Oral delivery of fluticasone powder improves esophageal eosinophilic inflammation and symptoms in adults with eosinophilic esophagitis.

Topical steroids are the primary medical therapy for eosinophilic esophagitis (EoE). Current steroid formulations are used off-label and designed for airway delivery. It is known that the efficacy of topical steroids depends on drug-mucosal contact time, which is related to its formulation. The purpose of this study is to examine the effectiveness of fluticasone administered by means of an orally administered powder formulation. We conducted a retrospective analysis of patients diagnosed with EoE based on current guidelines and who were treated with orally administered fluticasone powder. The primary outcome was histologic response (peak eosinophil density (eos/hpf)). Secondary outcomes included patient-reported symptoms (EoEQ) and endoscopic features measured by a validated instrument (EoE endoscopic reference score, EREFS). Forty patients were treated with fluticasone powder with doses of 500 to 1000 mcg b.i.d. A significant difference was found between pre- and posttreatment levels of eosinophilia (P < 0.0001). Seventy-five percent of patients achieved peak densities of <15 eos/hpf. Improvement was also demonstrated in dysphagia symptoms (P = 0.031) and endoscopic findings of furrows (P = 0.0001) and exudates (P = 0.0001). Oral fluticasone powder induced significant improvement in histopathology, symptoms, and endoscopic features of inflammation in adults with EoE. It offers an easy-to-administer formulation of a topical steroid that circumvents concerns with esophageal delivery of commonly used, aerosolized inhaler preparations.

Prospective assessment of disease-specific quality of life in adults with eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an important cause of upper gastrointestinal dysfunction in children and adults. The EoE-quality of life (QOL)-A was validated as a disease-specific measure of quality of life in EoE. This study characterized the extent of QOL concerns in a cohort of adult EoE patients and delineated the relationships between QOL and other disease activity measures. One hundred sixty-seven patients enrolled in this prospective cohort study. Patients with established and suspected EoE undergoing endoscopy at a single university-based medical center were recruited. EoE was diagnosed on the basis of the clinical criteria and histologic demonstration of ≥15 eos/hpf while on proton pump inhibition therapy. Sixty five patients undergoing repeat endoscopy during the enrollment period participated twice. Patients provided demographic information and completed symptom assessments and the EoE-QOL-A. Analyses included comparisons with overall QOL as well as QOL subscales. Outcome measures included endoscopic activity using a validated instrument, the EoE Endoscopic Reference Score, and histology. Overall QOL was significantly correlated with dysphagia frequency, intensity, and severity (P < 0.001). Patients who experienced a food impaction in the last 30 days had significantly worse overall QOL (P = 0.009). There was no correlation between overall QOL and years since diagnosis, symptom duration, endoscopic features, or histologic findings. Patient symptoms correlated with endoscopic features of edema, rings, and stricture severity. Histologic activity was highly correlated with severity of endoscopic features. Patients who underwent repeat endoscopy with histologic response demonstrated improved eating and social QOL; however, overall QOL was unchanged. In adults with EoE, patient reported QOL is associated with symptom severity but not endoscopic or histologic features. Disease-specific QOL may complement parameters of biologic activity in the assessment of overall disease burden in EoE.

Evaluation of esophageal distensibility in eosinophilic esophagitis: an update and comparison of functional lumen imaging probe analytic methods.

BACKGROUND: Distensibility evaluation of the esophageal body using the functional lumen imaging probe (FLIP) offers an objective measure to characterize patients with eosinophilic esophagitis (EoE), though this analysis may be limited by unrecognized catheter movement and esophageal contractility. The aims of this study were to report novel FLIP analytic methods of esophageal distensibility measurement in EoE and to assess the effect of contractility. METHODS: Nine healthy controls (six female; ages 20-49) and 20 EoE patients (four female; ages 19-64; grouped by degree of distension-mediated contractility identified on FLIP) were evaluated with a 16-cm FLIP device during step-wise balloon distension during upper endoscopy. A distensibility plateau (DP) was generated using multiple methods to identify the narrowest esophageal body diameter: (i) wavelet decomposition (WD), (ii) maximal diameter (MD), and (iii) FLIP Analytics software. KEY RESULTS: Distensibility was reduced in EoE patients compared with controls using the WD (p = 0.002) and MD (p = 0.001) methods; a trend was detected using the FLIP Analytics method (p = 0.055). Significant intra-subject differences were detected between methods among both patients and controls (p-values <0.001 to 0.025); the difference was more pronounced among subjects with a greater degree of contractility. DP was <19 mm among 7/9 controls with FLIP Analytics, 6/9 controls with WD, and 0/9 controls using the MD method. CONCLUSIONS & INFERENCES: Distension-mediated contractility affects distensibility measurement with the FLIP. Using software-based algorithms, particularly with a method that identifies the maximal-achieved diameters (MD), may improve objective distensibility measurement for clinical research and practice.

Prospective assessment of the diagnostic utility of esophageal brushings in adults with eosinophilic esophagitis.

Patients with eosinophilic esophagitis (EoE) undergo multiple endoscopies with biopsy for both diagnosis and assessment of treatment response, which is inconvenient and costly. Brush cytology has been examined in Barrett's esophagus to reduce the need for repeated endoscopic biopsies. The aim of this pilot study was to evaluate the ability of brush cytology to detect mucosal eosinophilia in patients with EoE. This prospective study included adults with untreated and treated esophageal eosinophilia undergoing endoscopy at a tertiary care center. Patients received paired brushings and biopsies at the proximal and distal esophagus. A blinded pathologist quantified the number of eosinophils and epithelial cells per high-power field (hpf) on the cytology slides. The ratio of eosinophils/epithelial cells was used to normalize the cytology specimens for density of cells collected. The main outcome measures were sensitivity and specificity of brush cytology, and correlation between cytology and histology. Twenty-eight patients enrolled. The average age of the cohort was 37.7 ± 10.4 years; 75% of subjects were male. The sensitivity of cytology was 67-69% at the proximal esophagus and 70-72% at the distal esophagus. The specificity was 61-67% proximally and 70-75% distally. Histology was not significantly correlated with the max ratio of eosinophils/epithelial cells per hpf or the absolute number of eosinophils on cytology slides. Cytology using esophageal brushing has limited sensitivity and specificity for the detection of esophageal mucosal eosinophilia. The presence of exudates on endoscopy increased the detection of eosinophilia, which could make cytology useful in pediatric EoE, which often has a more exudative presentation. Diagnostic yield may improve with alternative acquisition techniques or the incorporation of eosinophil degranulation proteins.

Eosinophilic oesophagitis: relationship of quality of life with clinical, endoscopic and histological activity.

BACKGROUND: Knowledge about determinants of quality of life (QoL) in eosinophilic oesophagitis (EoO) patients helps to identify patients at risk of experiencing poor QoL and to tailor therapeutic interventions accordingly. AIM: To evaluate the impact of symptom severity, endoscopic and histological activity on EoE-specific QoL in adult EoE patients. METHODS: Ninety-eight adult EoE patients were prospectively included (64% male, median age 39 years). Patients completed two validated instruments to assess EoE-specific QoL (EoO-QoL-A) and symptom severity (adult EoE activity index patient-reported outcome) and then underwent esophagogastroduodenoscopy with biopsy sampling. Physicians reported standardised information on EoE-associated endoscopic and histological alterations. The Spearman's rank correlation coefficient was calculated to determine the relationship between QoL and symptom severity. Linear regression and analysis of variance was used to quantify the extent to which variations in severity of EoE symptoms, endoscopic and histological findings explain variations in QoL. RESULTS: Quality of life strongly correlated with symptom severity (r = 0.610, P < 0.001). While the variation in severity of symptoms, endoscopic and histological findings alone explained 38%, 35% and 22% of the variability in EoE-related QoL, respectively, these together explained 60% of variation. Symptom severity explained 18-35% of the variation in each of the five QoL subscale scores. CONCLUSIONS: Eosinophilic oesophagitis symptom severity and biological disease activity determine QoL in adult patients with eosinophilic oesophagitis. Therefore, reduction in both eosinophilic oesophagitis symptoms as well as biological disease activity is essential for improvement of QoL in adult patients. Clinicaltrials.gov number, NCT00939263.

Dysregulation of the Wnt pathway in adult eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized pathologically by eosinophil infiltration. In addition to loss of barrier integrity, a dominant T Helper 2-associated immune response and strong allergic connection, the esophagus tissue undergoes dramatic changes, with frequent presence of mucosal rings, strictures, linear furrows, and trachealization. Although the inflammatory mechanisms behind this disease are being increasingly well understood, the structural features remain unexplained. We examined the expression of key members of the Wnt-signaling pathway in biopsies from patients with EoE. This pathway has been shown to be critically important in regulating cellular homeostasis, growth, and differentiation and to be dysregulated in several disease conditions. Biopsies from adult EoE patients were collected by endoscopy and mRNA extracted. After cDNA synthesis, the relative gene expression from key upstream (secreted frizzled-related protein 1) and downstream (c-myc and Cyclin D1) molecules in the Wnt pathway, as well as several Wnt pathway members (Wnt1, Axin1, low-density lipoprotein receptor-related protein 6, glycogen synthase kinase 3 beta, and ß-catenin), were determined. Biopsies from patients with EoE displayed significantly higher expression of secreted frizzed-related protein 1 than controls, as well as reductions in Cyclin D1 and c-myc. In contrast, there were no differences in the Wnt pathway molecules. The levels of expression of Cyclin D1 and c-myc, as well as ß-catenin, in EoE patients showed strong correlations with the frequency of esophageal eosinophils. Our findings suggest that although there are no changes in the overall levels of key Wnt pathway genes in adult EoE, there is evidence for dysregulation of upstream and downstream regulators of Wnt signaling. Importantly, the associations with eosinophilia suggest that these may participate in the pathogenesis of this disease and be markers of disease severity.

Practical approach to implementing dietary therapy in adults with eosinophilic esophagitis: the Chicago experience.

Eosinophilic esophagitis (EoE) is a chronic immune/antigen-mediated esophageal disease characterized by esophageal dysfunction and esophageal mucosal eosinophilia. Diet therapy is effective in the treatment of EoE in both children and adults. The role of food allergens is well established in the pathogenesis and treatment of eosinophilic esophagitis. Empiric elimination with a six-food elimination diet (avoiding milk, wheat, egg, soy, peanuts/tree nuts, and fish/shellfish) demonstrates remission in over 70% of adults with this disease. Dietary therapy in adult EoE is becoming more accepted by both patients and clinicians. Dietary therapy can be effectively implemented in clinical practice with appropriate dietary education, patient resources, and close communication with physician and clinical staff. The ability to identify specific food triggers to help tailor dietary therapy for long-term management allows for a return to consumption of most table foods. Furthermore, the diet approach avoids the need for chronic topical corticosteroid use and possible long-term side effects of these medications. The decision to proceed with dietary therapy should be decided by patient preference and available resources. A collaborative and multidisciplinary approach including gastroenterologists, allergists, nurses, and dietitians is essential in the success of this approach.

Bias-field controlled phasing and power combination of gyromagnetic nonlinear transmission lines.

Gyromagnetic Nonlinear Transmission Lines (NLTLs) generate microwaves through the damped gyromagnetic precession of the magnetic moments in ferrimagnetic material, and are thus utilized as compact, solid-state, frequency agile, high power microwave (HPM) sources. The output frequency of a NLTL can be adjusted by control of the externally applied bias field and incident voltage pulse without physical alteration to the structure of the device. This property provides a frequency tuning capability not seen in many conventional e-beam based HPM sources. The NLTLs developed and tested are mesoband sources capable of generating MW power levels in the L, S, and C bands of the microwave spectrum. For an individual NLTL the output power at a given frequency is determined by several factors including the intrinsic properties of the ferrimagnetic material and the transmission line structure. Hence, if higher power levels are to be achieved, it is necessary to combine the outputs of multiple NLTLs. This can be accomplished in free space using antennas or in a transmission line via a power combiner. Using a bias-field controlled delay, a transient, high voltage, coaxial, three port, power combiner was designed and tested. Experimental results are compared with the results of a transient COMSOL simulation to evaluate combiner performance.

The adult eosinophilic oesophagitis quality of life questionnaire: a new measure of health-related quality of life.

BACKGROUND: Eosinophilic oesophagitis (EoO) is a chronic disease characterised by significant symptoms and challenging treatment regimens. Health-related quality of life (HRQOL) is a useful way to direct patient care. EoO symptoms and treatment may impact patient HRQOL. Currently, there is no reliable and valid measure of adult EoO patient HRQOL. AIM: To validate the Adult Eosinophilic Oesophagitis Quality of Life (EoO-QOL-A) questionnaire as a measure of HRQOL in this population. METHODS: The EoO patients aged 18-70 recruited via an out-patient GI clinic and two EoO advocacy groups completed the preliminary EoO-QOL-A, demographic and clinical information, and measures of general HRQOL, psychological distress and EoO symptom severity. A subset of patients completed test-retest assessments. Scale reliability, internal consistency, factor structure, concurrent and convergent validity were evaluated. RESULTS: A total of 201 patients have participated. The study sample was primarily Caucasian, college-educated, and evenly split by gender. The average duration of disease was 7 years with duration of symptoms of 26 months prior to diagnosis. Patients reported were using both pharmacological and dietary treatments. Factor analysis yielded a 37-item, 5-factor structure: Eating/Diet Impact, Social Impact, Emotional Impact, Disease Anxiety and Choking Anxiety. The EoO-QOL-A demonstrated excellent internal consistency, split-half and test-retest reliability. Concurrent and convergent validity were supported by moderate correlations with established HRQOL measures, psychological distress and oesophageal symptoms. CONCLUSIONS: The EoO-QOL-A is a valid and reliable disease-specific HRQOL measure for adult EoO patients. Developing the Adult Eosinophilic Oesophagitis Quality of Life is an important step in guiding treatment practices, improving disease education and standardising research protocols.

Manometric features of eosinophilic esophagitis in esophageal pressure topography.

BACKGROUND: Although most of the patients with eosinophilic esophagitis (EoE) have mucosal and structural changes that could potentially explain their symptoms, it is unclear whether EoE is associated with abnormal esophageal motor function. The aims of this study were to evaluate the esophageal pressure topography (EPT) findings in EoE and to compare them with controls and patients with gastro-esophageal disease (GERD). METHODS: Esophageal pressure topography studies in 48 EoE patients, 48 GERD patients, and 50 controls were compared. The esophageal contractile pattern was described for ten 5-mL swallows for each subject and each swallow was secondarily characterized based on the bolus pressurization pattern: absent, pan-esophageal pressurization, or compartmentalized distal pressurization. KEY RESULTS: Thirty-seven percent of EoE patients were classified as having abnormal esophageal motility. The most frequent diagnoses were of weak peristalsis and frequent failed peristalsis. Although motility disorders were more frequent in EoE patients than in controls, the prevalence and type were similar to those observed in GERD patients (P=0.61, chi-square test). Pan-esophageal pressurization was present in 17% of EoE and 2% of GERD patients while compartmentalized pressurization was present in 19% of EoE and 10% of GERD patients. These patterns were not seen in control subjects. CONCLUSIONS & INFERENCES: The prevalence of abnormal esophageal motility in EoE was approximately 37% and was similar in frequency and type to motor patterns observed in GERD. Eosinophilic esophagitis patients were more likely to have abnormal bolus pressurization patterns during swallowing and we hypothesize that this may be a manifestation of reduced esophageal compliance.

Eosinophilic oesophagitis in adults.

Previously considered a rare condition, eosinophilic oesophagitis (EoE) has become increasingly recognized as an important cause of dysphagia and food impactions in adults. This is likely attributable to a combination of an increasing incidence of EoE and a growing awareness of the condition. EoE may occur in isolation or in conjunction with eosinophilic gastroenteritis. However, the burgeoning field is likely attributable to the variant that uniquely affects the oesophagus. Adults classically present with symptoms of dysphagia, food impactions, and heartburn. Typical endoscopic features include concentric mucosal rings, linear furrowing, white plaques or exudates and a narrow caliber oesophagus. In some cases, the endoscopic features may appear normal. For years, EoE went unrecognized because eosinophilic infiltration was accepted as a manifestation of reflux, which continues to be a confounding factor in some patients. Current consensus is that the diagnosis of EoE is established by 1) the presence of symptoms, especially dysphagia and food impactions in adults, 2) > or =15 eosinophils per high power field in oesophageal tissue, and 3) exclusion of other disorders with similar presentations such as GERD. Current understanding of EoE pathophysiology and natural history are limited but the entity has been increasingly linked to food allergies and aeroallergens. The main treatment options for EoE are proton pump inhibitors, dietary manipulation, and topical or oral glucocorticoids. This review highlights recent insights into EoE in adults although, clearly, much of the available data overlap with pediatrics and, occasionally, with eosinophilic gastroenteritis.

The extracellular matrix between the optic vesicle and presumptive lens during lens morphogenesis in an anophthalmic strain of mice.

Extracellular matrix material present during early lens morphogenesis in anophthalmic strain ZRDCT-Ch mice was studied histochemically by the Alcian blue 8GX pH 2.5, Alcian blue 8GX pH 2.5/periodic acid-Schiff combined, high iron diamine, and Van Gieson methods. Observed staining patterns were compared with results from an analysis of a normal strain of mice (E.H. Webster, Jr., A.F. Silver, and N.I. Gonsalves, 1983, Develop. Biol. 100, 147-157). No differences in constituents were found between the strains in staining patterns of the ectodermal basal lamina. However, the optic vesicle basal lamina in the anophthalmic strain was found to have a relatively lower staining intensity for sulfated glycosaminoglycan associated with it than was observed in the normal strain, although these mutant optic vesicles were morphologically normal. Results from this and the earlier study on normal mice indicate that one function of sulfated glycosaminoglycan in early lens morphogenesis may be to serve as a cementing medium between the optic and lens rudiments. This sulfated glycosaminoglycan deficiency on the anophthalmic optic vesicle basal lamina is temporally correlated with and may be causally related to precocious lens cup formation and frequently observed separation of the normally adherent eye rudiments. Conclusions drawn from this study are consistent with the speculation of H.B. Chase and E.B. Chase (1941, J. Morphol. 68, 279-301) that there may be abnormal contact between the optic vesicle and presumptive lens ectoderm in the mutant strain, although there is a differing view on the cause of the abnormal contact.

Histochemical analysis of extracellular matrix material in embryonic mouse lens morphogenesis.

Extracellular matrix material (ECM) present during mouse lens morphogenesis was studied histologically by the periodic acid-Schiff, Alcian blue 8GX, pH 2.5, high iron diamine, and Van Gieson methods, and enzymatically with bovine testicular hyaluronidase, Streptomyces hyaluronidase, malt diastase, and collagenase. The basal lamina of the optic vesicle prior to lens placode formation was found to be higher in glycosaminoglycan (GAG) content than was the ectodermal basal lamina. Upon apposition of the optic vesicle and presumptive lens ectoderm, the ECM plus basal laminae appeared as the equivalent of adding both optic vesicle-associated and ectodermal-associated basal lamina. The proposal is made that the initial triggering mechanism of lens morphogenesis consists of a cross-linking and polymerization of optic vesicle-associated GAG to ectodermal-associated glycoproteins resulting in a firm attachment between the structures. Basal lamina associated with the presumptive pigmented retina and also the more ventral part of the interface matrix were found to change from predominantly GAG in early stages to collagen deposits in more advanced stages, temporally coinciding with the appearance of differentiative markers in each structure. This pattern of GAG turnover and replacement by collagen during the course of development is also seen in mouse salivary gland morphogenesis (M. R. Bernfield, S. D. Banerjee, and R. H. Cohn (1972). J. Cell Biol. 52, 674-686.).

Effect of mersalyl on mitochondrial Mg++ flux.

The mercurial mersalyl has little effect either on rapid Mg++ binding by isolated rat liver mitochondria or on the total Mg++ content of these organelles measured after 0.75 min of incubation at 20 degrees C. The data do not support the previous suggestion that the increased permeability to K+ of mitochondria treated with mersalyl results from release of endogenous Mg++. An increased pH-dependence of unidirectional Mg++ flux into respiring rat liver mitochondria is suggested to arise indirectly from inhibition by mersalyl of pH shifts associated with exchanges of endogenous phosphate. In addition, mersalyl appears to have a stimulatory effect on Mg++ influx. Mersalyl also increases the average rate of unidirectional efflux of endogenous Mg++. The stimulatory effects of mersalyl on Mg++ flux are similar to, although quantitatively less than, the previously reported effects of mersalyl on mitochondrial K+ flux.

Wound healing in X-irradiated mammalian skin.

Certain parameters of wound healing were investigated in mouse skin given 950 rads and 3325 rads of X-irradiation at various times relative to wounding. Increased inflammation, delayed dermal regeneration, and delayed contraction were noted in all irradiated groups. The activation of surrounding hair follicles, a process that usually accompanies wounding in mouse skin, occurred earlier, over a shorter elapsed time, and over a greater area of skin in animals irradiated prior to wounding than in the controls or in those irradiated and wounded simultaneously. Epidermal mitotic activity in wounds made at the time of irradiation was initially depressed but recovered by the second postoperative day. Wounds in pre-irradiated animals gave an unexpected result. They responded with an immediate burst of mitotic activity without the usual 24-hr lag that was seen in controls. In the pre-irradiated specimens a substantial number of cells appeared to die after dividing.