Ajay Kaul

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management

Duchenne muscular dystrophy (DMD) is a severe, progressive disease that affects 1 in 3600-6000 live male births. Although guidelines are available for various aspects of DMD, comprehensive clinical care recommendations do not exist. The US Centers for Disease Control and Prevention selected 84 clinicians to develop care recommendations using the RAND Corporation-University of California Los Angeles Appropriateness Method. The DMD Care Considerations Working Group evaluated assessments and interventions used in the management of diagnostics, gastroenterology and nutrition, rehabilitation, and neuromuscular, psychosocial, cardiovascular, respiratory, orthopaedic, and surgical aspects of DMD. These recommendations, presented in two parts, are intended for the wide range of practitioners who care for individuals with DMD. They provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care. In part 1 of this Review, we describe the methods used to generate the recommendations, and the overall perspective on care, pharmacological treatment, and psychosocial management.

Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care

Optimum management of Duchenne muscular dystrophy (DMD) requires a multidisciplinary approach that focuses on anticipatory and preventive measures as well as active interventions to address the primary and secondary aspects of the disorder. Implementing comprehensive management strategies can favourably alter the natural history of the disease and improve function, quality of life, and longevity. Standardised care can also facilitate planning for multicentre trials and help with the identification of areas in which care can be improved. Here, we present a comprehensive set of DMD care recommendations for management of rehabilitation, orthopaedic, respiratory, cardiovascular, gastroenterology/nutrition, and pain issues, as well as general surgical and emergency-room precautions. Together with part 1 of this Review, which focuses on diagnosis, pharmacological treatment, and psychosocial care, these recommendations allow diagnosis and management to occur in a coordinated multidisciplinary fashion.

Gastrointestinal Microflora Studies in Late-Onset Autism

Some cases of late-onset (regressive) autism may involve abnormal flora because oral vancomycin, which is poorly absorbed, may lead to significant improvement in these children. Fecal flora of children with regressive autism was compared with that of control children, and clostridial counts were higher. The number of clostridial species found in the stools of children with autism was greater than in the stools of control children. Children with autism had 9 species of Clostridium not found in controls, whereas controls yielded only 3 species not found in children with autism. In all, there were 25 different clostridial species found. In gastric and duodenal specimens, the most striking finding was total absence of non-spore-forming anaerobes and microaerophilic bacteria from control children and significant numbers of such bacteria from children with autism. These studies demonstrate significant alterations in the upper and lower intestinal flora of children with late-onset autism and may provide insights into the nature of this disorder.

Coordinate Interaction between IL-13 and Epithelial Differentiation Cluster Genes in Eosinophilic Esophagitis

We have previously proposed that the pathogenesis of eosinophilic esophagitis (EE) is mediated by an IL-13–driven epithelial cell response associated with marked gene dysregulation including eotaxin-3 overproduction. In this study, we compared epithelial responses between healthy patients and those with EE, aiming to uncover molecular explanations for EE pathogenesis. Esophageal epithelial cells could be maintained for up to five passages, with 67% and 62% of cell lines reaching confluence in healthy controls and EE cases, respectively. Both sets of epithelial cells avidly responded to IL-13 at similar levels as assessed by eotaxin-3 production. Acidic pH increased cellular release of eotaxin-3 (4.6 ± 1.98 ng/ml versus 12.46 ± 2.90 ng/ml at pH 7.4 and 4, respectively; p < 0.05). Numerous epidermal differentiation complex (EDC) genes, such as filaggrin and SPRR3, were downregulated both in IL-13–stimulated esophageal epithelial cells and in EE biopsies specimens compared with healthy controls. Whereas the filaggrin loss of function mutation 2282del4 was overrepresented in EE compared with control individuals (6.1% versus 1.3% respectively; p = 0.0172), the decreased filaggrin expression was uniformly seen in all EE cases in vivo. Indeed, expression of the EDC genes filaggrin and involucrin was strongly decreased directly by IL-13. These results establish that the epithelial response in EE involves a cooperative interaction between IL-13 and expression of EDC genes.

A striking local esophageal cytokine expression profile in eosinophilic esophagitis.

BACKGROUND Eosinophilic esophagitis (EE) is an emerging worldwide disease that mimics gastroesophageal reflux disease. OBJECTIVE Early studies have suggested that esophageal eosinophilia occurs in association with T(H)2 allergic responses, yet the local and systemic expression of relevant cytokines has not been well characterized. METHODS A human inflammatory cytokine and receptor PCR array containing 84 genes followed by PCR validation and multiplex arrays were used to quantify cytokine mRNA in esophageal biopsies and blood samples. RESULTS Esophageal transcripts of numerous chemokines (eg, chemokine [C-C motif] ligand [CCL] 1, CCL1, CCL23, CCL26 [eotaxin-3], chemokine [C-X-C motif] ligand [CXCL] 1, and CXCL2), cytokines (eg, IL13 and ATP-binding cassette, subfamily F, member 1), and cytokine receptors (eg, IL5 receptor, alpha) were induced at least 4-fold in individuals with EE. Analysis of esophageal biopsies (n = 288) revealed that eotaxin-3 mRNA level alone had 89% sensitivity for distinguishing individuals with and without EE. The presence of allergy was associated with significantly increased esophageal expression of IL4 and IL5 mRNA in patients with active EE. We identified 8 cytokines (IL-4, IL-13, IL-5, IL-6, IL-12p70, CD40 ligand, IL-1α, and IL-17) whose blood levels retrospectively distinguished 12 patients without EE from 13 patients with EE with 100% specificity and 100% sensitivity. When applied to a blind, prospectively recruited group of 36 patients, the cytokine panel scoring system had a 79% positive predictive value, 68% negative predictive value, 61% sensitivity, and 83% specificity for identifying EE. CONCLUSION Evidence is presented that IL13 and IL5 associate with eosinophil and eotaxin-3 levels, indicating the key role of adaptive T(H)2 immunity in regulating eotaxin-3-driven esophageal eosinophilia in the absence of a consistent systemic change in cytokines.

Molecular diagnosis of eosinophilic esophagitis by gene expression profiling.

BACKGROUND & AIMS Gene expression profiling provides an opportunity for definitive diagnosis but has not yet been well applied to inflammatory diseases. Here we describe an approach for diagnosis of an emerging form of esophagitis, eosinophilic esophagitis (EoE), which is currently diagnosed by histology and clinical symptoms. METHODS We developed an EoE diagnostic panel (EDP) comprising a 96-gene quantitative polymerase chain reaction array and an associated dual-algorithm that uses cluster analysis and dimensionality reduction using a cohort of randomly selected esophageal biopsy samples from pediatric patients with EoE (n = 15) or without EoE (non-EoE controls, n = 14) and subsequently vetted the EDP using a separate cohort of 194 pediatric and adult patient samples derived from both fresh or formalin-fixed, paraffin-embedded tissue: active EoE (n = 91), control (non-EoE and EoE remission, n = 57), histologically ambiguous (n = 34), and reflux (n = 12) samples. RESULTS The EDP identified adult and pediatric patients with EoE with approximately 96% sensitivity and approximately 98% specificity, and distinguished patients with EoE in remission from controls, as well as identified patients exposed to swallowed glucorticoids. The EDP could be used with formalin-fixed, paraffin-embedded tissue RNA and distinguished patients with EoE from those with reflux esophagitis, identified by pH-impedance testing. Preliminary evidence showed that the EDP could identify patients likely to have disease relapse after treatment. CONCLUSIONS We developed a molecular diagnostic test (referred to as the EDP) that identifies patients with esophagitis in a fast, objective, and mechanistic manner, offering an opportunity to improve diagnosis and treatment, and a platform approach for other inflammatory diseases.

Gastrointestinal Conditions in Children With Autism Spectrum Disorder: Developing a Research Agenda

* Abbreviations: ASD — : autism spectrum disorder GI — : gastrointestinal 5-HT — : serotonin Autism spectrum disorders (ASDs) are a set of complex neurodevelopmental disorders defined behaviorally by impaired social interaction, delayed and disordered language, repetitive or stereotypic behavior, and a restricted range of interests. ASDs represent a significant public health issue with recent estimates indicating that as many as 1% of children in the United States are diagnosed with an ASD.1,2 Many individuals with ASDs have symptoms of associated medical conditions, including seizures, sleep problems, metabolic conditions, and gastrointestinal (GI) disorders, which have significant health, developmental, social, and educational impacts. Gastrointestinal complaints are a commonly reported concern for parents and may be related to problem behaviors and other medical issues such as dysregulated sleep (ATN Annual Registry Report, unpublished data, November 2009).3 Despite the magnitude of these issues, potential GI problems are not routinely considered in ASD evaluations. This likely reflects several factors, including variability in reported rates of GI disorders, controversies regarding the relationship between GI symptoms and the putative causes of autism, the limited verbal capacity of many ASD patients, and the lack of recognition by clinicians that certain behavioral manifestations in children with ASDs are indicators of GI problems (eg, pain, discomfort, or nausea).4–10 Whether GI issues in this population are directly related to the pathophysiology of autism, or are strictly a comorbid condition of ASD remains to be determined, but clinical practice and research to date indicate the important role of GI conditions in ASDs and their impact on children as well as their parents and clinicians.9 On November 15, 2009, a symposium addressing these issues was organized as an adjunct to the annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. A … Address correspondence to Daniel L. Coury, MD, Professor of Pediatrics and Psychiatry, The Ohio State University, Chief, Developmental & Behavioral Pediatrics, Nationwide Childrens Hospital, 700 Childrens Dr, Timken G-350, Columbus OH 43205-2696

A multicomponent behavioral program for oral aversion in children dependent on gastrostomy feedings

Objectives Describe outcomes in nine children with Nissen fundoplication and feeding gastrostomy treated in a multicomponent feeding program. The importance of comprehensive evaluation, appetite regulation, and family-focused intervention within a behavioral feeding program are discussed. Methods Prospective clinical intervention with dependent measures evaluated before treatment, after treatment, and at follow-up. Results Nine children (4 girls; mean age, 3.1 ± 1.2 years; range, 1.8–5.5 years) and their mothers were admitted for intensive treatment (mean duration, 11.4 ± 1.7 days; range, 5–16 days). At discharge, 4 of 9 (44%) children were weaned completely from gastrostomy feedings. The mean oral intake of all patients increased 50% from pretreatment to posttreatment assessment. At a mean of 3.1 ± 0.5 months (range, 2.4–3.6 months) after treatment, six of nine children were weaned completely from gastrostomy feedings. The percent of daily nutritional needs consumed orally increased from a pretreatment mean of 14.6% ± 21.2% (range, 0%–67%) to a posttreatment mean of 63.4% ± 18.3% (range, 34%–85%) and a follow-up mean of 88.1% ± 25.1% (range, 30%–100%). The mean percent ideal body weight for height was not compromised during intensive treatment. Conclusions Short-term intensive biobehavioral treatment was successful in improving oral intake and weaning from gastrostomy tube feeding in children with Nissen fundoplication and feeding gastrostomy.

Eosinophilic Esophagitis in Infants and Toddlers

Feeding refusal is often described in conjunction with the diagnosis of eosinophilic esophagitis (EE) in pediatric patients; however, there are little data regarding the specific clinical manifestations and effective management of this condition in very young children. The aim of this study was to evaluate the presentation of EE in infants and toddlers referred to the Interdisciplinary Feeding Team Clinic of a tertiary referral center and to document responses to treatment. Database matching was performed (from January 2000 to June 2003) to identify infants and toddlers diagnosed with EE who had been referred to the Interdisciplinary Feeding Team Clinic. Endoscopic features required for a diagnosis of EE included esophageal mucosal furrowing, erythema, exudates, or decreased vascular markings. Histologic features of EE were more than 24 eosinophils per high-power field (HPF), thickening of basal cell layer, and papillary (rete peg) lengthening or elongation. All study patients were treated with a combination of proton pump inhibitors (PPI) and fluticasone (swallowed). In addition, elemental diet was instituted in those documented to have a food allergy. Treatment success was defined by an improved oral intake, adequate weight gain, and improved endoscopic and histologic findings at 3–6-month followup. A total of 15 subjects [mean age = 19.9 months (SD = 9.7 months)] who fulfilled the entry criteria during the study period were identified. All 15 children had documented endoscopic improvement and 14/15 children had histologic resolution of EE after therapy. In 13 of the 15 children, this translated to clinical improvement as well.

Glucocorticoid-regulated genes in eosinophilic esophagitis: A role for FKBP51

BACKGROUND Eosinophilic esophagitis (EE) involves marked accumulation of eosinophils in the esophageal mucosa that responds to swallowed fluticasone propionate (FP) in a subset of patients. OBJECTIVES We aimed to uncover the mechanism of action of swallowed FP in patients with EE by providing evidence for a topical effect in the esophagus by identifying a molecular signature for FP exposure in vivo. METHODS Global microarray expression profiles, immunofluorescence microscopy, and cell signaling in esophageal tissue and cell lines were analyzed. RESULTS Thirty-two transcripts exhibited altered expression in patients who responded to swallowed FP treatment. Esophageal FK506-binding protein 5 (FKBP51) mRNA levels were increased (P < .05) in FP responders compared with those seen in control subjects and patients with untreated active EE. After FP treatment of esophageal epithelial cells, FKBP51 mRNA and protein levels were increased in a dose- and time-dependent manner by FP treatment in vitro. FP-induced FKBP51 was steroid receptor dependent because RU486 completely inhibited gene and protein induction. The half-life of FKBP51 mRNA was 16 to 18 hours independent of FP treatment. FKBP51 overexpression reduced FP action as assessed by FP inhibition of IL-13-induced eotaxin-3 promoter activity. CONCLUSIONS Our results suggest that swallowed glucocorticoid treatment directly affects esophageal gene expression in patients with EE. In particular, increased FKBP51 transcript levels identify glucocorticoid exposure in vivo and distinguish FP responders from untreated patients with active EE and patients without EE. In addition, FKBP51 reduces glucocorticoid-mediated inhibition of IL-13 signaling in epithelial cells in vitro, suggesting that FKBP51 might influence FP responsiveness. We propose that esophageal FKBP51 levels have diagnostic and prognostic significance in patients with EE.