Background Noninvasive sputum sampling has enabled the identification of biomarkers in asthmatic patients. Studies of discrete cell populations in sputum can enhance measurements compared with whole ...sputum in which changes in rare cells and cell-cell interactions can be masked. Objective We sought to enrich for sputum-derived human bronchial epithelial cells (sHBECs) and sputum-derived myeloid type 1 dendritic cells (sDCs) to describe transcriptional coexpression of targets associated with a type 2 immune response. Methods A case-control study was conducted with patients with mild asthma (asthmatic cases) and healthy control subjects. Induced sputum was obtained for simultaneous enrichment of sHBECs and sDCs by using flow cytometry. Quantitative PCR was used to measure mRNA for sHBEC thymic stromal lymphopoietin (TSLP) , IL33 , POSTN , and IL25 and downstream targets in sDCs (OX40 ligand OX40L , CCL17 , PPP1R14A , CD1E , CD1b , CD80 , and CD86 ). Results Final analyses for the study sample were based on 11 control subjects and 13 asthmatic cases. Expression of TSLP , IL33 , and POSTN mRNA was increased in sHBECs in asthmatic cases ( P = .001, P = .05, and P = .04, respectively). Expression of sDC OX40L and CCL17 mRNA was increased in asthmatic cases ( P = .003 and P = .0001, respectively). sHBEC TSLP mRNA expression was strongly associated with sDC OX40L mRNA expression ( R = 0.65, P = .001) and less strongly with sDC CCL17 mRNA expression. sHBEC IL33 mRNA expression was associated with sDC OX40L mRNA expression ( R = 0.42, P = .04) but not sDC CCL17 mRNA expression. Conclusions Noninvasive sampling and enrichment of select cell populations from sputum can further our understanding of cell-cell interactions in asthmatic patients with the potential to enhance endotyping of asthmatic patients.
Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The ...only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.
Abstract Treatment for severe symptomatic aortic stenosis has changed significantly in recent years due to advances in transcatheter aortic valve replacement (TAVR). Recent studies with the CoreValve ...prosthesis have demonstrated superior results as compared to surgical aortic valve replacement in patients at increased risk for surgery, but there are limited data on gender-related differences in patient characteristics and outcomes with this device. We compared baseline characteristics and clinical outcomes in women and men undergoing TAVR with the CoreValve prosthesis. A total of 3687 patients (1708 women, 1979 men) were included. At baseline women tended to be slightly older and to have increased frailty, but they had fewer cardiac comorbidities, higher left ventricular systolic function, less coronary artery disease, and fewer prior strokes. All-cause mortality was 5.9% for women and 5.8% for men at 30 days (P=0.87) and 24.1% and 21.3%, respectively, at 1 year (P=0.08). The incidence of stroke was 5.7% among women and 4.0% among men at 30 days (P=0.02) and 9.3% and 7.7%, respectively, at 1 year (P=0.05). Women had a higher incidence of bleeding, including more life-threatening bleeds, as well as a greater incidence of major vascular complications than men at 30 days. Device success was achieved in 86.9% of women and 86.1% of men (P=0.50). In conclusion, although there were significant baseline differences and procedure-related complications between women and men undergoing TAVR with the CoreValve prosthesis, this analysis found no significant difference in 30-day or 1-year mortality.
Objective The purpose of this study was to determine whether treatment with ampicillin together with dexamethasone and indomethacin delays preterm birth that is induced by intraamniotic group B ...Streptococcus in a nonhuman primate model. Study Design After contraction onset that was induced by group B Streptococcus (106 colony-forming units/mL), chronically instrumented rhesus macaques received either no treatment (controls; n = 6); ampicillin (n = 4); or ampicillin + dexamethasone + indomethacin (n = 5). Outcomes included the interval from contraction onset until delivery and concentrations of amniotic fluid inflammatory mediators. Results Mean interval from contraction onset until delivery was 33 ± 8.7 hours in controls, 82 ± 28.0 hours with ampicillin ( P = .18, vs controls), and 213 ± 50.8 hours with ampicillin + dexamethasone + indomethacin ( P = .004, vs controls). Ampicillin eradicated group B Streptococcus ; however, uterine activity, amniotic fluid cytokines, prostaglandins, and matrix metalloproteinase-9 remained elevated. Ampicillin + dexamethasone + indomethacin suppressed interleukin-1β, tumor necrosis factor-α, and prostaglandins E2 and F2α but did not alter matrix metalloproteinase expression or chorioamnionitis. Conclusion The combination of ampicillin + dexamethasone + indomethacin suppressed inflammation and significantly prolonged gestation.
Abstract Objective To evaluate diet quality and body mass index (BMI) by beverage patterns in children aged 2 to 11 years. Design Beverage patterns were formed using 24-hour dietary recall diet ...variables from the 2001-2002 National Health and Nutrition Examination Survey. Diet quality was assessed using energy, micronutrient intakes, and Healthy Eating Index (HEI) scores (a 100-point scale that measures adherence to the Dietary Guidelines for Americans ). Subjects/setting Children, aged 2 to 5 years (n=541) and 6 to 11 years (n=793), were selected from 2001-2002 National Health and Nutrition Examination Survey data. Statistical analysis Cluster analysis was used to identify beverage patterns in preschool and school-aged children. General linear models were used to compare HEI scores, energy, micronutrient intakes, and BMI across beverage clusters. Results Four and five beverage clusters were identified for preschool and school-aged children, respectively. In preschool children, mean HEI differed between the fruit juice cluster (79.0) vs the high-fat milk cluster (70.9, P <0.01); however, both fruit juice and high-fat milk clusters had the highest micronutrient intakes. Mean HEI differed significantly across beverage patterns for school-aged children (from 63.2 to 69.9, P <0.01), with the high-fat milk cluster having the best diet quality, reflected by HEI and micronutrient intakes. Adjusted mean BMI differed significantly across beverage clusters only in school-aged children (from 17.8 to 19.9, P <0.05). Conclusions Beverage patterns were related to diet quality among preschool and school-aged children, but were only related to BMI in school-aged children. Children from all clusters could benefit by consuming fewer calorically sweetened beverages and increasing micronutrient-dense foods.
We designed an obesity prevention intervention for American Indian families called Healthy Children, Strong Families using a participatory approach involving three Wisconsin tribes. Healthy Children, ...Strong Families promotes healthy eating and physical activity for preschool children and their caregivers while respecting each community's cultural and structural framework. Academic researchers, tribal wellness staff, and American Indian community mentors participated in development of the Healthy Children, Strong Families educational curriculum. The curriculum is based on social cognitive and family systems theories as well as on community eating and activity patterns with adaptation to American Indian cultural values. The curricular materials, which were delivered through a home-based mentoring model, have been successfully received and are being modified so that they can be tailored to individual family needs. The curriculum can serve as a nutrition and physical activity model for health educators that can be adapted for other American Indian preschool children and their families or as a model for development of a culturally specific curriculum.
Abstract Objective To report dietary intake and physical activity among preschool-aged children living in rural American Indian communities before participation in a family-based healthy lifestyle ...intervention and to compare data to current age-specific recommendations. Subjects/design One hundred thirty-five preschool-aged children, living in rural American Indian communities, provided diet and physical activity data before participating in a 2-year randomized healthy lifestyle intervention. Three 24-hour dietary recalls assessed nutrient and food and added sugar intake, which were compared to the National Academy of Science's Dietary Reference Intakes, the US Department of Agriculture's MyPyramid, and American Heart Association recommendations. Time watching television and moderate plus vigorous activity was compared to MyPyramid and American Academy of Pediatrics recommendations. Statistical analysis Nutrient, food group, added sugar intake, and time watching television and in moderate or vigorous activity were compared to recommendations by computing the percent of recommendations met. Nonparametric tests identified differences in diet and physical activity among age groups and normal and overweight children (body mass index <85th and ≥85th percentile). Results Average nutrient intakes met recommendations whereas food group intakes did not. Mean fruit and vegetable intakes for 2- to 3-year-olds were 0.36 c/day fruit and 0.45 c/day vegetables and, for 4- to 5-year-olds, 0.33 c/day fruit and 0.48 c/day vegetables. Both age groups reported consuming more than 50 g added sugar, exceeding the recommendation of 16 g. Overweight vs normal weight children reported significantly more sweetened beverage intake (8.0±0.10 vs 5.28±0.08 oz/day, P <0.01). On average, all children reported watching television 2.0 hours/day and significant differences were observed for total television viewing and nonviewing time between overweight and normal weight children (8.52±0.6 vs 6.54±0.6 hours/day, P <0.01). All children engaged in <20 minutes/day of moderate or vigorous activity. Conclusions Overall, children in this sample did not meet MyPyramid recommendations for fruits or vegetables and exceed added sugar intake recommendations. Television viewing time and time when the television was on in the home was highly prevalent along with low levels of moderate or vigorous activity. The Healthy Children Strong Families intervention we studied has potential for improving nutrition and physical activity among preschool-aged children living in rural American Indian communities.
IN BRIEF: Excess free-radical formation has been hypothesized to contribute to cancer, atherosclerosis, aging, and exercise-associated muscle damage. Antioxidant supplements such as vitamin C, ...vitamin E, and beta-carotene have been touted as beneficial for enhancing exercise performance and for preventing certain diseases. Before physicians routinely recommend supplements to prevent exercise-associated damage, more study will be required. Recommendations for the prevention of cardiovascular disease and cancer are more complex. Because study results have been contradictory, individual supplement recommendations must be offered with caution. Physicians must be cognizant of which supplements patients are taking and be prepared to discuss risks and benefits. The most beneficial prescription is probably a daily diet containing five to seven servings of fruits and vegetables.
Background There is no agreed upon definition of systemic corticosteroid response in asthmatic children. Moreover, pediatric severe therapy-resistant asthma (STRA) is heterogeneous, and thus response ...to steroids is unlikely to be uniform in all patients. Objective We sought to evaluate the utility of a multidomain approach incorporating symptoms, lung function, and inflammation to determine steroid responsiveness in pediatric patients with STRA. Methods Eighty-two children (median age, 12 years) with STRA received a clinically indicated dose of intramuscular steroid. Changes in 4 separate domains were assessed 4 weeks after intramuscular triamcinolone acetonide: normalization of (1) symptoms (Asthma Control Test score, >19/25 or 50% increase), (2) spirometric results (FEV1 ≥80% of predicted value or ≥15% increase), (3) fraction of exhaled nitric oxide levels (<24 ppb), and (4) sputum eosinophil counts (<2.5%). Fifty-four of 82 children had complete data in all 4 domains. Results Twenty-three (43%) of 54 children had a symptom response, 29 (54%) of 54 had a lung function response, 28 (52%) of 54 had a fraction of exhaled nitric oxide response, and 29 (54%) of 54 had a sputum eosinophil response. Although a similar proportion of children responded to systemic corticosteroids in each domain, there were no reliable predictors of a response pattern. Seven (13%) of 54 were complete responders (response in all domains), 8 (15%) of 54 were nonresponders (no response in any domain), and 39 (72%) of 54 were partial responders (response in ≥1 domain). Conclusions A multidomain evaluation of systemic steroid responsiveness using pragmatic clinical assessments confirms childhood STRA is heterogeneous and that a complete response in symptoms and inflammatory and physiologic parameters is rare. Individual response patterns to systemic steroids might be useful in guiding the choice of add-on therapies in each child as a step toward achieving personalized medicine.
Background Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in pediatric asthma is ...unknown. Objectives We sought to investigate the role of neutrophils and the IL-17A pathway in mediating pediatric severe therapy-resistant asthma (STRA). Methods Children with STRA (n = 51; age, 12.6 years; range, 6-16.3 years) and controls without asthma (n = 15; age, 4.75 years; range, 1.6-16 years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings, and biopsy. Neutrophils, IL-17A, and IL-17RA–expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells were stimulated with IL-17A and/or IL-22, with and without budesonide. Results Children with STRA had increased intraepithelial neutrophils, which positively correlated with FEV1 %predicted ( r = 0.43; P = .008). Neutrophilhigh patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in children with STRA. Submucosal and epithelial IL-17A–positive cells and BAL IL-17A and IL-22 levels were similar in children with STRA and controls. However, there were significantly more IL-17RA–positive cells in the submucosa and epithelium in children with STRA compared with controls ( P = .001). Stimulation of primary bronchial epithelial cells with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of budesonide. Conclusions A proportion of children with STRA exhibit increased intraepithelial airway neutrophilia that correlated with better lung function. STRA was also characterized by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in pediatric severe asthma pathophysiology.
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