Rachel Akers

Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis

Eosinophilic esophagitis (EE) is an emerging disorder with a poorly understood pathogenesis. In order to define disease mechanisms, we took an empirical approach analyzing esophageal tissue by a genome-wide microarray expression analysis. EE patients had a striking transcript signature involving 1% of the human genome that was remarkably conserved across sex, age, and allergic status and was distinct from that associated with non-EE chronic esophagitis. Notably, the gene encoding the eosinophil-specific chemoattractant eotaxin-3 (also known as CCL26) was the most highly induced gene in EE patients compared with its expression level in healthy individuals. Esophageal eotaxin-3 mRNA and protein levels strongly correlated with tissue eosinophilia and mastocytosis. Furthermore, a single-nucleotide polymorphism in the human eotaxin-3 gene was associated with disease susceptibility. Finally, mice deficient in the eotaxin receptor (also known as CCR3) were protected from experimental EE. These results implicate eotaxin-3 as a critical effector molecule for EE and provide insight into disease pathogenesis.

Interplay of adaptive th2 immunity with eotaxin-3/c-C chemokine receptor 3 in eosinophilic esophagitis.

Background: Pediatric eosinophilic esophagitis (EE) is a recently described disorder associated with atopy. Although studies of esophageal tissue suggest that Th2 cytokines and eotaxin-3 may be crucial in disease pathogenesis, little is known about the systemic immunological phenotypes of children with EE. Objectives: To define the phenotypes of peripheral blood eosinophils and lymphocytes in EE and to examine for correlations between these parameters and tissue eosinophil numbers and disease severity. Patients and Methods: Blood was collected from children with EE, atopic control children without EE, and nonatopic control children without EE. Flow cytometry was used to measure eosinophil expression of chemokine receptor 3 (CCR3) and interleukin-5 receptor-α (IL-5Rα), and intracellular lymphocyte expression of IL-4, IL-5, IL-13, interferon-γ, and tumor necrosis factor-α. Eosinophil numbers and eotaxin-3 mRNA levels were quantitated in esophageal biopsy specimens. Results: Compared with nonatopic control children, EE patients with active disease had increased peripheral blood eosinophil percentages, mean channel of fluorescence (MCF) of CCR3 on eosinophils, and percentage of CD4+ T cells expressing IL-5. Notably, these parameters positively correlated with esophageal eosinophil numbers. Eotaxin-3 tissue expression positively correlated with esophageal eosinophil numbers and peripheral blood eosinophil CCR3 MCF. The percentage of peripheral blood eosinophils, eosinophil CCR3 MCF, and CD4+ T cell expression of IL-5 were lower in EE patients in disease remission than in patients with active disease. Conclusions: Collectively, these studies demonstrate cooperation between systemic CD4+ Th2-cell–mediated immunity and an enhanced eosinophil-CCR3/eotaxin-3 pathway in EE pathogenesis. Furthermore, the imbalanced Th2 immunity and increased CCR3 expression are reversible with disease remission.

Use of the Autism Diagnostic Observation Schedule (ADOS) in a clinical setting

The aim of this study was to examine the Autism Diagnostic Observation Schedule (ADOS) as it is commonly used in clinical practice. ADOS classifications were compared to final diagnoses given by a multidisciplinary team to 584 children referred for evaluation for possible autism spectrum disorder (ASD) at the Cincinnati Children’s Hospital Medical Center. A total of 177 children were evaluated with a Module 1 (87 No Words), 198 with a Module 2 (90 < 5 years) and 209 with a Module 3. Of these, 142 (26%) were diagnosed with autism, 185 (32%) with non-autism ASD, and 257 (44%) with non-spectrum disorders. Sensitivities were moderate to high on both original and revised algorithms, while specificities were substantially lower than those previously reported. This difference is likely attributable to the composition of the sample that included many children with a broad array of developmental and behavioral disorders. The clinical impression of the team member who administered the ADOS was critical to the accuracy of the overall diagnosis. Using numeric scores alone resulted in misclassification from false positive results. The study highlights the importance of the qualitative interactions of the ADOS activities as well as the score in diagnostic decision making.

Fine Motor Function and Oral-Motor Imitation Skills in Preschool-Age Children With Speech-Sound Disorders

Preschool-aged children with speech-sound disorders may be at risk for associated deficits in fine motor function. The objectives of this study were 2-fold: (1) to determine whether abnormalities in fine motor function could be detected in 2- to 5-year-old children with speech-sound disorders and (2) to determine whether there was a correlation between abnormal oral-motor imitation skills and abnormal fine motor function. Thirty-two children with speech-sound disorders (6 female, 26 male) were prospectively evaluated from July 2003 to July 2005, and the Peabody Developmental Motor Scales and the Kaufman Speech Praxis Test for Children were administered. The presence of abnormal oral-motor imitation skills as measured by the Kaufman Speech Praxis Test was associated with below-average fine motor performance. This finding has important implications for evaluation and treatment of preschool children with severe speech-sound disorders.

The development of a research human milk bank.

Although there are well-established clinical human milk banks in the United States, there are no milk banks specifically intended to foster research on human milk. The authors’goalwas to establish a milk bank with a core data set to support exploratory and hypothesis-driven studies on human milk. Donations to the Cincinnati Children’s Research Human Milk Bank are accepted within the context of ongoing, hypothesis-driven research or on an ad hoc basis. Donors must give informed consent, and scientists wishing to use the samples must have Institutional review board approval for their use. Development of more research human milk banks can potentially provide resources for multidisciplinary collaboration and advance the study of human milk and lactation.

Results of the Sensory Profile in Children with Suspected Childhood Apraxia of Speech

Speech-sound disorders are common in preschool-age children, and are characterized by difficulty in the planning and production of speech sounds and their combination into words and sentences. The objective of this study was to review and compare the results of the Sensory Profile (12) in children with a specific type of speech-sound disorder, childhood apraxia of speech (CAS), and to explore the relationship between sensory processing and sound-production deficits. Participants were identified prospectively through an interdisciplinary apraxia clinic at a tertiary care pediatric hospital, and results of the Sensory Profile were compiled and reviewed. Thirty-eight children aged 3 to 10 years with suspected CAS were evaluated from July 2003 to July 2005. The results of the Sensory Profile indicated a difference for these children in several factor clusters when compared to typical peers from the normative population of the Sensory Profile. These findings imply that children with suspected CAS may present with differences in sensory processing in addition to speech impairment. When present, these differences in sensory processing could be addressed with specific therapeutic approaches through occupational therapy or consultation with an occupational therapist.

Evaluation of a Teleform-based data collection system: A multi-center obesity research case study

Utilizing electronic data capture (EDC) systems in data collection and management allows automated validation programs to preemptively identify and correct data errors. For our multi-center, prospective study we chose to use TeleForm, a paper-based data capture software that uses recognition technology to create case report forms (CRFs) with similar functionality to EDC, including custom scripts to identify entry errors. We quantified the accuracy of the optimized system through a data audit of CRFs and the study database, examining selected critical variables for all subjects in the study, as well as an audit of all variables for 25 randomly selected subjects. Overall we found 6.7 errors per 10,000 fields, with similar estimates for critical (6.9/10,000) and non-critical (6.5/10,000) variables-values that fall below the acceptable quality threshold of 50 errors per 10,000 established by the Society for Clinical Data Management. However, error rates were found to widely vary by type of data field, with the highest rate observed with open text fields.