical developmental outcome and even as a predictor for future outcomes.

A comparative analysis of clinical operation system and continuing education of pediatricians between Chinese and American children's hospitals / 中华医学教育探索杂志

For provincial children's hospitals and children's hospitals affiliated to medical colleges and universities with a high level of the diagnosis and treatment,they are the center of referral and need to retain pediatricians and build a high-level team of pediatricians.With the authors' own experience in Cincinnati Children's Hospital Medical Center in the US,this article briefly introduces the current clinical operation mode in American children's hospitals,especially the consultation system mainly composed of attending physicians and the mode of continuing medical education based on both clinical and scientific research.Such experience provides a reference for pediatricians in China.

Prenatal and postnatal evaluation for syringomyelia in patients with spinal dysraphism.

OBJECT: Syringomyelia can be diagnosed in isolation but is more commonly found in the presence of craniocervical junction anomalies or spinal dysraphism. The origin of syringomyelia has been hypothesized to be either congenital or acquired. The purpose of this study was to determine the incidence of syringomyelia within the fetal and postnatal population with neural tube defects (NTDs). METHODS: A review was performed of the authors' fetal MRI database of pregnancies with imaging between March 2004 and November 2011 for evaluation of an intrauterine anomaly detected via prenatal ultrasonography. Those cases with an NTD were then selected and a chart review was performed of all prenatal and postnatal imaging as well as available clinical history. RESULTS: A total of 2362 fetal MRI examinations were performed, and 109 of these were patients with an NTD. Of the 2362 studies reviewed, 2 cases of fetal syringomyelia were identified. Both fetal syrinxes were identified in fetuses with CSF flow disturbances (1 case each of encephalocele and myelomeningocele). Both fetal MRI examinations were performed late in gestation, at 31 and 38 weeks, respectively. The patient with an encephalocele was excluded from the spinal NTD population; therefore a syrinx was identified in 0.08% (2/2362) of the entire population of fetuses who underwent MRI, or 0.9% (1/109) of fetuses with a spinal NTD. Sixty-three of the 109 patients with an NTD had postnatal clinical data available for review. Twenty-nine (46%) of 63 had a syrinx identified during the follow-up period. Of this group, 50 patients had an open NTD and 27 (54%) of 50 developed a syrinx. Among the patients with an open NTD who developed a syrinx, only 7% did not have or develop hydrocephalus, compared with 35% of the patients who did not develop a syrinx (p < 0.05). There were nonsignificantly more frequent shunt revisions among those patients who developed a syrinx, and a syrinx developed in all patients who required surgical Chiari malformation decompression or tethered cord release. The initial identification of a spinal cord syrinx varied greatly between patients, ranging from 38 weeks gestation to greater than 4 years of age. CONCLUSIONS: These data suggest that syringomyelia is not a congenital embryonic condition. A syrinx was not identified in fetuses who underwent imaging for other intrauterine anomalies. In the population of patients with NTDs who are known to be at high risk for developing syringomyelia, the pathology was only identified in 2 third-trimester fetuses or postnatally, typically in the presence of hydrocephalus, shunt placement, Chiari malformation decompression, or tethered cord release. The study supports the authors' hypothesis that a syrinx is an acquired lesion, most likely due to the effects of abnormal CSF flow.

Experiences and enlightment from visiting Medical Center of Cincinnati Children's Hospital / 中华医学教育探索杂志

This paper summarized the features of pediatrician training in Cincinnati Children's Hospital Medical Center ( CCHMC ) , introduced their cultivation and appraisal system , compared American pediatrician training with Chinese training and absorbed advanced medical training experi-ences. CCHMC focus on training specialized skill, team spirit and communication ability of residents. Internal assessment and two-way selection help to retain the best fellows. Learning from advanced ex-periences, we hoped to improve the current pediatrician training system and contributed to medical and health services.